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36
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
Water drops maintain their round shape on a
at surface, but they spread sideways on an
inclined surface like a tree leaf, becoming at
with their round shape disrupted. This is because
the adhesive force between water and leaf is
stronger than the cohesion, causing water to
spread sideways without owing down
(Fig.2.34).
In case of mercury, however, stronger cohesion among the molecules than adhesive force
with other materials causes it to maintain its
round spherical form on a slanted surface while
sliding down. This phenomenon is attributed to
greater cohesion than adhesive force (Fig.2.35)
Some HA ller manufacturers explain how
their HA llers will not slide down a wall and
stick to it to promote the great cohesion of their
products, but the more accurate expression is that
llers stick to a wall thanks to their great adhesive force rather than cohesion.
In general, viscous uids form a spherical
form without getting spread thanks to cohesion
Fig. 2.34 Water: Adhesive force > Cohesive force
Fig. 2.35 Mercury: Cohesive force > Adhesive force
among their molecules and stick to other matters
thanks to adhesive force. Viscoelastic llers also
show these properties as they have the rheological properties of a viscous uid. There is cohesion among the particles of a ller through the
hydrogen bond of water molecules absorbed
through hydration in the manufacturing process.
Adhesive force that makes ller matters stick to
other matters is due to bond based on electronicionic differences between different matters rather
than hydrogen bonds among particles.
Of biphasic and monophasic HA llers manufactured in different methods, the latter shows the
properties of a viscous uid more prominently
and has greater cohesion as the nature of a viscous
uid than the former, which is close to the properties of an elastic material. Cohesion is natural
electric attraction between molecules and offers a
different concept of force from the articial crosslinking of HA molecules in ller particles. It is
basically the property of a viscous uid, and
monophasic llers have naturally stronger cohesion among their particles than biphasic llers as
they show viscosity more prominently based on
the bond structure of molecules. Of HA llers
comprised of high- molecular compounds with
basic viscosity, monophasic llers have higher
structural viscosity and form a lump easily with
their particles. Unlike biphasic llers, their particles stick together instead of spreading even after
being diluted in water (Fig.2.36).
Cohesion is not an indicator that is applied to
all viscoelastic materials to gure out their properties like the four indicators mentioned earlier.
Some llers should be injected into the human
body, unlike other viscoelastic materials. These
lers can be changed in their shapes by external
factors after an injection, which raises the need to
examine cohesion between their particles as it
can have impacts on the restoration of ller
shapes after changes. Cohesion is connected to
the degree of restoration of a shape change in
basic daily life after a ller injection. It is regarded
as an important indicator to tell the rheological
properties of llers in recent years when the most
proper ller is chosen according to its part and
goal of a procedure and the skin and soft tissue
conditions of the patients.
Biphasic HA filler Monophasic HA filler
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
Fig. 2.36 Comparison
of degree of aggregation
of particles and distance
between particles of
biphasic & monophasic
HA llers
37
Biphasic llers with a weak cohesion have a
strong nature as an elastic material. They have
good elasticity to withstand the external force of
pushing down. When a ller is deformed by force
above the elastic limit that it can endure to the
extent that it cannot return to its original shape, it
has poor abilities to restore its original shape to
some degree due to weak cohesion based on electric attraction among the molecules of its particles even after the removal of the force.
Monophasic llers with great cohesion, however,
have low elastic modulus as elastic material;
accordingly, they are deformed easily and considerably by external force. When the external
force is removed after a deformation above the
elastic limit, they restore back to their original
shapes to some degree based on the particles
holding together through the cohesion of a viscous uid.
Cohesion is not based on the solid bond of
molecules via cross-linking like the HA molecules of particles, which means that it can be easily broken by an external stimulus, unlike
elasticity. Greater cohesion does not necessarily
mean greater abilities of llers to maintain their
shapes against external force. Radix nasi and the
chin are not good candidates for a ller injection
as the injected ller should continue to withstand
a big external force from the strong ligament tissues and the hard skin that keeps pushing it down.
A good candidate is the front of the cheek where
there is no need for strong supportive force. Here,
a ller would form a proper shape; react softly to
the small force of daily life, such as the mouth
moving, and a touch on the skin; change its
shape; and restore back to its original shape once
the force is gone.
The researcher manipulated real products
comprised of gel mass and particles before the
nal product stage to compare results and determine the cohesion differences between biphasic
and monophasic HA llers due to their different
manufacturing processes:
When external force is applied to push down
and damage a ller cube form in a gel mass state,
the biphasic gel mass has high elasticity and thus
requires a greater force to break the form. The
monophasic gel mass is easily pushed down by a
small force, but it has a good deformation rate,
which means that it will eventually break after it
is pushed down in a wider area. The square gel
mass gets cracks as the gel mass cube breaks in
its form, which means that the material’s structure is broken by force above its elastic limit
regardless of its elastic modulus. In this case, a
complete elastic material will not restore back to
its original structure even after the external force
is removed. Since HA llers are viscoelastic,
their molecules will gather again and restore their
broken structure based on their cohesion as a viscous uid. HA molecules of monophasic gel
mass with high cohesion bond strongly to each
other, and the ller molecules gather and ll up
the broken cracks more easily. Once these cracks
are lled up, it is difcult to nd any traces left by
broken ller cubes from an external force with
38
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
the naked eye, which demonstrates the strong
bond of molecules (Fig.2.37).
Biphasic HA llers, on the other hand, basically have the properties of a viscous uid. Their
HA molecules gather at both ends of a broken
crack to some extent, but it is not as clear as the
case of monophasic gel mass. As the broken
cracks are not lled up completely, broken traces
are left behind (Fig.2.38).
These cases demonstrate cohesion differences
in HA ller gel mass between biphasic and
monophasic HA ller products. In a test, the
researcher pushed 1ml each of biphasic and
monophasic HA llers from Galderma company
out of a syringe, gathered them, pushed them
with a stick for deformation, and observed
changes to each of the ller products after the
push force was removed. When force above the
elastic limit was applied, the structure was broken in the HA gel mass, which was in the cube
state. The ller products made up of particles
were pushed down at. When the push force was
removed, the gel mass in the hard square form
had the HA molecules gather and ll up the broken cracks. The ller products had the HA particles gather and restored their spherical round
shapes like water and mercury. The monophasic
HA llers with high cohesion had deformation
even when using a small force as they were
pushed with a stick. Once the push force was
Fig. 2.37 Test for the ability of structural restoration by cohesion in monophasic HA gel mass
Fig. 2.38 Test for the ability of structural restoration by cohesion in biphasic HA gel mass
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
39
removed, the pressed part was restored to the
original shape to some extent thanks to cohesion
(Fig.2.39).
Biphasic HA llers with strong physical crosslinking among their HA molecules have good
elasticity to withstand external force and weak
cohesion among their particles as a viscous uid.
After force above their elastic limit was applied
to cause deformation and then removed, they
barely restored back to their original forms
through cohesion among their particles and
stayed in their deformed forms (Fig.2.40).
Cohesion test results hold clinical signicance
as they offer references to set rough criteria to
choose a ller. Fillers with high cohesion are
good at forming a shape in parts where external
force is not too strong. Even after they have a
deformation above their elastic limit, they display a decent ability to be restored back to their
original shapes to some extent. Fillers with high
cohesion are not always a good choice. Volume
created by cohesion is not a solid bond based on
a strong bridge. In parts where the skin and tissues are thick to receive support from a ller and
have a hard, strong external push force constantly
on the ller, it cannot help but stay in the pressed
and deformed form. As mentioned earlier, radix
nasi, chin, and parts with a deep groove require a
ller with high elastic modulus in order to withstand external push force and maintain their
forms. Fillers with low elastic modulus and high
cohesion spread in these parts instead of keeping
their satisfying forms. When llers with very low
elastic modulus and high cohesion are injected
Fig. 2.39 Test for the ability of structural restoration by cohesion in monophasic HA gel product
Fig. 2.40 Test for the ability of structural restoration by cohesion in biphasic HA gel product
40
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
for a natural form in parts where the external
force is not too strong and soft support over a
wide area is covered, the skin of the parts will
have the texture of swelling with water like a
water balloon instead of a rm feel that is favored.
It is also important to remember that viscoelastic materials change their rheological properties according to their deformation history as
explained in the preceding chapter. After a ller
of proper viscoelasticity is injected under soft
skin with proper thickness and tapped lightly, it
will show its properties as an elastic material
more prominently according to its deformation
history, so it will feel rm without being pressed
easily. If the same part is pushed down slowly,
the ller’s deformation history will change,
which causes the ller to show its properties
more prominently as a viscous uid. Once the
push force is removed after a slightly longer
duration, it will revive again more than the tapping case. A ller with only high cohesion has
lower elasticity; thus, it will not feel rm when
being tapped lightly. Its texture will feel like
water-soaked leather. When it is pressed softly, it
will suddenly withdraw. When the pushing nger
is removed slowly, it will have volume again like
water lling up. The skin will not feel a rm
swell up with a splash like it has absorbed water.
Table 2.1 shows elements that could affect the
cohesion of HA llers based on these clinical
phenomena (Table2.1).
Cohesion is created by HA molecules. Higher
HA concentrations and high molecules with
heavier molecular weights will lead to higher
cohesion of molecules bonding each other. Due
to differences in the manufacturing processes,
Table 2.1 Factors related to the cohesion of HA llers
1. Concentration of hyaluronic acid
2. Molecular weight of hyaluronic acid
3. Type & degree of cross-linking of HA ller
4. Degree & consistency of particle size of HA ller
5. Enough hydration during stirring stage for stable
hydrogen bond
6. Fluidity of HA ller (Phase angle value)
7. Whether or not free HA is added
monophasic llers with high viscosity have
greater cohesion than biphasic llers. In the process of blending HA powder in water to make a
product, more complete hydration will provide
enough amounts of hydrogen molecules and
enable stable hydrogen bonds among particles.
The size and uniformity of ller particles can also
have impacts on their cohesion. There will be a
higher cohesion when uniform particles of proper
size gather with a constant interval as particles
whose sizes widely vary gather. There will be
also differences in cohesion according to phase
angle (tangent δ), which shows the degree of uidity as the degree of viscosity against elasticity.
Here it is important to remember that higher
phase angles do not necessarily mean higher
cohesion. Under conditions of similar elastic
modulus, higher phase angles mean better viscosity and better cohesion to restore the original
shape after deformation. A phase angle of 0.25 or
higher, however, means that the properties of a
viscous uid are too strong and lower the elastic
modulus of parties to form shapes. The particles
do not form a clear shape and get mushy, which
renders their cohesion meaningless. For example,
llers that are heavily mixed with a free HA solution for convenient use and are based on a lot of
cross-linking and higher viscosity. Fillers diluted
with water have a uidity of 0.25 or higher, so
their elastic modulus is too low for viscosity, thus
developing properties not t for the goal of volume llers to form and maintain a shape.
At any rate, today’s trend is to choose a ller
that has the most appropriate properties by taking
into consideration the degree of viscoelasticity
and cohesion needed for different procedure
parts. As was mentioned earlier, however, cohesion is not one of the essential properties of all
viscoelastic materials like elasticity and viscosity. Since there are no basic methods that are
commonly used in rheology to measure cohesion,
there can be difculties with choosing the right
product. Therefore, the researcher introduced an
array of methods to infer cohesion helpful for
product choice and explained which of them
were objectively valid.
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
41
2.3.2.6 Many Dierent Methods
toMeasure Cohesion
Perceived Cohesion Test
This test examines how sticky a ller feels when
touched with a nger. A stronger stickiness
between particles means a stronger force of particles attracting each other and gathering. The
test offers no accurate numbers of cohesion based
on an objective experiment. It provides reference
data to compare stickiness felt by different operators in the test. As explained earlier, adhesive
force works more on stickiness to a nger than
cohesion, which suggests that the test does not
examine cohesion completely.
During the test, the participating medical professionals were asked to touch many types of llers with their hand; mark on a ve-point scale
how sticky a ller was to the hand, how much the
ller particles adhered to each other, and how
strong the molecular force was between resistant
particles against an attempt to separate them; and
check the grade of each ller. Products with an
overall grade close to 5 were estimated to have
good cohesion (Fig.2.41).
Dispersion Test
This test dyes 1ml of a HA ller with toluidine
blue and puts it in water to examine how well the
ller particles disperse in water. Fillers with weak
structural viscosity disperse easily in water, thus
having weak cohesion of particles to gather and
form a shape. There are ve grades of dispersion
from fully dispersed to fully cohesive (1, fully
dispersed; 2, partly dispersed; 3, partly dispersed/
partly cohesive; 4, partly cohesive; 5, fully cohesive) according to the degree in which the bond
of HA ller particles weakens in water.
Put dyed HA ller products in water to
observe; leave them in water for 15, 70, and 95s
and for 5 and 10min to see how much the ller
particles disperse; and grade the products according to dispersion by time to infer the cohesion of
each ller according to its grade. For 15~95s in
water, biphasic HA llers seem to be dispersed a
lot with their particles not strongly bonding with
each other, and monophasic HA llers maintain
their original shapes to some extent without dispersing. In a graph of connections between the
dispersion degree of each ller and their perceived cohesion explained earlier, the products
Fig. 2.41 Perceived cohesion test
42
Fig. 2.42 Dispersion test
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
with a high perceived cohesion grade had a high
grade in the dispersion test and showed their particles gathering without dispersing in water until
the 95s mark (Fig.2.42).
After 5min in water, however, even monophasic HA llers started to disperse due to hydration
by water. After 10min in water, they were dispersed fully. This dispersion test can infer cohesion as the degree of the bond between ller
particles was right after being put in water or during the initial time in water. The test has difculties with measuring differences after the passage
of time. As explained earlier, cohesion is signicant when viscosity is higher than elasticity in
llers with uidity of 0.25 or lower. It holds no
signicance in products whose ller particles are
too weak in elasticity and whose shapes are
deformed easily despite the strong force of particles gathering like viscous uid. It should be thus
kept in mind that llers with high cohesion
between their particles do not disperse easily in
water and thus record high numbers on the dispersion test even though their basic particles have
low elastic modulus.
Drop Weight Test
In this test, different llers are put in syringes
of the same size and dropped down through the
mouth of the syringe by gravity to examine how
long the ller particles maintain an elongated
form by adhering to each other without breaking in the middle before dropping on the oor.
On an assumption that llers holding together
and not breaking easily have more drops and
are heavier, the test weights the drops and estimates that a heavier drop weight means highly
cohesive llers with good structural viscosity
between particles. Biphasic llers have low
cohesion, thus breaking in the middle among
their particles and falling in small drops.
Biphasic llers recorded lighter results based
on the weight of each drop than monophasic
llers. Outcomes can, however, vary according
to the syringe capacity and mouth size. Filler
matter will not fall easily, and it gets attached to
the syringe mouth due to adhesive force, which
is the adhering force between the syringe and a
ller rather than cohesion, which is the attracting force between ller particles. The degree of
adhesive force can also have impacts on cohesion between ller matters. The drop weight
test has a hard time obtaining objective data
when comparing llers of similar cohesion
according to many different variables
(Fig.2.43).
Compression Force Test
This test applies force above the elastic limit of
a ller and breaks its properties as an elastic
material before removing the force and giving
the ller time to restore its structure based on
the cohesion of its HA molecules. The test then
measures an inverse gap between ller particles
due to slow and small deformation. A smaller
inverse gap means that the ller particles do not
have a gap between each other and hold together
tightly. The ller is thus estimated to have
strong cohesion among its particles.
Specically, force above the elastic limit of an
HA ller is applied to press the ller, which in
turn fails to maintain its original shape and has
deformation. In this case, the structure of the
ller particles breaks, which widens the distance
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
Fig. 2.43 Drop weight
test
43
between particles. When force above the elastic
limit of a biphasic HA ller is applied, the ller
will lose its elasticity and have deformation with
the distance between the widened particles. Even
after the force is removed, its particles will not
gather easily because biphasic HA lers have
weak cohesion as viscous uid; thus, they are
lacking the ability to restore the widened distance
between particles. The particles of a biphasic HA
ller will not get close to each other and will
remain distant even after the ller is given time to
restore its structure after the push force is
removed. When a small force is applied again,
even a very small force, to press the ller slowly,
its particles will widen the distance between each
other after losing their elasticity to withstand the
external force.
Monophasic HA llers have relatively low
elastic modulus, which means that they will have
deformation with the structure of their particles
broken even by smaller initial force to press than
biphasic HA llers. Once the push force is
removed, even after the structure of a monophasic HA ller is broken, by the force above its
endurable elastic limit, its particles will gather
again and narrow down the distance between
them due to its cohesion as a viscous uid. The
ller will thus restore back to its original form to
some extent. When a small force is applied to the
ller again after it is given some time for restoration, the monophasic ller will be able to withstand a force that is not very strong and keep its
structure with its particles holding together based
on their cohesion despite their weakened elasticity and lack of distancing from each other.
This experiment was conducted by Allergan to
highlight the advantages of its Juvederm ller as
a monophasic HA ller compared with Restylane
NASHA, a biphasic HA ller produced by
Galderma. As explained earlier, Allergan broke
the elasticity of the llers by applying a big force,
which gave them some time to restore their structures based on cohesion, applied small force to
the llers, and measured the degree of distancing
between particles. According to Allergan’s denitions, llers have low cohesion when their particles easily distance themselves from each other
even by a small force, and llers have great cohe-
44
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
sion when their particles do not distance themselves from each other because they can withstand
such a small force. Allergan converted the measured degree of cohesion into numbers and cohesivity used a new term to express them, but it is
not an ofcial term used in rheology. Based on
the measurements from its experiments, Allergan
formulated a formula: lifting capacity=G′ (gel
rmness and particle size) × cohesivity. Here,
lifting capacity refers to the ability of an HA ller
to form a shape. That is, it argued that both elastic
modulus G′ and cohesivity as the cohesion of a
ller should have impacts on the ller overcoming an external stimulus to form and keep a shape.
As far as the researcher is concerned, this formula can be right in some cases and wrong in
others. Its absolute application is not guaranteed
for an HA ller procedure.
G′ examines how long a ller can maintain its
original shape by withstanding and enduring the
external force pressed on it, and it can be
expressed to represent lifting capacity. The second external force that was used in Allergan’s
experiment to measure its new term—cohesivity,
which is dened as the cohesion of a ller—is
applied when the ller particles bond to each
other loosely through electric attraction after the
elasticity of the ller is broken. The second external force is not a big force to press the ller like
when elasticity is measured. Cohesivity does not
represent the ability of overcoming strong external force and continuing to maintain the original
shape. It represents the ability to softly restore
back to the original shape to some extent after
removing the external force to easily deform the
shape in parts where high elasticity is not necessary. The compression force test examines how
much a ller holds this ability.
In a test, Allergan pressed a ller to be very
at in order to destroy its elasticity, removed the
force, and gave it approximately 120s for its particles to gather again based on cohesion. The test
applied external force to examine the degree of
distancing between pillar particles due to a small
force after waiting for the ller to restore back to
its shape based on cohesion. The external force is
in a range of 0~1.2N based on the numbers in the
vertical section of the graph. These numbers have
big differences from the force that is commonly
applied to break the elasticity of llers. The test
increased force gradually over time after starting
with a small force. The test results show that the
biphasic HA ller Restylane NASHA needed
only 0.2N force to increase an inverse gap, which
is the distance between ller particles, to 1.2mm
and that the monophasic HA ller Juvederm
needed force to press to 1.2N, offering a simple
explanation that the latter had a greater force to
withstand compression force (Fig.2.44).
It should be noted that 1N is the force needed
to lift an object of approximately 0.1kg from the
ground. In daily life, we need 1 N of force to
press the computer keyboard.
The formula argued by Allergan is correct
when lifting capacity means a sense of volume
created by a ller restoring back to its original
shape to some extent through cohesion after a
small force from daily life causes deformation to
its shape and then is removed in parts where
external force onto the ller is not strong.
Fig. 2.44 Compression force test
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
45
However, it is not the correct expression when
dened by a sense of volume based on elasticity
for a ller to maintain its shape by resisting the
pressure to lift tough and strong tissues bonding
together tightly and push them down.
Creep Deformation andRecovery Test
This test predicts how much a ller will restore
back to its original shape and how well it will
maintain its basic form through the proper action
of cohesion, which is electric attraction between
ller particles based on their structural viscosity,
after the ller shape is deformed by pressing or
twisting stimuli in daily life following a ller
injection. The researcher believes that this is the
most useful test clinically.
Creep deformation refers to deformation that
increases gradually from a slow and continuous
stimulus. For instance, when a certain weight is
hung on a matter, it will elongate the matter’s
length. An elastic matter will have no further
deformation over time in addition to the initial
one by a weight within its elastic limit of withstanding the weight and maintaining its shape.
Once the weight is removed, however, it will
return to its original shape before deformation
due to its elasticity. When a weight above the
elastic limit of a matter is hung on the matter, its
form will break. Since it is elastic, the matter
will not restore back to its original shape with
the broken structure even after the weight is
removed.
If a weight is hung on a viscous uid, the matter will keep changing at a constant deformation
rate and ow down.
A viscoelastic material with both elasticity
and viscosity shows simultaneous properties as
an elastic material and viscous uid in reaction to
creep deformation caused by weight. The moment
the weight is applied, the matter will instantly
have deformation due to its elastic properties. If
the weight is within its elastic limit, its deformation will happen according to its deformation rate
and then stop. If the weight is above its elastic
limit, the viscoelastic material will increase in
length gradually over time due to its properties as
a viscous uid without breaking like an elastic
material.
The weight above the limit of a ller product
is pushed down on it to cause an instant elastic
deformation like a weight hung on a viscoelastic
material with a slow and continuous deformation
at the same time. The weight pushing down the
product will break its elasticity, causing continuous deformation. Following the passage of some
time, the weight is removed from the material.
Biphasic llers with strong properties as a viscoelastic solid barely restore back to their original
shapes due to their weak recovery based on the
cohesion of particles. In monophasic llers that
have high cohesion among particles due to their
strong viscosity, partial and entire creep deformation happens slowly from the initial deformation
by a bigger force than elasticity to the removal of
weight that will recover slowly over time. This
phenomenon of slow recovery by the cohesion of
ller particles is called creep recovery.
Creep deformation and recovery refer to slow
and gradual deformation and recovery after
deformation, which is above elasticity rather than
instant elastic deformation and recovery at the
initial stage of constant stimuli according to the
deformation history of a viscoelastic material.
The creep deformation and recovery test applies
force above elasticity to a viscoelastic material
and examines how much it has deformed by the
slow and continuous force and how much it
recovers after the removal of the force (Fig.2.45).
Viscoelastic matter shows a slow recovery
pattern to this slow creep deformation due to its
cohesion as the natural internal binding force of
its basic molecules as a viscous uid. Even the
same monophasic llers have cohesion differences according to several elements determining
cohesion, such as the degree of uidity as well as
the size and consistency of particles.
The researcher compared two monophasic
llers with a similar viscoelastic level and different particle sizes in the degree of creep deformation and recovery by cohesion. The llers
were put in a syringe and pushed out with no
weight on it in order to squeeze out the same
amount on the same area and compare them in
height. The second ller had a bigger space
between particles and thus created a volume of
greater height than the rst one (Fig. 2.46).