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M 600 V • I
C © ORIGINAL ARTICLES J D D
SPECIAL TOPIC
Eect of Dierent Crosslinking Technologies on Hyaluronic
Acid Behavior: A Visual and Microscopic Study of Seven
Hyaluronic Acid Gels
Patrick Micheels MD,a Didier Sarazin MD,b Christian Tran MD,c and Denis Salomon MDd
aPrivate Practice, Geneva, Switzerland
bLaboratoire Viollier, Geneva, Switzerland
cDepartment of Dermatology, HCU, Geneva, Switzerland
dCIDGE International Dermatology Clinic, Geneva, Switzerland
Background: The mechanical, rheological, and pharmacological properties of hyaluronic acid (HA) gels differ by their proprietary
crosslinking technologies.
Objective: To examine the different properties of a range of HA gels using simple and easily reproducible laboratory tests to better
understand their suitability for particular indications.
Methods and materials: Hyaluronic acid gels produced by one of 7 different crosslinking technologies were subjected to tests for
cohesivity, resistance to stretch, and microscopic examination. These 7 gels were: non-animal stabilized HA (NASHA® [Restylane®]), 3D
Matrix (Surgiderm® 24 XP), cohesive polydensied matrix (CPM® [Belotero® Balance]), interpenetrating network-like (IPN-like [Stylage®
M]), Vycross® (Juvéderm Volbella®), optimal balance technology (OBT® [Emervel Classic]), and resilient HA (RHA® [Teosyal Global Action]).
Results: Cohesivity varied for the 7 gels, with NASHA being the least cohesive and CPM the most cohesive. The remaining gels could
be described as partially cohesive. The resistance to stretch test conrmed the cohesivity ndings, with CPM having the greatest resis-
tance. Light microscopy of the 7 gels revealed HA particles of varying size and distribution. CPM was the only gel to have no particles
visible at a microscopic level.
Conclusion: Hyaluronic acid gels are produced with a range of different crosslinking technologies. Simple laboratory tests show how
these can inuence a gel’s behavior, and can help physicians select the optimal product for a specic treatment indication.
Versions of this paper have been previously published in French and in Dutch in the Belgian journal Dermatologie Actualité. Micheels P,
Sarazin D, Tran C, Salomon D. Un gel d’acide hyaluronique est-il semblable à son concurrent? Derm-Actu. 2015;14:38-43.
J Drugs Dermatol. 2016;15(5):600-606.
ABSTRACT
INTRODUCTION
Since their introduction in Europe in 1996, crosslinked hyal-
uronic acid (HA) gels have progressively replaced bovine
collagen as the preferred treatment for lling lines and
folds,1 and account for the vast majority of non-invasive aes-
thetic procedures used in daily practice.
In its native form, the chemical structure of HA is identical
across different species. This feature, along with its unique
viscoelastic and physicochemical properties, has led to the de-
velopment of numerous HA-based medical devices. However,
due to the short half-life of endogenous HA, chemical modica-
tions are required to obtain long-lasting gels.2 This is achieved
by a crosslinking process, which changes the 3-dimensional
structure of the HA chains and results in the formation of either
HA microspheres “pearls” or a jelly. While the risk of immu-
nogenicity to HA-derived products is generally low, the altered
structure of the 3-dimensional HA gels may result in them be-
ing recognized as foreign by the dermis.3,4
The raw material in the production of HA gels for aesthetic use
consists of pharmacological grade HA chains or HA powder of
the same purity, but with different molecular weights, which
may vary from 600 kDa to more than 2,500 kDa. The nal prod-
ucts differ in terms of their HA concentration and method of
crosslinking. Crosslinking methods may be either chemical or
physical, but in the eld of aesthetic medicine the crosslinking
agent that is used to stabilize the majority of HA-based dermal
llers currently on the market is 1,4-butanediol diglycidyl ether
(BDDE). The stability, biodegradability, and toxicity prole of
BDDE put it ahead of other crosslinking agents such as divinyl
sulfone.5 It should be noted that “natural” crosslinks in the form
of Van der Waals forces are also found in all HA preparations
developed for aesthetic use.
The basic crosslinking process takes place in 2 steps and is the
same for many currently used HA products that use BDDE as the
crosslinking agent: (1) dissolution in an alkaline medium and
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P. Micheels, D. Sarazin, C. Tran, D. Salomon
4. Optimal Balance Technology (OBT®)
This technology is used to produce the Emervel® range of HA
gels (Q-Med, Uppsala, Sweden). These have the same HA con-
centration (20 mg/mL) but, unlike the Restylane products that
differ only in their particle sizes, Emervel products differ in their
degrees of crosslinking as well as gel calibration, depending
on their indication. Thicker or thinner llers are obtained by
varying gel calibration, and rmer or softer llers by varying
crosslinking.
5. Cohesive Polydensified Matrix (CPM®)
Cohesive polydensied matrix (CPM®) technology is used for the
Belotero® range of products (Anteis S.A., Geneva, Switzerland,
a wholly owned subsidiary of Merz Pharmaceuticals GmbH)
and is based on a dynamic double crosslinking. In addition to
the classic crosslinking process, 2 additional steps are added:
the addition of a new amount of HA followed by a continua-
tion of the crosslinking process. This produces a monophasic
polydensied gel that combines high levels of crosslinked HA
with lighter levels of crosslinked HA in a cohesive matrix.9
6. Resilient Hyaluronic Acid (RHA®)
This is the crosslinking technology used in the Teosyal® (Teo-
xane Laboratories, Geneva, Switzerland) range of gels. The
linearization of the HA, and (2) addition of crosslinking agent
under temperature control. However, crosslinking techniques
differ from one manufacturer to another, and gels vary in the
nal amount of crosslinked HA they contain. These differences
modify the behavior of the gels so that injection techniques and
depths have to be adapted for the HA gel used. The terms used
to describe the properties of the different gels are dened in
Table 1.
At least 7 different types of crosslinking technology are used in
the production of current HA gels. All of these gels are available
with lidocaine, which is introduced during the crosslinking pro-
cess by the manufacturers.
1. Non-Animal Stabilized Hyaluronic Acid (NASHA®)
In this technique developed by Bengt Agerup MD, the addi-
tion of a small amount of BDDE introduces minute amounts of
crosslinks between the polysaccharide chains, resulting in the
formation of an entangled matrix.6 The degree of crosslinking
in the original matrix is estimated to be around 10% to 15%
and between 1% to 2% in the nal product.7 It is hypothesized
that the slightly viscous matrix thus obtained is dried and then
sieved or passed through cleaver lters of different diameters
to produce gel particle sizes adapted to the clinical indications
of the nal product. This process creates solid HA “pearls,”
which are then suspended in a non-crosslinked vector such as
NaCl 0.9% in phosphate buffer (phosphate buffered saline) or
a non-crosslinked HA gel. The number and size of the pearls
varies depending on the gel indication. The current study used
Restylane® (Q-Med, Uppsala, Sweden), a gel with an average
pearl diameter of 250 μm (100,000 pearls/mL).8
2. 3D Matrix
3D Matrix represents an advancement of Hylacross® tech-
nology, but unlike Hylacross is not yet US Food and Drug
Administration (FDA) approved (personal communica-
tion, Dr. P. Lebreton, Allergan). Surgiderm® products
(Allergan-Corneal Industry, Pringy, France) are formulated
with 3D Matrix and contain a high ratio of high molecular
weight HA to lower molecular weight molecules. In a single-
step crosslinking process, the high and low molecular weight
molecules are mixed. A greater number of BDDE molecules
are attached by both ends or extremities, resulting in more
efcient crosslinking.
3. Vycross®
This uses the same crosslinking technique as 3D Matrix, but
the proportion of high to low molecular weight HA is re-
versed, with Vycross® containing a higher proportion of low
molecular weight HA. It therefore contains less HA (lower HA
concentration) compared with 3D Matrix. Juvéderm Voluma®
is so far the only product using this technology to have
received FDA approval.
TABLE 1.
Definitions Used to Describe the Properties of Gels Produced
With Different Crosslinking Technologies
(Hydro)gel Water-soluble polymer crosslinked via
chemical or physical bonds.
Monophasic
A monophasic gel consists of a single phase
and is usually used to describe a gel looking
non-particulate (cohesive).
Biphasic
A biphasic gel traditionally describes a
particulate gel, which consists of a phase of
semi-solid crosslinked hyaluronic acid particles
suspended in a liquid phase.
Cohesivity/
cohesion
Cohesion represents the internal forces that unite a
solid or liquid particles. A gel is said to be cohesive
if it conserves its unity, its cohesivity or cohesion,
when placed into an aqueous solution (characteristic
of monophasic gels) at a low dilution, for instance
1:3, without agitation. In contrast, a gel is said to
be non-cohesive if it is unable to conserve its unity,
its cohesion, once placed into an aqueous solution
(characteristic of biphasic gels).
Monodensified
A gel is described as monodensied if it
consists of a single homogeneous crosslinking
grade/density zone inside the gel itself.
Polydensified
A gel is described as polydensied if it consists
of several crosslinking grades/density zones
inside the gel itself.
© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
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No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
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P. Micheels, D. Sarazin, C. Tran, D. Salomon
Cohesivity Test
When conducted in private practice, 0.6 mL of saline solution
(NaCl 0.9%) was combined with 2 drops of a coloring agent (Eco-
line® no.548 Talens® blue violine from the Royal Talens Society).
To this was added 0.2 mL of the HA gel to be tested by simple
pressure on the syringe plunger to avoid any change in the vis-
coelastic properties of each gel. No other distortion or stress was
applied. Finally, 2 drops of ethanol 70% were added and the re-
cipient gently rotated. Photos were taken before and after the
addition of the ethanol. Products were measured precisely us-
ing Omnican® syringes (Braun, Switzerland). The same test was
conducted in a private laboratory by coloring 40 mL of saline
serum with Ecoline 548. The investigators then placed 0.9 mL of
this colored saline solution in a Petri dish and added 0.3 mL HA
gel. Tests were performed a minimum of 3 times for each gel. The
different gels were observed visually and under a microscope
between slides to see if they remained as long, cohesive strands
or disintegrated into multiple stands or smaller particles.
Resistance to Stretch Test
We placed 0.2 mL of each gel on a Petri dish. The gels were then
pinched with an Adson’s plier to draw them out. A photo was taken
of the gel at maximum stretch and the length noted using a measur-
ing tape. The test was performed a minimum of 3 times for each gel.
Equipment
Each laboratory had its own camera, and photographic images
were taken with the following cameras: Nikon(R) digital camera
D 40 X, lens AF Micro Nikkor 60 mm; Sony® Cyber-shot; Nikon
DXM1200F; and Olympus SC100. Microscopic examinations
were performed with a Leica® MS5 and a Zeiss Axiokop 40.
RESULTS
Microscopic Examination
For the 4 HA gels available for testing in 2011-- NASHA, CPM,
3D Matrix, IPN-like -- a difference in viscosity was noted when
preparing the slides for examination, particularly when spread-
ing the gels, with NASHA being remarkable for having the least
viscosity. In addition, when rinsing with double distilled water, a
large amount of the NASHA gel was washed away. This was not
observed with the other gels. The most viscous gel was the IPN-
like and the most adherent was CPM. 3D Matrix had an adherence
between NASHA and IPN-like. Gels produced with the most recent
crosslinking technologies (Vycross, OBT, and RHA) were tested in
2014. Of these, RHA had the greatest viscosity and resistance to
spreading, but was poorly adherent to the glass slide. Vycross and
OBT were similar in having an important viscosity and resistance
to spreading, but less so than RHA. During rinsing, the adherence
of Vycross and OBT was also similar and greater than that of OBT.
Observation of the gels, with or without added lidocaine, un-
der a light microscope revealed some signicant differences in
structure (Figures 1 and 2).
technology produces gels with long HA chains stabilized by
natural and chemical crosslinks. Only a small amount of BDDE
is used to create the gels, which differ in their degree of cross-
linking (1.9%-4.0%) as well as their HA concentration.
7. Interpenetrating Network-Like (IPN-Like®)
The Stylage® range of gels (Laboratoires VIVACY®, Archamps,
France) use several individual crosslinked matrices, which un-
dergo an interpenetrating network-like (IPN-like®) process to
achieve a monophasic gel, resulting in an increased density of
crosslinking. The product also contains mannitol, which claims to
protect the gel to a certain extent from the effects of free radicals.
In this paper we report on simple and easily reproducible tests
that can be conducted in the laboratory to allow us to better un-
derstand the properties of HA gels produced by the 7 different
types of crosslinking technology.
METHODS
Tested Gels
Between 2006 and 2014, we tested HA gels available on the
Swiss market manufactured by one of the 7 different crosslink-
ing technologies: NASHA (Restylane), 3D Matrix (Surgiderm
24 XP), CPM (Belotero Balance), IPN-like (Stylage M), Vycross
(Juvéderm Volbella), OBT (Emervel Classic), and RHA (Teosyal
Global Action). All of the gels were available with lidocaine, in-
troduced during the crosslinking process by the manufacturers.
The tests were conducted on the gels as they became available,
with the last tests conducted in 2014 on Vycross, OBT, and RHA.
All gels were marketed for aesthetic indications (lling lines or
creating volume). The tests were conducted in private practice
as well as in private and university laboratories
Microscopic Examination
For microscopic examination, 0.1 mL of each gel was placed
on a glass slide and spread as for a hematological examina-
tion. The gel’s resistance to spreading was noted as a simple
estimate of their viscosity. The gels were then colored with tolu-
idine blue at 1 of 2 concentrations (depending on the laboratory
where the tests were realized): 0.1% and 0.069% for 30 seconds
to 60 seconds before being rinsed twice with double distilled
water. Adhesion to the slide during rinsing was examined. The
slide was then covered and placed under the microscope for
examination of the gel’s structure.
"Hyaluronic acid gels produced by one
of 7 dierent crosslinking technologies
were subjected to tests for cohesivity,
resistance to stretch, and microscopic
examination."
© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
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J D D
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P. Micheels, D. Sarazin, C. Tran, D. Salomon
NASHA
Hyaluronic acid particles were clearly emphasized and balloon-
shaped rather than a round pearl. The structure of the gel was
clearly non-cohesive and biphasic.
CPM
The gel had a very specic structure appearing as a continuous
network complex, with some areas of the gel having greater
staining and appearing more dense than others.
3D Matrix and IPN-Like
These gels had similar structures that were totally different
from NASHA or CPM. Compared with CPM, they appeared
lighter, less dense, and with less continuous networks.
RHA
The gel appeared as large grains of compressed particles with a
nice spreading. The gel resembled Vycross, but with larger par-
ticles. There was no real complex continuous network and the
gel could be described as non-cohesive or partially cohesive.
Vycross
When spread on the microscope slide, the gel appeared as ne
grains, ner than RHA and OBT. With magnication, the gel
appeared as many particles compressed closely together and
could be described as particulated, similar to NASHA. Vycross
could be described as a non-cohesive or partially cohesive gel.
OBT
On spreading, the gel appeared as ne grains, but not as ne as
Vycross. On magnication, the gel appeared as a more or less
continuous network comprising particles of different sizes with
an appearance similar to IPN-Like. OBT was also classed as a
non-cohesive or partially cohesive gel.
FIGURE 1. Appearance of hyaluronic acid gels (NASHA®, CPM® and
3D-Matrix) under the light microscope. The top row images were tak-
en at HCU, Geneva (toluidine blue, original magnification x12.5). The
bottom row images were taken at the Laboratory of Histopathology,
Viollier, Geneva (toluidine blue, original magnification x25).
FIGURE 2. Appearance of hyaluronic acid (HA) gels (Vycross®, OBT®,
and RHA®) under the light microscope. The top row images show a
macroscopic view of the HA gels Vycross, OBT®, and RHA colored
with toluidine blue. The images below show the appearance of the
same gels under the light microscope (original magnification x25).
© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
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P. Micheels, D. Sarazin, C. Tran, D. Salomon
University of Geneva, Department of Dermatology, in 2008 on
the 3 FDA-approved gels (Figure 3).10 The results illustrate the
cohesivity of the different gels, with NASHA being the least co-
hesive and CPM the most cohesive. The results were the same
for all gels, whether or not they contained added lidocaine.
Resistance to Stretch Test
For all the HA gels with the exception of CPM, it was not pos-
sible to draw out the gel to a distance greater than 1 cm to
2 cm without the gel breaking (Figure 4, Table 3). This was the
case whether lidocaine had been added by the manufacturer or
not; addition of liquid lidocaine to an HA gel may modify a product’s
cohesivity and change its viscoelastic properties. The CPM gel
could be drawn to a distance of 3.5 cm to 5 cm without break-
ing.
DISCUSSION
A simple set of tests that can be performed in private practice
or in a laboratory reveal large differences in the behavior of
currently available HA gels manufactured using different cross-
linking technologies. Crosslinking is required to slow down
the degradation of endogenous HA, but is also harnessed to
change the rheological properties of HA gels with consequenc-
es on the effectiveness of a product for a particular indication.
Cohesivity is used to assess the ability of a ller to resist de-
formation and maintain product integrity and, along with the
elastic modulus (G prime) of a gel, is an important determi-
nant of the lift capability of a ller. Cohesivity of gels can be
measured quantitatively by the amount of pressure required to
compress them between 2 plates. In a qualitative measure of
Cohesivity Test
Tests performed in private practice showed that the NASHA gel
dispersed immediately after contact with saline solution (Fig-
ure 3, Table 2). The addition of ethanol increased the dispersion.
CPM gel remained completely intact followed in descending
order by Vycross, OBT, RHA, 3D Matrix, IPN-like, and nally NA-
SHA. The same results were observed in tests performed at the
FIGURE 3. Cohesivity test. Investigators placed 0.9 mL of colored
saline solution in a Petri dish and added 0.3 mL hyaluronic acid gel.
Once placed in the solution, the NASHA® gel disintegrated into
multiple very small particles, indicating it was non-cohesive. Only
CPM® was truly cohesive, remaining as a continuous long strand.
The other gels split into multiple strands, indicating that they were
partially cohesive.
TABLE 2.
Behavior of Hyaluronic Acid Gels Produced by Different
Crosslinking Technologies After Contact With Saline Solution
Crosslinking
Technology Cohesivity Test Observation
NASHA®
Disintegration once in contact with saline
solution. Microscopic particles, “pearls,” of gel
visible. Particles are even palpable when the pure
gel is massaged between thumb and forenger.
3D Matrix
Gel disintegrates into multiple strands or
“sausages” after several seconds. Addition of
ethanol increases the process.
IPN-like®Gel disintegrates like 3D Matrix®.
CPM®
Gel remains perfectly cohesive with or without
the addition of lidocaine. It remains as a single,
long strand “continuous sausage,” even after the
addition of ethanol.
Vycross®Gel disintegrates as for 3D Matrix®.
RHA®Gel disintegrates as for 3D Matrix®.
OBT®Gel disintegrates as for 3D Matrix®.
© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
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J D D
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P. Micheels, D. Sarazin, C. Tran, D. Salomon
large pools. These patterns are consistent between patients and
therefore predictable.8
The ability of CPM to distribute homogenously across the tar-
geted area and into the surrounding tissues is due to the fact
that it contains variable zones of crosslinking density, with ar-
eas of higher crosslinking density (harder) interspersed with
areas of lower crosslinking density (softer).12 This creates a gel
that retains its integrity on injection and has high resistance to
cohesivity, we observed the dispersion of the gels after mixing
with a classic colored saline solution. Some of the gels dis-
persed completely, others partially, and one remained totally
cohesive. Products with high cohesivity such as CPM remain as
long continuous strands when mixed. In contrast, the non-co-
hesive gels are dispersed. A further measure of cohesivity was
provided by the resistance to stretch test. The results supported
the ndings above, with the CPM gel demonstrating the great-
est resistance to stretching (3.5 cm-5 cm), while the remaining
gels could not be stretched for distances greater than 2 cm.
Although simple, these easily reproducible laboratory tests can
help us understand how the different HA gels integrate with
the collagen and elastin bers of the dermis. Biopsies of hu-
man skin after injection have shown that the different HA gels
have a predictable histologic behavior, which differs by their
type of crosslinking.8,11 CPM, the only monophasic polydensi-
ed gel, demonstrates homogenous staining and penetrates
all the dermis in a diffuse and evenly distributed manner. Bi-
phasic products such as NASHA appear as large pools of HA
distributed as clumps or beads of material in the lower portion
of the dermis, with the upper and mid reticular dermis being
free of material. Monophasic monodensied products such
as 3D Matrix show HA material throughout the dermis, but in
FIGURE 4. Resistance to stretch test results. The length of stretch was measured against a metric scale (visible in the background of the lower images).
TABLE 3.
Behavior of Hyaluronic Acid Gels Produced by Different
Crosslinking Technologies in Resistance to Stress Test
Crosslinking
Technology
Maximum Distance Gel can be Drawn (cms)
(Minimum of 3 Tests)
NASHA®≤ 1.0
3D Matrix ≤ 1.5
IPN-like®≤ 2.0
CPM®3.5–5.0
Vycross®≤ 1.0
RHA®≤ 0.5
OBT®≤ 1.5
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AUTHOR CORRESPONDENCE
Patrick Micheels MD
E-mail:................……..................................... patrickscab@vtxnet.ch
deformation, for example in areas of high facial movement. The
product’s low viscosity also means that it is easily injected, with
little pressure, through small diameter needles. As a result of its
very homogenous tissue distribution, the CPM gel can be inject-
ed over a range of tissue depths, including very supercially, for
the correction of ne to deep lines. In contrast, Vycross technolo-
gy creates a gel with a crosslinked mixture of high (>1 MDa) and
low molecular weight (short chain) HA with a higher proportion
of the latter. This provides the gel with a high G prime (gel hard-
ness) and medium cohesivity, making it suitable for volumizing
and subcutaneous or supraperiosteal injection.
Light microscopy conrmed the particulate nature of each
product and revealed HA particles of varying size and distri-
bution. CPM was the only gel to have no particles visible at
a microscopic level. Among particulate llers, the shape of
the microspheres has previously been shown to be a factor in
foreign-body reactions, with granulomatous reactions occur-
ring less frequently after implantation of microspheres with
smooth surfaces.13 Irregular and sharp-edged particles may
also induce more severe granulomatous reactions.
CONCLUSION
With the wide choice of HA gels available on the market, it is
not always easy to select the best ller for a specic purpose.
Despite beginning with the same starting material, HA llers
are produced with a range of different crosslinking technolo-
gies. With a few simple and easily reproducible tests, we have
shown how these can inuence a gel’s behavior and con-
sequently require an adaptation of injection technique and
probably depth of injection.10
There is no single HA gel for all indications, each treatment
indication requiring a targeted product. Knowledge of the rheo-
logical properties of a gel, combined with proper selection of
injection technique and patients individual anatomy, (eg, skin
thickness and restrictions regarding nerves and blood vessels),
will help physicians select the right product to achieve optimal
cosmetic outcomes.
ACKNOWLEDGMENTS
We would like to thank the Laboratory of Histopathology,
Viollier, Geneva, Switzerland, for its precious and gracious col-
laboration, and for the use of its facilities. We would also like to
thank the manufacturers of the products used for their answers
to our questions. The authors wish to acknowledge the con-
tribution of Jenny Grice for assistance with translation of the
French text and for helping to nalize this manuscript. Editorial
assistance was funded by Merz Pharmaceuticals GmbH.
DISCLOSURES
The authors have no nancial disclosure related to the present
study. Medical writing was funded by Merz Pharmaceuticals GmbH.
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