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COSMETIC
Cohesivity of Hyaluronic Acid Fillers:
Development and Clinical Implications of a
Novel Assay, Pilot Validation with a Five-Point
Grading Scale, and Evaluation of Six U.S. Food
and Drug Administration–Approved Fillers
Hema Sundaram, M.D.
Rod J. Rohrich, M.D.
Steven Liew, M.D.
Gerhard Sattler, M.D.
Sergio Talarico, M.D.
Patrick Trévidic, M.D.
Samuel Gavard Molliard,
M.Sc.
Rockville, Md.; Dallas, Texas;
­ arlinghurst, New South Wales,
D
­Australia; Darmstadt, Germany; São
Paulo, Brazil; Paris, France; and
Geneva, Switzerland

Background: Biophysical characteristics of hyaluronic acid gel fillers reflect
individual manufacturing processes. They confer rheologic properties that provide scientific rationale with Evidence Level II clinical correlation for selection
of appropriate fillers for specific clinical applications. Cohesivity, a key property, maintains gel integrity, contributes to tissue support with natural contours,
and diminishes surface irregularities. In this publication, a new, standardized
visual assay for hyaluronic acid cohesivity is presented, applied, and discussed.
Methods: Colored hyaluronic acid gel specimens were automatically extruded
under standardized conditions into sterile water stirred at a constant rate.
Based on 90 digital images showing ratios of intact to dispersed gel during
assay of 10 Communauté Européenne–marked fillers, the five-point visual
Gavard-Sundaram Cohesivity Scale was developed. Six plastic surgeons and
dermatologists performed pilot validation of the scale, subsequently used to
evaluate six U.S. Food and Drug Administration–approved fillers.
Results: Validation of the Gavard-Sundaram Cohesivity Scale showed substantial repeatability and interrater consistency. Mean cohesivity scores from three
assays of each tested filler showed significant differences. Cohesivity was high
for Cohesive Polydensified Matrix (­Belotero Balance), medium-high for Hylacross (Juvéderm Ultra 2/Ultra XC and Ultra 3/Ultra Plus XC), low-medium
for Vycross (Juvéderm Voluma), and low for non–animal-stabilized hyaluronic
acid (Restylane and Perlane).
Conclusions: An evidence-based approach requires clinical corroboration of in
vitro data. This new, reproducible cohesivity assay may have value together with
elasticity (G') and viscosity measurements to understand and leverage distinct
tissue distribution patterns and clinical behaviors of different hyaluronic acid
products.  (Plast. Reconstr. Surg. 136: 678, 2015.)
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

T

here is growing interest in the biophysical
characteristics of cross-linked hyaluronic acid
gel fillers used for soft-tissue augmentation.

From Sundaram Dermatology, Cosmetic & Laser Surgery;
the Department of Plastic Surgery, University of Texas Southwestern Medical Center; Shape Clinic; Rosenpark Klinik;
Departamento de Dermatologia, Escola Paulista de Medicina, Universidad de São Paulo; Plastic, Reconstructive, and
Cosmetic Surgery; and Research Department, Anteis, S.A., a
wholly owned subsidiary of Merz Pharmaceuticals, GmbH.
Received for publication November 18, 2014; accepted April
7, 2015.
Copyright © 2015 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000001638

678

These characteristics reflect unique manufacturing processes and resultant physicochemical structures. They confer specific flow-related (rheologic)
properties—including elasticity, measured as elastic
modulus (G′); and viscosity, measured as complex
viscosity (η*) or as viscous modulus (G″). Rheologic
properties have been used as a scientific rationale
for selection of appropriate filler products for specific clinical applications (rheologic tailoring).1–5
From an evidence-based perspective, it is important
for in vitro data to be clinically correlated. Two controlled, split-face studies of Evidence Level II fulfill
the rheologic prediction that optimal nasolabial fold
correction requires a significantly smaller volume
of a higher than a lower G′ filler.6,7 Histopathologic

www.PRSJournal.com

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Volume 136, Number 4 • Hyaluronic Acid Filler Cohesivity Assay
and ultrasonographic studies also connect in vitro
data with clinical behavior, showing a correlation
between viscosity of a filler and its extent and pattern of tissue integration after in vivo intradermal
implantation.8–10 Evidence gaps still exist. The aim
of ongoing research is to bridge them.
Cohesivity has been identified recently as a key
characteristic of gel implants. It is defined as the
capacity of a material not to dissociate, because of
the affinity of its molecules for each other. Cohesivity is considered necessary for the solid and
fluid phases of a gel to remain intact, and thus
for gel integrity. Clinical studies of silicone gel
breast implants demonstrate that higher cohesivity results in better retention of shape and less
likelihood of folding or collapse.11,12 This confers
the potential to provide a natural breast contour,
and minimizes the risk of postoperative rippling.
Although the structural and dynamic requirements
Disclosure: Dr. Sundaram serves as a clinical investigator and/or consultant for Allergan, CosmoFrance, Croma, Evolus/Strathspey Crown, Galderma,
­HaoHai, Kythera, Merz, and Teoxane. Dr. Rohrich
has a book royalties relationship with Quality Medical Publishing and an instrument royalties relationship with Micrins. He serves as a consultant for the
Allergan Global Consensus. Dr. Liew is an advisory
board member for Allergan and Galderma Australia.
Dr. Sattler is a consultant and a member of the advisory boards of Allergan, Galderma, and Merz. He
has also participated in scientific trials with Allergan,
Galderma, and Merz as a clinical investigator; he
has received compensation for conducting the studies
in his research center. Dr. Talarico has no financial
information to disclose. Dr. Trévidic is an advisory
board member for Merz France. Mr. Gavard Molliard
is employed by Anteis S.A, Geneva, Switzerland, a
division of Merz Pharmaceuticals. Anteis S.A., now
a wholly owned subsidiary of Merz Pharma, provided
the logistical and financial support for execution of
this study. Unless stated otherwise, the soft tissue fillers discussed in this article were purchased from commercial sources.

Supplemental digital content is available for
this article. Direct URL citations appear in the
text; simply type the URL address into any Web
browser to access this content. Clickable links
to the material are provided in the HTML text
of this article on the Journal’s Web site (www.
PRSJournal.com).

of hyaluronic acid gel fillers differ in a number of
respects from those of silicone gel breast implants,
there is a common need to provide tissue support
or lift, with natural-appearing tissue contours and
avoidance of surface irregularities.
A previous publication described the assessment of hyaluronic acid cohesivity by linear
compression and dye diffusion testing, and postulated that cohesivity and elastic modulus (G′)
both contribute to lifting capacity of hyaluronic
acid fillers.13 However, there has been debate in
the literature as to what this testing actually measures, and its clinical significance.14 It is agreed by
researchers on both sides of the debate that cohesivity is difficult to measure.13,14 The methodology of the linear compression test suggests that it
primarily evaluates the capacity of the hyaluronic
acid gel to apply force, as would be required for
filling of wrinkles or folds. Although this is a clinically useful property, its relationship to cohesivity
is indirect and partial—a conclusion with which
the research team that originally devised the linear compression test has concurred.15 The testing
frequency of 5 Hz, commonly used in the past,
is now considered supraphysiologic, because the
forces to which a filler is exposed in vivo from
gravity and muscular movements correspond to
oscillation frequencies below 1 Hz.2,5 The dye diffusion test, although interesting, may be considered a qualitative indicator of gel capillarity and
of the centrifugal force applied to the gel during
testing, rather than a determination of gel cohesivity. The purpose of this study was to develop a
new, standardized protocol for measurement of
hyaluronic acid cohesivity; to validate it to determine its reliability, sensitivity, and repeatability;
and to use it for evaluation of six hyaluronic acid
fillers that are approved for aesthetic indications
by the U.S. Food and Drug Administration.

MATERIALS AND METHODS
Protocol for the Cohesivity Assay
The assay was performed under standardized
testing conditions, including temperature of 24 ±
1°C and humidity of 41 ± 3 percent. First, 0.1 mg of
toluidine blue (Standard Fluka for microscopy, reference no. 89640-SG; Sigma-Aldrich, St. Louis, Mo.)
was added as a coloring agent to 1 g of each hyaluronic acid gel specimen to be assayed. After mixing
of the specimens and toluidine blue for 3 minutes,
each colored gel specimen was drawn into a 1-ml
glass syringe (BD Hypak SCF, 1-ml-long, RF-PRTC;
Becton Dickinson Pharmaceutical Systems, Franklin

679
Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Plastic and Reconstructive Surgery • October 2015
Lakes, N.J.) and then extruded with an automated
device at a constant rate of 400  mm/minute into
a 1000-ml glass beaker containing 700 ml of sterile
water for injection and a 2.5-cm magnetic bar stirrer, from a fixed height of 2  cm above the water
surface. The gel and water mixture was stirred at a
constant rotational frequency of 160 rpm. On rare
occasions when the gel became entrapped by the
magnetic stirrer, the assay was aborted and restarted.
Digital videos and standardized digital images were
obtained at specific time points after extrusion of
each specimen into the beaker and commencement
of magnetic stirring. Cohesivity of each specimen
was assessed visually from these images as the ratio
of intact to dispersed gel at each time point.
Development of a Standardized Photographic
Reference Scale
The cohesivity assay was performed on 10 types
of Communauté Européenne–marked hyaluronic
acid gel specimen with different manufacturing

processes. Details of the hyaluronic acid specimens
are listed in Table 1. Based on review of 90 photographic images obtained from these assays (three
assays, three time points, and 10 specimens), the
five principal patterns of gel behavior listed in
Table  2 were identified. A five-point visual reference scale, the Gavard-Sundaram Cohesivity Scale,
was developed to illustrate these patterns (Fig. 1).
Validation of the Cohesivity Assay
A panel of six plastic surgeons and dermatologists that had not been trained by previous exposure
to any assay images served as raters to determine reliability, sensitivity, and repeatability of the cohesivity
assay (Table 3). Each rater was provided with a onepage document displaying the five-point GavardSundaram Cohesivity Scale shown in Figure 1. Using
this scale as a reference, raters were asked to score test
images obtained from two independent cohesivity
assays performed on each of 10 hyaluronic acid specimens. Test images were obtained during each of the

Table 1.  Ten Crosslinked Hyaluronic Acid Filler Specimens Used to Develop the Cohesivity Assay Reference Scale
Name of HA
Specimen

Manufacturing
Technology

Belotero Balance

CPM HA

Belotero Intense CPM HA
Belotero
Volume
Juvéderm
Ultra 2

CPM HA
Hylacross

Manufacturer

Total HA
U.S. FDA
Concentration
Approval Status
(mg/ml)

Anteis/Merz (Geneva, Approved
Switzerland)

22.5

Anteis/Merz (Geneva, Not approved
Switzerland)
Anteis/Merz (Geneva, Not approved
Switzerland)
Allergan (Pringy,
Approved
France)

25.5
26
24

Juvéderm
Ultra 3

Hylacross

Allergan (Pringy,
France)

Approved

24

Juvéderm
Volbella
Juvéderm
Volift

Vycross

Allergan (Pringy,
France)
Allergan (Pringy,
France)

Not approved

15

Not approved

17.5

Juvéderm
Voluma
Perlane

Restylane

Vycross

Vycross
NASHA

Allergan (Pringy,
France)
Galderma Q-Med
(Uppsala, Sweden)

Approved
Approved

20
20

NASHA

Galderma Q-Med
(Uppsala, Sweden)

Approved

20

U.S. FDA-Approved
Indication
Indicated for correction of moderate to severe facial wrinkles and
folds, such as nasolabial folds
N/A
N/A
Approved as Juvéderm Ultra XC
for correction of moderate to
severe facial wrinkles and folds,
such as nasolabial folds
Approved as Juvéderm Ultra Plus
XC for correction of moderate
to severe facial wrinkles and
folds, such as nasolabial folds
N/A
N/A
Indicated for cheek augmentation
to correct age-related volume
deficit in the midface
Name changed to Restylane Lyft
(with lidocaine), with indications
for correction of moderate to
severe facial folds and wrinkles,
such as nasolabial folds; subcutaneous to supraperiosteal implantation for cheek augmentation;
and correction of age-related
midface contour deficiencies
Indicated for correction of
­moderate to severe facial
wrinkles and folds, such as
nasolabial folds

HA, hyaluronic acid; FDA, Food and Drug Administration; CPM, Cohesive Polydensified Matrix; NASHA, non–animal-stabilized hyaluronic
acid; N/A, not applicable.

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Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Volume 136, Number 4 • Hyaluronic Acid Filler Cohesivity Assay
Table 2.  Principal Patterns of Hyaluronic Acid Filler
Gel Behavior Associated with Each Score on the
Gavard-Sundaram Cohesivity Scale

performed by Florilène Bouisset, Principal Biostatistician, Cytel, Inc., Geneva, Switzerland, using
SAS software (SAS Institute, Inc., Cary, N.C.).

Cohesivity Score

Repeatability
Repeatability was calculated as the agreement
for each rater between scores for the two test images
obtained at the same time point during separate,
independent assays of the same specimen (test
image 1 and test image 2). Calculation of repeatability was performed in this way for test images 1
and 2 obtained at each of the three time points during the assay, for each of the 10 specimens (three
time points, 10 specimens, and six investigators).
The kappa coefficient with Cohen-Fleiss weighting
was calculated for 95 percent confidence intervals,
to compare the score on the five-point Gavard-Sundaram Cohesivity Scale for test image 1 to the score
for test image 2.16 A kappa coefficient of 1 represents
perfect agreement between the scores for test image
1 and test image 2, whereas 0 suggests that any
apparent agreement could have occurred by chance
only. The statistical significance of the weighted
kappa coefficient was assessed with a 95 percent
significance level.17 To assess intertest reliability, the

1
2
3
4
5

Description
Fully dispersed
Mostly dispersed
Partially dispersed, partially cohesive
Mostly cohesive
Fully cohesive

two assays for each of the 10 specimens at time points
of 15, 70, and 95 seconds. Therefore, a total of 60 test
images (two assays, three time points, and 10 specimens) were provided for scoring. Each test image
was labeled with randomized letters and a number, so
that raters were blinded as to the types and names of
the assayed specimens and the time points at which
the images were taken. Three test images were displayed on each page of a 20-page scoring card. Figure 2 shows an example of a test scoring card.
Statistical Analysis
Independent statistical analysis of the cohesivity scores provided by the physician panel was

Fig. 1. Photographic images illustrate different hyaluronic acid filler gel behaviors. They range from fully dispersed
(noncohesive) with only powder-like gel fragments visible, to fully cohesive with only intact gel strands visible.

681
Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Plastic and Reconstructive Surgery • October 2015
Table 3.  Panel of Raters for Cohesivity Scale Validation
Name

Specialty

Hema Sundaram, M.D.
Rod J. Rohrich, M.D.
Steven Liew, M.D.
Gerhard Sattler, M.D.
Sergio Talarico, M.D.
Patrick Trevidic, M.D.

Dermatologist
Plastic surgeon
Plastic surgeon
Dermatologist
Dermatologist
Plastic surgeon

Country
United States
United States
Australia
Germany
Brazil
France

percentage of agreement between the two independent assays was determined by calculating the difference between the scores for test image 1 and test
image 2 for each specimen, time point, and rater.
Interrater Consistency
Interrater consistency was calculated to determine the agreement between raters for each test

Fig. 2. Example of a test scoring card used for validation of the cohesivity assay.

682
Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Volume 136, Number 4 • Hyaluronic Acid Filler Cohesivity Assay
image at each of the three time points (two test
images per time point, three time points, 10 specimens, and six investigators). The kappa coefficient
with Cohen-Fleiss weighting was computed for
each possible permutation of 2 × 2 pairwise raters.
The coefficients were then combined following
the Shrout and Fleiss methodology, to provide a
value for general interrater consistency when the
multiple raters scored the test images.18,19 The Landis and Koch categorization20 was used to indicate
the degree of agreement between raters, based
on the ranges of the kappa coefficients. Table  4
shows the relationship between the kappa coefficient value and degree of agreement, according
to this categorization. Interrater consistency for
each of the scores on the Gavard-Sundaram Cohesivity scale was also calculated as a weighted kappa
coefficient.
Evaluation of Six Hyaluronic Acid Fillers with the
Gavard-Sundaram Cohesivity Scale
After validation, the Gavard-Sundaram Cohesivity Scale was used to evaluate six U.S. Food
and Drug Administration–approved hyaluronic
acid soft-tissue fillers that are also Communauté
Européenne marked: one Cohesive Polydensified
Matrix hyaluronic acid product (Belotero Balance), two non–animal-stabilized hyaluronic acid
products (Restylane and Perlane), two Hylacross
hyaluronic acid products (Juvéderm Ultra 2 and
Ultra 3, the European equivalents of the U.S. products, Juvéderm Ultra XC and Ultra Plus XC), and
one Vycross hyaluronic acid product (Juvéderm
Voluma XC). Assay of each product and scoring
of standardized digital images at 70 seconds were
performed three times. After confirmation that
the results were consistent and reproducible, the
arithmetic mean of the cohesivity scores for each
product was calculated.

RESULTS
The results obtained on validation testing
of the Gavard-Sundaram Cohesivity Scale by the
physician rater panel are shown in Table  4. On
statistical analysis, repeatability of the five-point
Gavard-Sundaram Cohesivity Scale using the
weighted kappa coefficient was 0.94 (95 percent
CI, 0.92 to 0.96). Interrater consistency in scoring on the Gavard-Sundaram Cohesivity Scale,
based on the overall weighted kappa coefficient,
was 0.63 (95 percent CI, 0.59 to 0.66). Based on
the proposed categorization by Landis and Koch,
this consistency is considered substantial. Analysis
of each of the five individual scores on the scale
showed substantial consistency for scores of 1
(fully dispersed), 3 (partially dispersed, partially
cohesive), 4 (mostly cohesive), and 5 (fully cohesive), with kappa coefficients of 0.72, 0.66, 0.61,
and 0.73, respectively. There was fair consistency
for a score of 2 (mostly dispersed), with a kappa
coefficient of 0.27.
Table  5 shows the arithmetic means of
the scores on the validated Gavard-Sundaram
Cohesivity Scale for six U.S. Food and Drug
Administration–approved and Communauté
Européenne–marked hyaluronic acid fillers.
There were significant differences between the
cohesivity values for the tested products. Cohesivity values ranged from 1 to 5, with nonanimal stabilized hyaluronic acid (Restylane and Perlane)
having the lowest cohesivity, Vycross hyaluronic
acid (Juvéderm Voluma) having low to medium
cohesivity, Hylacross hyaluronic acid (Juvéderm
Ultra 2 and Ultra 3/Juvéderm Ultra XC and Ultra
Plus XC) having medium to high cohesivity, and
Cohesive Polydensified Matrix hyaluronic acid
(Belotero Balance) having high cohesivity. [See
Video, Supplemental Digital Content 1, which
demonstrates the Gavard-Sundaram Cohesivity
Assay for non–animal stabilized hyaluronic acid
(Restylane), http://links.lww.com/PRS/B406. See
Video, Supplemental Digital Content  2, which
demonstrates the Gavard-Sundaram Cohesivity

Table 4.  Interrater Consistency and Repeatability of the Gavard-Sundaram Cohesivity Scale, Determined by
Weighted Kappa Coefficients for Each Cohesivity Score and Overall Weighted Kappa Coefficient with 95 Percent
Confidence Intervals, and by Kendall Coefficient of Concordance
Cohesivity Score

Kappa

Standard Error

95% CI

p

1
2
3
4
5
Overall weighted kappa
Kendall coefficient of concordance

0.72126
0.27885
0.65666
0.61325
0.73034
0.62798
0.94752

0.033333
0.033333
0.033333
0.033333
0.033333
0.017488

0.65593–0.7866
0.21351–0.34418
0.59133–0.722
0.54791–0.67858
0.665–0.79567
0.5937–0.66225

<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

683
Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Plastic and Reconstructive Surgery • October 2015
Table 5.  Arithmetic Means of Raters' Scores on the
Validated Gavard-Sundaram Cohesivity Scale for Six
U.S. Food and Drug Administration–Approved and
Communauté Européenne–Marked Hyaluronic Acid
Fillers*
GS Cohesivity Score (1–5)
HA Filler Product
Belotero Balance
Juvéderm Ultra XC
Juvéderm Ultra Plus XC
Juvéderm Voluma
Perlane
Restylane

15 Sec

70 Sec

95 Sec

5.0
4.9
4.8
2.4
1.7
1.3

5.0
4.1
4.2
1.3
1.3
1.0

5.0
4.1
4.1
1.3
1.3
1.0

GS, Gavard-Sundaram; HA, hyaluronic acid.
*Perlane is now U.S. Food and Drug Administration–approved as
Restylane Lyft (with lidocaine).

Assay for non–animal-stabilized hyaluronic acid
(Perlane), http://links.lww.com/PRS/B407. See
Video, Supplemental Digital Content 3, which
demonstrates the Gavard-Sundaram Cohesivity
Assay for Hylacross hyaluronic acid (Juvéderm
Ultra 2/Juvéderm Ultra XC), http://links.lww.

Videos. Supplemental Digital Content 1 demonstrates the
Gavard-Sundaram Cohesivity Assay for non–animal stabilized
hyaluronic acid (Restylane), http://links.lww.com/PRS/B406.
Supplemental Digital Content 2 demonstrates the Gavard-Sundaram Cohesivity Assay for non–animal-stabilized hyaluronic
acid (Perlane), http://links.lww.com/PRS/B407. Supplemental
Digital Content 3 demonstrates the Gavard-Sundaram Cohesivity Assay for Hylacross hyaluronic acid (Juvéderm Ultra 2/
Juvéderm Ultra XC), http://links.lww.com/PRS/B408. Supplemental Digital Content 4 demonstrates the Gavard-Sundaram
Cohesivity Assay for Hylacross hyaluronic acid (Juvéderm Ultra
3/Juvéderm Ultra Plus XC), http://links.lww.com/PRS/B409.
Supplemental Digital Content 5 demonstrates the Gavard-Sundaram Cohesivity Assay for Vycross hyaluronic acid (Juvéderm
Voluma), http://links.lww.com/PRS/B410. Supplemental Digital
Content 6 demonstrates the Gavard-Sundaram Cohesivity Assay
for Cohesive Polydensified Matrix hyaluronic acid (Belotero Balance), http://links.lww.com/PRS/B411.

com/PRS/B408. See Video, Supplemental Digital
Content 4, which demonstrates the Gavard-Sundaram Cohesivity Assay for Hylacross hyaluronic
acid (Juvéderm Ultra 3/Juvéderm Ultra Plus
XC), http://links.lww.com/PRS/B409. See Video,
­Supplemental Digital Content 5, which demonstrates the Gavard-Sundaram Cohesivity Assay
for Vycross hyaluronic acid (Juvéderm Voluma),
http://links.lww.com/PRS/B410. See Video, Supplemental Digital Content 6, which demonstrates the
Gavard-Sundaram Cohesivity Assay for Cohesive
Polydensified Matrix hyaluronic acid (Belotero
Balance), http://links.lww.com/PRS/B411.]

DISCUSSION
This study presents a new, reproducible
method of measuring cohesivity, a key biophysical characteristic for hyaluronic acid fillers, based
on a standardized, five-point reference scale. Pilot
validation of the scale with a physician panel of six
physicians showed good repeatability. Despite the
panel having had no previous training by means
of exposure to images produced during the assay,
there was substantial interrater consistency for
all images except the one depicting a mostly dispersed product. Given the positive results from
this pilot validation, and that repeatability and
consistency of clinical validations are optimized
by prior training of the raters,21,22 a trained validation of the Gavard-Sundaram Cohesivity Scale
has been performed subsequently with a separate
physician panel. This demonstrates improvement
in repeatability and interrater consistency, in particular, for the mostly dispersed scoring. These
data are summarized in a subsequent publication,
which focuses on the clinical relevance of hyaluronic acid cohesivity in the context of previously
studied flow-related characteristics such as elasticity, viscosity, and tan delta.
A previous, peer-reviewed publication raised
awareness of cohesivity and made a commendable
attempt to assess it, using methodology including
linear compression testing.13 The testing method
presented here overcomes previous methodologic
challenges, and provides a reproducible assay for
direct measurement of hyaluronic acid filler cohesivity. The indirect and partial assessment of cohesivity by linear compression testing, developed by
the manufacturers of Hylacross and Vycross hyaluronic acid, yields results for these two product
types that are consistent with our new cohesivity
assay.23 This concordance underscores the growing appreciation that measurement of cohesivity
may be of value in understanding and leveraging

684
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Volume 136, Number 4 • Hyaluronic Acid Filler Cohesivity Assay
the individual tissue distribution patterns and
clinical behaviors of different hyaluronic acid
products.
The six U.S. Food and Drug Administration–
approved hyaluronic acid fillers that were evaluated are efficacious, safe, and well-tolerated. The
authors find them all of value in their clinical
practices. The aim of parsing their biophysical
characteristics is not to rank them, but to provide
a scientific rationale for the intuitive selection of
different products for specific clinical objectives.
In the context of clinical relevance, it is notable
that the patterns of tissue distribution after in vivo
intradermal filler implantation8–10 are predicted by
product viscosity together with cohesivity as measured by the assay presented in this publication.
Restylane, with high viscosity and low cohesivity,
disperses as microboluses in the dermis. Belotero
Balance, with low viscosity and high cohesivity,
distributes homogeneously within the dermis.
Juvéderm Ultra, with intermediate viscosity and
cohesivity, distributes with an intermediate pattern.
Selection of products and techniques for
injecting them based on their flow characteristics
is defined as rheologic tailoring. Groundbreaking
clinical, cadaveric, and computed tomographic
studies of facial fat compartments and their underlying bony anatomy24–34 have clarified that the primary objective of volume replacement is reinflation
of age-deflated soft tissues. A filler’s G′, cohesivity,
and water-binding capacity can all contribute to this
restoration of three-dimensional tissue support. It
can be visualized as a composite of layered tissue
expansion, with vertical and horizontal vectors; and
tissue projection, with more vertical, bolus-type vectoring predominantly from the deep tissues.
Application of this concept and the in vivo
tissue implantation data to the tested fillers links
their distinct rheologic balances to their clinical
characteristics. G′ is the primary determinant of
tissue projection, because it confers firmness and
resistance to muscular and gravitational forces.2,35
When Restylane and Perlane are implanted supraperiosteally and subcutaneously, their high G′ and
low cohesivity provide more tissue projection than
expansion. Cohesivity maintains affinity between
the gel molecules, and logically contributes more
to tissue expansion than to projection. When
Belotero Balance is implanted intradermally and
in the superficial subcutis, its low G′ and viscosity5 and high cohesivity provide tissue expansion
with a predominantly horizontal vector. Juvéderm
Voluma, Ultra Plus, and Ultra, with intermediate
G′ and cohesivity, provide an intermediate balance of tissue projection and tissue expansion.

CONCLUSIONS
When integrated with general patient considerations, specific ones pertaining to the target tissues, and the direct influence of injection depth
and implantation patterns, rheologic tailoring can
facilitate the achievement of clinical objectives.
By guiding the safe and appropriate use of fillers,
rheologic tailoring can help to optimize aesthetic
outcomes and potentially minimize complications. The development of reproducible assays,
such as the one described in this article for cohesivity, refines this process by enabling injectors to
appreciate variations in design engineering within
and between filler product families. This will be
increasingly important as new U.S. Food and
Drug Administration approvals increase the availability of fillers, and American practitioners transition to the use of full product families. Complete
hyaluronic acid filler families, available in Europe
and elsewhere, include products for deep volumization, midlevel implantation, and superficial
placement; and sometimes one or two additional
products for specific applications such as lip or
tear trough injection. Partial product families
are currently available in the United States; for
instance, the deep volumizer, Juvéderm Voluma,
without its midlevel and superficial partners (Volift
and Volbella); and the superficial/midlevel product, Belotero Balance, without its accompanying
deep volumizer, midlevel and superficial partners
(Belotero Volume, Intense and Soft respectively).
The Restylane/Emervel and Teosyal families also
have several products that are not available yet in
the United States. Each product within a family is
engineered differently and intended for different
clinical purposes. The concept that quantitative
and qualitative balances of fundamental scientific
properties influence filler behavior, and thus clinical outcomes, is discussed further in a subsequent
publication—with consideration of whether it can
be applied to other important characteristics, such
as malleability, palpability after implantation, and
extrusion force during injection.
Hema Sundaram, M.D.
Dermatology, Cosmetic & Laser Surgery
11119 Rockville Pike, Suite 205
Rockville, Md. 20852
hemasundaram@gmail.com

acknowLEDGMENT

The authors express their deep appreciation to David
J. Howell, Ph.D., a medical communications specialist
in San Francisco, California, for assistance with formatting of the manuscript and figures.

685
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Plastic and Reconstructive Surgery • October 2015
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