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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5214_Библиотеки_им_академика_М_И_Перельмана.pdf
46
HA filler with large particle size
Fig. 2.45 Creep
deformation and
recovery test
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
6.8~6.9mm
HA filler with small particle size
Fig. 2.46 Comparison of shape and size of HA ller gel with different particle size when there is no external
deformation
When a greater weight than elasticity is applied
to llers with similar viscoelasticity, they should
have a similar proportion of particles being
pressed down and the space between particles
should shrink back to the initial size. Even
though they shrink in the same proportion, the
ones with bigger particles have a wider particle
area and a bigger space between the particles,
which means that their absolute value of reduced
length is bigger and the height of the llers
pressed by the initial elastic deformation is
lower. Creep deformations happen slowly since
they are greater according to the size proportion
of the space between particles (Fig.2.47). After
the weight was removed, llers that had smaller
particles and narrower gaps between particles
restored back to their height based on cohesion,
which helped the particles gather more easily.
When they were compared in their original and
restored height with llers of bigger particles
after deformation was removed, they showed
better creep recovery to restore a shape
(Fig.2.48). Another test measured how well the
gap between ller particles would be maintained
without the ller spreading after centrifugal
force by rotation was applied to the ller. When
force was applied to make the ller spread outward due to rotation, the ller of smaller particle
size had better cohesion among the particles and
showed a lower degree of the ller spreading
outward (Fig.2.49).
A creep deformation and recovery test helps
to predict how much recovery strength common
ller products will show and how well they will
mRight after pressing : 2.5m
HA filler with large particle size
m
HA filler with small particle sizeHA filler with large particle size
HA filler with large particle size
n
Before rotation
2.3 Rheological Properties ofHA Fillers asViscoelastic Materials
47
m
1 hour later : 2m
HA filler with small particle size
Right after pressing : 2mm
1 hour later : 1m
Fig. 2.47 Comparison of response to creep deformation between HA ller gel with different particle size
2.6mm
Fig. 2.48 Comparison of creep recovery of HA ller gel with different particle size
Fig. 2.49 Comparison
of response to
centrifugal force by
rotation between HA
llers with different
particle size
HA filler with small particle size
Before rotation
After 30 seconds of rotation
After 30 seconds of rotatio
48
Monophasic HA filler Biphasic HA filler
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
maintain their forms based on cohesion after continuous deformations are applied and removed.
These experiment results show that basically
all biphasic HA llers have hard particles, suggesting that llers of bigger particles tend to have
an easy time with forming a big shape, high elasticity to withstand external force, and great abilities to form and maintain a structure. The particles
of monophasic HA llers are sticky and uid
rather than hard, which means that bigger particles do not necessarily mean greater abilities to
withstand external force. When viscoelasticity is
similar, llers of bigger particles have a higher
deformation rate to external changes and a greater
degree of deformation than llers of smaller particles due to a wide space between particles. They
have lower cohesion based on the tight gathering
of particles than llers of smaller particles. When
there is no external force working, llers of bigger particles demonstrate better abilities to create
an entire soft volume. It is thus needed to consider the density and thickness of the skin and
tissues in different parts of the face, the degree of
external force, and the scale of movements before
determining which monophasic ller is a good
choice.
Flexibility Test
This test examines how well llers can adjust to
pulling and stretching stimuli and maintain their
original shapes by causing their basic particle
structure to stretch and shrink by the stimuli of
pulling right and left or up and down on a plane.
Biphasic HA llers have a strong natural entanglement in which HA chains comprised of HA
molecules get entangled and hold together like a
skein in order to not get untangled. They are natural rm llers that lack the ability of stretching
and shrinking right and left or up and down due
to the entangled structure of HA molecules.
Basically, they rarely show good exibility.
Therefore, llers are cut halfway instead of an
elongated length as they spread sideways.
Monophasic HA llers in a structure of HA molecules bonding to each other in a simple pattern
without complicated entanglement show more
exibly their properties as a viscous uid, thus
allowing them to easily adjust to stretching and
shrinking. When such llers spread sideways,
they are not cut halfway and form a long band
based on the high exibility of the particle structure (Fig.2.50). One must note that the exibility of the nal monophasic HA ller products
depends on whether free HA is mixed to soften
their properties or not. One might simply assume
that llers with a softer touch have higher exibility at a similar viscoelastic level. When they
are mixed with free HA such as water, they get
diluted by absorbing water and thus feel soft on
the outside. Structurally, however, they contain
water molecules between their HA chains. When
such llers are pulled sideways, their structure
Fig. 2.50 Difference of exibility between monophasic and biphasic HA llers
2.4 Relationship Between Cross-Linking ofHA Fillers andDegradation intheHuman Body After aFiller…
49
breaks, which means that they are vulnerable to
pulling stimuli and have lower abilities to recover
than llers of similar viscoelasticity that are not
mixed with free HA. If you are looking for a
ller whose structure is not broken by the stimuli
of stretching and shrinking skin, which is good
at maintaining its original shape and can stay in
its original place for a long time in parts where
there are many movements, such as the corners
of the mouth, you should go beyond simply
checking how soft a ller is and nd out whether
free HA was mixed with the product at the nal
stage. In this way, you can be guaranteed good
outcomes and proper durations of a ller procedure for the parts where there are many movements right and left or up and down or for
patients who have particularly many facial
movements.
2.4 Relationship Between Cross-
Linking ofHA Fillers
andDegradation
intheHuman Body After
aFiller Injection
2.4.1 Degradation ofHA Filler
Materials
Hyaluronic acid (HA) in its natural state that does
not have cross-linking degrades and disappears in
a couple of days due to hyaluronidase, which is a
lyase that is naturally found in the human body. It
is thus essential to use a cross-linking agent for
the cross-linking of HA molecules in order to
increase the duration of a ller whether it is a
biphasic HA ller that emphasizes natural entanglement as a physical cross-link and uses a crosslinking agent as little as possible or a monophasic
HA ller that is made with increased amounts of
cross-linking agents as a chemical cross-link.
The most widely used cross-linking agent is
BDDE (1,4-butanediol diglycidyl ether). It has
an epoxide group at both its ends, and it is combined with the hydroxyl group (-OH) of HA molecule to form an ether bond.
HA llers cross-linked by BDDE gradually
degrade in two main processes after being
injected into the human body.
As a ller is injected, the syringe or cannula
inicts a mechanical injury on tissues, passing
through the skin and its soft tissues. Free radicals
are formed and cause oxidative degradation. The
syringe or cannula is pricked or manipulated to
inject a ller into the skin, during which the skin
and its soft tissues suffer acute tissue inammation that increases the activation of free radicals
in the injured part of the procedure temporarily.
Free radicals are smaller in size and can thus
move freely through pores between ller particles, penetrating the ller and destroying the
structure of ller particles (Fig.4-1).
There is an enzymatic degradation caused by
hyaluronidase, an enzyme that degrades HA, one
of the basic components of an HA ller product.
Hyaluronidase has heavy molecular weight and
cannot penetrate a ller space, only working on
the surface of the mass created by HA ller material (Fig.2.51).
Free radicals and hyaluronidase degrade long
and big HA chains (polysaccharides) into smaller
HA units (oligosaccharides), which undergo metabolic degradation in cells or at lymph nodes and
then enter the circulating system before being ltered and removed in the liver and kidney.
In HA ller products, HAs degrade and
metabolize into the two processes mentioned
above, which makes it unnecessary to pay much
attention to their discharge process. BDDEs used
as cross-linking agents to make a ller product;
however, they did not make any enzyme materials to melt them away, which means that they
should be discharged in other processes such as
hydrolytic degradation with water. BDDEs that
stay separate from HA molecules instead of
adhering to them through cross-linking action
can be toxic artifacts that cause an immune reaction. BDDEs combined with HA molecules go
through different treatment processes in the
human body according to the combination types.
The study examined the different combination
forms of BDDE and HA in nal HA ller prod-
50
Fig. 2.51 Difference of
action sites between free
radical and
hyaluronidase
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
Fig. 2.52 Type of chemical cross-linking
ucts according to the types and each type’s clinical signicance and treatment process in the
human body.
2.4.2 Degree andEciency
ofChemical Modication
2.4.2.1 Types ofChemical Modication
(Complete or Incomplete
Cross-Linked BDDE)
BDDEs that are used to cross-link HA molecules
can be divided into ones that react to HA backbones and those that do not. Reacted BDDEs
who have ethers at both ends and are connected
to HA are called fully reacted BDDEs and are
expressed as a complete cross-linking. When the
ether on only one end of a BDDE is connected to
HA, it is expressed as an incomplete crosslinking. Incompletely connected BDDEs hang on
hyaluronic acid chains like a pendant of a necklace, thus being called the pendant type
(Fig.2.52).
When BDDEs that do not react to HA and are
separate from it react to water and get hydrolyzed, they are called deactivated cross-linkers.
BDDEs that do not react to water and are left
behind are called residual cross-linkers. BDDEs
hydrolyzed by water molecules degrade into
glycerol and butanediol before being removed.
Some hydrolyzed BDDEs are discharged through
urine. Hydrolyzed BDDEs are nontoxic and nongenotoxic. If residual BDDEs that are left behind
without hydrolysis are fully removed in the man-
2.4 Relationship Between Cross-Linking ofHA Fillers andDegradation intheHuman Body After aFiller…
51
ufacturing process of HA llers, there is no need
to have big concerns about the toxicity of BDDEs.
When residual BDDEs are not fully removed
and injected into the human body, their epoxide
group can have a chemical reaction to the body
tissues. It has been reported that residual BDDEs
were observed to have no carcinogenic effects,
but they did have mutagenic potential in an animal experiment. Final residual BDDEs that are
not hydrolyzed by water molecules after their
cross-linking process with HA should thus be
removed thoroughly, to an undetectable level,
with cleaning and dialysis in the ller making
process. The FDA permission criteria for HA llers state that detected residual BDDEs should be
a maximum of 2 ppm (0.002 mg of BDDE in
1ml of HA gel).
BDDEs with the epoxide group cross-linked
with HA molecules are considered safe and do
not have a chemical reaction even after being
injected into the human body. It is known that
BDDEs left behind after the slow degradation
process of HA llers in the human body are not
usually reactivated and removed safely.
These days, concerns are rising regarding
the long-term safety of llers due to the action
of incompletely cross-linked pendant-type
BDDEs. It has been reported in previous studies that incompletely cross-linked BDDEs react
to water and have their toxicity lost after being
injected into the human body. Today HA llers
are common, which are heavily cross-linked for
higher viscoelasticity. The doses of llers used
have increased with the rising frequency of
ller injections. The amounts of pendant-type
BDDEs accumulated after injection are on the
rise. There is a suspicion that incompletely
cross-linked BDDEs that are left behind after
the degradation process of HA ller particles
and accumulated without being treated are
associated with side effects related to a delayed
immune reaction.
Of HA ller products with a similar level of
viscoelasticity, the products of low chemical
cross-linking are relatively safer. In the past when
there was no such knowledge, they launched HA
ller products that were extremely hardened by
the high proportion of cross-linking. These HA
llers caused many different problems and were
withdrawn from the ller market.
2.4.2.2 Degree ofChemical
Modication (MoD)
The HA types adhere to BDDEs and have a modication, whether they are C-MOD (complete
cross-link modied disaccharides) that are completely linked to BDDEs or P-MOD (pendant
modied disaccharides) that are incompletely
linked to BDDEs. The collective term for both
types is T-MOD (total modied disaccharides).
The ratio of MOD to show the degree of crosslinking between HA molecules and BDDEs in an
HA ller is called a cross-linking ratio or MoD
(degree of chemical modication). It represents
the number of HA monomeric units out of 100
linked to BDDEs (Fig.2.53).
When other conditions are the same, a higher
T-MOD means a hard ller with high viscoelasticity. To express this more accurately, even the
llers of the same T-MOD can have different
degrees of viscoelasticity since they have differences in C-MOD under T-MOD.HA llers with
Fig. 2.53 Cross-linking ratio of HA ller based on chemical cross-linking
52
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
high C-MOD, which represents complete crosslinking under T-MOD, are harder, strongly withstand degradation by enzyme materials, and last
longer.
Different HA ller products have differences
in MoD.Products with low MoD can be made to
have similar viscoelasticity with small amounts
of cross-linking agents. Basically, biphasic HA
llers use minimum BDDE and get hardened by
natural entanglement, having low MoD naturally.
Monophasic HA llers of the same rheological
properties have differences in MoD despite their
similar viscoelasticity. In this case, differences in
T-MOD are attributed to P-MOD by pendanttype BDDEs in which only one end is linked to
HA molecules under similar C-MOD involved in
complete cross-linking. Total MOD, including
P-MOD, is measured with NMR (nuclear magnetic resonance), and the process is extremely
complicated and difcult.
Most ller manufacturers thus calculate and
present only C-MOD with SEC/MS instead of
NMR based on a judgment that the basic structure of HA ller products is built by complete
cross-linking modied BDDEs and that pendantmodied BDDEs do not have much impact on
the ller structure.
The MoD of each HA ller product provided
by ller manufacturers is measured based on the
amount of complete cross-linked BDDEs used to
make the product. Generally, an MoD is in a
range of 1~10% based on complete-type crosslinking provided by manufacturers (Fig.2.54).
2.4.2.3 Eciency ofChemical
Modication (MoE)
It is important to consider that the ratio of complete type (C-MOD) representing complete
cross-linking and pendant type (P-MOD) representing incomplete cross-linking can have
impacts on the properties and safety of llers.
Even products of similar viscoelasticity can
have different MoD values according to the making process. A smaller amount of BDDEs as a
cross-linker is considered safe. In recent years,
the possible harmful nature of P-MOD has been
reported. A recent argument is that one should
check modication efciency (MoE), which represents the amount of BDDEs used to produce
HA llers of a certain viscoelasticity level and
provide MoD instead of the simple MoD itself. It
can be calculated in MoE=gel strength/MoD.
It will be ideal to have knowledge about the
total MOD, including the C-MOD and P-MOD
of all HA ller products, but the method to measure it is not easy. The data provided by manufacturers only covers C-MOD and no information
about P-MOD.One can only infer that the ratio
of complete cross-linking and pendant types in
each HA ller product was based on their clinical
patterns.
In the degradation process of HA llers in the
human body, BDDEs linked to HA molecules are
left behind in the degradation and removal process of HA by enzyme materials. Residual
BDDEs should be discharged out of the body in a
metabolic process.
Fig. 2.54
Determination of
modication degree of
HA llers based on
chemical cross-linking
2.5 Changes intheHuman Body After anHA Filler Injection
Fig. 2.55
Determination of
modication efciency
of HA llers based on
chemical cross-linking
53
BDDEs are basically regarded as toxic materials. When there are more BDDEs accumulated
than the amount discharged from the human
body, they can become a problem. Many papers
have raised questions about this. Some HA ller
products in the monophasic HA ller product
group that are using a considerable amount of
BDDEs are prone to delayed onset nodules after
several months of the procedure despite similar
viscoelasticity and no big differences in C-MOD
measurements. When clinical symptoms related
to delayed tissue reactions happen many days
after the procedure instead of right after, have
repeated frequently, and last long despite treatment, one can suspect a relatively high P-MOD
based on pendant-type BDDEs.
On a premise that BDDEs are used according
to the allowable limits, one can say that the total
amount of BDDEs is determined according to the
number of llers used during a certain period.
The US FDA sets upper limits to the amount
of HA llers for a certain period. Based on the
possible immune reaction of accumulated crosslinkers, they recommend that an adult of 60kg in
weight should limit the dose of an HA ller for a
year under 20 ml. If clients limit their total
amount of HA llers for a certain period, they are
less likely to have problems. It seems, however,
natural that HA ller products with smaller
amounts of BDDEs should be safer to
immunological toxicity caused by BDDEs than
other products of similar viscoelasticity. In this
sense, MoE can serve useful purposes.
HA ller manufacturers in the nation provide
MoD based on C-MOD, including no P-MOD,
which means that MoE is calculated based on the
gel strength value and C-MOD of each HA ller
product. Products with high MoE have lower
MoD than other products of similar viscoelasticity that are made technically with small amounts
of cross-linkers.
The gure below shows the MoE of products
currently used on the market. As far as MoE is
concerned, biphasic HA llers have better outcomes than monophasic HA llers due to the
characteristics of their manufacturing method
(Fig.2.55).
2.5 Changes intheHuman Body
After anHA Filler Injection
2.5.1 Changes inHistological
Human Responses toHA
Fillers
After a ller injection into the human body, its
biological tissues basically consider the ller
matters in the skin as foreign substances and
react accordingly. These tissue reactions come as
inammation, swelling, capsule formation, biostimulatory effect, and foreign body reactions.
54
2 Types ofFillers andRheological Considerations forHA (Hyaluronic Acid) Fillers
This happens in the following process: a foreign substance unfamiliar to the human cells
enters the human body, and tissue reactions begin
with plasma protein adhering to the surface of the
matter. They activate phagocytes, including
monocytes and macrophages, and have them
envelope the surface of the foreign matter. Then
the phagocytes on the surface of the foreign matter fuse together and create multi-nucleated giant
cells. Then autologous collagen is produced and
envelopes the foreign substance completely,
forming a high-density collagen capsule. This is
called a foreign body reaction.
HA is a natural polymer, thus hardly causing a
foreign body reaction in the human body. Used in
llers that last longer, synthetic polymers such as
PLLA and PCL cause a foreign body reaction
more easily and thus produce more collagen.
One of the microscopic histological tissue
reactions to an injected ller is the formation of
capsules around the ller. Capsules are generally
observed after 4weeks from an injection. The thin
lm observed right after an injection is a structure
created by subcutaneous tissues that are pressed.
After 4weeks from an injection, a grid-pattern
structure is formed by broblasts, new blood vessels, and collagen regeneration. As an HA ller is
gradually degraded and absorbed, the space of
this structure is gradually replaced with autologous tissues comprised of broblasts, connective
tissues, fat cells, and blood vessels.
Type III collagen, a type of collagen found in
the initial days of the cut treatment process,
makes a fast increase for the rst 8weeks as part
of the changes around the procedure part after a
ller injection. It accounts for approximately
13.8% of the ller volume after 4 weeks and
records the biggest volume after about 32weeks
when it accounts for an approximate average of
21.5% of the entire ller volume.
It has been conrmed that HA llers injected
into the human body are replaced partially with
autologous tissues in a tissue reaction with some
differences in degree. Today it is said that HA
llers last for 1~2 years or longer with differences in duration according to the different
amounts of hyaluronidase in different parts or
layers in the face. Doctors explain to their clients
that HA llers replaced with autologous tissues
will partially remain even after a couple of years
and that the original shapes before the ller injection will not return.
In some cases, HA llers injected into the
human body maintain their shapes longer than
average with less hollow effects than expected.
Histologically speaking, such cases benet from
abundant tissue reactions, the smooth replacement of the ller mass with autologous tissues,
and the prevention of HA ller degradation and
absorption by hyaluronidase, which could only
work on the surface of the mass thanks to the
think capsule layer based on the regeneration of
collagen enveloping the ller mass. One might
simply think that it would be great if llers were
not absorbed easily and lasted longer according
to their replacement by autologous tissues and
the thick capsule layer, but capsules enveloping
the ller can cause a biolm infection when they
are too many. It is safe not to believe that such
llers are great unconditionally. Good llers
should be safe and effective based on proper tissue reactions.
If there is a proper tissue reaction after a ller
injection, the ller would maintain its volume
and last longer. Today, doctors do not have to tell
their patients that an HA ller will disappear after
a couple of months as they did in the past.
Autologous tissues produced by a ller will
change according to the changes of human tissue
cells over time, and doctors can replenish a ller
accordingly. These days, patients receiving a
ller procedure are quite satised as their changed
forms last longer than expected despite the
absence of regular ller injections and do not
return to their original forms completely even
after considerable time has passed since the
injection.
Before choosing and injecting an HA ller
product, doctors take into consideration the fact
that there can be differences in changes to the
ller volume and its duration according to the
part of a procedure, the patient’s skin and soft tissue conditions, the injection layer, the ller’s
rheological properties, the injection method, and
the degree of tissue reactions to external stimuli
in the human body after the injection.
2.5 Changes intheHuman Body After anHA Filler Injection
55
2.5.2 Relationship Between
theRheological Properties
ofHA Fillers andChanges
intheShape ofFiller
Treatment Areas
HA llers are viscoelastic materials with uidity.
They can be injected through a thin pipe such as
a syringe and cannula and be restored back to
their original forms and functions as a ller after
an injection due to their viscoelastic characteristics. Fillers mainly serve two purposes: rst,
early llers mainly worked to correct hollow
parts in the dermis due to wrinkles; second, llers
increase the volume of the face skin and soft tissues to highlight their volume. Today, there are
various types of llers that are designed to
increase the face volume clinically.
Many tests have examined changes in the
human body based on changes to the shapes created by a ller injected into the body to highlight
volume. For the rst 4~8weeks, volume increases
thanks to the hydrophilic properties of HA llers.
The shapes created by an injected ller increase in
volume by about 1.8 times in Week 4 when the
volume reaches its peak. Then the volume gradually decreases, reaching 75% of the initial volume
in Week 16. In Weeks 16~64, the volume is maintained with no big differences from its initial state.
The maximum height of a shape created by an
HA ller decreases to two-thirds its level due to
the push force of tissues for the rst 4weeks from
the procedure. Since then, the height is maintained to some extent.
As for the width of a shape created by a ller
injection, it increases approximately 1.8 times for
the rst 4 weeks, similar to the entire volume.
The width maintains its enlarged state in Weeks
4~32 compared with the state right after the procedure. Since then, it gradually decreases until
Week 64 when it becomes similar to the initial
state.
When patients want to increase volume in
parts of the face with an HA ller, in many cases,
a ller is injected into a deeper layer than
SMAS.In a deeper layer than SMAS, there are
fewer planar movements of stretching and shrinking by the facial expression muscles, but external
pressure works actively to press the injected ller
via the SMAS layer and nearby ligament tissues.
Clinically speaking, soft llers with low elasticity can create relatively easily an intended shape
in this space. They have low resistance to the
external force pressed on them; however, their
shapes are not maintained correctly and easily
change or move. Hard llers with high viscoelasticity are difcult to inject and require greater
force to create an intended shape. Once they create a certain shape, it will not deform easily and
can be well maintained (Fig.5-1).
Fillers with high elasticity would be a good
choice for patients who want to inject a ller into
a deeper layer than SMAS and create and maintain a certain shape. Fillers with high elasticity,
however, tend to have the growing possibilities of
pressure on nearby tissues, feelings of irritation
and disrupted blood circulation felt by patients,
and tissue reactions. Thus, it is important to
choose a ller with a proper level of elasticity for
the procedure layer.
When llers are injected into a layer close to
the skin to correct wrinkles or make the skin supple, these parts contain facial muscle bers adjacent to the skin. Facial expression muscles move
and stretch the skin, which means that the ller is
more subjected to the force of stretching and
shrinking on the plane than the pressure to push
down. For a layer close to the skin, a ller with
high exibility would be a good choice.
Flexibility refers to the ability of stretching easily
without causing any discomfort when a patient
makes facial expressions by adjusting to such
planar movements and restoring back to the original shape when the patient makes no facial
expressions (Fig.2.56).
Soft llers with low viscoelasticity are needed
to have them spread evenly in this way. Good
examples include ller procedures around the
eyes. Fillers injected in the skin or right under it
should spread softly and evenly to some extent so
that the surface becomes smooth. Soft llers that
spread too easily cannot restore their original
shapes and deform easily even after a strong pulling force is applied and then removed. Only having soft llers is not necessarily having good
ones all the time.