May 2016
`Copyright © 2016
`
`Volume 15 • Issue 5
`Journal of Drugs in Dermatology
`
`600
`ORIGINAL ARTICLES
`SPECIAL TOPIC
`Effect of Different 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
`
` ABSTRACT
`
`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 polydensified 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 confirmed the cohesivity findings, 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 influence a gel’s behavior, and can help physicians select the optimal product for a specific 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.
`
` INTRODUCTION
`
`Since their introduction in Europe in 1996, crosslinked hyal-
`
`uronic acid (HA) gels have progressively replaced bovine
`collagen as the preferred treatment for filling 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 modifica-
`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 final prod-
`ucts differ in terms of their HA concentration and method of
`crosslinking. Crosslinking methods may be either chemical or
`physical, but in the field of aesthetic medicine the crosslinking
`agent that is used to stabilize the majority of HA-based dermal
`fillers currently on the market is 1,4-butanediol diglycidyl ether
`(BDDE). The stability, biodegradability, and toxicity profile 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
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`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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`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`601
`
`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
`final 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 defined 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 final product.7 It is hypothesized
`that the slightly viscous matrix thus obtained is dried and then
`sieved or passed through cleaver filters of different diameters
`to produce gel particle sizes adapted to the clinical indications
`of the final 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
`efficient 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
`
`Biphasic
`
`Cohesivity/
`cohesion
`
`Monodensified
`
`Polydensified
`
`A monophasic gel consists of a single phase
`and is usually used to describe a gel looking
`non-particulate (cohesive).
`
`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.
`
`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).
`
`A gel is described as monodensified if it
`consists of a single homogeneous crosslinking
`grade/density zone inside the gel itself.
`
`A gel is described as polydensified if it consists
`of several crosslinking grades/density zones
`inside the gel itself.
`
`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 fillers are obtained by
`varying gel calibration, and firmer or softer fillers by varying
`crosslinking.
`
`5. Cohesive Polydensified Matrix (CPM®)
`Cohesive polydensified 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
`polydensified 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
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
`If you feel you have obtained this copy illegally, please contact JDD immediately at support@jddonline.com
`
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`

`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`602
`
`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.
`
`"Hyaluronic acid gels produced by one
`of 7 different crosslinking technologies
`were subjected to tests for cohesivity,
`resistance to stretch, and microscopic
`examination."
`
` 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 (filling 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.
`
`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 significant differences in
`structure (Figures 1 and 2).
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
`If you feel you have obtained this copy illegally, please contact JDD immediately at support@jddonline.com
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`

`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`603
`
`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).
`
`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 specific 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 fine
`grains, finer than RHA and OBT. With magnification, 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 fine grains, but not as fine as
`Vycross. On magnification, 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.
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
`If you feel you have obtained this copy illegally, please contact JDD immediately at support@jddonline.com
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`

`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`604
`
`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.
`
`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 finally NA-
`SHA. The same results were observed in tests performed at the
`
`TABLE 2.
`Behavior of Hyaluronic Acid Gels Produced by Different
`Crosslinking Technologies After Contact With Saline Solution
`
`Crosslinking
`Technology
`
`NASHA®
`
`3D Matrix
`
`Cohesivity Test Observation
`
`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 forefinger.
`
`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®
`
`OBT®
`
`Gel disintegrates as for 3D Matrix®.
`
`Gel disintegrates as for 3D Matrix®.
`
`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 filler 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 filler. Cohesivity of gels can be
`measured quantitatively by the amount of pressure required to
`compress them between 2 plates. In a qualitative measure of
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`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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`

`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`605
`
`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).
`
`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 findings 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 fibers 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-
`fied 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 monodensified products such
`as 3D Matrix show HA material throughout the dermis, but in
`
`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
`
`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®
`
`3D Matrix
`
`IPN-like®
`
`CPM®
`
`Vycross®
`
`RHA®
`
`OBT®
`
`≤ 1.0
`
`≤ 1.5
`
`≤ 2.0
`
`3.5–5.0
`
`≤ 1.0
`
`≤ 0.5
`
`≤ 1.5
`
`© 2016-Journal of Drugs in Dermatology. All Rights Reserved.
`This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
`No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
`If you feel you have obtained this copy illegally, please contact JDD immediately at support@jddonline.com
`
`To order reprints or e-prints of JDD articles please contact sales@jddonline.com
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`

`Journal of Drugs in Dermatology
`May 2016 • Volume 15 • Issue 5
`
`P. Micheels, D. Sarazin, C. Tran, D. Salomon
`
`606
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
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`11.
`
`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 superficially, for
`the correction of fine 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 confirmed 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 fillers, 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 filler for a specific purpose.
`Despite beginning with the same starting material, HA fillers
`are produced with a range of different crosslinking technolo-
`gies. With a few simple and easily reproducible tests, we have
`shown how these can influence 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 finalize this manuscript. Editorial
`assistance was funded by Merz Pharmaceuticals GmbH.
`
` DISCLOSURES
`The authors have no financial disclosure related to the present
`study. Medical writing was funded by Merz Pharmaceuticals GmbH.
`
`
`
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