Tái Tạo Thể Tích Khuôn Mặt Bằng Filler – Kyle K. Seo (2021)

34
the gel particles to suit the desired clinical indica-
tion. This is not the case if a homogenizer is used,
as the resulting particle size is inhomogenous.
After grinding, the HA gel is filled into individual
syringes which are then transferred into an auto-
clave for sterilization [5].
A key consideration during the manufacture
of HA fillers is the in-process control of unde-
sired proteins, endotoxin, and residual cross-
linking agents. Proteins are a major cause of
inflammation and allergy; therefore, it is critical
to ensure the HA raw material meets the require-
ments of the European Pharmacopoeia (EP) for
protein content (<0.1% of the raw material). For
most commercially available HA filler products,
manufacturers endeavor to keep residual protein
levels at 10μg/mL or less to minimize the risk of
allergic reactions. Meanwhile, endotoxin levels
are controlled at 0.5 EU/mL (endotoxin unit) or
less as prescribed in the EP to avoid possible
pyrogenic and/or inflammatory reactions [5].
While the BDDE levels are also regulated at
below 2 ppm, in practice, BDDE is hardly ever
detected in a final HA filler product.
2.2.2.1 Production of HA Raw Material
Industrial manufacturing of HA raw material
(bulk HA) is based on either extraction from
rooster combs or microbial fermentation using
bacterial strains. During the nascent stages of HA
filler development, HA biopolymer extracted
from rooster combs was used for most products,
as the process generated HA with naturally high
molecular weight. For example, Hylaform®
(Genzyme Biosurgery), approved by the US FDA
in 2004, was made using HA derived from rooster
combs, which had molecular weight ranging
approx. 3000  kDa. However, commercial pro-
duction of HA from rooster combs was time-
consuming and expensive, involving numerous
process steps and considerable time to complete.
Furthermore, there were significant technical dif-
ficulties in eliminating possible viruses (avian) or
proteins and nucleic acids potentially remaining
in the animal tissue. Also, the serious incidences
with Bovine Spongiform Encephalopathy showed
that deadly diseases could be transfered between
species (animal> human) in ways previously not
known. The use of bacterially derived materials
are in that aspect regarded a much lower risk than
animal derived as bacteria are very different from
animal cells. As a consequence of these manufac-
turing and safety concerns, extraction of HA
from rooster combs eventually fell out of favor,
and instead bacterial fermentation became the
preferred method of obtaining HA [6]. Bacterial
Dissolution of HA
HA powder + NaOH solution
Cleaving into multiple small pieces
Homogenizer/Milling system
Gel filing/Pre-filled syringe filling
Sterilization of filled syringe
Washing with purified water or saline
Crosslinking agent
(BDDE)
Crosslinking
Cutting
Purification
Grinding
Syringe Filling
Sterilization
Fig. 2.5  Hyaluronic
acid filler manufacturing
process
2  Volumizing Fillers

35
fermentation is capable of generating HA at sig-
nificantly lower cost, in mass quantity, and with
greater ease with which to remove residual for-
eign proteins and endotoxins in-process com-
pared with extracting HA from rooster combs.
Streptococcus has been the bacteria most widely
used for microbial HA production, with
Streptococcus zooepidemicus being the most
used strain [6]. Restylane®, which represents the
first HA-based injectable filler to obtain US FDA
approval in 2003, is also based on HA extracted
from microbial fermentation, having a molecular
weight ranging approx. 1000  kDa. Driven  by
advances in fermentation technology, molecular
weight of HA obtained from microbial HA pro-
duction has progressively increased from below
2000  kDa during the early days to above
3000 kDa at present [6]. While microbial fermen-
tation can produce HA with higher purity free of
residual pathogens such as avian viruses com-
pared with HA of avian origin, the risk of con-
tamination with bacterial endotoxins, intracellular
organelle, and undesired proteins nonetheless
remains, for which complex and extensive purifi-
cation is required. To this end, the bacterial cells
are subjected first to centrifugation for cell sepa-
ration, and subsequently to dissolution in sodium
hydroxide (NaOH) solution. The resulting cell-
free solution then undergoes the subsequent pro-
cesses of ultrafiltration, adsorption onto activated
carbon or alumina, and alcohol precipitation to
remove any possible impurities or cell debris
(Fig.  2.6) which may remain  in the product.
These purification process  may differ between
manufacturers. The average molecular weight of
HA is controlled via e.g. fermentation conditions
and the handling during the purification process.
As explained, the purity of the HA raw mate-
rial is determined largely by the specific method
and degree of purification applied during the
manufacturing process. Key considerations in the
choice of HA raw materials are bacterial endo-
toxins and cell-derived proteins remaining in the
product, and whether their amounts fall within
the required specification. The respective extent
to which these impurities reside determines the
biological safety of the HA, and accordingly, its
clinical grade. HA raw material for industrial use
is classified as food grade, cosmetic grade, or
medical grade, with medical-grade HA further
broken down into  those for use as ophthalmic
formulations (eye-drops grade) or injectable
preparations (injection grade) depending on the
stringency of the purification required. Eye-drops
grade HA is used in the manufacture of eye drops,
contact lenses preservatives, and topical prepara-
tions for oral mucosal lesions, whereas injection-
grade HA is used for producing intraocular lens
implants, intraarticular injections, antiadhesion
agents (for preventing postsurgical tissue adhe-
Fermentation
Streptococcus sp.
Drum filter/Centrifuge
Ultra-filtration
Adsorption
Alcohol precipitation
Vacuum drying
Cell Separation
Purification – I
Purification – II
Precipitation
Drying
Fig. 2.6  Production of
HA raw material from
microbial fermentation
2.2  Hyaluronic Acid Fillers

36
sion), and injectable fillers, to name a few.
Injection-grade HA is generally 3–4 times more
expensive than eyedrop-grade HA used for oph-
thalmic formulations, with HA powders for
injection being of the highest purity among all
formulations of HA raw material [7].
Since the safety of injectable HA filler products
depends not only on the quality of additional puri-
fication steps undertaken during their manufacture
but also on the underlying HA raw material itself,
the quality and the purity of the source HA raw
material represents a necessary, if not sufficient,
component for determining the safety of the final
HA filler product. At the very least, therefore, HA
filler products satisfy the minimum standard for
quality if they are manufactured using HA raw
materials sourced from suppliers contained in the
US FDA’s list of Drug Master File and approved
by the European Directorate for the Quality of
Medicines & Healthcare (EDQM) [7]. As of 2020,
manufacturers of HA raw material contained in
the FDA’s list of DMF are as follows: LG Chem
LTD (Korean entity); Kewpie Corp, Kikkoman
Biochemifa Co, Kibun Food Chemifa Co. LTD,
Kyowa Hakko Kogyo Co LTD, Seikagaku Corp,
Shiseido Co LTD (Japanese entities); Bloomage
Biotechnology Corp LTD, Shandong Freda
Biochem Co LTD, Shandong Awa Biopharm Co
LTD (Chinese entities); Bioiberica SA, Contipro
AS, Fidia Farmaceutici SPA, Novozymes AS (EU
entities); Dermal Research Laboratories INC,
Lifecore Biomedical LLC, Maruha Nichiro Corp
(US entities). In this regard, LG Chem.’s YVOIRE®
is based on its own in-house HA formulation and
Neuramis® by Medytox Inc. is formulated with
raw HA supplied by Shiseido Co LTD
(Japan) while most HA filler manufacturers do not
disclose their source of HA raw material supply.
ing presented in the book Chance and
Necessity by the Nobel Prize laureate
Jaques Monod to interpret the process of
evolution. In essence, he postulates, it was
by pure coincidence that a cell embodying
the most rudimentary form of life was pro-
duced via some inexplicable and highly
unlikely sequence of biochemical reactions
among inorganic matter; and that today’s
lower or higher animals represent the nec-
essary product of the messy and complex
evolutionary process the cells subsequently
underwent. Upon first reading the book
back in university, I simply considered it to
be a clever, if rather paradoxical, set of
arguments in support of the theory of evo-
lution. With the passage of time, however, I
have come to appreciate how the ideas
espoused in Chance and Necessity bore
striking relevance to our own lives.
In 1998, while working as a research fel-
low at the Seoul National University
Hospital, Department of Dermatology, I
stumbled upon a fascinating study  by Dr.
Shelley published in the Journal of
American
Academy
of
Dermatology
involving the injection of botulinum toxin
on the patients’ palms for the treatment of
palmar hyperhidrosis. The fact that the
effects were found to last for up to
5–6  months struck me as particularly
intriguing. While clearly not a life-threaten-
ing condition or a contagious disease, focal
hyperhidrosis, especially, palmar hyperhi-
drosis, can be deeply distressing to the
patient himself, given how it hinders his
daily activities in a host of troubling ways.
Sweaty hands are subject to greater risk of
frostbites in the winter; also, when writing,
note taking, or completing written exams, it
requires the placement of a handkerchief
underneath the hand  so as not to wet the
paper. Wet clammy hands are neither ideal
for holding or shaking and can put the per-
son at an undue disadvantage in various
social interactions. The degree of anguish
felt by patients is such that according to one
Episode: Chance and Necessity
A roofer performing repair work on a tall
building inadvertently drops his hammer
which hits a passing pedestrian on the head
and kills him. While the roofer’s dropping
of the hammer was purely accidental, it
inevitably led to the deterministic event of
the pedestrian’s death. Such is the reason-
2  Volumizing Fillers

37
study, the emotional and psychological dis-
tress inflicted by hyperhydrosis was found
to be greater than that of chronic rheuma-
toid arthritis or chronic kidney failure.
Although some remedies for palmar hyper-
hydrosis are available, including topical
agents and oral medicine, the effects are
largely transient and minimal. In most
cases, patients are simply referred instead to
the thoracic surgery department to undergo
a more invasive endoscopic sympathec-
tomy. However, despite the permanent cure
it provides, sympathectomy is not without
its own share of problems, including the
risk of developing compensatory hyperhi-
drosis. Simply put, palmar hyperhydrosis is
a profoundly uninteresting business for an
average dermatologist.
It so happened that during my first year of
residency training at the SNUH, one of my
responsibilities was measuring the amount
of the sweat discharges of palmar hyperhy-
drosis patients as per the instructions of the
professor in the Dermatology Dept. It was
menial and time-consuming work; all the
more so, since the precision scale used for
the measurements was kept at a separate
office on the twelfth floor of the building.
Each trip to and from the office with the
patient took up to 30 minutes. Yet nothing
much materialized from those grueling daily
trips and tests other than a dissertation pub-
lished in the name of the professor in charge.
I couldn’t see what possible good it was
doing for the patient when eventually they
had to be whisked off to the thoracic surgery
department for the actual treatment.
With that gruelling memory still vivid in
my mind, it was absolutely mind-blowing
to learn that a single injection was capable
of providing up to months of relief for
palma hyperhydrosis patients. The under-
lying drug was affordably priced too, at
only about 60 USD per bottle of Botox®.
Upon further literature review, I discovered
that what scant research papers that  had
existed were still only in their infancy and
decided right there and then that I had
found my niche. Quickly, I put together a
research proposal within a matter of 3 days
and was set to go. The only hitch—how-
ever—was that the list price of about 60
USD  in the SNUH pharmacopeia had in
fact been a typo graphical error! To my dis-
may, it turned out a 0 in the last digit had
been omitted by error, meaning the actual
price was a whopping 600 USD. Two bot-
tles for injecting both hands would
cost 1,200 USD per treatment, and I had to
seriously ponder whether from the patient’s
perspective, 5–6  months of temporary
relief from sweaty hands would justify that
kind of cost. In the end, however, I decided
the treatment still had its appeal as a novel
noninvasive treatment involving the use of
injections and pushed ahead with the plan.
That’s how I first got started on my practice
with botulinum toxin. The rest I suppose is
history.
Sure enough, life works in mysterious
ways. Had it not been for the drudgery of
those sweat measurements, or that chance
perusal of the JAAD paper on palmar
hyperhidrosis, or the incorrectly listed
Botox® price in the SNUH pharmacopeia, I
wonder whether I would have ended up
performing botox procedures at all. We are
the ultimate product of the countless coin-
cidental events that have occurred in our
past. The only distinction between our lives
and the evolutionary process is that human
life does not stretch out for billions of
years, and hence requires some form of
exertion on our part to bridge the gap
between chance and the necessary outcome
that we desire. Similar to how we inevita-
bly discovered our life partners out of the
many random encounters in life, it is the
passion, devotion, and sweat, I suppose,
that ultimately turn mere accidents of yes-
terday into the well-earned fruits of tomor-
row (June 2019).
2.2  Hyaluronic Acid Fillers

38
2.2.2.2 Incorporation of Cross-Linking
Agent/Cross-Linking Reaction
Dissolved in water, HA powder changes into a
thick glue-like liquid with viscous texture simi-
lar to that of sweet and sour sauce, a state referred
to as free HA. Free HA hardly has any structure
or elasticity and is thus incapable of providing
support or projection in the tissue. If free HA is
injected as the filler  material, it will degrade
within a week due to the activity of endogenous
hyaluronidase or free radicals in the human tis-
sues. Thus, to confer elasticity to the free HA
and increase its duration in vivo, cross-linking is
introduced between the HA polymers to stabilize
the HA into a gel  form. Cross-linking can be
achieved either via physical or chemical meth-
ods. Each specific crosslinking procedure or gel
technology results in gels whose properties
depend on both physical and chemical factors.
The physical factor enhances the effect of the
chemical crosslinkers by entanglements between
the HA polymers. This produces a tight-knit net-
work of HA polymer chains (Fig.  2.7) that is
held together by only a few chemical cross-
linkers. For the chemical factors, the tempera-
ture at which the HA liquid (i.e., HA diluted in
water) reacts with the crosslinking agent and the
duration for which the HA reacts with the cross-
linker are the most important parameters for
binding the HA molecules to each other. A prime
example  of products whose properties are the
result of physical factors is  Restylane®. The
NASHA™ technology used to generate the gels
results in strong gels with a high G’ but with less
than 1% degree of modification (MoD), some-
thing that is of importance to assure a good
biocompatibility.
While physical cross-linking plays an impor-
tant part, the properties of a gel relies more on the
introduction of cross-linking agents to interlink
the HA molecules. Here, the cross-linking agent
plays a role comparable to gluten in wheat flour.
Unlike other grain, wheat flour mixed with water
produces a dough that is bouncy, stretchy, and
chewy, attributable primarily to the presence of
gluten in the wheat protein. During the kneading
of the dough, gluten in the wheat flour associates
with starch to form a reticulated gluten mem-
brane, which gives the dough its  elasticity and
allows it to hold its shape at rest and to stretch eas-
ily when pulled apart. In much the same fashion,
cross-linking agents bind to individual HA poly-
mer chains and join them together to build a tight
network of cross-linked HA, converting the HA
polymers from liquid to a gel form (Fig. 2.8). The
HA gel mass thus produced effectively forms a
united front against breakdown by free radicals.
Finally, similar to how wheat flour is divided into
hard, plain, and weak varieties depending on its
gluten content, HA filler products can be classi-
fied as either firm (i.e., with high viscoelasticity)
or soft (i.e., with low viscoelasticity) as deter-
mined by rheological measurments.
While various substances are available for use
as cross-linking agents, including 1,4-butanediol
diglycidyl ether (BDDE), divinyl sulfone (DVS),
and bişcarbodiimidie (BCDI), BDDE is the
cross-linking agent by far the most widely used
in the commercial production of HA fillers owing
to its unrivaled low toxicity profile [5]. The
a
b
Fig. 2.7  A prime
example of a physically
cross-linked HA is
NASHA technology
incorporated
in Restylane® (Photo:
Courtesy of Galderma)
2  Volumizing Fillers

39
median lethal dose (LD50) of BDDE adminis-
tered orally to rats is only 1134 mg/kg compared
with 32 mg/kg for DVS. Strict standards apply
against the amount of residual BDDE remaining
in the product as remnants of unreacted BDDE
can have a harmful effect on the human body.
However, at the current limit of <2 μg, the resid-
ual BDDE in HA filler products amounts to only
1/25 million of the fatal dose in an adult of 50 kg
[5]. Regardless, the industry remains committed
to further minimizing the residual BDDE by
increasing the reaction time or the reaction speed
during the cross-linking reaction and by remov-
ing BDDE debris to the maximum during the
cleaning and purification of the cross-linked HA
gel. Meanwhile, during the cross-linking pro-
cess, epoxide groups of BDDE react with the
hydroxyl groups of HA under alkaline condition,
forming
derivatives
of
1,4-butanediol
di-
(propane-2,3-diolyl) ether (BDPE) as shown in
Fig. 2.9 [8]. In so doing, however, some BDDE
molecules link with HA on both ends (“double-
linked BDPE”) while others join HA on one end
only in the form of a pendant (“mono-linked
BDPE”) (Fig. 2.10).
Fig. 2.8  Chemical cross-linking. Chemical cross-linking
agents, 1,4-butanediol diglycidyl ether (BDDE) bind to
individual HA polymer chains and join them together to
build a tight network of cross-linked HA (OBT™ technol-
ogy of Restylane®) (Photo: Courtesy of Galderma)
Fig. 2.9  During the
cross-linking process,
epoxide groups of
BDDE react with the
hydroxyl groups of HA
under alkaline condition,
forming derivatives of
1,4-butanediol
di-(propane-2,3-diolyl)
ether (BDPE)
2.2  Hyaluronic Acid Fillers

40
A higher degree of cross-linking with BDDE is
associated with prolonged duration of HA in the
tissue, as well as greater elasticity and cohesive-
ness of the HA gel. Accordingly, the degree of
cross-linking is a key factor in comparing the rhe-
ological properties of different HA products. The
major parameters for describing the degree of
cross-linking include degree of modification
(MoD), degree of substitution (DS), degree of
cross-linking (CrD), degree of cross-linking (DC),
and effective cross-linker ratio (CrR), which
are defined respectively as follows (Table 2.1) [8]:
(a) The degree of modification (MoD): the ratio
between the sum of mono-linked (pendant-
type) and double-linked BDPE and the total
number of HA monomers (disaccharide
units).
(b) The degree of substitution (DS): the ratio
between the HA disaccharides bound with
BDPE and the total number of HA mono-
mers (disaccharide units).
(c) The degree of cross-linking represented by the
acronym CrD: the ratio between BDPE resi-
dues that are double-linked and the total num-
ber of HA monomers (disaccharide units).
(d) The degree of cross-linking signified by the
acronym DC: the number of HA disaccha-
rides actually cross-linked relative to the
total number of HA disaccharides.
(e) Effective cross-linker ratio (CrR): the ratio of
double-linked BDDE in relation to the total
BDPE.
In all of the above terms, the denominator is
represented by the total number of HA monomer
units (disaccharide units), while the numerator
varies for each parameter. Simply put, MoD and
CrD signify the ratio of BDPEs cross-linked with
HA, while DS and DC represent the ratio of
cross-linked HA disaccharide units vis-a-vis the
total number of HA. Meanwhile, CrD represents
the ratio of BDDE that is double-linked with HA
(double-linked BDPE), whereas MoD covers the
ratio of both the mono- (pendant- shaped) and
double-linked BDPE.
By way of illustration, a CrD of 20% equates to
a DC of 40%, as DC represents double the value of
CrD. In each case, this implies that for each 10 HA
monomers (or disaccharide units) in the gel, two
BDDE molecules (CrD of 20%) or four HA disac-
charide units (DC of 40%) have been cross-linked.
Meanwhile, an MoD of 50% and CrR of 40%
results in a DS of 70%, as this implies that for each
10 HA monomers (or disaccharide units), links
have been formed with an average of five BDDE
molecules (MoD of 50%), of which only two are
double-linked BDDEs (CrR of 40%), and thus
seven of the ten HA disaccharide units are con-
nected to a BDDE (DS of 70%) (Fig. 2.11).
A high degree of cross-linking translates into
greater gel hardness and prolonged longevity.
Too much cross-linker content, however, ham-
pers ease of injection due to product aggregation,
undercuts HA hydrophilicity, and contributes
only  to causing immunogenic responses. Thus,
an adequate balance of cross-linking is one of the
OH
R1
OH
O
O
O
O
R1
R1
BDPE Classification
Free BDPE
Mono-linked BDPE
Mono-linked BDPE
Double-linked BDPE
H
H
HA
HA
HA
HA
H
H
R2
Fig. 2.10  Some BDDE
molecules link with HA
on both ends (double-
linked BDPE) while
others join HA on one
end only, in the form of
a pendant (mono-linked
BDPE)
2  Volumizing Fillers

41
essential elements of an ideal HA filler. In this
regard, a product with a low CrR, comprised pri-
marily of mono-linked BDPE rather  than
double-linked BDPE, tends to show a softer and
more flexible rheological property.
2.2.2.3 Hyaluronic Acid Concentration
As a result of the thermal exposure during the
sterilization process, all HA gels comprises both
crosslinked gel and an extractable part, often
denoted free HA. The free HA behaves as a lubri-
cant for facilitating the introduction of HA parti-
cles into the tissue and does not provide structural
support in and of itself. By way of example, while
both Restylane®(Galderma) and Juvéderm®
Voluma® (Allergan) have the same HA concen-
tration of 20 mg/mL, and contains a sililar free
HA concentration of between 20−30%.
Most commercial HA filler products currently
on the market have HA concentrations within the
range of 20–24 mg/mL. It is an accepted rule of
thumb that a higher HA concentration correlates
with higher elasticity and longer duration of
effect. Among local Korean brands, Cleviel®
mono-linked BDPE
double-linked BDPE
HA disaccharide
Fig. 2.11  A hypothetical structure of cross-linking between HA and BDDE including “double-linked BDPE” and
“mono-linked BDPE” (Figure modified from Ref. [8])
Table 2.1  Definitions of MoD, CrD, DS, and DC for modified HA fillers
Definition based on number of…
…cross-linker units/HA units
…substituted HA units/HA units
Parameter
Degree of modification (MoD)
Degree of substitution (DS)
Definition
n
n
linked cross linkers
HAdisaccharides
-
n
n
sustituted HA discaccharides
HA disaccharides
Determination
From NMR
DS = MoD + CrD = MoD × (1 + CrR)
Parameter
Degree of cross-linking (CrD)
Degree of cross-linking (DC)
Definition
n
n
doubled linked cross linkers
HA disaccharides
-
n
n
cross linked HA disaccharides
HA disaccharides
-
Determination
CrD = CrR × MoD
DC = 2 × CrD = 2 × CrR × MoD
CrR: Effective cross-linker ratio. Modified from Ref. [8]
2.2  Hyaluronic Acid Fillers

42
(Pharmaresearch Products, Korea), has a notably
high HA concentration of 50 mg/mL for maxi-
mum elasticity and longevity. However, the
downside of using a product with such high HA
concentration is that it requires greater extrusion
force during injection due to its hard, stiff tex-
ture; is not easily moldable after injection; and is
harder to dissolve with exogenous hyaluronidase.
Further, a higher HA concentration in HA fillers
is known to be associated with an increase in the
injected volume 2–4 weeks posttreatment due to
the hydration of the cross-linked HA molecules
[9]. In this respect, Juvéderm® Ultra™, with an
HA concentration of 24  mg/mL and manufac-
tured using the HYLACROSS™ technology, was
particularly prone to causing undesired swelling
or irregularity post-treatment due to the satura-
tion of the HA molecules. Hence, subsequent
releases of Juvéderm® fillers, which embody
VYCROSS™ technology, have notably lowered
their HA concentrations to avoid such problems.
For example, Juvéderm® Voluma™ indicated for
deep (subcutaneous) volume restoration contains
20 mg/mL of HA, Juvéderm® Volift™ for deep
wrinkle correction contains 17.5  mg/m of HA,
while Juvéderm® Volbella™ for fine lines and
wrinkles including periorbital rhytids contains
15 mg/mL of HA in the product.
2.2.2.4 Monophasic vs. Biphasic HA
Often HA fillers are classified as monophasic and
biphasic HA, based on their specific manufactur-
ing processes. In the manufacturing of HA fillers,
once the cross-linking reaction is complete, the
HA gel is then transferred into a homogenizer or
grinder where it is crushed into fine particles that
can easily pass the needle. Biphasic HA is
obtained at this stage by ‘sieving’ the HA gel
through sizing screens of specified diameters,
which produces HA particles of the desired size.
By comparison, monophasic HA does not
undergo particle sizing process and, as such, con-
sists of a homogeneous gel containing particles
of mixed shapes and sizes. Consequently, bipha-
sic HA is firmer, more elastic and particulate in
its feel with a granular consistency, while mono-
phasic HA has a softer and smoother, more fluid
texture with a soft cohesive consistency. In this
respect, Restylane® SubQ™, which had the larg-
est particle size among the Restylane® range of
products, consisted  of granules so large they
were actually visible to the naked eye, measuring
almost 1 mm in diameter [10].
However, scientifically speaking, categorizing
HA fillers as monophasic or biphasic is not rele-
vant, as all HA gels consist of gel particles when
examined under the microscope (Fig. 2.12). As it
happens, the term, ‘monophasic HA filler’ was ini-
tially advocated by Juvéderm® for the purpose of
differentiating their soft HA filler from the origin-
ial NASHA™ filler, Restylane® with firm gel char-
acteristics. However, the term monophasic HA gel
actually represents an oxymoron since a gel, by
definition, exists as a mixture of liquid phase
within a solid phase, hence, at the very minimum,
is biphasic in its physical property. By this logic,
a
b
Fig. 2.12  Particles of HA fillers (Courtesy of Galderma). All HA gels consist of gel particles packed together. (a)
Biphasic HA fillers. (b) Monophasic HA fillers
2  Volumizing Fillers

43
one may argue that a biphasic HA filler should
more aptly be described as a triphasic gel [11].
Moreover, some HA fillers often classified as
monophasic HA fillers such as Restylane® Volym
e and Restylane® Refyne using OBT™ technology
also demonstrate almost uniform particle size
resulting from the ‘sieving’ process during the
manufacture for optimal homogenicity. That not-
withstanding, these terms are often adopted in
clinical practice as a shorthand for characterizing
different HA fillers to assist the understanding of
treating physicians. Therefore, it bears noting that
the terms, ‘monophasic’ and ‘biphasic’ as men-
tioned in this book is used for the purpose of con-
venience only. However, to best characterize HA
fillers in a manner that facilitates the selection of a
certain filler for a certain clinical indication, scien-
tifically sound rheologic tests such as rheometry
should be used.
In terms of their rheological properties,
firm  biphasic HA fillers tend to display higher
elasticity and viscosity than soft monophasic HA
(Table 2.2), which allows better retention of shape
against external deformation and stronger lifting
capacity [11]. Biphasic HA is, therefore, better
suited for placement at the deeper planes where
they can provide deep tissue lift or support for
facial volume depletion but are less suitable for
superficial injection in the dermis and are not eas-
ily moldable postinjection.
In contrast, monophasic HA tends to have
lower elasticity and viscosity but demonstrates
higher levels of cohesivity compared with biphasic
HA which exist as individual grains of gel parti-
cles gathered together like sand. Cohesivity is yet
another important rheological determinant that
informs the ability of a product to resist external
deformation. Significantly, in the study by
Sundaram et  al., Belotero® Balance™ and
Juvéderm® Ultra Plus™ (both soft  monophasic
HA fillers) showed the highest cohesivity scores
while Restylane® as a biphasic HA filler demon-
strated the lowest cohesivity (Table  2.2). [13]
Softer HA fillers with a lower G’ and a higher
cohesivty  are more suitable than firm fillers for
injection in areas of high facial movement such as
the forehead, nasolabial folds, and cheek, as mono-
phasic HA fillers can more effectively recover
their original shape without dissociating upon
deformation from facial muscular movements. In
addition, owing to their lower viscosity, monopha-
sic HA fillers can produce smooth results even
when placed superficially in the dermis as they
spread more easily through the tissue plane and
can provide easy molding postinjection [14].
Due to its hydrophilic nature, HA filler can
expand in volume within 2–4 weeks of placement
and, in so doing, may cause unwanted lumpiness
and irregularity, especially in areas with thin tis-
sue coverage such as the periorbital region
(Fig. 2.13). Such postinjection swelling from the
hydration of HA molecules appears to occur more
significantly in soft monophasic HA fillers than in
firm  biphasic HA fillers  while other conditions
such as HA concentration should be also consid-
ered (Fig.  2.14) [15]. The postinjection swell-
ing of HA filler can be measured by ‘the swelling
factor’ measurement which is indicative of a HA
gel’s hydration (saturation) status [17]. When near
saturation (closes into equilibrium), a gel will not
exhibit appreciable swelling after injection.
Below equilibrium (unsaturated), a gel will read-
ily take up water from the surrounding fluid until
it reaches hydration equilibrium. Gel fluid uptake
characteristics vary from product to product and
are dependent on  hyaluronic acid concentration
and limited by the extent of crosslinking. In gen-
eral, as the extent of crosslinking is increased in
firm HA fillers with high  G’,  swelling factor is
decreased. Conversely,  softer gels with  a lower
degree of crosslinking and  lower G’ products
have higher swelling factor. It may be also postu-
lated that this is partly due to the greater tendency
of soft  monophasic HA to spread in the tissue,
which causes a larger gel surface area to come
into contact with water in the tissue. This is in
contrast with the less spreading biphasic HA fill-
ers that integrate into the tissue in a more targeted
manner and thus has more limited surface area per
volume in the tissue. Notably, Juverderm®
Ultra Plus™, based on the HYLACROSS™ tech-
nology with an HA concentration of 24 mg/m and
Belotero® Volume™ incorporating the CPM™
technology with an HA concentration of 26 mg/m
are monophasic HA products noted for their sig-
nificant postinjection swelling (Table 2.2). Thus,
2.2  Hyaluronic Acid Fillers

44
Table 2.2  Rheological properties, cohesivity levels, and clinical volumizing capacity of the nine HA fillers
Product
reference
Lifting
capacity
GSa
cohesivity
score
Shear-stress properties
at 0.7 Hz
Static compression
properties at
1.5 mm
Dynamic compression properties at 0.7 Hz
G’ (Pa)
G” (Pa)
tan
δ
Fɴ (N′)
E′ (Pa)
E″ (Pa)
tan δc
BELOTERO®
Balance
+
5
63 ± 3
34 ± 2
0.54 ± 0.04
0.51 ± 0.02
31,457 ± 1132
18,541 ± 472
0.59 ± 0.03
BELOTERO®
Intense
lidocaine
++
4
130 ± 3
52 ± 2
0.40 ± 0.02
1.16 ± 0.03
59,150 ± 1469
32,235 ± 622
0.54 ± 0.02
BELOTERO®
Volume
lidocaine
+++
3
300 ± 5
57 ± 1
0.19 ± 0.01
0.95 ± 0.03
111,044 ± 2250
58,047 ± 1880
0.52 ± 0.01
JUVEDERM®
Volbella
+
2
174 ± 4
28 ± 1
0.16 ± 0.01
0.15 ± 0.01
12,003 ± 400
25,270 ± 1015
2.11 ± 0.08
JUVEDERM®
Volift
++
2
279 ± 6
39 ± 2
0.14 ± 0.01
0.22 ± 0.01
21,994 ± 378
44,287 ± 1316
2.01 ± 0.05
JUVEDERM®
Voluma
+++
2
314 ± 5
17 ± 1
0.06 ± 0.00
0.33 ± 0.02
41,747 ± 947
60,382 ± 1898
1.45 ± 0.02
RESTYL®
ANE lidocaine
+
1
677 ± 13
136 ± 3
0.20 ± 0.01
0.23 ± 0.01
8,456 ± 256
32,469 ± 854
3.84 ± 0.17
Restylane®
Lyft lidocaine
++
1
716 ± 9
110 ± 4
0.15 ± 0.01
0.30 ± 0.01
9,507 ± 216
35,184 ± 735
3.70 ± 0.04
JUVEDERM®
Ultraplus XC
++
4
143 ± 5
36 ± 2
0.26 ± 0.02
0.98 ± 0.02
65,554 ± 1891
23,856 ± 330
0.36 ± 0.02
Mean ± SD
aGavard-Sundaram Cohesivity Scale (Ref. [13]). Data modified from Ref. [12],
2  Volumizing Fillers

45
they are unsuitable for injection in thin-skinned
areas of the face; even when used for contouring
and sculpting, it is preferable to dilute the product
with saline at a 6:4 ratio with six parts HA and
four parts saline, respectively (see Sect. 3.1.3).
2.2.3
Choice of HA Filler
The three key factors to consider in choosing a
filler product are safety, longevity, and price as the
author has routinely highlighted in lectures since
the early 2000s (Fig. 2.15). Among those, safety
takes first priority, since injectable fillers essen-
tially represent external substances introduced into
the human body. On this score, HA outperforms all
other types of soft tissue fillers currently on the
market. Not only does it involve minimal risks of
adverse reactions, but the injected HA filler is also
readily reversible with injection of hyaluronidase
should any problems occur, effectively restoring
the patient back to the pretreatment condition. In
light of recent concerns over the cases of inflamma-
tion from delayed-type hypersensitivity reactions
to HA fillers, incidence of delayed type hypersensi-
tivity has also become a significant safety criterion
for selecting a HA filler product.
While HA fillers were previously understood to
last between 6 months and 1 year following their
injection, it has been the author’s observation that
the duration of effect often extends beyond this
suggested timeframe, lasting even longer up to
5–10 years with maintenance treatments repeated
2–3 times. While monophasic HA filler Juvéderm®
Voluma and BELOTERO® Volume tend to outlast
biphasic HA and variations seem to exist between
different patients and different facial regions
treated, there appears to be almost no significant
difference in filler longevity among different
HA filler brands as long as they have similar volu-
mizing capacity. If anything, products containing
too much cross-linker content for increased lon-
gevity tend to require more careful handling as
Fig. 2.13  Postinjection swelling at the  tear trough
occurred in the right side which was injected with mono-
phasic HA filler (Juvederm® Ultra™), while the left side
injected with biphasic HA filler (Restylane®) showed no
postinjection swelling
5
4
3
2
3D image measure
1
0
B
J
R
Y
Total
30 min
3 days
2 weeks
4 weeks
12 weeks
24 weeks
Fig. 2.14  Time trends in 3D image measurement accord-
ing to filler type. No significant difference was observed
between fillers B and J. The 3D measure were greater with
filler B than with filler R at all times except for 30 min.
Moreover, the 3D measures were greater with filler B than
with filler Y at 2, 4, and 24  weeks. (B: Belotero® J:
Juvéderm® R: Restylane® Y: YVOIRE®) (Cited from Ref.
[15])
2.2  Hyaluronic Acid Fillers

46
they are generally more resistant to dissolution
with hyaluronidase.
Price is no doubt an important consideration
for any practitioner concerned for his business’s
bottom line. However, with the drop in the price
per mL of HA filler to below half that of the early
2000s, HA filler prices have come to represent
significantly less of a concern for an average prac-
titioner.  That notwithstanding, the price of HA
filler per syringe still matters in the case of full
face volumization which requires at least 6–10 ml
to be used in one session. In this respect, it is a
welcome development that due to the fierce com-
petition in the domestic market, Korean HA filler
brands are now available at even 20–40 USD per
1 mL syringe while providing comparable quality,
as their prices have fallen to 1/5–1/10 the price of
imported HA fillers during the early 2000s. This
has driven HA fillers to compare favorably with
autologous fat graftautologotraua in Korea and to
eventually replace fat for facial volumization.
Deciding among the vast array of HA filler prod-
ucts flooding the market can be overwhelming for
the practitioner. However, selecting the right HA
filler for a procedure is in many respects analogous
to choosing the right golf club for a shot. Similar to
how a driver that is great for driving is not necessar-
ily best for putting a ball, there is an art to picking
the perfect HA filler with the right rheologic prop-
erty for the right indication. Also, just as a typical
golfer’s bag contains an assortment of golf clubs
each of a different brand, such as an XXIO iron, a
PING driver, and a Scotty Cameron putter, the prac-
titioner may consider using a mix of different HA
products from different manufacturers he feels most
comfortable using. Personally, my favorite filler
brand to use almost exclusively during the first 10+
years of practicing soft tissue filler treatments was
Restylane®. Over the past 5–6 years, Belotero® HA
fillers have been added as a favored choice.
Essentially, the best choice of HA filler to use is a
judgment call made by each practitioner based on
his level of comfort with the product, the target area
and plane of injection and the rheologic property of
the product, that is, elasticity and cohesivity of HA,
degree of HA concentration, and degree of cross-
linking (Fig.  2.16), etc. Therefore, it is often the
case that a combination of different HA filler brands
can be used for treating different facial regions of a
given patient, for example, by using Restylane® for
the nose or tear trough in conjunction with Belotero®
Volume  for the anterior malar or sunken
cheeks. Alternatively, different HA products within
the same family of HA filler may be deployed in
different subunits of a given  facial area. A good
example is the use of Belotero® Volume to volumize
the body of the lips and Belotero® Balance  to
enhance the vermillion border.
Selecting HA filler Based on  Facial
region; As a general rule of thumb, the use of
firm  biphasic HA  filler with higher G’ such
as Restylane® is advised in treating areas of thin
overlying skin such as the periorbital region,
including the lower pretarsal roll, tear trough, and
upper eyelids, to avoid unfavorable postinjec-
tion  swelling due to the water absorption  by
the HA molecules. For this reason, firm biphasic
HA fillers  with higher G’ are also suitable  for
augmenting the nasal dorsum where the skin is
thin as well. Generally speaking, products with
higher G’, large particle sizes or higher HA con-
centration are suitable for indications requiring
volumetric augmentation as they provide better
structural support regardless of softer monopha-
sic or firmer biphasic HA filler. On the other
hand, softer  monophasic HA fillers  with rela-
tively higher G’ and higher  cohesivity such as
Fig. 2.15  The three key factors to consider in choosing a
filler product
2  Volumizing Fillers

47
Belotero®
Volume, 
Juvéderm®
Voluma
and  Restylane® Volyme  are generally prefera-
ble for volumizing areas of high mobility such as
the submalar depression, nasolabial fold,  fore-
head and temples where substantial  dynamic
force is imposed by the  underlying  muscular
movements. Treatment of the lips which require
a  soft, smooth texture consistent to the touch
should be performed exclusively with softer
monophasic HA products with lower G’  such
as  Belotero® Intense, Restylane® Kysse, and
Juverderm® Ultra XC.  By contrast, a harder
stiffer biphasic HA filler is preferred  in areas
such as the chin and nasal bridge where firm,
crisp texture is desired.
Selecting HA filler Based on Skin Quality;
For patients with thinner skin, where product pal-
pability/visibility is an important consideration,
products with lower G’ values are generally most
appropriate. Lower G’ products such as
BELOTERO®
Intense,
Restylane®
Defyne,
Juvéderm® Volift and Juvéderm® Ultra Plus XC
are softer and more easily distributed in the
tissue.
Selecting HA filler  Based on Plane  of
Injection; In general, firmer products with higher
G’ values are indicated for deeper planes of injec-
tion and are applied to support a greater degree of
correction, whereas lower G’ (softer) products
are indicated for more superficial planes of injec-
tion and less severe corrections. The higher G’
products  are suitable for indications requiring
volumetric augmentation as they provide better
structural support in the deep tissue.  For areas
such as the malar cheek, chin, and jawline, where
the product can be placed against the bone for
projection, a higher G’ products such as
BELOTERO®
Volume,
Restylane®
Lyft
and  Juvéderm® Voluma  will provide a greater
advantage over a lower G’ product because it will
have greater resistance to the compression forces
inherent
in
the
deeper
injection
plane.  Meanwhile,  thinner, softer  HA prod-
ucts  with lower G’ such as  BELOTERO®
HA
Concentration
Volumizing
capacity
Modeling
capacity
HA Filler
Price
Area of injection
Duration effect
Post injection
swelling
No migration
Safety
Lidocaine
Free HA
amount
Rheological
Properties
Product purity
Cross-linking
technology
Cross-linking
ratio
Fig. 2.16  Key factors in choosing HA filler products (Modifed from Merz Institute of Advanced Aesthetics)
2.2  Hyaluronic Acid Fillers

48
Soft,  Restylane® Skinbooster Vital, Restylane®
Fynesse, and Juvéderm® Volbella are better suited
for making finer intradermal corrections or deli-
cate refinements. See Choice of Filler by Each
Indication for further detail.
2.2.4
Rheological Properties of HA
Filler (Table 2.2)
It is often said it’s a poor craftsman that blames
his tools; however, part of being a master crafts-
man is knowing one’s tools. In volumizing filler
treatments, utilizing the right choice of HA for a
given clinical indication marks the starting point
for producing excellent aesthetic outcomes.
Selecting the ideal HA is, in many respects, anal-
ogous to choosing the right golf club for a shot.
Similar to how a driver that is great for driving is
not necessarily best for putting a ball, there is an
art to picking the perfect HA filler with the right
rheologic characteristics for a given indication.
Different regions of the face have varying levels
of skin thickness and tension, muscle activity,
and tissue density, for which each filler has its
own place. In this respect, knowledge of each
filler’s rheological attributes is key to deciding
which product to use and where. Rheology,
which deals with the flow of matter, is especially
pertinent to filler procedures as HA gels as bipha-
sic materials demonstrate properties of both liq-
uid and solid at the same time.
Rheology is defined as the study of flow-
related properties, the understanding of which
has been crucial for the manufacture and process-
ing of materials across a wide array of industries
ranging from paint, ink, ointment to adhesives,
which exhibit both the viscose behavior of liquid
and elastic behavior of a solid. HA fillers being
gels also constitute a biphasic material consisting
of both liquid and solid components. Thus,
numerous studies have attempted to investigate
the rheology of different HA fillers to establish
their clinical behavior and compare their relative
strengths and weaknesses in achieving the desired
aesthetic outcome. Indeed, understanding these
rheological properties can help predict the behav-
ior of different HA fillers during and after implan-
tation
in
the
tissue,
thus
allowing
the
optimal selection of HA filler for a given clinical
application, hence leading to the coining of the
term “rheologic tailoring” [11].
Both during and after its implantation in the
tissue, HA is subject to a complex array of defor-
mation forces, to which different products behave
differently according to their intrinsic rheological
properties. During injection, the HA filler is sub-
ject to shear deformation as it is extruded from
the syringe through the small needle or cannula.
Once implanted in the tissue, the product is then
exposed to mechanical stresses of varying vec-
tors and intensity such as gravity, shearing by
movement of  the facial musculature, and com-
pressive deformation exerted by the overlying
skin tissue. Of these, lateral shearing arises in
two possible scenarios. First is when the HA
filler is placed between two different anatomical
tissue layers, for example between the deep fat
pad and the muscle plane as in the case of deep
injection for hollow cheeks. In this case, each
horizontal layer that interfaces the HA can apply
a different level of shear stress on the implanted
HA filler. Second is when the HA filler is injected
within the same anatomical tissue layer, but the
portion of the HA situated closer to the muscle
surface is subject to a greater degree of shearing
than the other parts. Meanwhile, compression
represents a vertical deformation force applied
on the HA filler not only when the face is in
repose (i.e., static state) by the overlying skin tis-
sues but also during facial movement (i.e.,
dynamic state) by the facial musculature. The
amount of compression force acting on the
injected HA is greater in the deep planes such as
the supraperiosteal or subcutaneous layer than in
the superficial dermal layer. The ability to resist
the various  deformation forces and retain the
original shape without being displaced from the
implanted location constitutes an essential ele-
ment of a volumizing HA filler.
2.2.4.1 Elasticity
Elasticity represents the ability of the gel to
recover its original shape after deformation,
which is the most important rheologic property
for the filler. For example, disposable earplugs
2  Volumizing Fillers

49
made of polyurethane are characterised by high
elasticity while honey is not. Also, while both are
gels, molded gelatin demonstrates higher elastic-
ity compared with chocolate  pudding with a
lower elasticity (Fig. 2.17). Elasticity of an HA
filler can be expressed using different rheological
parameters according to the type of deformation
force applied. The elasticity of a gel under shear-
stress (i.e., horizontal stress) is represented by the
elastic modulus (G’), which measures the hard-
ness or stiffness of a gel and thus its ability to
resist deformation under applied shear pressure
(Fig. 2.18a). On the other hand, the elasticity of a
gel under compression (i.e., vertical stress) is
measured by normal force (FN) in static mode
and by elastic modulus (E′) during facial muscle
movement, that is, in dynamic mode [12]
(Fig. 2.18b). The severity of dynamic forces that
contribute to the deformation of hyaluronic acid
filler products implanted differs depending on the
plane of injection. While the shear force is severer
in the superficial (dermis) plane and the muscular
layer, compression force becomes severer in
the  deeper planes (the  deep subcutaneous fat
layer and supraperiosteal layer) (Fig.  2.18c).
Various factors may influence the G’ and E′ of an
HA filler, including HA concentration, degree of
cross-linking, the ratio of double-linked/pendant-
type (mono-linked) BDPE in the gel, the propor-
tion of free form HA in the gel, and the
manufacturing process employed. Generally
speaking, HA gels with higher HA concentration
and degree of cross-linking have a high G’, while
those with a higher composition of mono-linked
BDPE or free-form HA in the gel are associated
with a lower G’. Also, with the particle size being
equal, biphasic HA gels generally have a higher
G’ in comparison to monophasic HA (Fig. 2.19).
In terms of clinical implication, it follows  that
products with a high elastic modulus G’ are
not suitable for areas requiring a smooth, even
feel such as the lips since the palpability of the
hard, rubbery gel texture would be undesirable.
Conversely, products with a higher G’ can be
expected to provide a more effective targeted lift
given their tendency not to spread and retain the
original shape in the implanted area (Fig. 2.20).
Thus, they are regularly used in clinical practice
for volume projection in the deep tissue planes.
In short, a higher G’ correlates to a material with
a greater volumizing capacity as clinically proven
in the controlled split-face study by Monheit
et  al. performed in 140 patients [17]. Similar
observations have been obtained with respect to
the compression parameters FN and E′, with
higher FN and E′ values correlating with a higher
volumizing capacity [12]. That said, it is relevant
to note that harder stiffer products with higher
elasticity require greater extrusion force during
injection, as well as the use of larger, thicker nee-
dles or cannulas. Also, since these products do
not provide easy molding and spread ability, they
are better placed in the deep tissue planes rather
than in the superficial layers.
2.2.4.2 Viscosity
Viscosity is defined as the ability of a fluid to
resist deformation or its tendency to stick together
without fragmenting when stressed. For example,
refrigerated butter or peanut butter has high vis-
cosity and thus does not spread easily on toast,
whereas room temperature butter has low viscos-
ity and thus glides easily along the surface when
spread (Fig. 2.21). Viscosity is measured by vis-
cous modulus (G″) or complex viscosity (η*) in
terms of shear deformability and by viscous
modulus (E″) in terms of compressive deforma-
tion. Complex viscosity (η*) describes the gel’s
ability to resist extrinsic shear deformation; in
other words, the ability to resist being spread.
When the shear force falls within a certain range
(within the linear viscoelastic range), the η*
decreases in proportion to the increase in shear
stress exerted [11]. Viscous modulus (G″)’ is a
measure of a gel’s ability to dissipate energy
when shear force is applied (Fig. 2.22). Within
the linear viscoelastic range, G″ is known to be
proportionate, if not entirely identical, to the
complex viscosity (η*). However, for biphasic
HA fillers, η* is considered to be a more accurate
indicator than G″ for predicting their clinical
behavior and is thus more widely used [11].
While HA fillers with higher viscosity require
greater extrusion force as they do not inject
smoothly, once implanted in the tissue, they can
resist a greater amount of shearing stress without
2.2  Hyaluronic Acid Fillers

50
Fig. 2.17  Molded
gelatin represents higher
elasticity compared with
chocolate pudding
which has lower
elasticity
a
b
Shear Force
Compression stress
G´
FN
c
Fig. 2.18  (a) The
elastic modulus (G′).
The elasticity of a gel
under shear-stress (i.e.,
horizontal stress) is
represented by the
elastic modulus (G′). (b)
The elasticity of a gel
under compression (i.e.,
vertical stress) is
measured by normal
force (FN) in static
mode. (c) Dynamic
forces that contribute to
deformation of
hyaluronic acid filler
products implanted in
the superficial (dermis)
and deep planes (deep
fat pad and
supraperiosteal) of soft
tissues
2  Volumizing Fillers

51
a
b
Fig. 2.19  Biphasic HA gels generally have a higher G′ in comparison to monophasic HA (Courtesy of Galderma) (a)
NASHA cube (Biphasic HA gel). (b) OBT cube (monophasic HA gel)
800
700
600
Midule d° elslasticite´G´ -Pascal
500
400
300
200
100
0
SubQ
Perlane
Restylane
Belotero®
Volume
Juvederm
Voluma
Juvederm
Ultra+
Balotero®
Intense
Juvederm
Ultra
Softer
Firmer
Elastiticity, the gel hardess (G’)
Belotero®
Balance
Fig. 2.20  Elastic modulus (G′), Hardness of 9 HA fillers (Modified from Merz Institute of Advanced Aesthetics)
2.2  Hyaluronic Acid Fillers

52
140
120
100
80
60
40
20
0
Belotero®
Balance
Belotero®
Intense
Juvederm
Volbella
Juvederm
Volift
Juvederm
Voluma
Juvederm
Ultra 3
Restylane
Perlane
Restylane
Iidocaine
Belotero®
Volume
Viscosty - G'' (Pa)
Fig. 2.22  Viscous modulus (G″)’ of 9 HA fillers (Modified from Merz Institute of Advanced Aesthetics)
Fig. 2.21  Peanut butter
has high viscosity and
thus does not spread
easily on toast, whereas
room temperature butter
has low viscosity and
thus glides easily along
the surface when spread.
(Modified from Merz
Institute of Advanced
Aesthetics)
2  Volumizing Fillers

53
spreading, thus ensuring retention of shape and
structural integrity. This makes them ideal for
injection in areas of high facial muscle movement
or in the deep tissue planes where they can provide
deep volume projection. Conversely, more fluid
HA fillers with less viscosity are easier to inject
and flow more evenly through the tissue and are
thus suitable for superficial placement in the der-
mis. In the study by Rosamilia et al. [18] based on
the Belotero® range of HA fillers, Belotero® soft, a
softer product with lower viscosity, was shown to
spread more readily into the tissue compared to
Belotero® Volume™, a less fluid product with
higher viscosity. Meanwhile, biphasic HA fillers,
being particulate in matter, are generally known to
have a higher viscosity than monophasic HA [19].
Based on such rheological differences, when
injected intradermally in the dermis, Belotero®
Balance™ as monophasic HA has been shown to
demonstrate more homogenous integration in the
tissue compared with the micro bolus pattern of
tissue integration of the biphasic Restylane® with
higher viscosity [14].
2.2.4.3 Tan Delta (δ)
Since fillers are viscoelastic materials that exhibit
the properties of both viscosity and elasticity,
their behavior cannot be defined appropriately
based on a parameter describing the characteris-
tics of either a solid or fluid alone. This under-
standing has led to the proposal of various
secondary rheologic calculations derived from
the primary rheological parameters. Among
these, tan delta (δ) is a relatively commonly used
modulus, which measures the ratio of the viscous
modulus G” over the elastic modulus G’ (G”/G’)
in a given material [11]. In other words, tan δ is a
complex modulus that considers the overall bal-
ance of elasticity and viscosity of a given HA gel.
A tan δ value of less than 1 denotes that the prod-
uct is more elastic than viscous, while a tan δ
greater than 1 signifies a predominance of vis-
cosity over elasticity. Since most HA fillers tend
to exhibit a more elastic than a fluid behavior,
their tan δ values are typically less than 1, with
some harder, more elastic fillers showing a tan δ
value even lower than 0.2. Even within the same
family of HA fillers, products indicated for deep
volume correction tend to demonstrate lower tan
δ values. Meanwhile, tan δC (E″/E′) is the corre-
sponding viscoelastic modulus for describing the
gel behavior under applied compression force
[12]. However, tan δC (E″/E′) values appear to
deviate from the tan δ (G”/G’) values in that the
tan δC was less than 1 for the Belotero® range of
products and Hylacross™-based Juvéderm®
Ultra™, that is, products with high tan δ values;
1–2 for VYCROSS™-based products; and
greater than 3 for the Restylane® range of prod-
ucts whose tan δ value was the lowest among the
tested products (i.e., less than 0.2). From this, it
follows that HA behaves differently under shear-
stress than under dynamic compression [11]. It is
also relevant to note that HA placed in the deep
tissue is exposed not only to shear stress but also
to compression, with the amount of compression
force being greater in the deep planes than in the
superficial layer.
2.2.4.4 Cohesivity
Cohesivity describes a material’s tendency not to
dissociate due to the internal attraction of the
molecules for each other. For example, honey is a
highly cohesive material, while sand grains are
far less cohesive (Fig. 2.23). The cohesivity of an
HA filler represents the degree to which it
remains intact in the tissue without dissociating
following its implantation. For want of an objec-
tive evaluation protocol, the cohesivity of HA
fillers is measured using a standardized 5-point
visual scale referred to as the Gavard-Sundaram
Cohesivity Scale (The “GS Cohesivity Scale”).
[13] The GS Cohesivity Scale ranges between a
value of 1 (fully dispersed) and 5 (fully cohesive)
(Fig.  2.24). In general, with the particle size
being identical, biphasic HA fillers tend to be less
cohesive than monophasic HA fillers. As is turns
out, Restylane® as a biphasic HA has a cohesivity
score of 1 on the GS Cohesivity Scale, whereas
the monophasic Belotero® Balance™ has the
highest cohesivity of 5 [12, 13]. Even among
monophasic HA fillers, significant variations
exist in their cohesivity scores, reflecting differ-
ences in the underlying manufacturing process
employed. For example, within the same
Juvéderm family of HA fillers, Juvéderm® Ultra
2.2  Hyaluronic Acid Fillers

54
Plus™ (Juvéderm® Ultra 3™) incorporating the
HYLACROSS™ technology has a cohesivity
score of 4, while Juvéderm® Voluma™ embody-
ing the VYCROSS™ technology has a signifi-
cantly lower cohesivity of 1 [12].
The most notable clinical significance of
cohesivity lies in its ability to contribute to the
lifting capacity of HA fillers, as with elasticity.
This has been well elucidated in the split face
nasolabial fold study comparing the treatment
effect of Belotero® Intense vs. Restylane® Lyft in
20 subjects [20]. Needless to say, elasticity is the
key factor in determining the lifting capacity of
hyaluronic acid fillers. Given such, the above
study is remarkable in that it demonstrated that
Belotero® Intense with a G’ of only 111  Pa
(o.7  Hz) was able to yield volumizing effects
comparable to that of Restylane® Lyft having a
G’ of 549 Pa. Thus, it can be postulated that, in
spite of its lower G’, Belotero® Intense was able
to effectively close the gap with Restylane® Lyft
by virtue of its significantly higher cohesivity of
4  compared with Restylane® Lyft’s score of 1.
The influence of cohesivity on the volumizing
capacity of the filler is particularly relevant when
treating areas of high mobility such as the nasola-
bial folds, marionette lines, and the forehead. In
the author’s experience, low cohesivity products
a
b
Fig. 2.24  The GS Cohesivity Scale*. (a) Restylane®; Score of 1 at 90 s (fully dispersed). (b) Belotero® Balance; Score
of 5 at 90 s (fully cohesive). *Gavard-Sundaram Cohesivity Scale (Ref. [13])
Fig. 2.23  Honey
represents a highly
cohesive material, while
sand grains are far less
cohesive (Courtesy of
Merz Institute of
Aesthetic Academy)
2  Volumizing Fillers

55
such as Restylane® SubQ are generally more sus-
ceptible to clumping or separation when sheared
by the rigorous muscle activity in these areas,
while Belotero® Volume tends to more effectively
hold its ground and retain its original shape.
Conceivably, such differences may also account
for the equivalence in the lifting capacity between
the Belotero® Intense  and Restylane® Lyft,
despite the much lower shear elastic modulus
(G’) of the Belotero® range.
2.2.4.5 Clinical Implications (Table 2.3)
A direct head-to-head rheometric comparison can
be elusive between products that have been for-
mulated using different manufacturing processes.
Indeed, the same product is often be found to
show varying rheometric values in different stud-
ies depending on the underlying test parameters
applied. Therefore, when evaluating the rheology
of different HA gels, it is more relevant to com-
pare products within the same brand family rather
than across different families. Rheometric values
of products belonging to different brands may be
useful only to the extent they may help elucidate a
general tendency or pattern.
Thicker, firmer fillers with high viscoelasticity
are generally harder to inject and thus require the
use of thicker needles or cannulas. For example,
even though Belotero® Volume as a monophasic gel
may even pass a 30-G needle as extrusion of mono-
phasic HA is not constrained by the size of the
injection tool, the product apparently feels much
stiffer when extruded through a 25-G cannula than
when passed through a thicker 23-G cannula.
Soft, fluid products with low viscoelasticity
such as Restylane® Vital, Belotero® Soft, and
Juvéderm® Volbella are suitable for superficial
injection in the dermis as they will spread more
Table 2.3  Clinical implications of rheological properties (see each indications)
Indications
Area
Appropriate rheological
properties
Recommendation
Volumization under
thin skin
Tear trough
Palpebromalar groove
Biphasic, low to moderate
viscoelasticity
Restylane®,
Restylane® Skinbooster Vital
Intradermal
injection
Hydrolifting
Fern pattern
technique
Thick skin area
Monophasic or
Biphasic with low viscosity
Belotero® Balance,
Restylane® Skinbooster Vital,
Juvéderm® Volbella
Thin skin area
(periorbital region
and neck)
Monophasic with low
viscosity
Belotero® Soft
Volumization and
projection
Temporal region
Highest G’ values within
each product range
Restylane® Lyft,
Restylane® Volym, Belotero®
Volume, Juvéderm® Voluma
Juvéderm® Volux
Hyperdynamic areas
Forehead,
Nasolabial fold,
Marionette line
Chin
Monophasic with high
elasticity and cohesivity
Belotero® Volume
Juvéderm® Voluma
Juvéderm® Volux
Nasal dorsum
Biphasic with high elasticity
Restylane® Lyft
Jawline, and lateral
malar
Biphasic or monophasic with
high elasticity
Restylane® Lyft,
Restylane® Volume,
Belotero® Volume, Juvéderm®
Voluma
Double layering
Deep layer
Biphasic with high elasticity
Restylane® Lyft
Superficial layer
Monophasic
with high elasticity
Belotero® Volume
2.2  Hyaluronic Acid Fillers

56
readily through the tissue plane. Generally speak-
ing, soft  monophasic HA  fillers with lower G’
such as Belotero® Soft, and Juvéderm® Volbella
flows more evenly and integrates homogeneously
into the tissue, thus creating less irregularity or
Tyndalling than biphasic HA that are thicker and
stiffer in texture. On the other hand, their higher
spreadability means that  soft  monophasic HA
fillers present significantly more surface area to
free
radicals
and 
endogenous
hyaluroni-
dase enzymes than firm biphasic HA, resulting in
more rapid degradation. Indeed, in the author’s
experience, when Restylane® and Belotero® were
used for intradermal injection in the nasolabial
folds (via fern pattern technique) or in the facial
skin (via hydro lifting technique), Restylane®
appeared to provide longer duration, lasting for
more than 1 year while Belotero® Balance seemed
to last for a shorter period. This observation is in
agreement with the findings from  the study by
Tran et al., which compared the biointegration of
different HA fillers in the dermis based on their
viscoelastic properties. According to the study,
while Belotero® Balance was shown to provide
more homogeneous integration within the tissue,
it appeared to have less of the product remaining
118 days later than Restylane® [14].
Hence, the author’s preferred approach when
performing hydrolifting treatments is to use
Belotero® Balance in patients with photoaged or
thin skin, or in areas of the face with thin tissue
coverage such as the periorbital region, and
Restylane® or Restylane® Vital in patients with
normal skin thickness.
Meanwhile, where the aim is to provide vol-
ume and projection, it is more preferable to
choose a thicker, firmer HA filler such as
Restylane®
Lyft,
Belotero®
Volume,
and
Juvéderm® Voluma that have the highest G’ val-
ues within each product range. Restylane® Lyft,
as a biphasic HA filler with high elasticity, and
thus a rather hard gel texture, is better suited for
placement in areas where the bone lies just under
the skin, such that palpability of the hard product
does not become an issue. A further consider-
ation in using Restylane® Lyft is that owing to the
relatively low cohesivity of the Restylane® range
of HA fillers, it is usually better placed in areas of
low mobility such as the nasal dorsum, jawline,
and lateral malar where the product is not submit-
ted to intense contraction of the surrounding
musculature. Notably, the temporal region can be
treated using either a biphasic or a monophasic
HA, despite the repetitive contraction of the tem-
poralis m, since the thick temporalis fascia over-
lying the implanted filler prevents the creation of
visible irregularities. Meanwhile, a strong mono-
phasic HA with high cohesivity such as Belotero®
Volume is usually most suitable in the hyperdy-
namic areas of the forehead, the cheeks, chin,
nasolabial folds, marionette lines, and anterior
malar.
Monophasic HA fillers, being soft fillers with
less viscoelasticity, are ideal for placement in
areas such as the lips and cheeks that must be soft
and smooth in their  feel. On the other hand,
firmer and more elastic biphasic HA fillers are
better suited for implantation in areas where the
underlying bone is directly palpable, such as the
nasal dorsum, jawline, and the malar, While, by
extension, the forehead may also be considered
an area suitable for treatment with biphasic HA,
in practice, that is not the case. Instead, given the
dynamic muscle activity and limited space avail-
able for filler placement in the area, softer mono-
phasic HA with a higher cohesivity and more
homogeneous tissue integration represents a bet-
ter option for forehead augmentation. On the
other hand, biphasic HA fillers are better suited
for placement in areas of thin overlying skin such
as the periorbital region, including the lower pre-
tarsal roll and the tear trough, owing to the ten-
dency of monophasic HA fillers with lower G’ to
retain water when implanted in these regions.
Meanwhile, when  HA filler is injected in
boluses into the dermis or subdermis, it can pro-
duce the  so-called Tyndall effect (Fig.  2.25), a
bluish discoloration that is visible to the eye
caused by preferential scattering of light by the
superficially implanted HA filler. This phenome-
non, which should more accurately  be termed
“Rayleigh scattering”, occurs when light passing
through air or liquid is scattered by the dispersed
air or water particles whose sizes are smaller
than the wavelength of light [21]. As it happens,
light of shorter wavelength is scattered much
2  Volumizing Fillers

57
more strongly; thus, blue light, which has a short
wavelength, is preferentially reflected back to the
eye. This explains why the sky appears blue, as
does the water in a clear pond. By comparison, a
Tyndall effect, in its true sense, is what is seen
when light produces a visible beam while travel-
ing through a colloidal substance that has particle
sizes ranging between 1 and 1000 nm in diameter
[22]. It is for this reason that the car headlight
flashed into fog will produce a luminous beam.
Hence, while Rayleigh scattering should be the
proper term, considering that the term Tyndall
effect is more routinely used for describing the
unsightly bluish hue appearing in implanted HA
fillers, we will refer to the phenomenon as the
Tyndall effect for the sake of our present discus-
sion. A Tyndall effect occurs most often if the HA
filler is placed too superficially in the dermis or in
large volumes at the subcutaneous level in deli-
cate thin-skinned areas of the face such as the
pretarsal roll or the tear trough. While it has been
proposed in this regard that Belotero® tends to
produce less Tyndalling when implanted in the
thin-skinned periorbital region such as in the pre-
tarsal roll and the tear trough, care is warranted in
interpreting these findings. The underlying
hypothesis supporting the finding is that unlike
biphasic HA, which has a microbolus distribution
pattern when injected in the dermal tissue,
Belotero® has low viscosity and soft consistency
which allows it to spread through the dermis in a
more fluid, homogeneous pattern, with no dis-
crete filler particles causing potential scattering
of blue light [11]. However, it bears pointing out
that, in clinical practice, tear trough correction is
performed by placing a fine layer of volume sub-
dermally using the retrograde linear thread tech-
nique, as opposed to an intradermal injection in
the superficial dermis. On this basis, it is hard to
conclude Belotero® confers a particular benefit
over other products for tear trough correction.
The same applies to when it is used for pretarsal
roll augmentation, in which volume  is actually
placed at the subcutaneous level during the
retraction of the needle.
Instead, in my own practice, I have anecdotally
observed cases of Tyndalling after inject-
ing Belotero® Volume™ in large volumes (>1 mL)
in the single earlobe. Based on such clinical expe-
rience, it is the author's view that no product can
be  absolutely free from the risk of  Tyndalling
when deposited in areas of thin tissue coverage or
in large volumes in  the subcutaneous tissue.
Granted, Belotero® has been shown to produce
less Tyndalling in the superficial dermis. However,
when it comes to tear-trough or pretarsal roll aug-
mentation, the target depth of injection is not in
the superficial dermis. If anything, the hydrophi-
licity of monophasic HA may serve only to con-
tribute to the risk of Tyndalling in these areas; and
as such, biphasic HA fillers may instead represent
a better option, though this point remains a sub-
ject of a future split-face clinical study.
Restylane®, as a biphasic HA, has a rather
hard, rubbery gel texture reflecting its high G’
and viscosity and possesses great tissue lifting
capacity as a firm, less spreading filler. While its
high viscoelasticity inhibits smooth injection
flow and its low gel spread makes it less mold-
able on injection, its high tissue lifting capacity
makes the product ideal for placement in the deep
tissue plane where it can provide good structure
and projection.
When used for double-layering technique,
biphasic HA such as Restylane® can be combined
with the placement of monophasic HA in the
superficial layer for optimum results. Monophasic
HA fillers provide better malleability and thus are
ideally suited for superficial layering. For
instance, when augmenting the infraorbital ante-
Fig. 2.25  Tyndall effect after injection of HA fillers for
tear trough correction
2.2  Hyaluronic Acid Fillers

58
rior malar, it is more practicable to first place a
biphasic HA in the deep tissue plane for overall
volume and lift and to refine any remaining sur-
face depressions with a monophasic HA in the
superficial plane (Table 2.4).
2.3
Major HA Filler Products
2.3.1
Restylane®: The Golden
Standard of HA Fillers
(Fig. 2.26)
Restylane® (Galderma, Sweden) is the first HA
filler approved by the FDA in the US in 2003,
following its CE certification in Europe in 1996.
Today, Restylane® is considered the gold stan-
dard of HA fillers based on its globally estab-
lished safety and efficacy profile. As of 2020,
more than 40 million treatments have been per-
formed
worldwide
using
Restylane®.
Significantly, Restylane® represents the first HA
filler to embody the nonanimal stabilized hyal-
uronic acid (NASHA™) technology. While the
use of non-animal HA is no longer a distinguish-
ing feature among the commercial HA fillers
available today, as most are based on nonanimal
HA derived from bacterial fermentation, back
when Restylane® was first launched, NASHA™
was a truly innovative feature, such that it was
incorporated into the product name, as existing
HA gels had all  been based on rooster comb
Table 2.4  Volumizing HA fillers with higher volumizing capacity
Trade name
Restylane®
Lyft™
Restylane®
Volyme™
Juvéderm®
VOLUMA™
Juvéderm®
VOLUX™
Belotero®
Volume™
Manufacturer
Galderma
(Sweden)
Galderma
(Sweden)
Allergan
(France)
Allergan
(France)
Merz
(Switzerland)
Manufacturing
technology
NASHA™
OBT™
Vycross™
Vycross™
CPM™
Monophasic or
Biphasic
Biphasic
Monophasic
Monophasic
Monophasic
Monophasic
HA
concentration
20 mg/mL
20 mg/mL
20 mg/mL
25 mg/mL
26 mg/mL
MoD(%)
less than 1%a
6–8%
4%
6–7%
5.1%a
Needle
29G ½″
27G ½″
27G ½″
27G ½″
27G ½″
30G ½″
Injection level
Subcutaneous/
Supraperiosteal/
Deep dermis
Subcutaneous/
Supraperiosteal
Subcutaneous/
Supraperiosteal/
Deep dermis
Subcutaneous/
Supraperiosteal
Deep dermis/
Subcutaneous/
Supraperiosteal
Trade name
YVOIRE®
Y-Solution™720
YVOIRE® Contour™
Neuramis®
Volume™
e.p.t.q.®
S500™
Manufacturer
LG Chem
(Korea)
LG Chem
(Korea)
Medytox
(Korea)
JETEMA
(Korea)
Manufacturing technology
S-HICE™
HICE™
SHAPE™
2CM™
Monophasic or biphasic
Biphasic
Biphasic
Monophasic
Monophasic
HA
concentration
20 mg/mL
22 mg/mL
20 mg/mL
24 mg/mL
MoD(%)
3.3%
2.0%
not disclosed
1.89(%)
Needle
27G½″
23G½″
27G½″
27G½″
Injection level
Subcutaneous/
Supraperiosteal
Subcutaneous/
Supraperiosteal
Deep dermis
Subcutaneous
Subcutaneous/
Supraperiosteal areas
aYang B, Guo X, Zang H, Liu J. Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by
SEC/MS. Carbohydr Polym. 2015 Oct 20;131:233–9.
2  Volumizing Fillers

59
extracts. Meanwhile, the term “stabilized” in
NASHA
signifies
the
characteristics
of
Restylane® as a strong HA gel with a low degree
of modifcation consisting only of gel particles of
the same size.
Utilizing the patented NASHA™ technology
for stabilizing the HA gel instead of chemical
cross-linking with BDDE allows Restylane® to
achieve less than 1% of MoD (degree of modifi-
cation) in the final product (Fig.  2.7).
Consequently, it is able to minimize potential
complications arising from the modification of
HA by the cross-linking agent and thus assures
optimum biocompatibility. Meanwhile, each
product within the Restylane® family represents
an elastic biphasic HA filler containing gel parti-
cles of its own specified size (Fig.  2.27). In
ascending order of the gel particulate size, the
product range includes Restylane® Skinbooster
Vital Light, Restylane® Skinbooster Vital,
Restylane®, and Restylane® Lyft (previously
Restylane®
Perlane)
(Table 
2.5).
While
Restylane® SubQ had also been included in the
portfolio mix, featuring the largest particulate
size, it was subsequently discontinued in 2018.
Meanwhile, it is also significant to note that
Restylane® had embraced the so-called ‘tissue-
tailored concept’, by which products are tailored
to different clinical indications and depths of
injection as early as the beginning of the 2000s
during its inception, which has since become a
standard feature of most HA filler brands today.
Accordingly, Restylane® Skinbooster Vital, for
example, which consists of smaller gel particles,
is indicated for superficial injection in the dermis
for the treatment of fine lines and loss of elastic-
ity; Restylane® Lyft with a larger gel particulate
size is commonly used for deep injections directly
above the periosteum or in the subcutaneous tis-
sue for restoration of volume deficit; Restylane®
Skinbooster Vital Light featuring the finest parti-
cle size is targeted for use in delicate, fine-
skinned areas, including the periorbital and neck
regions. Meanwhile, the classic Restylane® has
Fig. 2.26  Restylane® products
2.3  Major HA Filler Products

60
an intermediate particle size, which makes it suit-
able for injection in the deep dermis for the cor-
rection of average folds.
In 2009, Restylane® products with the addi-
tion of 0.3% lidocaine became available, ensur-
ing greater patient comfort. In 2010, the Emervel
family of HA fillers incorporating the OBT™
(optimal balance technology) technology was
approved in the EU, which in 2016 was renamed
and integrated into the Restylane® brand, thus
expanding the scope and versatility of the
Restylane® product range (Fig.  2.8). OBT™
products are soft (monophasic) HA fillers with
the same HA concentration of 20  mg/mL,
but  with differences in the degree and type of
cross-linking, as well as particle size. The MoD
of OBT™ fillers is within a range of 6–8% and
varies depending on the product. While products
using the OBT™ technology are often classified
as  soft monophasic HA, they  also demon-
strate near constant particle size as the result of
‘sieving’ undertaken  during their manufacture
for  optimal homogenicity.  The products with
small particle size and with a low cross-linking
are designed for superficial injection (e.g.,
Restylane® Fyness), whereas the products with
lager particle size and with high cross-linking
are designed for deeper and volumizing injection
(e.g., Restylane® Volyme™). They are character-
ized as having a softer and more flexible gel tex-
ture
than
NASHA™
products.
Products
incorporating the OBT™ technology include
Restylane®
Fyness,
Restylane®
Kysse,
Restylane® Refyne, Restylane® Defyne, and
Restylane® Volyme™.
Ranging from very soft to very firm HA fill-
ers, the Restylane® range of products is
extremely versatile, and finds it use in most
indications. The firm NASHA™ product
Restylane® Lyft™ possesses a higher tissue-
supporting capacity, which makes it suitable for
use for volume restoration. Owing to its rela-
tively low postinjection swelling, the NASHA™
product Restylane® also becomes the filler of
choice for treating the nasal dorsum, tear trough,
and other areas of the face covered by thin over-
lying skin. On the other hand, the soft OBT™
product Restylane® Refyne is optimized for use
in the superficial dermis to avoid potential
­irregularities due to its malleability and
­spreadability. Also, the soft OBT™ Restylane®
products
are
recommended
instead
of
firm    NASHA™  Restylane® Lyft™  for use in
dynamic treatment areas such as the marionette
lines and the forehead .
2.3.2
Juvéderm®: The First Original
Soft HA Filler (Fig. 2.28)
Juvéderm® (Allergan, France) was CE approved
in Europe in 2004 and approved by the FDA in
the US in 2006. Juverderm® is the first original
soft (monophasic) HA filler developed using the
HYLACROSS™ technology in response to the
firm HA filler, NASHA™ range of products
(Table 2.6). Whereas Restylane® as firm (bipha-
sic) HA filler, is a gel displaying granular consis-
tency, Juvéderm® has a smooth and homogeneous
gel texture characteristic of monophasic HA. As
a smooth, spreading filler with low viscoelastic-
ity, Juverderm® provides greater ease of injection
and easy molding, which makes it particularly
suitable for placement in the superficial plane.
Despite its low viscoelasticity Juverderm® is also
ideal for volumizing and contouring by virtue of
its high cohesivity. Within the Juvéderm® range
of products, Juvéderm® Ultra™ and Juvéderm®
Ultra
Plus™
are
formulated
using
the
HYLACROSS™ technology with the same HA
concentration of 24 mg/mL, though featuring dif-
ferent percentages of cross-linking, with 6% for
Fig. 2.27  Microscopic image of Restylane® Lyft (left
bigger particles) and Restylane® (R) superscript) demon-
strating NASHA™ gel particles with different sizes
(Courtesy of Galderma)
2  Volumizing Fillers

61
Fig. 2.28  Juvéderm® products
Table 2.5  Restylane® products
Trade name
Restylane®
Lyft
Restylane®
Lidocaine
Restylane®
Skinbooster
Vital
Restylane®
Skinbooster
Vital Light
Manufacturing
Technology
NASHA™
NASHA™
NASHA™
NASHA™
Monophasic or
biphasic
Biphasic
Biphasic
Biphasic
Biphasic
HA
concentration
20 mg/mL
20 mg/mL
20 mg/mL
12 mg/mL
Lifting capacity
+++
++
+
+
Size of Needle
29G ½
29G ½
29G ½
29G ½
Injection level
Subcutaneous/
Supraperiosteal/
Deep dermis
Mid to deep dermis
Superficial to mid
dermis
Superficial to
mid dermis
Particular Size
650 μm
300 μm
Trade name
Restylane®
Fynesse™
Restylane®
Refyne™
Restylane®
Defyne™
Restylane®
Volyme™
Restylane®
Kysse™
Manufacturing
technology
OBT™
OBT™
OBT™
OBT™
OBT™
Monophasic or
biphasic
Monophasic
Monophasic
Monophasic
Monophasic
Monophasic
HA
concentration
20 mg/mL
20 mg/mL
20 mg/mL
20 mg/mL
20 mg/mL
Lifting capacity
+
++
+++
++++
+++
Size of Needle
30G ½
30G ½
27G ½
27G ½
30G ½
Injection level
Upper dermis
Mid to deep
dermis
Deep dermis/
Subcutaneous
Subcutaneous/
Supraperiosteal
Upper dermis
2.3  Major HA Filler Products

62
Juvéderm® Ultra™ and 8% for Juvéderm® Ultra
Plus™. Due to its higher percentage of cross-
linking, Juvéderm® Ultra Plus™ provides greater
cohesivity and tissue lifting capacity and thus is
commonly utilized for adding of volume in the
deep plane [9].
However, due to their high HA concentration
(24  mg/mL) and use of high-molecular-weight
HA, HYLACROSS™ products are much more
susceptible to hydration (i.e., swelling of the gel)
and can draw in twice as much water as products
built on VYCROSS™ technology [9]. Lumpiness
and irregularity have thus been noted as common
side effects of HYLACROSS™ products on
account of such post-injection swelling.
To address such a drawback, VYCROSS™
was introduced as an evolution for delivering
both reduced swelling and enhanced stability. To
achieve this, VYCROSS™ combines both high-
and low-molecular-weight HA to produce an HA
gel matrix that integrates more efficiently into the
tissue at lower HA concentrations (Fig.  2.29).
Having a mixture of low-molecular-weight HA
(short chains) and high-molecular-weight HA
Fig. 2.29  HYLACROSS™ vs. VYCROSS™ technology (Courtesy of Allergan)
Table 2.6  Juvéderm products
Trade name
Juvéderm®
VOLITE™
Juvéderm®
VOLBELLA™
Juvéderm®
VOLIFT™
Juvéderm®
VOLUMA™
Juvéderm®
VOLUX™
Manufacturing
technology
Vycross™
Vycross™
Vycross™
Vycross™
Vycross™
Monophasic or
biphasic
Monophasic
Monophasic
Monophasic
Monophasic
Monophasic
HA
concentration
12 mg/mL
15 mg/mL
17.5 mg/mL
20 mg/mL
25 mg/mL
Lifting capacity
+
++
+++
++++
++++
Size of needle
32G ½′
30G ½′
30G ½′
27G ½′
27G ½′
Injection level
Intradermal
Superficial/
intradermal/
lips mucosa
Deep dermis/
lips mucosa
Subcutaneous/
Supraperiosteal/
deep dermis
Subcutaneous/
Supraperiosteal
Trade name
Juvéderm®
Ultra XC
Juvéderm®
Ultra Plus XC
Manufacturing technology
Hylacross™
Hylacross™
Monophasic or biphasic
Monophasic
Monophasic
HA concentration
24 mg/mL
24 mg/mL
Cross-linking level
6%
8%
Needle
30G ½’
27G ½’
Injection level
Middermis
Middermis and/or deep dermis
2  Volumizing Fillers

63
(long chains) during cross-linking can create a
tighter and more efficient binding among HA
molecules than would be possible based on the
use of high-molecular-weight HA alone. The
efficiency of the VYCROSS™ cross-linking
technology can be best illustrated by an analogy
to mixing up a bowl of spicy mixed noodles
(bibim-myeon similar to bibimbap (Korean mixed
rice) but with cold noodles) after pouring the
sauce over it. Here, one would find that cutting up
portions of the noodle with scissors allows the
sauce to blend in more thoroughly and evenly and
into the noodle strands. Likewise, VYCROSS™
is an efficient method for producing more thor-
oughly cross-linked and  densely-packed HA
molecules that provide greater stability with min-
imum hydration.
As with other major HA filler families, the
VYCROSS™ range also includes a complemen-
tary mix of products designed to match different
clinical indications based on varying gel
properties.
Juvéderm® Voluma™, 20 mg/mL, which repre-
sents the very first product formulated using the
VYCROSS™ technology, has the highest HA
concentration (20 mg/mL) and elasticity within
the VYCROSS™ range, which allows it to pro-
vide maximal tissue lift when placed in the deep
tissue planes as a volumizing HA filler. In 2013,
Juvéderm® Voluma™ was FDA-approved for cor-
rection of midface volume deficit. Noted for its
ability to produce long-lasting results, Juvéderm®
Voluma™ also became the first HA filler to receive
FDA approval for 24 months duration of correc-
tion. Juvéderm® Volift™, which contains a lower
HA concentration of 17.5 mg/mL, has intermedi-
ate rheological properties that fall somewhere
between those of Juvéderm® Voluma™ and
Juvéderm® Volbella™ and shows 30% less hydra-
tion than Juvéderm® Voluma™ [9].
Juvéderm® Volift™ is suited for injection in the
deep dermis or the subcutaneous plane, not only
for filling in etched-in lines and wrinkles such as
the nasolabial folds and perioral lines but also for
volume augmentation in areas such as the fore-
head. Meanwhile, Juvéderm® Volbella™ is a soft
spreading filler with an HA concentration of
15 mg/mL, thus possesses the lowest viscoelas-
ticity and cohesivity within the product range.
Juvéderm® Volbella™ is appropriate for injection
in the dermis for softening superficial wrinkles
and tear trough deformities as well as for adding
subtle volume to the lips.
All of the products within the Juvéderm® fam-
ily, including not only Juvéderm® Ultra™ and
Juvéderm® Ultra Plus™ but also the entire
VYCROSS™ range, are currently available with
0.3% lidocaine to provide comfort during treat-
ment, with each formulation having been duly
approved
by
the
USFDA. 
Juvéderm®
Ultra is Juvéderm® Ultra XC without lidocaine
and Juvéderm® Ultra Plus  is Juvéderm® Ultra
Plus XC without lidocaine. 
2.3.3
Belotero®: HA Filler
with a Reputation for Safety
(Fig. 2.30)
The Belotero® range of products is manufactured
and marketed by Merz Pharmaceuticals GmbH
(Germany) and was originally developed by
Anteis S.A., Switzerland, under the trade name
Esthélis® (Table 2.7). Belotero® obtained CE cer-
tification in 2005 and was approved by the US
FDA in 2011. Though a relative latecomer to the
market, Belotero® has been widely recognized
over the years for its favorable safety and efficacy
profile as a monophasic HA filler. The Belotero®
product line is built on the Cohesive Polydensified
Matrix (CPM™) technology involving a second
application of HA molecules to cross-link with
the residual BDDE remaining after initial cross-
linking. This results in a highly cohesive yet fluid
gel matrix unique to Belotero®, where varying
degrees of cross-linking coexist within the same
gel substance (Fig. 2.31). The presence of high-
density zones in the gel confers volumizing
capacity and longevity to the product, while the
less viscose low-density zones provide greater
ease of injection and more homogenous product
distribution/integration into the tissue. Containing
several density grades within the same product
also allows it to maintain better resilience and
structural integrity against outside deformation
forces applied by the facial musculature subse-
quent to its injection. Studies show that products
incorporating the CPM™ technology are signifi-
2.3  Major HA Filler Products

64
Table 2.7  Belotero® products (particle size and MoD is not disclosed by the company)
Trade name
Belotero®
Soft™
Belotero®
Balance™
Belotero®
Intense™
Belotero®
Volume™
Monophasic
or biphasic
Monophasic
Monophasic
Monophasic
Monophasic
HA
concentration
20 mg/mL
22.5 mg/mL
25.5 mg/mL
26 mg/mL
Lifting capacity
+
++
+++
++++
Size of Needle
30G ½
30G ½
27G ½
27G ½
27G ½
30G ½
Injection level
Superficial to mid-dermis
Mid to deep dermis
Deep dermis
Subcutaneous
Deep dermis
Subcutaneous
Supraperiosteal
Fig. 2.30  Belotero® products
2  Volumizing Fillers

65
cantly more cohesive than those based on
VYCROSS™ or NASHA technologies [13].
CPM™ products are also shown to demonstrate
higher elastic modulus E′ and normal force FN
than VYCROSS™ or NASHA products under
applied compressive pressure [15]. It is for these
reasons that Belotero® is able to demonstrate
volumizing capacity comparable to that of
NASHA products, despite having a significantly
lower G’. Notably, cohesivity  plays a signifi-
cant role in the HA filler’s volumizing effect as it
allows the product to maintain its volume and
shape even in dynamic treatment areas such as
nasolabial folds, marionette lines, and the
forehead.
Apart from its proven efficacy, another advan-
tage of Belotero® lies in its favorable safety and
tolerability profile. By virtue of its lower viscos-
ity, Belotero® penetrates the dermis in a more dif-
fuse and distributed manner, which allows it to
create a smooth, even result with less Tyndalling.
Most significantly, there have been no reported
cases of granulomas from Belotero® injection
since its release in 2005. It also involves the low-
est incidence of delayed immune-related compli-
cations among available HA fillers to date.
The Belotero® range also includes a spectrum
of products suited to varying indications and
depth of injection. Belotero® Volume™ has the
highest HA concentration (26  mg/mL) and the
highest degree of cross-linking among the
CPM™ products, and thus the highest shear elas-
tic modulus G’ and elastic modulus E′. It is thus
suitable for placement in the deep tissue plane for
restoration of facial volumes. Belotero® Intense™
has an HA concentration of 25.5  mg/mL and
intermediate viscoelasticity that falls between
that of Belotero® Volume™ and Belotero®
Balance™. Nonetheless, it is still ideal for facial
volume restoration as its FN (normal force) and
cohesivity are higher than those of Belotero®
Volume™. It is thus indicated for injection in the
deep dermis or the subcutaneous tissue for cor-
rection of deeper lines (e.g., nasolabial folds) or,
alternately, for adding of volume in the lips or the
forehead. Belotero® Balance has an HA concen-
tration of 22.5 mg/mL and low viscosity and elas-
ticity but has the highest cohesivity among the
CPM™ products. As a soft, spreading filler,
Belotero® Balance™ has an even and diffuse
integration into the tissue, which makes it suit-
able for superficial injection in the dermal plane.
It is appropriate not only for correction of moder-
ate lines but also for hydro lifting injections in the
dermis for improved skin elasticity, as well as for
accentuating the vermillion border. Finally,
Belotero® Soft™ has the lowest HA concentra-
tion (20  mg/mL) and degree of cross-linking
among the CPM™ products and thus demon-
strates the lowest viscoelasticity. Conversely
though, it is these very characteristics that confer
a soft, spreadable texture, which makes it ideal
for use in the superficial dermis or in areas of thin
tissue coverage such as the periorbital region and
the neck.
2.3.4
YVOIRE®: Korea’s First HA Filler
(Fig. 2.32)
YVOIRE® is Korea’s first HA filler developed in
2011 with the HICE™ (High Concentration
Equalized) cross-linking technology) (Table 2.8).
LG Chem (Korea)’s YVOIRE® products are
biphasic HA filler, classified according to the par-
ticle size of the hyaluronic acid to suit their pur-
pose and use. HICE™ cross-linking technology
is LG Chem’s own unique manufacturing tech-
Fig. 2.31  Belotero® CPM™ technology (Courtesy of
Mertz)
2.3  Major HA Filler Products

66
Fig. 2.32  YVOIRE® products
Table 2.8  YVOIRE® products
Trade name
Y-Solution™
360
Y-Solution™
540
Y-Solution™
720
YVOIRE® Classic
S™
YVOIRE®
Classic Plus™
Manufacturing
technology
S-HICE™
S-HICE™
S-HICE™
HICE™
HICE™
Monophasic or
biphasic
Y-phasic
Y-phasic
Y-phasic
Biphasic
Biphasic
HA
concentration
12 mg/mL
20 mg/mL
20 mg/mL
22 mg/mL
20 mg/mL
Lifting capacity
+
+++
++++
++
++
Size of Needle
29G ½″
27G ½″
27G ½″
27G ½″
30G ½″
27G ½″
30G ½″
Injection level
Upper dermis
Deep dermis
Subcutaneous/
Supraperiosteal
Deep dermis
Deep dermis
Particle size
230μm
360μm
360μm
400μm
400μm
Trade name
YVOIRE® Volume
S™
YVOIRE® Volume
Plus™
YVOIRE® Contour™
YVOIRE® Contour
Plus C™
Manufacturing
technology
HICE™
HICE™
HICE™
HICE™
Monophasic or
biphasic
Biphasic
Biphasic
Biphasic
Biphasic
HA
concentration
22 mg/mL
20 mg/mL
22 mg/mL
20 mg/mL
Lifting capacity
+++
+++
++++
++++
Size of Needle
27G ½″
27G ½″
23G 1″
23G 1″
Injection level
Deep dermis
Subcutaneous
Subcutaneous/
Supraperiosteal
Subcutaneous/
Supraperiosteal
Subcutaneous/
Supraperiosteal
Particle size
900μm
900μm
1300μm/
350μm
1300μm/
350μm
2  Volumizing Fillers

67
nology, which can obtain high cross-linking effi-
ciency even if small amounts of cross-linking
agent is added by evenly dispersing cross-linking
agents and high concentrations of high-molecu-
lar-weight HA. As a result of the cross-linking
technology, YVOIRE® is a filler product that has
been steadily used for more than 10 years and is
recognized for its high elasticity and safety by
using the  least amount of cross-linking agent.
From the hyaluronic acid raw material to the final
product, LG Chem directly conducts the research
and
handles
the
manufacturing
process.
Hyaluronic acid raw material used in YVOIRE®
has been listed on Drug master file (DMF) of US
FDA and certified by European EDQM (European
Directorate for the Quality of Medicines &
Healthcare) ensuring overseas recognition of the
relevant safety and technologies in overseas
countries.
YVOIRE® Classic™/Classic plus™ has the
smallest particles (350–400μm) and low elastic-
ity  and is suitable for wrinkle improvement.
YVOIRE® Volume™/Volume plus™ which has
larger particles (800–900μm) than Classic has
higher elasticity suitable universally for most
volumizing needs. When YVOIRE® Classic™ or
YVOIRE® Volume™ were applied in the random-
ized, split-face designed, evaluator-blind studies
with 58 and 57 subjects with moderate-to-severe
NLFs compared to Restylane® or Lyft™, respec-
tively, the nasolabial fold-correcting effects and
safety profiles were comparable (p < 0.05) [23].
YVOIRE® Contour™/Contour plus™ which is
suitable for areas requiring lifting capacity has the
highest elasticity. As YVOIRE® Contour/Contour
plus has a dual particle composition which allows
the voids between the large particles (1400μm) to
be filled with smaller particles (350μm, it pro-
vides constant injection force, resulting in a
smooth and natural facial appearance. In the ran-
domized, split-face, evaluator-blind clinical study
with 83 subjects for anteromedial malar augmen-
tation, there were no statistical difference
(p < 0.05) in the effectiveness and safety profiles
of YVOIRE® Contour when compared to
Restylane® Sub-Q at 26 and 52 weeks after treat-
ment [23]. Plus products contain lidocaine to
reduce pain caused by injection. HA concentra-
tion of products without lidocaine is 22 mg and
HA concentration of plus products with lidocaine
is 20 mg. Immediately after treatment, more than
90% of subjects who were treated with YVOIRE®
Classic plus or YVOIRE® Volume™ plus reported
reduced pain when compared with those who
were treated with YVOIRE® Classic or YVOIRE®
Volume™, respectively in the randomized, split-
face, evaluator-blind studies. That said, the clini-
cal effectiveness and safety profiles of YVOIRE®
Classic plus™ or Volume plus™ were compara-
ble to those of YVOIRE® Classics or Volume™ s,
respectively [27].
YVOIRE® Y-solution™ was developed to
increase cohesivity, usually lower in biphasic fill-
ers. To satisfy both high elasticity and cohesivity,
YVOIRE® Y-solution™ embodies the S-HICE™
(Superior, Stable High Concentration Equalized)
cross-linking technology that is more advanced
than HICE™  to achieve higher cohesivity.
S-HICE™ is an upgraded technology that
increases the  sustainability and cohesiveness
between particles in the form of small particles
through various particlization processes. Based
on the S-HICE™ cross-linking technology,
YVOIRE®
Y-solution™
is
Y-phasic™
filler with high lifting capacity achieved by com-
bining the advantages of a monophasic filler with
a high cohesivity and a biphasic filler with high
elasticity. YVOIRE® Y-solution™ was first
launched in Korea in 2018 with three products
in its lineup including Y-solution 360™,
Y-solution 540™, and Y-solution 720™. All
YVOIRE® Y-solution™ products contain lido-
caine and its HA concentration is, respectively,
12 mg, 20 mg, and 20 mg with MoD being 2.4%,
3.5%, and 3.3% respectively.
2.3.5
Neuramis®: Representative
Korean Soft HA Filler
(Fig. 2.33)
Neuramis® is a range of monophasic hyaluronic
acid fillers developed by Medytox Inc. (Korea)
(Table  2.9). Since the  first product Neuramis®
Deep obtained CE marking in 2011, a spec-
trum  of products containing lidocaine were
2.3  Major HA Filler Products

68
Table 2.9  Product specification of Neuramis® lidocaine series
Trade name
Neuramis®
Light Lidocaine™
Neuramis®
Lidocaine™
Neuramis®
Deep Lidocaine™
Neuramis®
Volume Lidocaine™
Manufacturing
technology
SHAPE™
SHAPE™
SHAPE™
SHAPE™
Monophasic
or biphasic
Monophasic
Monophasic
Monophasic
Monophasic
HA
concentration
20 mg/mL
20 mg/mL
20 mg/mL
20 mg/mL
Lifting
capacity
+
++
+++
++++
Size of Needle
30G × 3/16″
30G × 1/2″
27G × 1/2″
27G × 1/2″
Injection level
Superficial to mid dermis
Mid to deep dermis
Mid to deep dermis
Subcutaneous
Supraperiosteal
Fig. 2.33  Neuramis® products
2  Volumizing Fillers

69
developed, namely, Neuramis® Light Lidocain,
Neuramis®
Lidocaine,
Neuramis®
Deep
Lidocaine™, and Neuramis® Volume Lidocain™.
Currently, Neuramis® Deep™ and Neuramis®
Deep Lidocain™, and Neuramis® Volume
Lidocaine™ have  obtained CE certificate.
Through a unique manufacturing process referred
to as “SHAPE™ (Stabilized Hyaluronic Acid &
Purification Enhancement)” technology, tailored
cross-linking of hyaluronic acid is formed result-
ing in a highly cohesive hyaluronic acid gel. No
uncross-linked hyaluronic acid is added, and the
final products contains hyaluronic acid at the
concentration of 20 mg/mL. For the safety and
quality of the products, it uses only highly quali-
fied hyaluronic acid registered in FDA Drug
Master Files and European Directorate for the
Quality of Medicines and Healthcare. Hyaluronic
acid concentration of all products is 20 mg/mL.
Neuramis® lidocaine series offers four prod-
ucts with different degrees of cross-linking to suit
various needs (Table  2.9). Neuramis® Light
Lidocaine™ is a lightly cross-linked hyaluronic
acid intended to be injected in the dermis for the
improvement of fine wrinkles. Neuramis®
Lidocaine™ and Neuramis® Deep Lidocaine™
are intended to be used for the restoration of tis-
sue in mid to deep dermis. In a randomized spilt-
face clinical trial, Neurmis® Deep Lidocaine™
demonstrated significantly better  correction of
the nasolabial folds, compared with Restylane®
Lyft™ for up to 24  weeks (p  <  0.05) [29].
Neuramis® Volume Lidocaine™ is the most
heavily cross-linked hyaluronic acid product
intended to be injected into subcutaneous and/or
supraperiosteal layer. In a randomized, double-
blinded, comparative study, Neuramis® Volume
Lidocaine™ showed similar results compared
with Juvederm® voluma™ for the efficacy and
safety in restoration of mid-facial volume deficit
in 88 subjects [30].
2.3.6
e.p.t.q.®: HA Filler with a Top
Priority on Safety (Fig. 2.34)
e.p.t.q.® (epitique) (JETEMA, Korea), a mono-
phasic hyaluronic acid filler was developed in
2017 by applying 2CM™ (2 Crosslinking
Method) technology and acquired a CE marking
for e.p.t.q.® lidocaine in 2020. 2CM™ Technology
employs not only a chemical cross-linking but
Fig. 2.34  e.p.t.q.® products
2.3  Major HA Filler Products

70
also a physical cross-linking so that maximum
cross-linking efficiency can be achieved with a
minimum amount of BDDE to create a rigid and
stable hive structure. e.p.t.q.® has a modification
degree (MoD) in the  1% range with minimal
input of cross-linkers for excellent safety, but still
retains high cohesiveness. Leveraging a grinding
technology called the Downing Process, e.p.t.q.®
has fine and uniform particles. Thanks to
these fine particles, e.p.t.q.® can be injected with
thin needles (30G). Typically, products contain-
ing large-sized gel particles should not be used
with thin needles due to the potential effects on
particle size and rheological equilibrium [31].
e.p.t.q.® is categorized by its viscoelasticity:
S100, S300, S500 (Table  2.10) [29]. All three
have a hyaluronic acid concentration of 24 mg/
mL and contain lidocaine to ease the pain.
While e.p.t.q.® is a monophasic filler with softer
gel formulation, it has uniform particle size with
excellent molding. In addition, owing to the man-
ufacturing process  focusing on the safety issue
such as  minimum cross-linker  content (MoD
of 1% range), the incidence of inflammatory reac-
tion from delayed type hypersensitivity seems to
be as low as less than 0.1% based on the author’s
experience using 2,000 syringes for last 2 years.
2.4
Other Types of Injectable
Fillers
2.4.1
Collagen Fillers
As a key component of the dermal matrix respon-
sible for the skin’s strength and resilience, collagen
was the first material ever to be used as soft tissue
fillers. The first collagen-based fillers approved for
use by the USFDA in the early 1980s were the
bovine-based
ZYDERM®1
(bovine
collagen
35 mg/mL), ZYDERM® 2 (bovine collagen 65 mg/
mL), and ZYPLAST® (bovine collagen 35 mg/mL,
cross-linked with glutaraldehyde) (Allergan. CA,
US) fillers [3]. The Japanese version, that is, Koken
Atelocollagen® (Koken Co. Japan), was also derived
from a bovine source. Due to their animal origin,
however, these bovine collagen fillers required a
skin allergy test to be performed 4 weeks prior to
treatment, though a negative testing did not rule out
the risk of an allergic response. With the subsequent
advent and dominance of HA fillers, however,
bovine collagen fillers soon went out of use glob-
ally, which led Allergan to eventually end the pro-
duction of ZYDERM® and ZYPLAST® in 2010.
Meanwhile, EVOLENCE® (Johnson & Johnson.
Table 2.10  e.p.t.q. products
Trade name
e.p.t.q.®
Lidocaine
S100™
e.p.t.q.®
Lidocaine
S300™
e.p.t.q.®
Lidocaine
S500™
Manufacturing
technology
2CM™
2CM™
2CM™
Monophasic or
biphasic
Monophasic
Monophasic
Monophasic
HA
concentration
24 mg/mL
24 mg/mL
24 mg/mL
Lifting capacity
+
+++
++++
Size of Needle
27G 1/2″
27G 1/2″
27G 1/2″
Injection level
Dermis
Deep dermis
Subcutaneous
Particle size
310μm
310μm
310μm
MoD (%)
1.18
1.53
1.89
2  Volumizing Fillers

71
New Jersey, US) is a porcine collagen filler (porcine
collagen 30  mg/mL), which obtained USFDA
approval in 2008 [3]. The benefits of EVOLENCE®
were that they were cross-linked, therefore provided
longer-lasting results over the previous collagen fill-
ers and did not require allergy testing. Despite these
advantages, however, Johnson & Johnson was also
compelled to discontinue EVOLENCE® in 2009
due to the declining market interest in collagen-
based fillers. Meanwhile, COSMODERM® and
COSMOPLAST® (Allergan, CA) are human tissue-
derived collagen fillers approved by the USFDA in
2003 but were subsequently discontinued in 2010.
Comment: While collagen fillers broke new
ground by pioneering the market for injectable
dermal fillers, their value today is mostly histori-
cal, as they have been rendered practically obso-
lete by the risk of immunogenic reactions and the
short duration of effect lasting for only
3–6 months. That said, it should be accepted that
collagen fillers provided good moldability and
spread easily into the tissues while being free of
problems of Tyndalling, which made them ideal
for treating fine wrinkles in delicate thin-skinned
areas such as the periorbital region.
2.4.2
Permanent Injectables
2.4.2.1 PMMA (Polymethyl
Methacrylate)
Polymethyl Methacrylate (PMMA) is a substance
routinely used in orthopedic surgical practice as
bone cement for the human body (Fig.  2.35).
BellaFill® is (Suneva Medical Inc., US) a PMMA-
based permanent filler containing smooth-
surfaced PMMA microspheres ranging 30–50μm
in size designed to avoid macrophage phagocyto-
sis [31, 31] (Fig.  2.36). In 2006, injectable
PMMA was approved by the USFDA under the
trade name ArteFill® (Artes Medical, US) upon
which ArteFill® became the first permanent soft
tissue filler to obtain USFDA approval. ArteFill®
was rebranded as BellaFill® in 2014. BellaFill® is
composed of PMMA microspheres suspended in
3.5% bovine collagen at a 1:4 ratio [30]. Over
time, collagen is reabsorbed and PMMA micro-
spheres acts as a scaffold to biostimulate collagen
synthesis. To the extent the product contains
bovine collagen as the carrier substance, it is nec-
essary to perform a skin allergy test before treat-
ment with BellaFill®. Side effects, though rare,
include foreign body reaction, granuloma, con-
tour deformity, and inflammation [30]. Caution
must be taken in its use since PMMA is a syn-
thetic compound not reversible with a reversal
agent should problems occur.
Comment: Permanency of fillers implies that
any potential complications arising from such
fillers are also permanent. To avoid life’s unpleas-
ant surprises, practitioners, except perhaps  for
the most daring, are well-advised to stay away
from these permanent solutions.
2.4.2.2 PAAG (Polyacrylamide Gel)
Polyacrylamide gel (PAAG) is a high polymer
used as an ingredient in the manufacture of soft
contact lenses (Fig. 2.37). Permanent soft tissue
filler containing PAAG was developed for the
first time in 1980 in Ukraine under the tradename
Interfall® and was awarded CE certification in
2001 in Denmark under the tradename Aquamid®
CH2
CH3
COOCH3
n
C
PMMA (=Polymethylmethacrylate)
Fig. 2.35  PMMA molecular formula
Fig. 2.36  BellaFill® is a PMMA-based permanent filler
containing smooth-surfaced PMMA microspheres rang-
ing 30–50μm in size. (Courtesy of Artes Medical)
2.4  Other Types of Injectable Fillers

72
(Contura International A/S, Denmark). Aquamid®
is a hydrogel product combining 2.5% cross-
linked polyacrylamide and 97.5% water and is
reputed to have natural texture and favorable bio-
compatibility [31]. Granuloma, contour deforma-
tion, and product migration have been often
observed, however, following its application
[33]. Fortunately, the product can be removed
even several years post-treatment by administer-
ing saline 2–3 times the volume of the injected
PAAG, followed by 3–5 min of intense massage
and puncture with an 18-G needle or incision,
after which the product can be substantially
squeezed out (Fig. 2.38) [32, 33]. In the wake of
the negative publicity surrounding the complica-
tions from Amazing gel® (FuHua High Molecular
weight company, China) injections for breast
augmentation, PAAG has largely fallen out of
favor and is practically no longer in use. While
Aquafilling® (Czech), consisting of PAAG (2%)
and water (98%) was introduced to the market a
few years ago claiming to be reversible with nor-
mal saline, Aquafilling® injections, as with
Aquamid®, cannot be dissolved away simply
using a reversal agent (Fig. 2.39).
2.4.3
Collagen-Stimulating Fillers
Prior to 2000, soft tissue fillers were developed
primarily for use as volumizers or filling agents,
Fig. 2.38  Removal of Aquamid® by squeezing out
a
b
Fig. 2.39  (a) Removal of Aquafilling® by squeezing out. (b) Sonography of Aquafilling®
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH
CH
CH
CH
CH
CH
NH2
NH2
NH2
NH
NH2
NH
C=0
C=0
C=0
C=0
C=0
C=0
n
PAAG (Polyacrylamide gel)
Fig. 2.37  PAAG molecular formula
2  Volumizing Fillers

73
with collagen-based or HA fillers injected to pro-
vide replacement volume for facial deflation.
From 2000 onwards, however, the prevailing
trend in soft tissue filler development shifted
away from replacement fillers toward biodegrad-
able high polymers capable of inducting collagen
biostimulation in the injected area while they
themselves were slowly degraded in the body.
These collagen-stimulating fillers, also referred
to as biostimulating fillers, are known to provide
better longevity compared with HA fillers. Key
examples
include
calcium
hydroxylapatite
(CaHA), PLLA, PDLLA, PCA, and PDO-based
fillers. On the flip side, however, the use of bios-
timulating fillers presents associated risks and
challenges, including individual variability in
collagen synthesis, nodule formation from over-
production of collagen, and surface irregularity
from elevated nodules. Most significantly, results
of collagen-stimulating fillers remain irreversible
in case of misplacement or complications.
Accordingly, their use should be avoided in
unforgiving facial areas with thin overlying skin,
such as the periorbital region or the labial mucosa.
2.4.3.1 Calcium Hydroxylapatite
(CaHA) Filler
Calcium Hydroxylapatite (Ca10(PO4)6(OH)2) or
CaHA is the main mineral of which the teeth and
bones are composed. Similar in composition to
gallstones or urinary stones, it has been long used
in orthopedic surgical procedures or dental appli-
cations as dental filling material or dental regen-
eration material. Calcium hydroxylapatite fillers
consist of 30% CaHA and 70% sodium carboxy-
methylcellulose (CMC), glycerine, and sterile
water. The CaHA is composed of smooth micro-
spheres ranging 25–45μm in diameter designed
to avoid macrophage phagocytosis (Fig.  2.40).
Once placed in the soft tissue, CaHA micro-
spheres elicit neocollagenesis at the injection site
while they themselves slowly disintegrate into
calcium and phosphate ions, and are completely
removed from the system [34] (Fig.  2.41).
Meanwhile, the gel carrier, sodium carboxymeth-
ylcellulose (CMC), provides initial volume dur-
ing the first few weeks or months of injection,
after which it gradually dissipates away, leaving
in its place new collagen to fill the space [35].
Radiesse® (Merz, Germany) was the first
CaHA filler to be approved by the USFDA in
2001 for use in vocal fold insufficiency treatment
and bone void filling (Fig.  2.42). In 2006, it
received US FDA approval for the correction of
severe facial wrinkles and/or facial lipoatrophy in
individuals with human immunodeficiency virus
(HIV). Though composed principally of calcium,
Radiesse® does not ossify or calcify in the soft
tissue or the periosteum into which it has been
placed [36]. There have been no reported cases of
bone generation occurring as a result of Radiesse®
injection in the soft tissue [34]. This is because,
a
b
Fig. 2.40  The scanning electron microscope of the CaHA (Courtesy of Merz Institute of Advanced Aesthetics). (a) The
CaHA is composed of smooth microspheres ranging 25–45μm in diameter. (b) Partially degraded CaHA microspheres
2.4  Other Types of Injectable Fillers

74
theoretically, new cell growth into the implanted
CaHA is consistent with the surrounding tissue,
and new cells do not differentiate into other cell
types [34].
While Radiesse® is known to provide longev-
ity lasting for several years, the patient may ini-
tially perceive the effect as being temporary and
short-lived as the gel carrier deflates after the first
few weeks or months of injection. In such case, it
is helpful to provide a touch-up injection
1–2 months posttreatment [36]. It also bears not-
ing that Radiesse® injections can be highly pain-
ful as the product’s pH levels (6.8–8.0) fall
outside the pH range of the human body.
Reconstituting 1.3  mL Radiesse® with 0.2  mL
lidocaine before the injection can significantly
help to reduce the pain [36]. Radiesse® also tends
to cause greater initial swelling than HA fillers,
perhaps due to its gel carrier substance. Hence, it
is best to avoid large volume injections of
Radiesse® into the same site during a single ses-
sion. Instead, it is preferable to use a stepwise
approach with treatments spaced 2–4 weeks apart
until the desired outcome is reached. A notable
complication of Radiesse® is the formation of
hard nodules when injected as boluses in places
such as the thin-skinned periorbital region or lip
mucosa. Surgical removal or treatment with tri-
amcinolone local injection is required in case
nodules are formed [37]. Conversely, granuloma
formation due to foreign body reaction is not that
frequent in Radiesse® compared with other per-
manent fillers, PLLA or even HA fillers [37–39].
Complaints of contour irregularity or overcorrec-
tion within the first 2 weeks of treatment can be
addressed by puncturing the injection site using
an 18-G needle and manually extracting the prod-
uct out through the puncture site. However, in
case substantial time has passed since the initial
treatment, this is no longer an option, and surgi-
cal removal or triamcinolone injections becomes
the only available option.
Comment: Radiesse® was acclaimed as a new
milestone in facial volumization when it first
came to market. However, its initial popularity
and versatility were soon limited by drawbacks
such as significant initial swelling, potential nod-
ule formation upon bolus injection, and the risk
of overgrowth of collagen fibers which may deter
cannula advancement during subsequent second
or third treatments. Moreover, as the product
could not be dissolved away with a reversal
agent, facial volumization with Radiesse® left no
room for errors. These factors combined to
restrict the widespread use of Radiesse® in facial
volumization applications. However, the colla-
gen biostimulating effect of Radiesse® has been
popularly used for skin-tightening purposes by
diluting the product two- to three-fold with saline
and lidocaine and injecting it superficially into
the subdermis [40]. Examples include rejuvena-
tion of crepey skin in the neck and the dorsum of
the hand.
Fig. 2.41  Calcium hydroxyl apatite microspheres act as
scaffolds while eliciting neocollagenesis at the injection
site (Sirus Red stain) (Courtesy of Merz Institute of
Advanced Aesthetics)
Fig. 2.42  Radiesse® products
2  Volumizing Fillers

75
2.4.3.2 PCL Filler (Fig. 2.43)
Polycaprolactone (PCL) is a type of bioresorb-
able polymer that has long been used in the medi-
cal field as resorbable surgical sutures (Fig. 2.44).
Polycaprolactone (PCL)-based soft tissue filler is
marketed
as
Ellansé™
(AQTIS
Medical,
Netherlands). Ellansé™ represents a biodegrad-
able high polymer filler consisting of 30% PCL
suspended
in
70%
carboxymethylcellulose
(CMC) as the gel carrier. Similar to Radiesse®,
PCL-based Ellansé™ consists of smooth micro-
spheres with particulate size ranging 25–50μm to
avoid macrophage phagocytosis. When injected,
PCL microspheres promote new collagen forma-
tion in the surrounding tissue and gradually break
down into water and CO2, after which they
are eliminated from the system. The gel carrier,
sodium carboxymethylcellulose (CMC), pro-
vides immediate volume correction during the
initial weeks or months and dissipates in
3  months, to be  replaced by new collagen. In
sum, apart from the differences in the active
ingredient, Ellansé™ shares many similarities
with Radiesse® in terms of the composition,
mechanism
of
action,
indication,
and
complications.
2.4.3.3 PLLA (Poly-l-Lactic Acid)
(Fig. 2.45)
Poly-l-lactic acid (PLLA) is a bioresorbable bio-
compatible polymer that has been widely used in
the medical practice since the 1970s as absorb-
able surgical sutures or as intra-bone implants,
pins, and plates in orthopedic surgery or dental
procedures (Fig.  2.46). Sculptra® (Galderma,
Switzerland) is a formulation consisting of
freeze-dried powder of poly-l-lactic acid
(PLLA). It received CE certification in 1999 and
obtained USFDA approval for the treatment of
facial lipoatrophy in patients with human immu-
nodeficiency
virus
(HIV)
in
2003
[41].
Subsequently in 2009, it was FDA approved for
the correction of facial wrinkles and folds in the
US market. Once placed in the tissue, PLLA
gradually breaks down to lactic acid monomers
over the course of 24 months via nonenzymatic
hydrolysis [42]. In the process, it creates con-
trolled inflammation at the injected area to elicit
collagen production [43]. The lactic acid is sub-
sequently metabolized to carbon dioxide and
water and naturally excreted from the body [44].
The PLLA microparticles present in the product
are in the form of irregular crystals instead of
smooth microspheres. Sculptra® only contains
PLLA particles 40–60μm in diameter to avoid
macrophage phagocytosis [44]. Other compo-
nents present in the powder apart from PLLA
include Mannitol and Sodium. Sculptra® is
available in a 367.5 mg dose vial, with each vial
containing PLLA 150 mg, sodium carboxymeth-
ylcellulose (CMC) 90 mg and mannitol 127.5 mg.
CMC is included to ensure even distribution of
PLLA particles [45] while mannitol is added to
produce a firm, homogenous cake in the final
process of freeze-drying [46].
Fig. 2.43  Ellansé™ products
O
O
(CH2)3
C
n
Fig. 2.44  PCL molecular formula
2.4  Other Types of Injectable Fillers

76
Unlike Radiesse® or EllanséTM, which incor-
porate gel carriers, Sculptra® comes in the form
of freeze-dried powder and thus requires recon-
stitution with sterile distilled water (hereinafter
“distilled water”) 2–72 h prior to use [47, 48].
Given the presence of Mannitol in the powder,
distilled water rather than saline should be used
to ensure adequate osmolarity. Although the rec-
ommended reconstitution volume is 5  mL per
vial [48, 49], the prevailing trend among injectors
is to use a higher reconstitution volume of 10 mL
to minimize the risk of nodule formation [50].
Rather than reconstituting with distilled water
alone, it is preferable to add 1–2 mL of 1% lido-
caine to 8–9 mL of distilled water for diluting the
product to minimize discomfort during the injec-
tion [50]. Regarding the reconstitution time, it is
advisable to reconstitute the product at least
1 day prior to use. The wisdom of reconstituting
the product in advance with distilled water and
leaving the reconstituted material to sit for suffi-
cient hydration is to ensure uniform dispersion of
the aggregated PLLA microparticles in the mix-
ture and prevent clumps of product from causing
nodules. While storage of up to 3  days after
hydration is described in the pharmacopeia, the
reconstituted Sculptra® can be stored for up to
3–4  weeks at refrigeration, provided necessary
safeguards are in place to prevent contamination
[50]. PLLA in itself is insoluble in water and thus
becomes suspended when reconstituted with dis-
tilled water. CMC and mannitol, on the other
hand, are soluble and, following reconstitution
with distilled water, undergo hydration. Thus, it
is recommended that the vial of Sculptra®, once
hydrated with distilled water, is gently agitated
just before injection to ensure even and homoge-
nous dispersion of PLLA. The suspension is then
transferred from the vial into a 1 mL syringe for
injection into the tissue. To avoid bruising and
inadvertent intravascular injection of Sculptra®, it
is recommended to use a 23-G cannula for deliv-
ering the product evenly into the deep subcutane-
ous or supraperiosteal plane. The one area
reserved for using a 21-G needle is the temporal
region covered by thick fascia, which cannot be
easily penetrated with a cannula.
The injection volume required to cover the
entire face, including the anteromedial malar,
anterior cheek (buccal hollows), and temporal
fossa, ranges from 1 vial up to 2 vials per session
depending on the extent of facial volume loss
[48]. By facial regions, the volume of product
injected is 1–2 mL for the anteromedial malar,
Fig. 2.45  Sculptra® products
CH3
CH3
H
H
C
C
C
C
O
O
O
O
n
Fig. 2.46  PLLA molecular formula
2  Volumizing Fillers

77
2–4 mL for the anterior cheek, and 1–3 mL for
the temple per side. As a general rule of thumb,
one vial per session should suffice in case the
temples do not require treatment. Where treat-
ment is necessary also in the temples or severe
facial volume deflation is present, up to two vials
may be needed in a single session. To avoid the
appearance of nodules, it is critical to refrain
from superficial injections or injection in thin-
skinned areas such as the periorbital region.
Accordingly, the forehead and the nose with thin
overlying skin are not suited for treatment with
Sculptra®. PLLA should also be avoided in
dynamic areas such as the perioral region and the
lip vermillion (Fig.  2.47). Immediately upon
completing the injection, it is helpful to thor-
oughly massage the treated areas to distribute the
PLLA evenly throughout the tissue to avoid nod-
ule formation. In addition, it is recommended
that patients be instructed to massage the treat-
ment areas for 5 min, 5 times a day, for 5 days
after treatment (5-5-5-regimen) [51].
The immediate postinjection volume effect
from Sculptra® is attributable to the direct vol-
ume replacement provided by the reconstituted
material including distilled water, which disap-
pears within 2–3  days starting from the very
next day. New collagen production from PLLA
injection kicks in 4 weeks from treatment and
reaches the peak after the third month, with the
collagen biostimulation from the injection last-
ing for more than 25  months. Treatment with
Sculptra® typically requires around three injec-
tion sessions spaced 3–4  weeks apart for the
best effect [51].
However, unlike other volumizing fillers such
as HA, which allow customization of the desired
volume by the physician or patient, the result of
Sculptra® is subject to individual variability in
new collagen formation in the treated area.
Therefore, the risk exists that results may not be
visible even after completing the full three
rounds of treatment. Treatment with Sculptra®
thus requires corresponding effort on the part of
the patient to maximize collagen formation, for
example, by avoiding weight loss, eating a
healthy diet rich in protein, and maintaining reg-
ular, quality sleep. Concerning adverse reac-
tions, a common complication of Sculptra® is
nodule formation due to uneven placement of
product in the tissue or the aggregation of PLLA
microparticles in the injected product. The best
prevention strategy is to use a thin and uniform
suspension diluted to 10 mL and to make sure it
is injected evenly in the tissue. It also helps for
the patient to periodically massage the treated
areas during the first week. It bears noting that
nodules are more prone to occur in thin-skinned
regions including the periorbital and forehead
regions. They typically appear in the size of a
lentil or pea 1–2 months after injection and per-
sist until resolved in less than a year. In the
interim, a vigorous deep massage may be
attempted to mechanically  crush the nodules
apart [52, 53]. If there is no improvement, it may
be worthwhile to consider subcising the
clumped-up PLLA particles with a needle fol-
lowing intralesional injection of saline in the
treated area. Meanwhile, granulomas represent
Fig. 2.47  PLLA should be avoided in thin-skinned areas
such as the periorbital region, the forehead and the nose,
and in dynamic areas such as the perioral region and the
lip vermillion
2.4  Other Types of Injectable Fillers

78
another complication of Sculptra®, which should
be distinguished from nodules (Fig.  2.48).
Granulomas typically occur 3–6 months postin-
jection as a result of excessive foreign body
reaction [51, 53]. Though they appear in the
form of nodules or papules, histologically, they
represent foreign body granulomas. The granu-
loma may be accompanied by skin discoloration,
edema, and erythema. Possible treatments for
granulomas include injections of intralesional
triamcinolone or 5-FU [54].  If the granuloma
does not respond to intralesional injections, fol-
lowing up with surgical removal is advised.
Vigilance is required as granulomas left untreated
can persist for more than 10 years.
Comment: As a biostimulator that offers to
stimulate the body’s own collagen production,
Sculptra® can be a compelling alternative for
patients who seek rejuvenation but are reluctant
to use injectable fillers due to their aversion to
implanting a foreign substance in their face. The
drawback, however, is that results of Sculptra®
depend heavily on the body’s reaction to build
natural collagen, which may vary significantly
among individuals; thus, outcomes may be lim-
ited  if not almost negligible in some patients.
Granted, this seeming weakness may translate, in
marketing-speak, as an advantage of Sculptra® in
building subtle yet natural volume over time.
Recently, the PLLA has also been used as a bios-
timulator, enhancing not only skin elasticity but
also the appearance of pores, scars, skin tone, and
complexion via superficial injection into the sub-
dermis [42].
2.4.3.4 P-d,l-LA (Poly-d,l-Lactic Acid)
PDLLA (poly-d,l-lactic acid) is a stereoisomer
of polylactic acid comprised of d-and l-lactic
acids arranged in alternating order to form an
irregular chain structure. Unlike PLLA (poly-
l-lactic acid) consisting only of tightly packed
l-lactic acids, the d- and l-isomers comprising
PDLLA are spaced farther apart, resulting in a
weaker intermolecular linkage. This gives the
resulting material, PDLLA, a soft, friable prop-
erty with reduced hardness and an amorphous
shape, unlike the PLLA particles that are crystal-
line in shape [55].
Lenisna® (VAIM, Korea) and Juvelook®
(VAIM, Korea) are products containing reticu-
lated foamy microspheres of PDLLA obtained by
dissolving the amorphous PDLLA particles in a
mixture of DMSO (dimethylsulfoxide) and EC
(ethylene carbonate) and microspraying the con-
tent (Fig. 2.49). Lenisna® and Juvelook® received
CE certification in 2020 and was approved for
use in Europe. A notable advantage of Lenisna®
and Juvelook® is that they contain HA in place of
CMC, albeit in a non-cross-linked form, which
allows these products to provide immediate vol-
ume correction during the initial period of
treatment.
A vial of Lenisna® contains 200 mg of freeze-
dried power of PDLLA (PDLLA 170  mg, HA
30 mg), while Juvelook® comes in a 50-mg dose
vial (PDLLA 42.5 mg, HA 7.5 mg.) That said,
Juvelook® does not simply represent a smaller
repackage dosage unit of Lenisna®, as it is formu-
lated specifically to contain only PDLLA micro-
spheres sized 50μm or smaller. Consequently, the
average particle size of Juvelook® is 24μm (20–
50μm) in diameter compared with 51μm (50–
80μm) of Lenisna®. This allows Juvelook® to be
placed directly into the dermis to produce skin
regeneration without concerns of nodule forma-
Fig. 2.48  Granuloma in the infraorbital area due to the
inappropriate injection of Sculptra®
2  Volumizing Fillers

79
tion, which distinguishes it from Sculptra®,
though it provides reduced longevity and volume
projection compared with Lenisna® [55].
The microspheres present in Lenisna® and
Juvelook® are comprised of a multi-pore spongi-
form structure, causing them to undergo a more
rapid process of hydrolysis from within
(Fig. 2.50). As a consequence, when hydrolyzed,
these products progressively break down into lac-
tic acid monomers within a span of 1–1.5 years.
As with PLLA, PDLLA also creates inflamma-
tion in the injected area during its degradation,
eliciting collagen production, albeit at reduced
duration
and
amount
compared
with
PLLA.  However, this point can simultaneously
serve as a strength, as it implies a lower risk of
nodularity and granuloma formation. Lenisna® is
suitable for volume replenishment, similar to
Sculptra®, via injection in the deep subcutaneous
plane; by comparison, Juvelook®, consisting of
finer particles, is designed primarily for skin
regeneration via intradermal injection in the skin.
As with Sculptra®, Lenisna®
, and Juvelook®
come as freeze-dried powder which is not sus-
pended in a gel carrier but instead requires recon-
stitution with sterile distilled water before
injection. Considering that the power contains
mannitol, distilled water rather than saline should
be used for the reconstitution to ensure adequate
osmolarity. Regarding the dilution volume,
Lenisna® is reconstituted with 6 mL of distilled
water, to which 1 mL lidocaine is added; while
Juvelook® is reconstituted with 4 mL of distilled
water, to which 1  mL lidocaine is added [56].
Given Lenisna® and Juvelook® consist of multi-
pore microspheres and saturate more easily than
Sculptra®, they can be used right away following
30–60 min of hydration. Nonetheless, it can be
helpful to use a vortex generator to agitate the
vial for approx. 20  min before injection or to
reconstitute the product 1  day or preferably
1 week prior to use. The reconstituted products
can be stored for up to 3–4 weeks in a refrigera-
tor,
provided
care
is
taken
to
avoid
contamination.
Immediately before use, it is recommended
to gently shake the hydrated vial of Lenisna® or
Juvelook® to obtain an even and homogenous
suspension. The suspension is then transferred
from the vial into a 1-mL syringe for injection
into the tissue. To avoid bruising and inadver-
tent intravascular injection, it is recommended
to use a 23-G cannula for delivering the product
evenly into the deep subcutaneous or supraperi-
osteal plane. The one area reserved for using a
21-G needle is the temporal region, covered by
a
b
Fig. 2.49  PDLLA products. (a) Lenisna®. (b) Juvelook®
2.4  Other Types of Injectable Fillers

80
thick fascia that is hard to penetrate with a can-
nula. When using the product for volume
replacement, it is recommended to use 0.7 mL
of reconstituted Lenisna® further diluted with
0.3 mL of saline [56]. This produces an effect
comparable to using Sculptra® reconstituted to
10  mL.  The volume of product injected per
treatment area (per side) is 1–2  mL for the
anteromedial malar, 2–4  mL for the anterior
cheek, and 1–3 mL for the temple. One vial per
session should suffice if the temples do not
require treatment. Where no treatment is neces-
sary for the temples or where severe facial vol-
ume deflation is present, up to two vials may be
needed for a single session. Combination with
cross-linked HA may be considered in patients
who desire instant volume addition or wish to
avoid repeat treatments. In such case, the use of
0.7 mL of reconstituted Lenisna® further diluted
with 0.3 mL of cross-linked HA is advised [56].
The relevant injection volume should be
equivalent to 1.5–2 times the amount that would
have been injected using only cross-linked
HA.  While results may appear insufficient ini-
tially, the volume becomes progressively evident
after the fourth week, as collagen production
from PDLLA injection starts to kicks in. One
advantage of Lenisna® is the minimal risk of nod-
ule formation even when placed superficially into
the skin. This gives the product greater versatil-
ity, to be applied not only for facial volume
replenishment but also for skin tightening. When
used for skin rejuvenation, it is recommended to
add 0.5 mL of saline to 0.5 mL of the reconsti-
tuted Lenisna® for placement into the subdermis.
Immediately upon completing the injection, it is
helpful to massage the treated areas to distribute
the PDLLA evenly throughout the tissue,
although more softly than when massaging in
Sculptra®. Patients should be instructed to rub the
a
b
c
d
Fig. 2.50  The scanning electron microscope of the PDLLA (Courtesy of Vaim)
2  Volumizing Fillers

81
treatment areas for 3  min, 3 times a day, for
3 days after treatment (3-3-3-regimen) [56].
The biggest advantage of Juvelook® its ability
to be placed directly in the dermis to provide
skin tightening, as it involves minimal risk of
nodularity even when placed very superficially
in the skin. The PDLLA injected in the dermis
can act as a biostimulator, enhancing not only
skin elasticity but also the appearance of pores,
scars, skin tone, and complexion as is the case
with PLLA [57]. Juvelook® may be used either
alone or in combination with cross-linked HA or
other skin-boosting ingredients such as PDRN,
placenta extracts, and exosome. Caution is
required in areas of reduced dermal thickness,
such as the periorbital region. That being said,
nodules formed by Juvelook® are known to
resolve within a month upon repeated massage
using a radiofrequency device, as the application
of heat combined with strong pressure can be
effective in removing PDLLA microspheres that
have a multi-porous structure and a melting
point of 55–60 °C, more than 10 °C lower than
that of PLLA.
References
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Soft tissue augmentation. Philadelphia: Elsevier;
2018. p. 3–6.
2. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its
nature, distribution, functions and turnover. J Intern
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2  Volumizing Fillers