Rheological Properties and In Vivo Performance

Characteristics of Soft Tissue Fillers

Christopher K. Hee, PhD,* Garrett T. Shumate, BS,* Vic Narurkar, MD,†
Aude Bernardin, PhD,* and Darin J. Messina, PhD*

BACKGROUND Physicochemical properties and performance in nonclinical animal models can provide
insights into soft tissue filler performance.

OBJECTIVE To evaluate the in vivo performance of fillers with different compositions and physicochemical
properties.

MATERIALS AND METHODS Physicochemical properties were measured in vitro. Rat models were devel-
oped and used to compare lift capacity, resistance to deformation, and tissue integration. Four homogeneous
hyaluronic acid (HA) fillers, 2 nonanimal stabilized HA (NASHA) fillers, and 1 calcium hydroxylapatite/car-
boxymethyl cellulose (CaHA/CMC) filler were evaluated.

RESULTS Filler lift capacity correlated better with filler composition/type (homogeneous > NASHA > CaHA/
CMC) than with specific rheological properties. The CaHA/CMC filler had high initial resistance to deformation
relative to other groups; all HA fillers exhibited lower initial resistance to deformation, which increased over
time. Homogeneous HA fillers were integrated with surrounding tissue, whereas integration within particle-
based fillers (NASHA and CaHA/CMC) was variable, with some areas void of tissue.

CONCLUSION The animal models provide a platform to make comparative evaluations among fillers. The
results indicated that biological interaction plays an important role in how the filler performs. Rheology alone
was not sufficient to understand filler performance but was most useful when comparing within fillers of
similar composition.

C. K. Hee, G. T. Shumate, A. Bernardin, and D. J. Messina are employees of Allergan, Inc. V. Narurkar serves
as an investigator for Allergan. This study was sponsored by Allergan, Inc., Irvine, CA. Editorial assistance
(manuscript editing and formatting) was provided to the authors at their request by Peloton Advantage,
Parsippany, NJ and funded by Allergan Inc.

ver 2.3 million filler procedures were performed
O in the United States in 2014, of which 78% used
hyaluronic acid (HA)-based injections, 11% used
calcium hydroxylapatite/carboxymethyl cellulose
(CaHA/CMC) fillers, and the remaining 11% used
other materials (e.g., poly-L-lactic acid).1 Although
most HA-based fillers are comprised of the same
components (HA cross-linked with 1,4-butanediol
diglycidyl ether), variations in HA raw material, cross-
linking density, and manufacturing processes can result
in products with a wide array of physicochemical
properties. For example, cross-linked HA fillers can be
homogeneous or particles suspended in a carrier.2,3
Additionally, fillers comprised of other materials,
including CaHA/CMC, provide options with different
physicochemical properties.4,5
Fillers are traditionally characterized by rheology (i.e.,
physical response to applied forces). These properties,
along with certain assumptions, have been used to
predict how fillers will perform clinically. For instance,
a filler with a higher G9 value (i.e., firmer or more
elastic) is assumed to resist tissue forces better and
provide better lift than a filler with a lower G9
value.2,3,6–8 Although individual rheological proper-
ties are able to provide a framework for understanding

*Allergan, Inc., Irvine, California; †Bay Area Laser Institute, San Francisco, California

© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2015;41:S373–S381 DOI: 10.1097/DSS.0000000000000536

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 DERMAL FILLER PERFORMANCE
some of the differences between fillers, direct trans-
lation of specific properties to clinical performance
becomes difficult, as performance is influenced by
a variety of filler characteristics (e.g., G9, cohesivity,
HA concentration, water uptake) and application (e.g.,
plane of injection, location, volume injected).
As a supplement to rheological data, animal models
can be used to predict performance of fillers in a bio-
logical environment over time. Combining the 2 data
sets provides a platform for comparing the perfor-
mance of different fillers and, in combination with
an understanding of the physicochemical properties,
can be a useful tool when designing or selecting a filler
for a specific desired indication. To this end, 3 novel
animal models were developed to study the compar-
ative lift capacity, resistance to deformation, and tissue
integration of fillers with varying compositions and
physicochemical properties.
Methods
Products
The fillers evaluated in this study were Hylacross cross-
linking technology (homogeneous): Juvéderm Ultra Plus
XC (HYC-24L+; Allergan, Inc., Irvine, CA); Vycross
cross-linking technology (homogeneous): Juvéderm
Volbella with Lidocaine (VYC-15L; Allergan, Inc.),
Juvéderm Volift with Lidocaine (VYC-17L; Allergan,
Inc.), and Juvéderm Voluma with Lidocaine (VYC-20L;
Allergan, Inc.); nonanimal stabilized HA (NASHA)
cross-linking technology (particle-based): Restylane-L
(RES-L, Medicis Aesthetics Inc), Perlane-L (PER-L;
Medicis Aesthetics Inc., Scottsdale, AZ); and CaHA/
CMC (particles in carrier): Radiesse (RAD) (Merz
Aesthetics, Raleigh, NC). With the exception of RAD,
all products contained 0.3% lidocaine.
In Vitro Experiments
Physicochemical properties were determined in vitro.
Rheological measurements were conducted on 3 lots of
each filler using a rheometer at 5 Hz with 0.8% strain
with a C35/2 degrees geometry. Resistance to com-
pression was determined by measuring the maximum
normal force of the filler while compressing at 0.8 mm/
min for 2 minutes with a 25-mm plane geometry.2
S374 DERMATOLOGIC SURGERY
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For water uptake, 0.1 mL of filler was mixed with
0.7 mL of phosphate buffer by repeated syringe–
syringe passes over 1 hour. Any buffer that was not
taken up by the filler was dyed using a blue-dyed latex
bead solution (catalog #L1398, Sigma-Aldrich, St.
Louis, MO). The maximum absorption ratio was
calculated as the percentage difference between the
initial gel percentage (12.5%) and the final gel per-
centage (height of nondyed phase/total height of gel
and buffer).
For microscopic appearance, samples were extruded
directly from the syringe onto a clean glass slide and
gently spread with a spatula without any other prep-
aration (e.g., dilution or drying) and brightfield images
taken.
In Vivo Experiments
Animal models were developed using a clinically rel-
evant three-dimensional (3D) imaging tool to compare
specific in vivo performance characteristics relevant to
the functions of filling and volumizing, that is, the
capacity to lift/project overlying tissue, the ability to
resist deformation, and the integration of the filler with
surrounding tissue. Filler was injected in the sub-
cutaneous plane to generate comparative data in the
lift capacity and resistance to deformation models.
This tissue plane and location of injection allow for
a consistent, defined bolus that can be measured by 3D
imaging and incorporates the tension forces of the
overlying skin. For tissue integration, an indication-
specific plane of injection was used. Sprague Dawley
rats (Charles River Labs, Wilmington, MA) aged 2 to 4
months were used for all in vivo studies. Animals were
anesthetized by isoflurane inhalation and humanely
euthanized by CO2 exposure. The Animal Care and
Use Committee approved the studies.
For lift capacity and resistance to deformation studies,
animals received 125 mL of filler as a subcutaneous
bolus overlying the skull using a 27-gauge half-inch
needle. The bolus projection was assessed using
a Canfield Vectra M1h 3D imaging system (Canfield
Scientific, Fairfield, NJ). For the lift capacity study,
3D images were captured of unmanipulated boluses
at serial time points (immediately after injection, 1
 HEE ET AL

day, and 1, 2, 4, and 12 weeks after injection; n = 10/ Results

group), and the mean height of the bolus was deter-
mined using the 3D images. For the resistance to In Vitro Experiments
deformation study, decrease in mean height after
Physicochemical properties are listed in Table 1. The
application of a standardized force to the bolus was
energy stored and given back after shear stress (G9,
evaluated over 2 days (n = 6/group/time point). At
elastic modulus) and the energy dissipated during
each postinjection time point (immediately, 1 and 2
shear stress due to friction (G$, viscous modulus) were
days), an image was captured; a 319 g force was then
highest in the CaHA/CMC filler, followed by the
mechanically applied to the bolus for 3 seconds (to
NASHA particle-based fillers, and lowest for the
represent the force of a thumb), and another image
homogeneous fillers. The resistance to compression, as
was subsequently captured. Resistance to deforma-
a measure of cohesivity, was also highest in the CaHA/
tion was calculated as the percent decrease in mean
CMC fillers. The resistance to compression in the
height of the filler before and after application of the
homogeneous group of fillers was stratified, with
force.
HYC-24L+ having higher resistance to compression
than VYC-15L, VYC-17L, and VYC-20L. The
For tissue integration, injections were performed on
NASHA particle-based fillers had resistance to com-
either the back or flanks of the animal (n = 8/group/
pression similar to the homogeneous fillers.
time point). Each animal received either sub-
cutaneous bolus injections (200-mL) on the back
Maximum water uptake, which relates to potential for
using a 27-gauge half-inch needle or intradermal
an increase in filler volume due to the absorption of
linear thread injections (20-mL) on the flanks deliv-
water, is reported in Table 1. In this assay, the
ered in a retrograde manner using a 27-gauge 1.25-
homogeneous fillers exhibited varying capacities to
inch needle. The injected filler and surrounding tissue
take up water, with VYC-15L, VYC-17L, and VYC-
were explanted at 1 and 4 weeks, fixed in 10% neutral
20L fillers taking on less water (100%–250%) than
buffered formalin, embedded in paraffin wax, and
HYC-24L+ (425%–475%). The NASHA particle-
sectioned (5 mm) using a rotary microtome. Sections
based fillers took on less water (65%–115%) than the
were stained using hematoxylin and eosin (catalog
homogeneous fillers. RAD was not evaluated as the
#7111 and 7221; Richard-Allan Scientific, Kalama-
composition of the filler did not allow for measure-
zoo, MI) and Van Gieson/colloidal iron (catalog
ment in this assay.
#KTCIRPT, American MasterTech, Lodi, CA, USA).
Stained sections were imaged using a NanoZoomer
Representative microscopic images of the respective
2.0HT (Hamamatsu Photonics K.K., Hamamatsu
filler types are shown in Figure 1. The homogeneous
City, Japan). A histopathologist masked to treatment
fillers (Figure 1A) are smooth, with cross-linked units
made observations, including extent of tissue sur-
that are shapeless and not visible as defined particles.
rounding and integrated with the filler and inflam-
The NASHA particle-based fillers (Figure 1B) have
matory cell response.
cross-linked units that are visible within the carrier.
The CaHA/CMC fillers (Figure 1C) have CaHA par-
Statistical Analysis ticles visible within the CMC gel carrier.

For lift capacity, a 2-way repeated-measure analysis

of variance (ANOVA) was performed to identify
differences among fillers, both overall and at individual
time points. For resistance to deformation, a 2-way
ANOVA was performed to identify differences within
fillers over time and among fillers at individual time points.
Tukey’s multiple comparison test was used for pairwise
comparisons. Significance was determined at p < .05.
In Vivo Experiments
Lift capacity data are presented in Table 2 and Fig-
ure 2. Maximum mean height was observed immedi-
ately after injection, followed by a decrease in mean
height over time. Significant differences within indi-
vidual time points and over the duration of the study
(Overall Lift) are presented in Table 2. The relative

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 DERMAL FILLER PERFORMANCE

TABLE 1. In Vitro Properties of Soft Tissue Fillers (mean 6 SD)

Maximum HA
Type of G9 at 5 Hz G$ at 5 Hz Compressive Water Uptake Concentration
Material Products (Pa) (Pa) Force (gmf) (%) (Mg/mL)
Homogeneous HYC-24L+ 244 6 14 76 6 2 78 6 3 425–475 24
VYC-15L 274 6 14 41 6 2 18 6 2 100–150 15
VYC-17L 317 6 19 42 6 3 24 6 2 160–210 17.5
VYC-20L 353 6 32 40 6 1 35 6 2 200–250 20

NASHA Particle-Based RES-L 710 6 40 204 6 10 26 6 1 65–115 20

PER-L 849 6 93 198 6 29 27 6 1 65–115 20

CaHA/CMC RAD 2782 6 620 1075 6 181 225 6 17 N/A N/A

differences in mean height over time can be seen in
Figure 2A for homogeneous fillers and in Figure 2B
for particle-based fillers. Differences between the
lift curves can be seen within groups of fillers based
on composition. Additionally, mean height over
time is presented for the fillers with the highest G9
from each category of filler (homogeneous filler,
NASHA particle-based filler, and CaHA/CMC)
(Figure 2C).
Resistance to deformation data is shown in Figure 3.
All HA fillers had a relatively low resistance to defor-
mation immediately after injection (32.4%–40.5%),
as shown by the high percent decrease in mean height,
and this resistance to deformation significantly
increased (p # .0318) in the HA groups over time.
Conversely, RAD had a relatively high resistance to
deformation (14.1%) immediately after injection,
which was significantly different than all other groups
at this time point (p # .001) and did not significantly
change over the course of the experiment.
Tissue integration was assessed at 1 and 4 weeks after
injection. VYC-20L and PER-L were assessed as
a subcutaneous bolus, consistent with their clinically
indicated injection depth (Figure 4). VYC-20L
exhibited some host tissue ingrowth as early as 1 week
after injection with well-defined collagenous tissue
distributed throughout the injected filler at 4 weeks.
The tissue ingrowth observed for PER-L was more
variable than with VYC-20L at both 1 and 4 weeks,
with some areas exhibiting tissue ingrowth and other
areas void of tissue. HYC-24L+, VYC-15L, VYC-17L,
RES-L, and RAD were injected through linear
threading in the intradermal plane, consistent with
their clinically indicated injection depth for filling
wrinkles and folds (Figure 5). HYC-24L+, VYC-15L,
and VYC-17L were observed to be distributed within

Figure 1. Representative microscopic images of types of filler materials including (A) homogeneous, (B) NASHA particle-
based, and (C) CaHA/CMC (magnification, ·131).

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 HEE ET AL

the spaces in the dermal tissue at both 1 (data not

0.84 6 0.02*†‡xk

0.91 6 0.02*†‡xk
shown) and 4 weeks (Figure 5, A–C). Variable distri-

0.76 6 0.02*‡k

0.74 6 0.02*
Overall
bution was observed within the spaces in the dermal
0.66 6 0.02

0.69 6 0.02

0.67 6 0.02
tissue for RES-L, with some areas of integration and
some large aggregates void of tissue (Figure 5D). RAD
exhibited less distribution within the tissue at 4 weeks
(Figure 5E). Macrophage and lymphocyte infiltration
0.67 6 0.04*†‡k¶
12 Weeks

0.56 6 0.13k¶
was only observed with RAD and ranged from slight
0.48 6 0.09k

0.47 6 0.08k
0.39 6 0.12
0.46 6 0.13

0.24 6 0.10
to severe at both 1 and 4 weeks.

Discussion
0.81 6 0.07k
0.62 6 0.08
0.60 6 0.16
0.64 6 0.17

0.61 6 0.12
0.65 6 0.12

0.46 6 0.12

Soft tissue fillers are designed to lift the tissue and add
4 Weeks

volume to improve the aesthetic appearance of wrin-

kles, folds, or volume lost during aging. Although
physicochemical properties (e.g., rheology, HA con-
0.89 6 0.15*†‡xk

0.93 6 0.06*†‡xk

centration, water uptake potential) are an effective

2 Weeks

way to measure differences among fillers, they are

0.59 6 0.08
0.70 6 0.13

0.65 6 0.11
0.67 6 0.08

0.56 6 0.15

difficult to translate to clinical performance, as the

filler’s properties likely changes upon interaction with
the tissue environment over time. As a result, novel
animal models were developed to assess relevant per-
0.96 6 0.12*†‡xk

0.87 6 0.10*‡xk

formance attributes of various fillers exhibiting dif-

1 Week

0.87 6 0.15k
0.77 6 0.13

0.69 6 0.14
0.71 6 0.16

0.63 6 0.12

ferent physicochemical properties to better evaluate

the impact of the biological environment over time.
This provides a platform to understand which per-
TABLE 2. Lift Capacity of Dermal Fillers (Mean Height [mm 6 SD])

formance attributes may be most indicative of clinical

1.08 6 0.10*†‡xk

performance for a specific indication.

1.00 6 0.14*‡x
1 Day

0.72 6 0.14
0.85 6 0.12

0.70 6 0.17
0.77 6 0.23

0.82 6 0.17

An understanding of the capacity of a filler to lift is

essential to predict the ability of a filler to function as
¶Increased compared to HYC-24L+, within time point (p < .031).

a volumizer or effectively correct wrinkles. Fillers with

*Increased compared to VYC-15L, within time point (p < .038).
†Increased compared to VYC-17L, within time point (p < .042).
‡Increased compared to RES-L, within time point (p < .017).
xIncreased compared to PER-L, within time point (p < .010).
1.19 6 0.13*†‡

greater lift may potentially be more useful in volumizing

kIncreased compared to RAD, within time point (p < .036).
1.10 6 0.10*

1.03 6 0.10*

1.02 6 0.16*
1.08 6 0.10*

1.14 6 0.11*
0.83 6 0.15
0 Days

applications where projection is required and those

with less lift more suitable for more superficial appli-
cations, including filling of folds or wrinkles where
a softer gel may be more desireable.6,7,9–11 In comparing
HYC-24L+
Product

VYC-15L
VYC-17L
VYC-20L

the volumizing fillers based on lift alone, VYC-20L

RES-L
PER-L

RAD

exhibited greater lift than PER-L. This is consistent with

clinical assessments demonstrating the volumizing
capabilities of VYC-20L.12,13 Similarly, fillers such as
NASHA Particle-Based
Type of Material

HYC-24L+, VYC-17L, VYC-15L, and RES-L had less

lift capacity, which is more consistent with their clinical
Homogenous

indication, including filling of wrinkles and folds.

CaHA/CMC

Historically, G9 has been used to predict and describe

the lift capacity of a filler.2,3,6,8,10 In evaluating the

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 DERMAL FILLER PERFORMANCE

Figure 2. Average mean height over the 12-week lift capacity experiment for (A) homogeneous HA fillers, (B) particle-based
fillers (NASHA and CaHA/CMC), and (C) the highest G9 in each category (homogeneous, NASHA particle-based, and CaHA/CMC).

rheological properties of the products tested in this
study, G9 and G$ were stratified among products of
different compositions (i.e., CaHA/CMC >> HA
particle-based fillers > homogeneous HA fillers).
Although the relationship of G9 across filler types would
suggest that lift capacity would be greatest in the CaHA/
CMC fillers and lowest in the homogeneous fillers, in
actuality, the lift capacity did not follow the same trend
(Figure 2C). When looking at all fillers as a group (Fig-
ure 6, dashed line), lift did not correlate with increasing
G9. Although G9 was not predictive of lift capacity when
evaluating all fillers together, G9 had a positive

Figure 3. Resistance to deformation of dermal fillers (% decrease in mean height [mm/mm 6 standard deviation]). *Sig-
nificantly increased versus RAD, within time point (p # .001); †significantly decreased versus day 0, within group (p # .032);
‡significantly decreased versus day 1 (p # .002).

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 HEE ET AL

Figure 4. Subcutaneous tissue integration of (A) VYC-20L and (B) PER-L at 4 weeks after Van Gieson/colloidal iron staining.
Colloidal iron stains mucopolysaccharides (i.e., HA) blue and Van Gieson stains collagen red and muscle brown. The
subcutaneous bolus (blue) can be seen underlying the panniculus muscle (brown), with different amounts of tissue inte-
gration (red) within the fillers.

correlation to the overall lift capacity when fillers of
similar composition/cross-linking technology were
grouped (Figure 6, solid or dotted lines). Evaluation of
other physicochemical parameters (G$, compressive
force, HA concentration) did not show a consistent
relationship with overall lift, either across all fillers or
within groups of similar compositions/cross-linking
technologies (data not shown). This analysis suggests
that other parameters besides physicochemical param-
eters may influence the performance of a filler. One
possible contributor is filler composition. For example,
RES-L, PER-L, and RAD are fillers that exhibited lift
initially but decreased starting at day 1 (Table 2 and
Figure 3B). The retention, or lack thereof, of the carrier
over time is not measured through rheological testing
but may affect the ability to maintain lift over time.
Conversely, a filler such as HYC-24L+, with a higher
relative water uptake, exhibited greater lift from day 1
through 2 weeks compared to all groups except VYC-
20L. However, at time points past 2 weeks where the
filler would not be expected to continue to take up
water, the lift for HYC-24L+ decreases, resulting in
significantly less lift than VYC-20L and PER-L at 12
weeks. Although not investigated here, additional fac-
tors such as degradation may also play a role.
Resistance to deformation, which is relevant to the
ability to sculpt and massage a filler to achieve the
desired effect, is also an important attribute of fill-
ers.11,12 The resistance to deformation is a function of
the physicochemical properties, including cohe-
sivity.2,8 The observed immediate resistance to defor-
mation (i.e., percent decrease from pre-to-post force)
was consistent with the measured cohesivity of the

Figure 5. Intradermal tissue integration of (A) HYC-24L+, (B) VYC-15L, (C) VYC-17L, (D) RES-L, and (E) RAD at 4 weeks after
Van Gieson/colloidal iron staining. Colloidal iron stains mucopolysaccharides (i.e., HA) blue and Van Gieson stains collagen
red and muscle brown. The filler (blue) is observed within the collagenous dermis (red).

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 DERMAL FILLER PERFORMANCE

Figure 6. Plot of overall lift versus G9. Linear relationships between overall lift (from Table 2) and G9 (from Table 1) are
shown for products of similar composition/cross-linking technology (homogeneous VYC HA fillers [solid line] and NASHA
particle-based fillers [dotted line]) and for all groups combined (dashed line).

fillers, with significantly more resistance to deforma-
tion observed in the CaHA/CMC filler, which had
a 3- to 12.5-fold greater cohesivity than the other fill-
ers. The relatively lower resistance to deformation
observed at early time points in this animal model for
the HA-based fillers is consistent with clinical obser-
vations that describe VYC-20L and VYC-15L as easy
to sculpt and massage.11,12,14 Although this is a desired
property at the time of injection, increased resistance
to deformation over time is preferred to prevent
inadvertent alteration of the correction. In contrast to
RAD, which had a relatively high resistance to defor-
mation at all time points, HA-based fillers exhibited an
increased resistance to deformation over time. It is
notable that some degree of deformation was observed
at the 1 and 2 day time points, suggesting that some
degree of malleability was maintained, as opposed to
a filler that is solid within the tissue. This change in the
resistance to deformation over time is likely due to the
interaction of the filler with the tissue, including water
uptake and distribution/integration of the filler. The
importance of this relative degree of resistance may be
dependent on indication. For instance, in volumizing
applications (i.e., supraperiosteal or subcutaneous
injection), a higher resistance to deformation over time
may be desired to prevent spreading of the filler, which
could lead to loss of projection.3,4,7,9 As the plane of
injection becomes more superficial, qualities associ-
ated with a lower resistance to deformation (e.g.,
moldability and spreadability) are more desirable.
VYC-20L exhibited the greatest change in moldability
over time compared to other groups, suggesting it
would perform well in volumizing applications. Con-
versely, the remaining products, with the exception of
RAD, have profiles (lower resistance to deformation at
day 1 and 2 compared to VYC-20L) suggesting use-
fulness in intermediate-depth and superficial-depth
applications. RAD is an outlier among these products,
as the resistance to deformation was relatively high
immediately after injection and did not change with
time, which may limit its use in highly mobile areas (e.g.,
lips) or in anatomically unforgiving areas (e.g., the
periocular region).4,5
In addition to physical performance attributes, the
ability of a filler to provide a natural look and feel is
desirable. This has been observed clinically, with
a significant improvement in the natural look, soft-
ness, and appearance of lips for VYC-15L compared
to RES-L.14 This study investigated the ability of the
filler to distribute or integrate with the surrounding
tissue, as this may relate to how the filler looks and
feels within the tissue. For example, a filler that is
integrated with the tissue may look and feel more like
natural tissue compared to a filler that remains segre-
gated from the tissue. The results of these studies
showed different distribution and integration patterns
at 1 and 4 weeks for homogeneous fillers (HYC-24L+,
VYC-20L, VYC-17L, and VYC-15L) compared to
particulate fillers (RES-L, PER-L, and RAD). The

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homogeneous fillers consistently distributed within
the tissue (intradermal injection) or integrated with the
surrounding tissue (subcutaneous injection). Alterna-
tively, the particle-based HA fillers (RES-L and PER-L)
and CaHA/CMC filler (RAD) exhibited variable tissue
integration in their respective injection planes. These
observations are consistent with previous preclinical
and clinical histologic observations.5,11,15–17
Conclusion
The studies described here are the first to use in vivo
animal models to evaluate filler performance attrib-
utes, which rely not only on the filler’s physicochemi-
cal properties but also the interaction with the
biological environment. It was demonstrated that
rheology alone (e.g., G9) is insufficient to understand
clinical performance. The animal models have been
shown to be a useful tool for characterizing the relative
performance attributes of different fillers. This relative
characterization enables a better understanding of
which fillers may be best suited for specific indications.
Acknowledgments The authors thank Sebastien Pierre,
PhD, Allergan, Inc., for his critical review and input.
References
1. American Society of Plastic Surgeons. 2014 cosmetic plastic surgery
statistics. Arlington Heights: ASPS National Clearinghouse of Plastic
Surgery Procedural Statistics; 2014.
2. Pierre S, Liew S, Bernardin A. Basics of dermal filler rheology. Dermatol
Surg 2015;41(Suppl 1):S120–6.
3. Sundaram H, Voigts B, Beer K, Meland M. Comparison of the
rheological properties of viscosity and elasticity in two categories of soft
tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol
Surg 2010;36(Suppl 3):1859–65.
4. Emer J, Sundaram H. Aesthetic applications of calcium hydroxylapatite
volumizing filler: an evidence-based review and discussion of current
concepts: (part 1 of 2). J Drugs Dermatol 2013;12:1345–54.
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
HEE ET AL
5. Jacovella PF. Calcium hydroxylapatite facial filler (Radiesse):
indications, technique, and results. Clin Plast Surg 2006;33:511–23.
6. Gold M. The science and art of hyaluronic acid dermal filler use in
esthetic applications. J Cosmet Dermatol 2009;8:301–7.
7. Gilbert E, Hui A, Waldorf HA. The basic science of dermal fillers: past
and present Part I: background and mechanisms of action. J Drugs
Dermatol 2012;11:1059–68.
8. Stocks D, Sundaram H, Michaels J, Durrani MJ, et al. Rheological
evaluation of the physical properties of hyaluronic acid dermal fillers. J
Drugs Dermatol 2011;10:974–80.
9. Carruthers A, Carruthers J. Non-animal-based hyaluronic acid fillers:
scientific and technical considerations. Plast Reconstr Surg 2007;120:
33S–40S.
10. Carruthers J, Cohen SR, Joseph JH, Narins RS, et al. The science and
art of dermal fillers for soft-tissue augmentation. J Drugs Dermatol
2009;8:335–50.
11. Ho D, Jagdeo J. Biological properties of a new volumizing
hyaluronic acid filler: a systematic review. J Drugs Dermatol 2015;
14:50–4.
12. Fischer TC. A European evaluation of cosmetic treatment of facial
volume loss with Juvederm Voluma in patients previously treated with
Restylane Sub-Q. J Cosmet Dermatol 2010;9:291–6.
13. Few J, Cox SE, Paradkar-Mitragotri D, Murphy DK. A multicenter,
single-blind randomized, controlled study of a volumizing hyaluronic
acid filler for midface volume deficit: patient-reported outcomes at 2
years. Aesthet Surg J 2015;35:589–99.
14. Raspaldo H, Chantrey J, Belhaouari L, Saleh R, et al. Juvéderm volbella
with lidocaine for lip and perioral enhancement: safety and effectiveness
in a prospective, randomized, controlled trial. Plast Reconstr Surg Glob
Open 2015;3:e321.
15. Tran C, Carraux P, Micheels P, Kaya G, et al. In vivo bio-integration of
three hyaluronic acid fillers in human skin: a histological study.
Dermatology 2014;228:47–54.
16. Fernandez-Cossio S, Castano-Oreja MT. Biocompatibility of two novel
dermal fillers: histological evaluation of implants of a hyaluronic acid
filler and a polyacrylamide filler. Plast Reconstr Surg 2006;117:
1789–96.
17. Flynn TC, Sarazin D, Bezzola A, Terrani C, et al. Comparative
histology of intradermal implantation of mono and biphasic hyaluronic
acid fillers. Dermatol Surg 2011;37:637–43.
Address correspondence and reprint requests to: Christopher
K. Hee, PhD, Allergan, Inc., 2525 Dupont Drive, Irvine, CA
92612, or e-mail: Hee_Charlie@Allergan.com
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