journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298

Available online at www.sciencedirect.com

www.elsevier.com/locate/jmbbm

Research Paper

Key importance of compression properties

in the biophysical characteristics of hyaluronic
acid soft-tissue fillers

Samuel Gavard Molliardn, Séverine Albert, Karine Mondon

Anteis SA, a wholly owned subsidiary of Merz Pharmaceuticals GmbH, Chemin des Aulx 18, 1228 Plan-les-Ouates,
Switzerland

ar t ic l e in f o abs tra ct

Article history:
Received 4 February 2016
Received in revised form
30 March 2016
Accepted 1 April 2016
Available online 8 April 2016
Hyaluronic acid (HA) soft-tissue fillers are the most popular degradable injectable products
used for correcting skin depressions and restoring facial volume loss. From a rheological
perspective, HA fillers are commonly characterised through their viscoelastic properties under
shear-stress. However, despite the continuous mechanical pressure that the skin applies on
the fillers, compression properties in static and dynamic modes are rarely considered.
In this article, three different rheological tests (shear-stress test and compression tests in

Keywords: static and dynamic mode) were carried out on nine CE-marked cross-linked HA fillers.

Hyaluronic acid fillers Corresponding shear-stress (G0 , tan δ) and compression (E0 , tan δc, normal force FN) parameters

Biophysical characteristics were measured. We show here that the tested products behave differently under shear-stress

Rheology and under compression even though they are used for the same indications. G0 showed the

Compression properties expected influence on the tissue volumising capacity, and the same influence was also

Volumising capacity observed for the compression parameters E0 .

Fibroblasts stimulation In conclusion, HA soft-tissue fillers exhibit widely different biophysical characteristics and
many variables contribute to their overall performance. The elastic modulus G0 is not the only
critical parameter to consider amongst the rheological properties: the compression para-
meters E0 and FN also provide key information, which should be taken into account for a better
prediction of clinical outcomes, especially for predicting the volumising capacity and probably
the ability to stimulate collagen production by fibroblasts.
& 2016 Elsevier Ltd. All rights reserved.

1. Introduction Thanks to its favourable biophysical properties, HA is used

Hyaluronic acid (HA) is a naturally occurring linear polysac-
charide composed of repeating disaccharide units of N-
acetyl-D-glucosamine and D-glucuronate. HA is omnipresent
in the human body and occurs in almost all biological tissues
and fluids (Anderegg et al., 2014; Volpi et al., 2009).
in a broad range of medical applications, e.g. as adjuvant for
cataract surgery in ophthalmology (Mencucci et al., 2015), as a
viscosupplement for the treatment of osteoarthritis in rheu-
matology (Ammar et al., 2015), and for filling wrinkles and/or
restoring facial volume in aesthetic medicine (Alam et al.,
2008; Kogan et al., 2007; Volpi et al., 2009).

n
Corresponding author.
E-mail address: samuel.gavard@yahoo.fr (S. Gavard Molliard).

http://dx.doi.org/10.1016/j.jmbbm.2016.04.001
1751-6161/& 2016 Elsevier Ltd. All rights reserved.
 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298 291

HA soft-tissue fillers are commonly used in aesthetic

Indicated for the treatment of mid and/or deep depressions of the skin and
Indicated to fill deep wrinkles and folds, as well as to restore and enhance

Indicated for the treatment of deep skin depressions, face contouring, and
Indicated for the treatment of fine lines and medium-sized depressions of

Indicated for shaping the contours of the face, the correction of folds, and
medicine to treat signs of facial ageing (Bass, 2015;
Humphrey et al., 2015; Monheit, 2014; Pons-Guiraud, 2015).

Indicated to fill moderate facial wrinkles and folds as well as for lip

Indicated to restore facial volume, e.g. to enhance cheeks or chin

In 2014, 2.3 million treatments with injectable filler products
were performed in the United States alone and more than

the skin, as well as for enhancement and pouting of the lips

soft-tissue volume (e.g. contour of the face, lip volume, etc.)

volume restoration, as well as for restoration of lip volume

70% of these procedures were done with cross-linked HA

Indicated for correction of wrinkles and lip enhancement

fillers (ASPS, 2014). This represents the second most common
minimally invasive cosmetic procedure, after treatment with
botulinum toxin type A.
The HA soft-tissue fillers currently on the market are
chemically cross-linked, in order to improve the biophysical
characteristics and the in vivo duration of the products

for lip definition and enhancement

Indicated to restore facial volume (Edsman et al., 2012). Most of them are manufactured using
1,4-butanediol diglycidyl ether (BDDE) as cross-linking agent
(Ågerup et al., 2005; De Boulle et al., 2013; Wende et al., 2016).
CE registered indications

The cross-linking process connects the linear HA chains

together, transforming them into a three-dimensional net-
work. Performing this process according to different manu-
lip enhancement

facturing technologies leads to hydrogels with specific

enhancement

rheological properties, cohesivity levels, and matrix struc-

tures (Flynn et al., 2015; Stocks et al., 2011; Sundaram and
Cassuto, 2013; Sundaram and Gavard Molliard, 2015;
Sundaram et al., 2015; Tran et al., 2013).
Manufacturing technology HA content (mg/

Rheology is a very valuable and powerful tool to charac-

terise such a wide variety of HA hydrogels. The rheological
properties allow the researchers to understand how a HA
soft-tissue filler deforms and reacts under mechanical stress,
22.5

25.5

17.5
ml)

such as during injection or after gel implantation, both on the

26

15

20
20

20

24

short and long term. Consequently, rheology can help clin-

icians to select both the best product and the best injection
technique for each specific indication and facial region. This
strategy, which is called ‘rheological tailoring’, facilitates the
achievement of the clinical objectives set by the clinicians
(Sundaram and Cassuto, 2013; Sundaram and Fagien, 2015;
Hylacross
CPM HA

CPM HA

CPM HA

Vycross

Vycross

Vycross
NASHA

NASHA

Sundaram et al., 2015).

In most current research, the rheological characterisation
of the cross-linked HA fillers is based on the assessment of
the viscoelastic parameters G0 (elastic modulus), G00 (viscous
Allergan (Pringy, France)

Allergan (Pringy, France)

Allergan (Pringy, France)

Allergan (Pringy, France)

modulus), and tan δ(G00 /G0 ). These parameters are measured

Galderma (Uppsala,

Galderma (Uppsala,

by oscillatory shear-stress experiments (Baumann et al., 2009;

Anteis (Geneva,

Anteis (Geneva,

Anteis (Geneva,

Bogdan Allemann and Baumann, 2008; Edsman et al., 2012;

Manufacturer

Switzerland)

Switzerland)

Switzerland)

Gold, 2009; Sundaram and Cassuto, 2013; Sundaram and

Sweden)

Sweden)

Fagien, 2015; Sundaram et al., 2015). However, the contribu-

Table 1 – CE-marked cross-linked HA fillers.

tion of the static and dynamic compression forces exerted by

the skin tissues on the fillers, after their implantation in
different layers of the skin, has seldom been discussed in the
RESTYLANE lidocaine

literature. Therefore, this article aims to highlight the impor-

Restylane PERLANE
JUVÉDERM Volbella

JUVÉDERM Voluma
BELOTERO Volume
BELOTERO Balance

BELOTERO Intense

JUVEDERM Ultra 3

tance of taking into account the compression properties in

Product reference HA product name

JUVÉDERM Volift

the characterisation of HA filler products, in order to com-

plete the information currently provided by the common
lidocaine

lidocaine

lidocaine

lidocaine

shear-stress parameters.
This study consists of two main tasks: (1) determining the
common shear-stress parameters G0 , G00 and tan δ,as well as
the compression parameters in dynamic and static mode E0
(elastic modulus), E00 (viscous modulus), tan δc (E00 /E0 ), and FN
(normal force) of nine Conformitée Européenne (CE)-marked
cross-linked HA fillers; and (2) investigating the importance of
these in vitro parameters on the volumising capacity of the
H
D
A

G
C
B

HA soft-tissue fillers in clinical applications.

292 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298
2. Materials and methods
2.1. Materials
Nine CE-marked HA soft-tissue fillers cross-linked with BDDE
were purchased from commercial sources (Table 1). They
were all extruded at 50 mm/min through the needles pack-
aged with each product using an automated extrusion system
(LLOYD Instruments from Ametek, Berwyn, USA). Then, they
were subjected to oscillatory shear-stress and compression
tests with a DHR-2 rheometer equipped with a dynamic
mechanical analyser (DMA) module (TA Instruments, New
Castle, USA).
The fillers were produced using different manufacturing
technologies: CPMHA (Cohesive Polydensified Matrix Hya-
luronic Acid) for the range of BELOTERO products (Gel A to
C); Vycross for JUVÉDERM Volbella, Volift and Voluma pro-
ducts (Gel D to F); NASHA (Non-Animal Stabilized Hyaluronic
Acid) for RESTYLANE lidocaine and Restylane PERLANE lido-
caine products (Gel G and H), and finally Hylacross for
JUVÉDERM Ultra 3 (Gel I). Two full ranges of products invol-
ving superficial, midlevel and deep volumising fillers were
investigated (products from CPM HA technology and Vycross
technology). A superficial and midlevel volumisers were
tested for the NASHA technology and a midlevel volumiser
was also studied for the Hylacross technology.
2.2. Oscillatory shear-stress test
The oscillatory shear-stress test was performed at a tem-
perature of 25 1C in shear-stress – oscillation mode at 1.0% of
strain, within the linear viscoelastic region, with a 40 mm
plate/plate aluminium geometry and a 1.0 mm gap between
the parallel rheometer plates. The measurements were car-
ried out over a frequency range of 0.1–10 Hz. The values of the
G0 , G00 , and tan δ parameters were measured at the physiolo-
gically oscillation frequency of 0.7 Hz.
2.3. Compression test in static mode
The compression test in static mode was performed at a
temperature of 25 1C in normal force mode, with a 40 mm
plate/plate aluminium geometry: 1.4 g of gel was placed
between the two plates and the upper plate was set in contact
with the gel and lowered toward the bottom plate, thus
Gel G Gel I
Cohesivity score=1 Coheivity score=4
Fig. 1 – Examples of cohesivity scores. Cohesivity of three different cross-linked HA fillers, with corresponding cohesivity
scores obtained at 95s according to the cohesivity assay developed by Sundaram et al. (2015).
compressing the gel. The normal force (FN) was measured
for a gap between the parallel plates of 1.5 mm.
2.4. Compression test in dynamic mode
The compression test in dynamic mode was performed at a
temperature of 25 1C in compression – oscillation mode at
1.0% of strain, within the linear viscoelastic region, with a
40 mm plate/plate aluminium geometry and a 1.0 mm gap
between the parallel rheometer plates. The measurements
were carried out over a frequency range of 0.1–10 Hz. The
values of the E0 , E00 , and tan δc parameters were measured at
the physiologically oscillation frequency of 0.7 Hz.
2.5. Data analysis
All measurements were carried out in triplicate. Data were
expressed as the mean7standard deviation (SD). Coefficients
of variation lower than 10% were considered as satisfactory.
Results were evaluated statistically using Student's t-test
with a level of significance fixed at α¼0.05.
3. Results and discussion
3.1. Description of the tested CE-marked cross-linked HA
fillers
Previous work has demonstrated that cross-linked HA fillers
have different biophysical properties, i.e. different rheological
properties, cohesivity levels, and HA matrix structures (Flynn
et al., 2015; Pierre et al., 2015; Sundaram and Cassuto, 2013).
The physical differences between the HA fillers can be
easily visualised with the cohesivity assay recently developed
by Sundaram et al. (2015), the cohesivity being defined as the
capacity of a material not to dissociate due to the mutual
affinity between its components. Using this assay, the visual
patterns of the HA filler gels were used to assign a cohesivity
score from 1 (fully dispersed) to 5 (fully cohesive). For
instance, Fig. 1 shows images of gels G, I, and A, whose
respective cohesivity score were 1, 4, and 5. The cohesivity
scores obtained for the nine cross-linked HA fillers are
summarised in Table 2 according to the results presented
by Sundaram and Gavard Molliard (2015), showing the diver-
sity of the HA soft-tissue fillers on the market.
Clinically, the nine cross-linked HA fillers assessed in this
work are all intended for facial soft-tissue augmentation.
Gel A
Coesivity score=5
 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298 293

Based on their approved indications, some of them are

0.5970.03
0.5470.02
0.5270.01
2.1170.08
2.0170.05
1.4570.02
3.8470.17
3.7070.04
0.3670.02
superficial to midlevel volumisers (defined in this article as

Dynamic compression properties at 0.7 Hz

category VC1, which stands for “volumising capacity of level

tan δc
1”), others are mid-level volumisers (defined as category VC2,
for “volumising capacity of level 2”) and the last ones are

58,04771880
25,27071015
44,28771316
60,38271898
deep volumisers (defined as category VC3, for “volumising

18,5417472
32,2357622

32,4697854
35,1847735
23,8567330
capacity of level 3”). The volumising capacity categories of the
E0 0 (Pa)

nine cross-linked HA fillers are presented in Table 2.

3.2. Influence of shear-stress properties on the volumising

31,45771132
59,15071469
111,04472250

65,55471891
capacity of the HA fillers
12,0037400
21,9947378
41,7477947
84567256
95077216
Several studies have demonstrated the crucial importance of
E0 (Pa)

rheological properties in the evaluation of HA soft-tissue

fillers (Pierre et al., 2015; Sundaram and Fagien, 2015). The
improved knowledge and understanding of such properties
Static compression properties at
Table 2 – Rheological properties, cohesivity levels, and clinical volumising capacity of the nine tested cross-linked HA fillers.

has attracted considerable interest in rheological tailoring by

the clinicians, because this approach facilitates the achieve-
ment of clinical objectives by assisting the selection of the
most appropriate product for each application (Sundaram
and Cassuto, 2013). The elastic modulus G0 , the viscous
modulus G00 , and their tan δ (G00 /G0 ) are the common rheolo-
gical parameters used for characterising HA fillers. They are
0.5170.02
1.1670.03
0.9570.03
0.1570.01
0.2270.01
0.3370.02
0.2370.01
0.3070.01
0.9870.02
1.5 mm

measured under dynamic shear-stress at a physiologically

FN (N)

relevant oscillation frequency in order to mimic as close as

possible the shear-stress applied in vivo on the implant by
the tissues. The shear-stress can occur in two different
0.5470.04
0.4070.02
0.1970.01
0.1670.01
0.1470.01
0.0670.00
0.2070.01
0.1570.01
0.2670.02
Shear-stress properties at 0.7 Hz

clinical situations. First, when the filler is placed between

tan δ

two different anatomical tissue layers, for instance between

the bone and the deep fat pad or between the deep fat pad
and a muscle (as in the case of deep implantation in the
G0 0 (Pa)

3472
5272
5771
2871
3972
1771
13673
11074
3672

cheek area). Second, when the filler is implanted into one

single layer of the skin, in which the movements of the
muscles induce different shear-stresses in the sub-layers,
due to their different structure, as in the case of the papillary
677713
6373
13073
30075
17474
27976
31475

71679
14375
G0 (Pa)

and the reticular dermis.

In this work, the nine cross-linked HA fillers were char-
Data obtained at 95s according to (Sundaram and Gavard Molliard, 2015).
Mean7SD
Mean7SD
Mean7SD
Mean7SD
Mean7SD
Mean7SD
Mean7SD
Mean7SD
Mean7SD

acterised by their rheological parameters G0 , G00 , and tan δ

during dynamic shear-stress tests (Fig. 2a) and the values at
0.7 Hz were compared in Table 2. Very different shear-stress
properties were obtained for products with similar claimed
volumising capacities. For example, gels indicated for a
volumising capacity of 2 (VC2) have G0 ranging from 130 to
GS cohesivity

716 Pa, and tan δ ranging from 0.14 to 0.40. Consequently, gel
C with G0 ¼ 300 Pa and tan δ¼ 0.19 should belong to the
scorea

category of products with a volumising capacity of 2 (VC2),

5
4
3
2
2
2
1
1
4

even though, according to clinical indications and experience,

it possesses a volumising capacity of 3 (VC3). Therefore, it is
Volumising capacity

hard to reach a univocal interpretation of these data. How-

ever, once we focus on a given manufacturing technology, a
significant influence of G0 on the space-filling capacity
emerges: the higher the G0 within the product range, the
higher the volumising capacity of the product (Fig. 3). This
(VC)

VC1
VC2
VC3
VC1
VC2
VC3
VC1
VC2
VC2

observation is consistent with the results of the controlled

split-face study in 140 patients performed by Monheit et al.
(2010).
The relation between the elastic modulus G0 and the
reference
Product

ability of a product to lift tissues makes G0 one of the

parameters of choice for characterising the shear-stress
H
D
A

G
C
B

E
F

a
I

properties of cross-linked HA fillers. However, tan δ is also

294 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298

1000
A
900
800 B

700 C
600 D

G'(Pa) 500 E
400
F
300
G
200
H
100
0 I
0 2 4 6 8 10
Frequency (Hz)

4.00
A
3.50
B
3.00
C
2.50
D
FN(N)

2.00 E
1.50 F
1.00 G
0.50 H
0.00 I
1 1.5 2 2.5 3
Gap (mm)

A
2,00,000
B

C
1,50,000
D
E'(Pa)

1,00,000 E

F
50000 G

H
0 I
0 2 4 6 8 10
Frequency (Hz)

Fig. 2 – Representative patterns of the behaviour of nine cross-linked HA fillers under shear-stress tests (a), static (b) and
dynamic compression tests (c).

relevant in this context, because its combination with G0 fully
defines the overall shear-stress properties of a product. The
tan δ parameter provides additional valuable information on
the viscous properties of the gel, which permits to evaluate,
for instance, the tissue integration of the implant (Sundaram
and Cassuto, 2013).
Based on these observations, the most suitable deep
volumising product for a given manufacturing technology is
expected to be the implant with the highest G0 and the lowest
tan δ.
3.3. Influence of the compression properties on the
volumising capacity of HA fillers
Once injected in the skin, a cross-linked HA filler is subject to
various mechanical stresses that can result in either a shear-
stress or a compression on the implant. As previously men-
tioned, the shear-stress parameters G0 and tan δ are exten-
sively described in the literature, whereas only limited
information is available on the compression properties of
HA fillers (Borrell et al., 2011; Pierre et al., 2015). Due to the
 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298
Fig. 3 – Elastic modulus versus claimed volumising capacity.
Influence of the elastic modulus G0 on the volumising
capacity (VC) of the nine tested cross-linked HA fillers
according to each manufacturing technology (CPM: cohesive
polydensified matrix; Vycross; NASHA: non-animal
stabilized hyaluronic acid; Hylacross).
constant compression forces that are applied on the implant
throughout its in vivo life, the compression properties in both
static and dynamic environments can provide valuable addi-
tional information for understanding the behaviour of a gel
after implantation. In order to evaluate such properties, two
distinct compression tests were performed on the nine
selected cross-linked HA fillers: one in static mode (mimick-
ing the permanent pressure of the skin), and one in dynamic
mode (mimicking the mobile compression forces applied on
the filler during facial expressiveness).
The normal forces FN of the fillers were measured in static
mode (Fig. 2b, Table 2). This provides key information on the
capacity of the implants to resist vertical compression, and
therefore of their capacities to lift the tissues. The viscoelastic
properties of compression, i.e. E0 , E00 , and tan δc of the HA
fillers were determined during an oscillatory compression
test in dynamic mode (Fig. 2c) and the values at 0.7 Hz were
compared in Table 2.
The normal forces FN measured for a gap of 1.5 mm range
between 0.22 and 1.16 N, independently on the volumising
capacity of the gels. Gels with the highest volumising capa-
city (VC3, for example products C and F) were expected to
have the highest FN, but this relation was not observed. For
instance, gel C has almost the same value of FN as gel I, which
is intended for a lower volumising indication. Similarly,
turning to the compression results in dynamic mode, deep
volumising products do not exhibit the highest elastic mod-
ulus E0 : product F (VC3) has an elastic modulus inferior to the
one of products A, B, and I, which have a lower volumising
capacity (VC2).
Again, once the data are analysed by manufacturing
technologies, the compression parameters FN and E0 , espe-
cially E0 , show an influence on the volumising capacity
(Fig. 4): FN tends to increase with the volumising capacity
(Fig. 4a), except for product B, which has a volumising
capacity of 2 (VC2) and shows the highest FN. This unexpected
result could be explained, at least partly, through the cohe-
sivity, which affects the measurement of the compression
properties in static mode. Gel C, with a lower cohesivity of 3,
has a higher ability to dissociate and thus generates a lower
FN than gel B, which has a higher cohesivity (score¼4). This
higher ability to dissociate could induce a partial horizontal
295
Fig. 4 – Normal force and elastic modulus versus claimed
volumising capacity. Influence of (a) the normal force FN and
(b) the elastic modulus E0 on the volumising capacity (VC) of
the nine tested cross-linked HA fillers according to each
manufacturing technology (CPM: cohesive polydensified
matrix; Vycross; NASHA: non-animal stabilized hyaluronic
acid; Hylacross).
movement of the gel out of the geometry with the continuous
increase of the mechanical pressure, leading to a decreased
quantity of gel under the geometry and therefore a lower
normal force; the normal force being dependent on the gel
quantity under the geometry.
The elastic modulus values clearly increased with the
volumising capacity of the fillers (Fig. 4b). Thus, in addition
to G0 , both compression parameters FN and E0 , especially E0 ,
showed an influence on the space-filling capacity: the higher
the value of E0 , the higher the volumising capacity. However,
this correlation is only valid for each considered manufactur-
ing technology.
As for the shear-stress tests, the tan δc parameter obtained
after dynamic compression can be useful to understand the
viscoelastic behaviour of the material under oscillatory com-
pression. The tan δc value varies considerably amongst the
nine tested cross-linked HA fillers, ranging from 0.52 to 3.84. In
particular, tan δc is o1 for the products made with Hylacross
and CPM HA technologies, around 2 for the gels obtained with
the Vycross technology, and 43 for gels prepared with NASHA
technology. Gels with tan δco1 are thus more elastic than
those with tan δc41.Differences are also present in the viscoe-
lastic properties of gels enduring either shear-stress or com-
pression. The range of gels that showed the highest tan δ(0.19–
0.54) under shear-stress (gels A, B, C and I) exhibited low tan δc
values (0.36–0.59) under compression. Identically, the range of
gels that showed the lowest tan δ (0.06–0.20) had a tan δc above
2 or 3. Therefore, soft-tissue fillers behave entirely differently
296 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298
under shear-stress and under dynamic compression, i.e. under
horizontal and vertical mechanical stress, respectively.
On the other hand, it is also important to mention that the
clinical importance of the compression properties most
probably depends on the placement of the HA fillers in the
tissues (Fig. 5). In the superficial layers of the skin, i.e. in the
dermis, an implant already subject to the shear-stress of the
skin also experiences a slight compression from the skin.
This compression would become more marked in deeper
layers, due to the pressure of the upper layers of the skin.
Further in vivo studies are needed in order to confirm the
present hypothesis about the relative contributions of the
compression forces on the behaviour of a product implanted
in different skin layers.
3.4. Potential key role of the compression properties in the
collagenesis mechanism
The dermal extracellular matrix (ECM) provides strength and
resiliency to the skin and is mainly composed of collagen
fibrils produced by fibroblasts (Quan et al., 2013). It has been
demonstrated that, due to skin aging, the dermal collagen
undergoes enzyme-catalysed cleavage, which compromises
the mechanical environment of the dermis and impairs
fibroblast attachment to the ECM (Quan et al., 2013). This
phenomenon generates a collapsed morphology of the fibro-
blasts and, therefore, a down-regulated production of col-
lagen and an up-regulated production of collagen-degrading
matrix metalloproteinases (MMPs) (Fisher et al., 2002, 2008;
Fligiel et al., 2003; Varani et al., 2006, 2001). It was recently
found that the enhancement of the structural support of the
ECM by injections of cross-linked HA soft-tissue fillers stimu-
lates the fibroblasts by creating elongated cells, with subse-
quent increase in the production of procollagen I and
collagens I and III for at least 12 weeks after the fillers
injection (Paliwal et al., 2014; Quan et al., 2013; Wang et al.,
2007). This mechanism of induction of collagen synthesis is
relevant for explaining, at least partially, that the observed
C
DERMIS
Shear
HA filler
HYPODERMIS
MUSCLES
Fig. 5 – Stress applied on HA filler. Scheme illustrating the mechanical stress applied by the skin on a HA filler on different
implantation sites, in the dermis (a) and in the hypodermis (b). Red and blue arrows denote shear-stress and compression
forces (C), respectively.
clinical persistence of the filling effect lasts longer than the
biological availability of the HA soft-tissue filler in the dermis
(Landau and Fagien, 2015).
Taking this finding into account, we infer that HA fillers
may have an ability to apply a mechanical pressure on
fibroblasts. Therefore, once implanted, HA fillers with high
compression parameters E0 and FN should have a better
ability to mechanically stimulate the synthesis of de novo
collagen by elongation of the fibroblasts.
Consequently, the knowledge of the compression proper-
ties, obtained in static and in dynamic mode as in this work,
is not only useful to better predict the volumising capacity of
a cross-linked HA filler, but presumably it can also support a
better understanding of the mechanical ability of the filler to
apply a pressure on the fibroblasts leading to their elongation,
thus activating them and creating a structural support that is
highly beneficial for counteracting the aging of the dermal
environment. Further in vitro and in vivo studies are needed
to confirm the latter hypothesis.
4. Conclusions
HA soft-tissue fillers play an increasingly important role in
minimally invasive aesthetic procedures and a broad palette
of products is now available to the clinicians. In this context,
there is a growing interest in the biophysical characteristics
of cross-linked HA fillers, whose understanding is essential
for optimising the selection and usage of the most relevant
products for the intended treatment.
The rheological parameters G0 and tan δ are commonly
used to characterise HA fillers, in particular G0 , due to its
known clinical correlation with the volumising capacity. The
present article highlights the additional importance of the
compression parameters E0 , tan δc, and FN for the character-
isation of the fillers. As studied on nine CE-marked products,
these parameters give additional key information on the
volumising capacity and behaviour of the HA fillers when
C
DERMIS
Shear
HA filler
HYPODERMIS
MUSCLES
 journal of the mechanical behavior of biomedical materials 61 (2016) 290 –298
implanted in the skin tissues, both at rest and during facial
movement. The influence of E0 on the volumising capacity
was demonstrated for each investigated manufacturing tech-
nology: the higher the E0 , the higher the capacity to lift
tissues. It was also suggested that the knowledge of E0 and
FN compression parameters is particularly important for
fillers intended to be applied in the deep layers of the skin,
and is probably also important for assessing the ability of HA
fillers to mechanically stimulate the production of collagen
by the fibroblasts. Further research, in combination with
clinical investigations, is needed for confirming the present
conclusions and for improving the qualitative and quantita-
tive understanding of the relative contributions of the various
key biophysical parameters, e.g. G0 , tan δ, E0 , FN, tan δc, and
cohesivity level in clinical applications, in order to offer safe
and optimal aesthetic treatments to the patients.
Disclosure
Mr. Samuel Gavard Molliard, Mrs. Séverine Albert, and Dr.
Karine Mondon are employed by Anteis SA, Geneva, Switzer-
land, a division of Merz Pharmaceuticals. Anteis SA, now a
wholly owned subsidiary of Merz Pharma, provided the
logistical and financial support for the execution of
this study.
Acknowledgements
Not applicable.
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