Hyaluronic Acid Fillers

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Hyaluronic Acid Fillers
Science and Clinical Uses
Karol A. Gutowski, MD*
INTRODUCTION
Facial aging may manifest as skin texture and
color changes, formation of fine lines and deeper
creases, more pronounced active wrinkles, and
overall facial soft tissue decent. Decreased skin
tone, fat loss, and underlying bony changes
contribute to the loss of facialfullness. Each of these
components of facial aging can be addressed by
specific treatments such as medical grade skin
care and resurfacing, neuromodulators, and
soft tissue fillers. Althoughnot a substitute for surgi-
cal rejuvenation, nonsurgical options are more
accepted by patients owing to convenience, lower
initial cost, less downtime, and fears of “going under
the knife.” In this environment, hyaluronic acid (HA)
fillers have become in leading tool in not only
maintaining a youthful facial appearance, but also
for enhancing facial features in younger patients.
HYALURONIC ACID FILLER COMPOSITION
Although HA fillers may seem to be similar, they
actually each have different physical properties
that differentiate them, making proper product
choice important when used for facial rejuvena-
tion. Factors such as HA concentration, amount
of cross-linking, particle size, extrusion force,
and elastic modulus (G0) influence product selec-
tion and indications. Therefore, there is no univer-
sal HA filler. Although there is some overlap in their
clinical uses, they should not be considered inter-
changeable in all situations.
This section highlights of a more detailed anal-
ysis of HA fillers by Kabik and colleagues.
1
HA is
found in human tissue but the injectable products
are obtained from animal or bacterial sources. The
HA molecule itself is a glycosaminoglycan disac-
charide composed of alternately repeating units
of D-glucuronic acid and N-acetyl-D-glucosamine.
At physiologic pH, HA binds water extensively,
providing “fullness” in the tissue. HA may be modi-
fied by chemical cross-linking between HA
strands, which increases product firmness, mak-
ing it more resistant to stress, and also making it
more resistant to in vivo enzymatic degradation
resulting in a longer duration of filler effect.
Although each product has a listed HA filler
concentration, there may be variation in the
amount of soluble versus insoluble HA. Because
the soluble HA is metabolized rapidly, it does not
contribute to clinical effectiveness. Therefore,
listed HA concentrations may not truly reflect
product performance.
Conflicts of Interest: None.
Disclosures: The author is an instructor for Bellafill (Suneva Medical), a non-hyaluronic based fillers mentioned
in this article.
Division of Plastic Surgery, University of Illinois, Chicago, IL 60611, USA
* 820 South Wood Street, Suite 515 CSN, Chicago, IL 60612-7316.
E-mail address: Karol@DrGutowski.com
KEYWORDS
Hyaluronic acid Soft tissue fillers Juvederm Restylane Voluma Belotero
KEY POINTS
Hyaluronic acid (HA) injections are an integral part of facial aesthetics.
HA products are similar but not interchangeable.
Individual patient assessment and an understanding of facial aging is necessary for optimal results
with HA injections.
Clin Plastic Surg 43 (2016) 489–496
http://dx.doi.org/10.1016/j.cps.2016.03.016
0094-1298/16/$ – see front matter Ó2016 Elsevier Inc. All rights reserved.
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The rheology of HA fillers is complex and labora-
tory measurement differences may not translate to
clinical differences. However, a products’ G0may
be used to describe its firmness or ability to “lift”
tissue. A high G0product will require more applied
stress to deform it, whereas a low G0product will
deform with little applied stress.
In clinical terms, low G0HA products may be bet-
ter for fine lines and wrinkles and where firmness is
not desired, for example in the lips. High G0prod-
ucts may be better suited for deeper tissue eleva-
tion such as moderate to severe nasolabial folds
and malar enhancement. Reported G0measure-
ments in Pascal units are listed in ascending order
2
:
Finally, because HAs bind water, they may result
in tissue swelling after injection. This is partially
dependent on HA molecule modifications and
the amount of cross-linking.
PATIENT ASSESSMENT
Proper patient assessment includes not only the
area of their present concern, but an overall facial
assessment and plans for future treatments. In
middle-aged and older patients, HAs typically are
combined with neuromodulators and medical
grade skin treatments to achieve proper facial
rejuvenation. Despite patient hopes, not all facial
aging can be improved with fillers. A discussion
of why more invasive treatments are appropriate
may be needed. Likewise, expectations that 1 or
2 syringes of a product will give dramatic results
will also need to be addressed. Lip enhancements
may only need 1 or 2 mL of an HA, but moderate
facial aging may require 1 to 2 mL in each temple,
malar region, nasolabial fold, and perioral area.
Eight to 10 mL of HA (or more) may be used in
some patients to achieve a “liquid facelift.” If
high filler volumes are being considered, other
longer acting products such as L-poly-lactic acid
(Sculptra) and polymethyl methacrylate (Bellafill)
should be discussed. Calcium hydroxylapatite
(Radiesse) is another option for deeper injections
to achieve tissue elevation, such as in the malar
or temple regions.
A written informed consent should be obtained
before the first injection session. Standard photo
documentation of the area being treated and the
entire face should be done before any treatment.
Because many of the changes from filler injections
are subtle, consistent before and after images are
important in measuring outcomes and educating
patients.
ETHNIC AND GENDER CONSIDERATIONS
Not all ethnic groups have similar needs and this
should be taken into account. For example,
whereas Caucasian patients may seek injections
to address age-related changes, Asian patients
may be younger and be seeking changes in facial
shape. The “T zone” (forehead, nose, cheeks, and
chin) can be projected in such cases to reshape
the face.
3
Ethnic groups with darker skin types,
such as African Americans,
4
may have fewer fine
lines and wrinkles and will focus more on volume
loss. Latino patients may have unique cultural con-
siderations that can influence treatment.
5
Men are
more likely to focus on regaining stronger male
features, such as in the chin, and also present for
nasolabial fold and tear trough correction.
6
INJECTION PREPARATION AND TECHNIQUE
Depending on the injection site and size of needle
used, analgesic modalities include topical anes-
thetics, ice packs, distraction techniques, local
anesthetic injections, and nerve blocks. Some
HA products are available with lidocaine mixed in
the syringe, which decreases injection discomfort.
The injection site should be cleaned in a wide
area with appropriate skin disinfectant. Dry
iodine-based solutions can be wiped off with an
alcohol pad to allow assessment of skin color for
signs of blanching or intravascular injection. Tech-
nique should be as aseptic as possible because
late infections and biofilm formation can occur.
For intradermal injections, short 29-G needles
work well. When using a more viscous HA product,
30-G and 31-G needles can be used. For subder-
mal injections, longer 27-G or 29-G needles are
useful. More recently, disposable blunt-tipped in-
jection cannulas have been favored for subdermal
and deeper injections because they may cause
less bruising and are less likely to result in an intra-
vascular injection.
Specific injection technique depends on the in-
jection site, tissue plane, and clinical problem be-
ing treated. Small bolus injections (0.05–0.1 mL)
are appropriate for deep and supraperiosteal in-
jections such as for malar elevation or filling in
the prejowl sulcus. Fine lines and wrinkles are
best treated with smaller volume linear injections
of product into the dermis, parallel to the line being
injected. Elevation of more superficial tissue, such
Belotero Balance 128
Juvederm Ultra XC 207
Juvederm Ultra Plus XC 263
Voluma 398
Restylane-L 864
Restylane Lift-L 977
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490

as the lip corners or cheek hollows, can be done
with a cross-hatching technique of linear perpen-
dicular injections. A fanning technique from a sin-
gle injection point is useful to highlight or elevate
an area. Low injection pressure and small volume
injections will prevent overcorrection. If tissue
swelling makes it difficult to assess the results,
the injection can be stopped and repeated in 1 to
2 weeks.
After the injection, the area should be palpated
to check for any lumps or unevenness, which
can me massaged until smooth. Cool gel packs
are useful immediately after injection to reduce
swelling and bruising. Patients can resume regular
activities, but should be instructed not to massage
or otherwise manipulate the treatment area.
Follow-up evaluation is suggested at 2 weeks to
determine if additional injections are needed. If any
nodules are seen, they may still be able to be
manipulated and made smooth. If an area is obvi-
ously overcorrected, or the patient is not satisfied
with the results, HA fillers (unlike non-HA fillers)
can be reversed with hyaluronidase. A human re-
combinant hyaluronidase (Hylenex, Halozyme
Therapeutics) is preferable to animal derived hyal-
uronidase. Small amounts of HA may be dissolved
with 15 to 30 units of hyaluronidase, although more
may be needed (50–100 units) for larger amounts
or in products with high HA cross-linking.
HA products are not intended to be stored for
use after opening the syringe. However, if used un-
der sterile conditions, they may be stored for at
least 2 months without any bacterial growth.
7
PRODUCT COMPOSITION AND AVAILABLE
PRODUCTS
Worldwide, there are many HA injectable products
with indications for both facial aesthetic and other
uses. The products mentioned below will be
limited only to HA fillers approved by the US
Food and Drug Administration (FDA) for facial aes-
thetics as of January 2016.
Juvederm Ultra, Juvederm Ultra Plus, and
Voluma
The Juvederm and Voluma groups of products are
made by Allergan Inc. (Irvine, CA).
Juvederm Ultra has the lowest G0(207 Pa) and
Juvederm Ultra Plus has a slightly higher G0
(263 Pa). Both are made with proprietary Hyla-
cross technology, which allows high water uptake
by the HA gel after injection. This may cause more
“swelling” and the appearance of overcorrection.
Voluma has the highest G0in the Allergan HA prod-
uct group (398 Pa) and is approved for malar
augmentation. Volift (G0340 Pa) and Volbella (G0
271) are similar to Voluma, but are not currently
FDA approved. These last 3 products use proprie-
tary Vycross technology and absorb less water
than Juvederm Ultra or Juvederm Ultra Plus.
8
Restylane, Restylane Silk, and Restylane Lyft
The Restylane group of products is made by Gal-
derma (Uppsala, Sweden) and each product also
has specific properties. Restylane Silk is a low G0
small particle HA that is FDA approved for lip
augmentation and treatment of perioral lines. It is
also useful for fine lines in other areas, tear
troughs, and in places where less filler “lift” is
needed.
9
Restylane has a high G0(864 Pa),
whereas Restylane Lyft (formerly called Perlane)
has the highest G0(977 Pa) of the FDA-approved
HA products.
Belotero Balance
Belotero Balance is approved for mid to deep
dermal injections for correction of moderate to se-
vere facial wrinkles and folds and is considered a
superficial to midlevel volumizer. It has a low G0
(128 Pa), which makes it appropriate for treating
fine lines and wrinkles.
10
Other Belotero products
not yet FDA approved include Belotero Volume
(a deep volumizer), Belotero Intense (a midlevel
volumizer), and Belotero Soft (a superficial
volumizer).
Unlike Voluma, Juvederm, and Retylane prod-
ucts, Belotero Balance available in the United
States does not contain lidocaine for injection
comfort. However, it may be mixed with 0.15 mL
of 1% lidocaine per 1 mL of product for a more
comfortable injection. The formulation of Belotero
may produce less Tyndall effect (a visible bluish
discoloration of the HA when injected in the super-
ficial dermis), making it useful for fine lines, areas
of thin skin, and superficial injections.
DURATION OF EFFECT
Studies to determine the duration of clinical
improvement after HA injections frequently use
standardized assessment scales with patient and
physician reported scores. A 1- or 2-point
improvement on a 5-point scale is considered
effective. These same studies may allow for touch
up injections and corrections during the study
phase. For Juvederm products, Restylane prod-
ucts, and Belotero Balance, duration is frequently
at least 6 months, with some patients seeing re-
sults up to 1 year. Voluma has a reported duration
of 1 to 2 years.
Clinical experience shows that there is wider
variability in the time needed before retreatment.
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This may be based on injection technique, injec-
tion site, and individual patient HA metabolism or
just owing to initial treatment undercorrection,
which becomes evident after swelling resolves.
Therefore, patients should be advised that, in
some cases, the duration of results may be shorter
than expected and retreatment, or a different
product, may be needed.
FACIAL TREATMENT STRATEGIES
Each patient will have unique goals and expecta-
tions as well as underlying anatomic variability
and stages of aging that need to be considered
when planning treatment. A full facial analysis by
the injector, combined with patient education
and agreement with the treatment plan, will help
to achieve a favorable outcome. In many cases,
a neuromodulator may be used to prevent lines
and wrinkles that form with movement (active
lines) and HAs can be used for lines that are pre-
sent at rest (static lines).
11
The following facial re-
gions can be improved with HA fillers; most of
these are not FDA-approved indications and
should be considered “off-label” uses.
Forehead Lines
Mild to moderate static lines in the forehead
should first be addressed with a neuromodulator
injection to the frontalis muscle to treat the under-
lying cause. In most cases, these line will improve
after a few months. If needed, deep dermal low to
moderate G0HA injections can be used to fill in any
residual static lines.
Temples
Temple hollowness is a sign of aging usually not
noticed by patients and needs to be brought to
their attention. Once addressed, the results can
be dramatic.
12
Deep injection in the supraperios-
teal plane, starting from the depression superior
lateral to the orbital rim and tapering to the hairline
with a high G0HA can lift and revolumize the
hollowness.
Superior Orbital Rim
Although not a common injection area, the supe-
rior orbital rim can be enhanced for a more mascu-
line appearance, or to provide the appearance of
slight brow elevation by using a high G0HA in the
subdermal or supraperiosteal plane.
Glabella
Vertical glabellar lines, sometime called the “11’s”
are a common initial complaint of patients seeking
facial enhancement. As with forehead lines, the
first step is to treat the underlying corrugator mus-
cle contractions with a neuromodulator. Then, if
need after a few months, a low to moderate G0
HA intradermal or subdermal injection can be
used to fill in residual static lines. Care should be
taken because this area may be more prone to
filler-associated skin necrosis.
Crow’s Feet
As in the forehead and glabella, active lines are
first treated with neuromodulator injections to the
orbicularis oculi muscle. Although rarely needed,
low to moderate G0HA intradermal injections can
be used for static lines.
Upper Eyelid
Upper orbital hollowness, including sequelae of fat
pad removal, has been improved with HA injec-
tions.
13
This should be done very carefully and
only by experienced injectors who are familiar
with the anatomy in this region.
Tear Troughs and Lower Eyelid Bags
For patients with tear troughs and mild to moder-
ate lower orbital fat pads, a moderate G0HA injec-
tion in the supraperiosteal plane can fill in the
trough (Fig. 1) and make the lower lid fullness
less noticeable.
14
This area is less forgiving than
other facial regions, because the thin skin may
make the HA product more visible and palpable.
Therefore, undercorrection followed with a touch
up 2 weeks later if needed is a reasonable
approach. Prolonged swelling and late edema
are also common and HA products have lasted
up to 5 years in this facial zone.
15
In some moder-
ate cases, and most severe cases of lower orbital
fullness, a blepharoplasty is more appropriate.
Earlobes
Deflated earlobes and creases can be improved
with small injections of HA fillers.
Malar
High cheek bones are frequently desired by
younger women, and loss of malar volume is com-
mon in older women and men, as well as in pa-
tients with malar hypoplasia. High G0HA fillers
can be injected in the supraperiosteal plane of
the malar prominence and low to moderate G0
HA can be used more superficially for refined
enhancement (Fig. 2). In some cases, adding vol-
ume to the malar area can soften nasolabial folds,
but overfilling should be avoided to prevent an un-
natural appearance when smiling and so as not to
make cheek hollowness more obvious.
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492

Submalar and Cheek Hollowness
Cheek hollowness in the submalar area is
commonly associated with advanced aging,
weight loss, or in very physically active patients
with a low body mass index. Revolumization with
subcutaneous HA fillers can restore a more youth-
ful appearance and improve cheek wrinkles owing
to facial deflation (Fig. 3).
Nose
Minor nasal imperfections and deformities can be
improved with HA fillers.
16
Small dorsal humps
can be “reduced” by adding supraperiosteal vol-
ume above and below the hump to crease a
straight dorsum. Likewise, some dorsal deviations
can be camouflaged with fine supraperiosteal in-
jections on the concave side. Minor tip changes
can be made with careful subcutaneous injections.
Higher G0HA fillers may be better to provide more
structural support as the nasal skin tends to be
tight and can deform low G0products.
Lips
Perhaps owing to popular cultural influences, lip
enhancement in younger patients and correction
of lip volume loss in older patients is frequently
requested. Low and moderate G0HA products
are used commonly (Fig. 4). Proper assessment
and aesthetic judgement are critical because over-
done lips are easy to produce. In older patients
with a thin lip and long vertical upper lip, a surgical
lip lift may be a better option. During and after HA
injection, swelling is common and it is wise to limit
injection volumes to 1 mL, then reevaluate and
retreat in 1 to 2 weeks.
Peri Oral, Lip Lines, and Downturned Lip
Corners
Vertical upper and lower lip lines should first be
managed with low-dose neuromodulator injec-
tions to control the underlying orbicularis oris mus-
cle contributions. Fine lines can be injected with
low G0prime intradermal injections
17
and the
downturned lip corners may need higher G0HAs
for improvement. If the depressor anguli oris mus-
cle is contributing to the downturned lip, a neuro-
modulator injection may be added.
Nasolabial Folds
Most early indications and studies were done on
HA injections to improve nasolabial folds. More su-
perficial lines respond well to intradermal injec-
tions of low to moderate G0products. Deeper
folds respond better to higher G0HAs in the subcu-
taneous tissue (Fig. 5).
Fig. 2. Before and after high G0hyaluronic acid injection for malar elevation (Restylane Lyft, 1.5 mL per side).
Fig. 1. Before and after low G0hyaluronic acid injection for tear trough improvement (Juvederm Ultra, 0.5 mL per
side).
Hyaluronic Acid Fillers 493

Marionette Lines
Similar to nasolabial folds, marionette lines
respond well to HA injections (Fig. 6). In the lower
face, conservative amounts should be used
because too much volume may make the lower
face too full and unattractive.
Jaw Line, Prejowl Sulcus, and Chin
The appearance of mild jowls can be minimized by
filling in the sulcus between the jowl and chin with
a supraperiosteal high G0HA injection (Fig 7).
Overcorrection or attempts to improve a larger
jowl may make the jaw look to large and “heavy.”
Posterior to the jowl, and at the mandibular angle,
injections can refine the jawline or give a more
masculine jaw appearance. Likewise, modest
chin augmentation can be achieved with
injections.
SAFETY OF HYALURONIC ACID FILLERS
Although generally considered safe when used by
appropriately trained injectors, there are associ-
ated risks and potentially serious complications.
Mild swelling and bruising can be expected; rarely,
persistent swelling may occur, especially in the
lower orbital area. Palpable lumps, nodules, and
granulomas are not common when proper injec-
tion technique is used. More serious complica-
tions usually involve an intravascular injection,
which can cause significant tissue necrosis and
blindness. A recent FDA warning calls attention
to these events.
18
All those who inject fillers should know the
specific anatomy of the area they are treating so
as to minimize the risk of intravascular injection.
Suggested techniques for safe injections include:
Avoiding injections in an area with large blood
vessels;
Use of a blunt cannula instead of a sharp
needle (where appropriate);
Pulling back the syringe plunger before
injection; and
Slow injection with observation for tissue
blanching.
In the event of an intraarterial injection, which
typically presents with immediate skin blanching
and occasionally pain, immediate treatment is
mandatory. Skin and soft tissue necrosis may
result even if preventative actions are taken.
Fig. 3. Before and after moderate G0hyaluronic acid cheek revolumization (Voluma, 1 mL per side).
Fig. 4. Before and after low G0hyaluronic acid lip enhancement (Juvederm Ultra Plus, 1 mL split between upper
and lower lip).
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494

Fig. 5. Before and after high G0hyaluronic acid injection for nasolabial fold improvement (Restylane, 1 mL per
side).
Fig. 6. Before and after moderate G0hyaluronic acid marionette line correction (Voluma, 0.5 mL per side).
Fig. 7. Before and after high G0hyaluronic acid injection in the prejowl sulcus (Restylane, 0.4 mL per side).
Hyaluronic Acid Fillers 495

Likewise, any vision changes during or immedi-
ately after an injection need to be considered as
an intravascular injection and treated as an emer-
gency. Intravenous injections may present hours
or days later with blue or purple skin discoloration
and tissue slough.
As soon as an intravascular injection is
recognized, a preplanned protocol should be
activated
19
:
1. Stop the injection.
2. Inject hyaluronidase under the dermis of the
affected area; 100 units or more may be
required.
3. Administer 1 aspirin orally.
4. Massage the area to break up any residual
HA.
5. Apply warm compress.
6. Consider sildenafil (Viagra) for vasodilation.
7. Consider applying nitropaste to affected area.
8. Reassess every 1 hour and inject more
hyaluronidase if needed.
9. Consider hyperbaric oxygen referral if there is
a risk of tissue loss.
10. Antibiotics or steroids are not indicated.
If a vision change occurs, an ophthalmologist
should be notified immediately and a retrobulbar
hyaluronidase injection should be done with
1 hour.
SUMMARY
HA fillers have expanded treatment option for
facial aging and are often combined with other
nonsurgical modalities such as neuromodulators
and skin treatments. They are accepted by the
public and should be offered by all plastic
surgeons who perform facial rejuvenation.
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