Biochemistry, Physiology, and Tissue Interactions of

Contemporary Biodegradable Injectable Dermal Fillers

Jennifer L. Herrmann, MD,*† Rachel K. Hoffmann, MD, MSEd,‡ Chloe E. Ward, MD,x
Joshua M. Schulman, MD,k and Roy C. Grekin, MD¶

BACKGROUND Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and
rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydrox-
ylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of
the optimal injectable product based on the chemical composition, the physiologic interactions with sur-
rounding tissue, product longevity, and a thorough understanding of potential adverse reactions.

OBJECTIVE To review and describe the biochemistry, physiology, and tissue interactions of the most com-
monly used contemporary biodegradable dermal fillers.

METHODS A thorough review of the literature was performed with additional review of pertinent clinical
cases and corresponding histopathology.

RESULTS This article provides a comprehensive review of the biochemistry, physiology, and potential tissue
interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties
of each product and how they contribute to specific physiologic and adverse tissue reactions is described.

CONCLUSION Understanding of the innate differences in the physical properties, and physiologic responses
to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events.

The authors have indicated no significant interest with commercial supporters.

s public awareness and acceptance of fillers has

A grown, so have the number of injections performed
annually. In 2016, 2.6 million dermal filler injections
Endogenous Hyaluronic Acid

To fully appreciate the HA filler group, HA should be

reviewed in its native form. Hyaluronic acid is a natu-
were performed, an increase of 2% from 2015, and
ral glycosaminoglycan composed of glucuronic acid
298% from 2000.1 Soft tissue fillers offer a less invasive
and N-acetyl glucosamine disaccharide units (Figure
alternative with less downtime than traditional surgical
1). Up to 30,000 units can be linked together, forming
interventions. In the United States, the most commonly structures with molecular weights reaching 107 Da.2 It
used nonpermanent fillers are hyaluronic acid (HA), is highly water-soluble due to the presence of 1 salt
calcium hydroxylapatite (CaHA), and poly-L-lactic acid (2COO2 Na+) and 4 hydroxyl (2OH) groups per
(PLLA). Of the 2.6 million filler injections performed in disaccharide. The hydroxyl groups participate in
2015, 2.38 million (92%) were biodegradable, and 2 hydrogen bonding with water, stabilizing the solvated
million (77%) were HA.1 A thorough understanding of state. The salt group dissociates, resulting in a more
the differences between the biology, mechanisms of favorable, lower energy state. Hyaluronic acid sur-
action, and tissue reactions allows clinicians to rounds extracellular spaces, and is associated with
successfully and safely use these products. proteins and cells.3–6 It is a component of the dermis,

*Moy-Fincher-Chipps Facial Plastics/Dermatology, Beverly Hills, California; †Divison of Dermatology, Harbor-UCLA

Medical Center, Torrance, California; ‡Department of Dermatology, New York University School of Medicine, New York,
New York; xDivision of Dermatology, University of Ottawa, Ottawa, Ontario, Canada; kDermatopathology Service,
Northern California Veteran Affairs Health Care System, Sacramento, California; ¶Department of Dermatology,
University of California, San Francisco, San Francisco, California

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2018;0:1–13 DOI: 10.1097/DSS.0000000000001582

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 CONTEMPORARY DERMAL FILLERS

Streptococcus equi species of bacteria and purified by

alcohol precipitation to remove reactive antigens.17
However, this product should not be used in people
with a known hypersensitivity to streptococcal or
gram-positive bacteria, or in patients with known
lidocaine hypersensitivity, for products containing
lidocaine. Hylaform fillers are composed of purified
HA derived from rooster combs and are contra-
indicated in patients with known hypersensitivity to
avian proteins.

Figure 1. Hyaluronic acid (HA) disaccharide. Hyaluronic

acid polymers are derived from HA disaccharides. Cross-Linking

To overcome the short half-life of free HA polymers,

vitreous of the eye, hyaline cartilage, synovial joint
manufacturers cross-link HA units using 1,4-
fluid, and umbilical cord.7,8 Its biologic functions
butanediol diglycidyl ether (BDDE), divinyl sulfone,
range from structural support to embryonic develop-
or 2,7,8-diepoxyoctane (DEO).17 Cross-linking sta-
ment, cellular proliferation and differentiation, cell
bilizes the superstructure through intermolecular
signaling, and wound healing.2,9,10 Critical to these
bonds, slowing enzymatic and free radical degrada-
functions are its helical structures that can be modified
by pH, neighboring proteins, and macromolecules. tion. Note that non–cross-linked HA is liquid. Cross-
linking of fluid HA provides structure and adhesive
An average human body contains about 15 g of HA, stick, creating a gel.18 BDDE, the most commonly used
half of which is located in the skin.11 In the dermis, the cross-linking agent, is considered safe and non-
high flexibility of HA polymers and their hydrophi- reactive.19 Trace residual amounts of unreacted BDDE
licity enables them to fill empty spaces within the remain through purification only. In Allergan’s range
extracellular network.12 Through a dynamic exchange of fillers, the remaining unreacted BDDE is reported at
of water molecules with its environment, HA hydrates less than 2 parts per million.19 The unreacted BDDE
and cushions the skin. Enzymes such as hyaluronidase epoxide groups are neutralized over time through
and free radicals continuously degrade free HA poly- hydrolysis. The degradation by-products of cross-
mers. Cleaved fragments are cleared by the lymphatics linked HA, uncrosslinked HA, and unreacted BDDE
and ultimately converted to carbon dioxide and water have all been described as harmless at the concen-
in the liver. The half-life of native HA is 1 to 2 days.7,13 trations found in fillers, or are already found in the
Although HA is abundant in neonatal skin, pro- skin.19 There remains controversy, however, as to
duction declines with age, resulting in a structurally whether cross-linkers can introduce toxicity.8,22
weakened dermis and visible signs of aging.14 Researchers are now considering potential alternative
cross-linking agents, such as urea.8
Exogenous Hyaluronic Acid

Because the basic monomeric unit of HA does not Cross-linking is measured as the percentage of disac-
show specificity for any organ or species, HA is con- charide units bound to a cross-linking molecule. For
sidered immunologically inert.15 Reports of delayed example, a 1% cross-linked gel has 1 cross-linking
hypersensitivity reactions are rare, estimated to be less molecule for every 100 HA monomers. Higher degrees
than 1 in 5,000.16 Such reactions are likely related to of cross-linking translate to stiffer gel products resis-
impurities in the manufacturing process. Excellent tant to deformation.20 Note that exceptionally high
host tolerance as well as its viscoelastic and hydrating percentages of cross-linking may decrease product
properties make HA an ideal soft tissue filler. In the hydrophilicity. Rarely, this can provoke a foreign
exogenous form, HA is synthesized primarily from body reaction by the host’s immune system, which

2 DERMATOLOGIC SURGERY

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HERRMANN ET AL

could be further compounded by increased longevity the hardness of a product.8,24 These rheologic prop-
from cross-linking.20 erties provide a framework for understanding how
shear stresses, vertical forces, and compression forces
Particle Sizing from muscle movement may deform a filler
product.8,24
Although cross-linking is critical to creating a lasting
HA product, the process effectively creates a large gel-
Dermal fillers must be viscoelastic (G9 < G*) to inject
like mass that must be “sized” to pass through a nee-
under high strain through a needle, yet remain elastic
dle.17 Sizing can be accomplished using sieves or
to provide lasting results resistant to the shear defor-
homogenization, creating biphasic and monophasic
mation forces in soft tissue.24 Split-face trials have
gels, respectively. Biphasic or particulate products
shown that the ideal nasolabial fold correction
consist of cross-linked particles with an average par-
requires a smaller volume of a higher G9 filler.25–27
ticle size proportional to the grade of sieve used.21 The
However, gels with a higher G9 may feel firmer under
particles are suspended in free or minimally cross- skin because they resist deformation. This can lead to
linked HA, which acts as a lubricant, enhancing ease of more discomfort and swelling than with lower G9
injection. The G9 of biphasic gels is high and thus they products.21 The addition of lidocaine can enhance
are harder.8 Particle size influences injection locations, patient comfort during injection without substantially
depth, injection fluency, and product degradation compromising the rheologic properties of the filler.29
times. Products with larger particle sizes are typically
used for deeper injections, are stiffer to inject, and last Cohesivity
longer in tissue.20 Monophasic or nonparticulate HA
gels are monodensified if cross-linked once, or poly- The cohesivity of the gel refers to the tendency to hold
densified if continuously cross-linked.21–23 These form or shape under stress, proportional to the degree of
products are sized through homogenization, yielding attraction between the cross-linked HA units. It increases
gels with a smooth consistency, a broader distribution with both cross-linking degree and HA concentration.8
of particle size, and a lower G9 value (see next sec- Low cohesivity between the gel particles can lead to
tion).23 As such, they are softer and more easily separation from the deposit and filler migration.24 A
injected than biphasic products.8 Currently, only correlation between filler viscosity, and the pattern and
Juvéderm has monophasic, nonparticulate products. degree of tissue integration has been shown in ultra-
sound studies.25 Fillers with low cohesivity are often
Rheology—Hardness and Viscosity preferred for correction of small rhytides because they
are easier to mold and spread evenly in the skin. High-
Rheology, the study of flow and deformation of cohesivity fillers, however, are better suited for revolu-
materials between liquids and solids, is used to mizing larger areas of loss.24 Efforts have been made to
understand the mechanical properties of HA fillers and quantify the viscosity of various fillers,30 including the
their implantation into soft tissue.8,24 The particle size, recently developed 5-point Gavard–Sundaram Cohe-
HA concentration, and cross-linking all influence the sivity Scale, which the authors report reproducibly
rheology of a product.21 Several concepts are used to measures filler cohesivity.25 This reference scale classifies
describe the gel properties of fillers: G* (the complex HA fillers into high cohesivity groups (Belotero Balance;
modulus) measures the total energy needed to deform Merz Inc., Raleigh, NC) with cohesive polydensified
a material during sheer stress, and reflects the hardness matrix technology (CPM), medium-high cohesivity
of a gel. G* is calculated from a summation of G9 (the (Juvéderm Ultra XC and Ultra Plus XC; Allergan, Irvine,
elastic modulus or storage modulus) and G$ (the vis- CA) with Hylacross technology, low-medium cohesivity
cous or loss modulus), which are determined by (Juvéderm Voluma XC; Allergan) with Vycross tech-
a rheometer. G9 measures the elasticity of a material or nology, and low cohesivity (Restylane Lyft; Galderma
how much it can recover its shape after shear defor- Laboratories, L.P., Fort Worth, TX) with nonanimal
mation (G9G*).24 G9 is thus often used to quantify stabilized hyaluronic acid (NASHA) technology.

[Link]MONTH 2018 3

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

4
DERMATOLOGIC SURGERY

CONTEMPORARY DERMAL FILLERS

TABLE 1. Properties of FDA-Approved Hyaluronic Acid Fillers.†

Cohesivity
Particle Size Score
HA Conc. (mm); Mono (at 95 s)25/
Product Indicationx,28 Cross-linking (mg/mL) vs. Biphasic (gm force)29 G9 (Pa) Durationk,34
Hyaluronic acid with
lidocaine (0.3%)
Juvéderm Vollure Mid to deep dermis, moderate BDDE; Vycross 17.5 (n/a); mono (2)/30 34029 18 mo
XC (Volift in to severe wrinkles and folds
Europe) (i.e., NLF); age 21+ (yr).
Juvéderm Volbella Lip augmentation, perioral BDDE; Vycross 15 (n/a); mono (2)/19 16030/27129 12 mo
XC rhytides; age 21+.
Juvéderm Voluma Deep (subQ or supraperiosteal) BDDE; Vycross 20 (n/a); mono 1.3/40 39829 24 mo
XC injection for cheek
augmentation; age 21+.
Juvéderm Ultra XC* Mid to deep dermis for BDDE; 24 (n/a); mono 4.1/96 2825/17021/20729 12 mo
correction of moderate to Hylacross;
severe facial wrinkles and 9%8
folds (i.e., NLFs), lip
augmentation; age 21+.
Juvéderm Ultra Mid to deep dermis for BDDE; 24 (n/a); mono 4.1/112 7525/10518/20021/26329 12 mo
Plus XC* correction of moderate to Hylacross;
severe facial wrinkles and 11%8
folds (i.e., NLF).
Restylane Refyne Mid to deep dermis for BDDE; 20 (2); Bi (2)/(2) (2) 12 mo
and Defyne moderate to severe facial XpresHAn
wrinkles and folds (i.e., NLF); (aka OBT)
age 21+.
Restylane Lyft with Moderate to severe facial BDDE; NASHA; 20 Variable, avg 1.3/(2) 54125/58818 12 mo
lidocaine wrinkles and folds (i.e., NLF), (2) 650; Bi
(previously subcutaneous to
Perlane)* supraperiosteal implantation
for cheek augmentation; age
21+.
Restylane Silk Lip augmentation and perioral BDDE; NASHA 20 Bi (2)/(2) (2) 12 mo
rhytides; age 21+.
© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

TABLE 1. (Continued )

Cohesivity
Particle Size Score
HA Conc. (mm); Mono (at 95 s)25/
Product Indicationx,28 Cross-linking (mg/mL) vs. Biphasic (gm force)29 G9 (Pa) Durationk,34
Restylane-L Lip augmentation, mid to deep BDDE; 20 30018,21; Bi 1/(2) 66018,21 12 mo
Injectable Gel* dermis for correction of NASHA; 1%8
moderate to severe facial
wrinkles and folds (i.e., NLF);
age 21+.
Prevelle Silk Mid to deep dermis for DVS; 20%8 4.5–6 350; Bi (2)/(2) 230–260,18 w/o 4 mo
(Hylaform)*‡ correction of moderate to lidocaine (Hylaform)
severe facial wrinkles and 140–22021
folds (i.e., NLF).
Hydrelle (Elevess) Mid to deep dermis for BCDI 28 20021; Bi (2)/(2) 32921 6 mo
correction of moderate to
severe facial wrinkles and
folds (i.e., NLF).
Hyaluronic acid
Captique Injectable Mid to deep dermis for DVS; 20%8 4.5–6 50021; Bi (2)/(2) (2) 6 mo
Gel moderate to severe facial
wrinkles and folds (i.e., NLF).
Belotero Balance Injection into facial tissue to BDDE; CPM; (2) 22.5 (2); Bi 5/(2) (2) 6 mo
smooth wrinkles and folds,
especially around the nose
and mouth (i.e., NLF).

Vycross—links both high and low molecular-weight hyaluronic acid; Hylacross—various degrees of cross-linking of mainly high molecular-weight hyaluronic acid; XpresHAn (aka OBT)—
Optimal Balance Technology—combines a varied number of contacts between HA molecules with differently sized gel particles to achieve different results (information from product websites).
*denotes there is an FDA-approved version without the addition of lidocaine that is not listed but has similar properties.
†not all FDA-approved fillers are listed.
‡Modified avian HA (rooster comb) source; others synthesized from Streptococcus bacteria.
xplease refer to most up to date FDA indication prior to treatment.
kStudies have shown longer duration in clinical practice.34
(2), information not available; avg, average; BDDE, 1,4-butanediol diglycidyl ether; BCDI, p-phenylene bisethyl carbodiimide; CMP, cohesive polydensified matrix technology = cross-linked HA

HERRMANN ET AL
sizes with variable densities; DVS, divinyl sulfone; FDA, Food and Drug Administration; HA, hyaluronic acid; n/a, not applicable; NASHA, nonanimal stabilized hyaluronic acid; NLF, nasolabial
[Link]MONTH 2018

fold; w/o, without.

5
 CONTEMPORARY DERMAL FILLERS

Molecular Weight

Molecular weight also determines the biologic and

physicochemical properties of HA.8,31 Molecular
weight of HA is proportional to the number of
repeating disaccharides (Figure 1). There are low
Figure 3. Poly-L-lactic acid (PLLA). (A) L-lactic acid mole-
molecular-weight forms of HA, and high molecular- cule. (B) Poly-L-lactic acid is composed of repeating L-lactic
weight forms, greater than 1,000 kDa. Most cosmetic acid units.
HA products contain high molecular-weight polymers
and range from 500 to 6,000 kDa.18 Juvéderm Vol- reported toxicities.35 The microspheres are designed
uma XC, however, mixes high molecular-weight pol- with macropores or micropores. Macroporous CaHA
ymers with some low molecular-weight polymer is osteoinductive and readily permits fibrovascular
chains, using Vycross technology to improve cross- ingrowth through pores that reach up to 500 mm in
linking efficiency.29 This product lasts up to 24 diameter.36,37 Products with macroporous CaHA are
months,8,28,32 whereas most other Food and Drug used as a scaffold for repairing bony defects because
Administration (FDA)-approved HA fillers last they induce and are slowly replaced by new bone.36,37
between 6 and 12 months (Table 1).8,18,29,30,33 How- By contrast, cosmetic CaHA is microporous with
ever, it has been found that the results for other HA pores measuring 2 to 5 mm. This is too small to permit
fillers may have a longer lasting effect clinically, with osseointegration, and to date, there have been no
one study showing up to 18 months for Restylane documented cases of Radiesse forming bone after
(Galderma Laboratories, L.P.).34 Table 1 synthesizes injection into soft tissue.20
various FDA-approved HA filler properties. However,
in reviewing this table, it is important to consider the Poly-L-Lactic Acid
inherent variations in the reported rheologic proper-
Poly-L-lactic acid is an immunologically inert polymer
ties that are calculated at different times, under dif-
of L-enantiomeric lactic acid (Figure 3). Lactic acid
ferent conditions, yielding widely variable results.21
polymers have been used safely in medicine for 3
decades. They degrade into naturally occurring ster-
Calcium Hydroxylapatite eoisomers, which ultimately get excreted as carbon
dioxide and water.38–40 Cosmetic PLLA, commercially
Cosmetic CaHA is a synthetic, biocompatible, bio-
available as Sculptra Aesthetic (Sculptra Aesthetic;
degradable soft tissue filler, commercially available as
Galderma Laboratories, L.P.), comprises powdered
Radiesse (Radiesse; Merz Inc.). It is composed of
PLLA microparticles ranging from 40 to 65 mm,
CaHA microspheres suspended in an aqueous
mannitol, and sodium carboxymethylcellulose.40 The
glycerin–sodium carboxymethylcellulose carrier gel
product is reconstituted with sterile water, with or
(Figure 2). The high viscosity and elastic properties of
without lidocaine. It must be left to hydrate at room
the gel keep the 20 to 45 mm CaHA microspheres in
temperature for at least 24 hours to ensure that
solution before and during injection.35 Because CaHA
a smooth hydrocolloid suspension of PLLA particles in
is identical in composition to the mineral portion of
the carrier gel is achieved. If inadequately hydrated
bone and teeth, immunogenicity is negligible. It has
and super-concentrated PLLA is injected, nodule for-
been used in multiple medical applications with no
mation can occur.40

Physiologic Tissue Reactions

Physiologic reactions when implanted into the skin are

determined by the physical and biochemical properties
Figure 2. Calcium hydroxylapatite (CaHA). Cosmetic CaHA of soft tissue fillers. Ideally, an adverse reaction of the
microspheres are composed of calcium and phosphate. surrounding tissue should not occur. Inflammation

6 DERMATOLOGIC SURGERY

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HERRMANN ET AL

must be limited to prolong product longevity, yet more suitable for superficial placement. Large aggre-
controlled such that stimulation of collagenesis is gates of biphasic gels distort and push collagen bun-
predictable with stimulatory fillers. The body’s local dles causing tissue swelling and pain. Conversely, such
reaction to foreign body through phagocytosis is stretching of collagen fibers may stimulate fibroblasts
arguably the most important factor in determining to synthesize new collagen, a desired effect ultimately
filler longevity.20 In this process, tissue enzymes and enhancing the performance of the filler. At least one
free radicals breakdown filler product into fragments
report has documented increased dermal production
that are removed by circulating macrophages and
of collagen after injection of the biphasic NASHA
subsequently, lymphatic channels. Particle size, shape,
filler, commercially available as Restylane (Galderma
and hydrophilicity influence phagocytosis.20 In gen-
Laboratories, L.P.).45
eral, particles larger than 15 to 20 mm in diameter
resist phagocytosis. Hyaluronic acid, CaHA, and
Longevity of HA fillers is determined by particle size,
PLLA particles exceed this size range. With Radiesse,
manufacturing processes, volume, location of injec-
larger microspheres help prevent unwanted release of
tion, and host metabolism.20 Hyaluronic acid prod-
bone-resorptive cytokines by macrophages.20 For
ucts typically last 6 to 12 months. As mentioned,
particles smaller than 15 mm, shape becomes more
Juvéderm Voluma XC can last 24 months due to the
important for phagocyte recognition and attach-
cross-linking of high and low molecular-weight HA.8
ment.41 Hydrophilic particles better resist phagocy-
Smaller particles have a greater total surface area
tosis, but become increasingly hydrophobic if
exposed for enzyme and free radical degradation and
opsonized.20 For each of the major classes of injectable
fillers, manufacturers have manipulated particle
properties to maximize product efficacy and longevity
while minimizing undesired effects.

Hyaluronic Acid Tissue Integration

and Longevity

Once injected into the skin, HA provokes a mild

inflammatory reaction at the host-tissue border.42 This
is followed by a gradual fibrous ingrowth, which
anchors the gel to the surrounding host tissue, pre-
venting product migration.42,43 Manufacturing tech-
niques influence how fillers spread in tissue after
injection. Biphasic gels form large aggregates distrib-
uted regularly throughout the dermis and seem to push
apart collagen bundles (Figure 4A).23,44 Monophasic
monodensified gels form smaller aggregates, whereas
monophasic polydensified gels integrate uniformly
into the surrounding tissue, due to their broad spec-
trum of particle sizes (Figure 4B).23,44 Such differences
have clinical implications. If injected too superficially,
the larger aggregates of polyphasic gels may appear
blue beneath the skin as longer-wavelength light is
transmitted and shorter-wavelength blue light is
refracted. This is known as the Tyndall effect. Because Figure 4. Hyaluronic acid (HA) in vivo. (A) Biphasic HA
aggregates pushing apart dermal collagen bundles. (B)
monophasic polydensified gels fill extracellular spaces Monophasic HA dispersed in the dermis (Hematoxylin and
most similarly to endogenous HA, these products are eosin, original magnification ·100).

[Link]MONTH 2018 7

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 CONTEMPORARY DERMAL FILLERS

last a shorter time in tissue. Suspension in a large a shell of fibrin, fibroblasts, and macrophages. By 9
amount of uncrosslinked HA can also shorten half- months, microspheres become deformed, irregular,
life.23 When free HA is rapidly degraded, cross-linked and begin to disappear. They are broken down into
particles become exposed to attack. This can be dem- calcium and phosphate ions, which presumably get
onstrated in vitro by adding hyaluronidase to HA eliminated from the body, much like small pieces of
products. Biphasic gels liquefy more quickly than bone. Visible correction in the appearance of the skin
monophasic gels.46 Presumably, biphasic cross-linked and rhytides typically ranges from 10 to 14 months,
particles become more available to hyaluronidase after influenced by the amount of product injected and host
the non–cross-linked fraction is consumed. By con- metabolism.49
trast, enzymes penetrate only the outermost gel surface
of monophasic products; thus, more time is needed for Poly-L-lactic acid generates a similar subclinical
their breakdown. inflammatory response, ultimately resulting in colla-
gen production. Because the product is much more
Calcium Hydroxylapatite and Poly-L-Lactic Acid dilute than CaHA, the immediate “fill” effect dimin-
Tissue Integration and Longevity ishes more quickly as water is absorbed and PLLA
particles are distributed at lesser density. A capsule of
Both cosmetic CaHA and PLLA are considered stim-
macrophages, lymphocytes, mast cells, and fibroblasts
ulatory fillers. They both stimulate fibroblasts and
surrounds these particles at 1 month after implanta-
induce collagen synthesis.47 Unlike HA products that
tion.50 By 3 months, capsular thickness and cell density
fill tissue directly, stimulatory fillers volumize more
have decreased by 20%, and surrounding collagen
than they fill. Although injection creates the appear-
fibers have increased. At 6 months, the capsule is 20%
ance of immediate augmentation due to mechanical
thinner, composed almost entirely of collagen. By 18
expansion of the surrounding tissue, this effect is
months, the new collagen fibers persist, whereas the
transient.48 The carrier gel disappears over 1 to 3
inflammatory response has largely resolved.50 Com-
months, and a controlled subclinical inflammatory
pared with the scaffold of CaHA microspheres, PLLA
host response ensues, encapsulating product micro-
microparticles are degraded more slowly, creating
particles, leading to fibroplasia and eventual collagen
a prolonged inflammatory response. This leads to
biosynthesis (Figure 5). This ultimately creates grad-
more collagen synthesis and longer-lasting clinical
ual, naturally appearing volume that persists as filler
results. On average, correction is visualized for 18 to
particles degrade and inflammation fades.49
24 months.49

With cosmetic CaHA, fibrin has been shown to sur-

round product microspheres at 1 month after injec- Adverse Tissue Reactions
tion.43 At 3 months, microspheres are encapsulated by
With all soft tissue filler injections, erythema, swelling,
bruising, pain, and pruritus are common and occur
almost immediately. These reactions are caused by
disruptions in the vasculature and dermal structures.
With HA fillers, pain and swelling tend to increase
with concentration of HA. The hydration level of HA
products is below equilibrium; thus, they bind large
amounts of water when injected into tissue.17 Pain,
erythema, swelling, and pruritus typically self-resolve
within a few days. Lidocaine can be added to certain
products through manufacturing or reconstitution to
Figure 5. Poly-L-lactic acid (PLLA) fibrous capsule. Fibrous attenuate pain and pruritus. Although rare, inadver-
encapsulation of PLLA microparticles is responsible for
tissue volumizing by this stimulatory filler (Hematoxylin
tent intra-arterial injection can lead to tissue necrosis,
and eosin, original magnification ·40). scarring, and blindness in the most severe cases.40 A

8 DERMATOLOGIC SURGERY

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HERRMANN ET AL

thorough knowledge of anatomic vasculature, injec- common around the mouth as CaHA traverses the
tion of small amounts of product at slow speeds, and orbicularis oris muscle to form deposits under the
assessment for intra-arterial placement through needle submucosa of the inner lip.55,56 With PLLA, nodules
reflux can help avoid such catastrophic outcomes. usually result from incorrect reconstitution or poor
Some providers preferentially select HA products to injection technique. Shaking the product immediately
mitigate these risks, as hyaluronidase injections can be after adding water, suboptimal crystal hydration
done to breakdown the HA filler and potentially cir- leading to in vivo hydration, and a poor suspension at
cumvent a complication. Animal-derived hyaluroni- the time of injection can all result in an uneven distri-
dase products from ovine and bovine testicular bution of the product in the tissue, giving it a lumpy
hyaluronidase are commercially available as Vitrase appearance.57 Regarding the injection technique, care
(Vitrase; ISTA Pharmaceuticals Inc., Irvine, CA) and must be taken to avoid depositing a lump of excess
Amphadase (Amphadase; Amphastar Pharmaceut- product at the fan apex, or needle insertion point,
icals Inc., Rancho Cucamonga, CA), respectively. when a fanning motion is used to disperse product.
Hylenex (Hylenex; Halozyme Therapeutics, San Similarly, superficial injection of product and place-
Diego, CA) is the only FDA-approved recombinant ment into muscles should be avoided because com-
human hyaluronidase. It is considered less immuno- plications like those seen with CaHA can occur.
genic, and is often used in cosmetic practice.8 Adverse
reactions can be further divided into inflammatory and Inflammatory Adverse Reactions
noninflammatory, which may be immediate or
delayed. Infection
Adverse reactions after filler injection can be inflam-
Noninflammatory Adverse Reactions matory in nature. Although uncommon, infection
after filler treatment can occur. Infections can be
Noninflammatory reactions include the appearance of caused by bacteria, viruses, fungi, including Candida,
papules and nodules. Noninflammatory nodule for- or can be polymicrobial.58 The most common viral
mation early on may be related to injection technique, infection after injection of fillers is herpes simplex
excessive filler use, superficial placement, the use of an virus.46 In individuals with a history of oral herpes
inappropriate product for a given indication, sub- outbreaks, pretreatment with acyclovir, valacyclovir,
sequent muscular activity, product impurities, or or famciclovir is generally recommended.46 Nodule
irregularities of filler surfaces.51–54 With HAs, higher formation can be due to bacterial infections both in the
product viscosities and sticky syringes can result in early phase within a few weeks, or delayed months to
a sudden accidental release of too much gel, poten- years after injection.54 Erythema and pain can help
tially resulting in a nodule. Massage, hyaluronidase, differentiate infectious early nodules from non-
or simple incision and product expression is often inflammatory early nodules.53 If a single facial abscess
curative. Rarely, if a large amount of product is develops, the cause is usually skin contamination. If
deposited after depot injection, formation of a sur- multiple abscesses occur, the cause is most often from
rounding fibrous capsule occurs.46 This results in product contamination. Early on single facial abscess
a nodule that becomes more prominent with capsular is generally due to Staphylococcus aureus or Strepto-
contraction. Insertion of a large bore needle to break coccus pyogenes.52 Later-onset infections occurring
through the capsule and aspiration of product may be greater than 2 weeks after injections may be more
necessary for correction.46 generalized and may be due to atypical organisms
(such as mycobacteria and Escherichia coli). The risk
In addition to proper dilution and reconstitution, deep of infection can be mitigated by skin cleansing,
placement is critical with CaHA. Nodules from CaHA working in a clean space, and by following product
usually result from injections that are either too handling and storage guidelines. In some cases, the
superficial or from placement of product within the development of biofilms can complicate filler injec-
muscle fibers. Intramuscular placement is particularly tions.51,59 Biofilms are heterogeneous structures of

[Link]MONTH 2018 9

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 CONTEMPORARY DERMAL FILLERS

bacterial colonies irreversibly bound to foreign body reaction. In the case of PLLA, histologic examination
material.51 They secrete a self-made extracellular can help distinguish between nodules and granulo-
polymeric slime layer that interferes with immune matous inflammation. A nodule appears as a mass of
system recognition. This allows for up to 1,000-fold product surrounded by scattered foreign body giant
improved resistance to antibiotics.60,61 Because cul- cells, whereas a true granuloma appears as product
tures are typically negative, biofilms are best detected fragments surrounded by a palisaded wall of multi-
by molecular techniques such as polymerase chain nucleated giant cells, attempting to isolate the foreign
reaction.62 Biofilm bacteria can remain dormant for body from surrounding tissue (Figure 6).64 This is in
months to years before spontaneously becoming distinct contrast to the purposeful stimulation of
active, in the right environmental conditions. Biofilms subclinical inflammation that is responsible for fibro-
may cause abscesses, granulomatous inflammation, plasia and tissue augmentation seen with stimulatory
and recurrent infections.20 Treatment using antibiotics fillers. The occurrence of true granulomas is difficult to
and anti-inflammatories is sometimes successful. predict; however, they may occur more often in
Because biofilms are difficult to detect and eradicate, patients with known granulomatous disease. There
effort should be focused on their prevention. Antimi- have been reports of filler inducing granulomatous
crobial skin preparation and limited needle insertion plaques in sarcoidosis patients, with development of
through mucosal surfaces with high proximity to oral sarcoidal granulomas around filler particles (Figure 7).
flora are advisable. A study using a porcine skin model Treatment of granulomas is challenging. Intralesional
demonstrated no significant difference between alco- steroids, 5-fluorouracil, or a combinational approach
hol, povidone iodine, and chlorhexidine in reducing are frequently used.68 Surgical excision is usually not
the biofilm bacterial burden of S. aureus. The bacterial recommended, given their poorly defined clinical
burden was reduced 3 logs during the wiping process.
In the same study, using an in vitro injection model
with artificial silicone skin, the fanning technique was
found to increase the risk of transferring skin flora
compared with serial puncture and linear threading.
The risk of transferring viable bacteria was also
increased with lower-gauge (wider bore) needles and
superficial injections.63

Granulomatous Inflammation
Granulomatous inflammation after injection has been
reported with nearly all soft tissue fillers.64–66 How-
ever, the incidence of clinically significant granulomas
in practice is estimated to be only 0.01% to 0.1%.67
Unfortunately, the term granuloma has been used
inconsistently in the literature, ranging from clinically
palpable nodules to large inflammatory lesions
showing histological evidence of polymorphonuclear
foreign body type giant cells. Granulomatous inflam-
mation is most accurately defined as a systemic,
adverse, type IV hypersensitivity reaction.68 In a true
Figure 6. Poly-L-lactic acid (PLLA) granuloma. (A) A nodule
granulomatous process, all sites initially injected with of granulation tissue contains the product “foreign mate-
the same product should simultaneously react. The rial” from surrounding tissue (Hematoxylin and eosin,
original magnification ·20). (B) Multinucleated giant cells
presence of only a few foreign body giant cells on engulf individual PLLA microparticles (Hematoxylin and
histopathology does not constitute a granulomatous eosin, original magnification ·200).

10 DERMATOLOGIC SURGERY

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HERRMANN ET AL

References
1. ASPS, A.S.o.P.S. 2016 National Plastic Surgery Statistics: Cosmetic &
Reconstructive Procedure Trends. 2017. Available from: https://
[Link]/News/Statistics/2016/2016-plastic-
[Link]. Accessed June 27, 2018.

2. Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the

giant. J Biol Chem 2002;277:4585–8.

3. Bertolami CN, Berg S, Messadi DV. Binding and internalization of

hyaluronate by human cutaneous fibroblasts. Matrix 1992;12:11–21.

4. Day AJ, Sheehan JK. Hyaluronan: polysaccharide chaos to protein

organisation. Curr Opin Struct Biol 2001;11:617–22.

5. Evanko SP, Wight TN. Intracellular localization of hyaluronan in

proliferating cells. J Histochem Cytochem 1999;47:1331–42.

6. Knudson CB. Hyaluronan receptor-directed assembly of chondrocyte

pericellular matrix. J Cell Biol 1993;120:825–34.

7. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature,

distribution, functions and turnover. J Intern Med 1997;242:27–33.

8. Fallacara A, Manfredini S, Durini E, Vertuani S. Hyaluronic acid fillers

in soft tissue regeneration. Facial Plast Surg 2017;33:87–96.

9. Boraldi F, Croce MA, Quaglino D, Sammarco R, et al. Cell-matrix

interactions of in vitro human skin fibroblasts upon addition of
hyaluronan. Tissue Cell 2003;35:37–45.

10. Anderegg U, Simon JC, Averbeck M. More than just a filler—the role of
hyaluronan for skin homeostasis. Exp Dermatol 2014;23:295–303.

11. Romagnoli M, Belmontesi M. Hyaluronic acid-based fillers: theory and

practice. Clin Dermatol 2008;26:123–59.

12. Evanko SP, Tammi MI, Tammi RH, Wight TN. Hyaluronan-dependent
pericellular matrix. Adv Drug Deliv Rev 2007;59:1351–65.

13. Tammi R, Säämänen AM, Maibach HI, Tammi M. Degradation of

newly synthesized high molecular mass hyaluronan in the epidermal
and dermal compartments of human skin in organ culture. J Invest
Dermatol 1991;97:126–30.
Figure 7. Sarcoidal granulomatous response to CaHA
filler. (A) Sarcoidal granulomas developed in response to 14. Toole BP. Hyaluronan in morphogenesis. Semin Cell Dev Biol 2001;12:
79–87.
dermal CaHA injection with Radiesse in a patient with
known sarcoidosis (Hematoxylin and eosin, original mag- 15. Brandt FS and Cazzaniga A. Hyaluronic acid fillers: Restylane and
nification ·100). (B) Multinucleated giant cells contain Perlane. Facial Plast Surg Clin North Am 2007;15:63–76, vii.
product particles (Hematoxylin and eosin, original mag-
16. Friedman PM, Mafong EA, Kauvar AN, Geronemus RG. Safety data of
nification ·400). CaHA, calcium hydroxylapatite.
injectable nonanimal stabilized hyaluronic acid gel for soft tissue
augmentation. Dermatol Surg 2002;28:491–4.

borders, and the risk of fistula or abscess formation, 17. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers.
J Cosmet Laser Ther 2008;10:35–42.
and scarring.69
18. Kablik J, Monheit GD, Yu L, Chang G, et al. Comparative physical
properties of hyaluronic acid dermal fillers. Dermatol Surg 2009;35
(Suppl 1):302–12.
Conclusion
19. De Boulle K, Glogau R, Kono T, Nathan M, et al. A review of the
metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic
Since its inception, soft tissue augmentation has pro-
acid dermal fillers. Dermatol Surg 2013;39:1758–66.
gressed from filling lines to more comprehensively
20. Bentkover SH. The biology of facial fillers. Facial Plast Surg 2009;25:
sculpting faces and rejuvenating nonfacial sites. A better 73–85.
understanding of product differences in composition, 21. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers:
physical properties, and their associated tissue reactions a comprehensive review. Facial Plast Surg 2009;25:86–94.

allows clinicians to more thoughtfully select and cor- 22. Monheit GD, Prather CL. Juvederm: a hyaluronic acid dermal filler. J
Drugs Dermatol 2007;6:1091–5.
rectly inject products to achieve specific clinical goals.
23. Flynn TC, Sarazin D, Bezzola A, Terrani C, et al. Comparative
With better anticipation of tissue reactions, complica- histology of intradermal implantation of mono and biphasic hyaluronic
tions and undesired outcomes can be minimized. acid fillers. Dermatol Surg 2011;37:637–43.

[Link]MONTH 2018 11

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 CONTEMPORARY DERMAL FILLERS

24. Pierre S, Liew S, Bernardin A. Basics of dermal filler rheology. Dermatol 43. Gogolewski S, Jovanovi M, Perren SM, Dillon JG, et al. Tissue
Surg 2015;41(Suppl 1):S120–S126. response and in vivo degradation of selected polyhydroxyacids:
polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-
25. Sundaram H, Rohrich RJ, Liew S, Sattler G, et al. Cohesivity of
hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater
hyaluronic acid fillers: development and clinical implications of a novel
Res 1993;27:1135–48.
assay, pilot validation with a five-point grading scale, and evaluation of
six U.S. Food and Drug Administration-approved fillers. Plast Reconstr 44. Tran C, Carraux P, Micheels P, Kaya G, et al. In vivo bio-integration of
Surg 2015;136:678–86. three hyaluronic acid fillers in human skin: a histological study.
Dermatology 2014;228:47–54.
26. Moers-Carpi M, Vogt S, Santos BM, Planas J, et al. A multicenter,
randomized trial comparing calcium hydroxylapatite to two hyaluronic 45. Quan T, Wang F, Shao Y, Rittié L, et al. Enhancing structural support
acids for treatment of nasolabial folds. Dermatol Surg 2007;33(Suppl of the dermal microenvironment activates fibroblasts, endothelial cells,
2):S144–S151. and keratinocytes in aged human skin in vivo. J Invest Dermatol 2013;
133:658–67.
27. Monheit GD, Baumann LS, Gold MH, Goldberg DJ, et al. Novel
hyaluronic acid dermal filler: dermal gel extra physical properties and 46. DeLorenzi C. Complications of injectable fillers, part I. Aesthet Surg J
clinical outcomes. Dermatol Surg 2010;36(Suppl 3):1833–41. 2013;33:561–75.

28. US Food and Drug Administration. Soft Tissue Fillers Approved by the 47. Christensen LH. Host tissue interaction, fate, and risks of degradable
Center for Devices and Radiological Health. 2017. Available from: https:// and nondegradable gel fillers. Dermatol Surg 2009;35(Suppl 2):1612–9.
[Link]/MedicalDevices/ProductsandMedicalProcedures/
CosmeticDevices/WrinkleFillers/[Link]. Accessed June 27, 2018. 48. Burgess CM, Quiroga RM. Assessment of the safety and efficacy of
poly-L-lactic acid for the treatment of HIV-associated facial
29. Goodman GJ, Swift A, Remington BK. Current concepts in the use of lipoatrophy. J Am Acad Dermatol 2005;52:233–9.
Voluma, Volift, and Volbella. Plast Reconstr Surg 2015;136(5 Suppl):
139s–148s. 49. Schierle CF, Casas LA. Nonsurgical rejuvenation of the aging face with
injectable poly-L-lactic acid for restoration of soft tissue volume.
30. Borrell M, Leslie DB, Tezel A. Lift capabilities of hyaluronic acid fillers. Aesthet Surg J 2011;31:95–109.
J Cosmet Laser Ther 2011;13:21–7.
50. Humble G, Mest D. Soft tissue augmentation using sculptra. Facial
31. Chun C, Lee DY, Kim JT, Kwon MK, et al. Effect of molecular weight Plast Surg 2004;20:157–63.
of hyaluronic acid (HA) on viscoelasticity and particle texturing feel of
HA dermal biphasic fillers. Biomater Res 2016;20:24. 51. Rohrich RJ, Monheit G, Nguyen AT, Brown SA, et al. Soft-tissue filler
complications: the important role of biofilms. Plast Reconstr Surg 2010;
32. Carruthers J, Carruthers A, Tezel A, Kraemer J, et al. Volumizing with 125:1250–6.
a 20-mg/mL smooth, highly cohesive, viscous hyaluronic acid filler and
its role in facial rejuvenation therapy. Dermatol Surg 2010;36(Suppl 3): 52. De Boulle K. Management of complications after implantation of fillers.
1886–92. J Cosmet Dermatol 2004;3:2–15.

33. Sundaram H, Voigts B, Beer K, Meland M. Comparison of the 53. De Boulle K, Heydenrych I. Patient factors influencing dermal filler
rheological properties of viscosity and elasticity in two categories of soft complications: prevention, assessment, and treatment. Clin Cosmet
tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Investig Dermatol 2015;8:205–14.
Surg 2010;36(Suppl 3):1859–65.
54. Chiang YZ, Pierone G, Al-Niaimi F. Dermal fillers: pathophysiology,
34. Narins RS, Brandt FS, Dayan SH, Hornfeldt CS. Persistence of prevention and treatment of complications. J Eur Acad Dermatol
nasolabial fold correction with a hyaluronic acid dermal filler with Venereol 2017;31:405–13.
retreatment: results of an 18-month extension study. Dermatol Surg
55. Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety
2011;37:644–50.
and efficacy of calcium hydroxylapatite for soft tissue augmentation of
35. Graivier MH, Bass LS, Busso M, Jasin ME, et al. Calcium nasolabial folds and other areas of the face. Dermatol Surg 2007;33
hydroxylapatite (Radiesse) for correction of the mid- and lower face: (Suppl 2):S122–S126; discussion S126–7.
consensus recommendations. Plast Reconstr Surg 2007;120(6 Suppl):
56. Tzikas TL. Evaluation of the Radiance FN soft tissue filler for facial soft
55s–66s.
tissue augmentation. Arch Facial Plast Surg 2004;6:234–9.
36. Costantino PD, Friedman CD, Lane A. Synthetic biomaterials in facial
57. Vleggaar D, Fitzgerald R, Lorenc ZP. Understanding, avoiding, and
plastic and reconstructive surgery. Facial Plast Surg 1993;9:1–15.
treating potential adverse events following the use of injectable poly-L-
37. Berlin AL, Hussain M, Goldberg DJ. Calcium hydroxylapatite filler for lactic acid for facial and nonfacial volumization. J Drugs Dermatol
facial rejuvenation: a histologic and immunohistochemical analysis. 2014;13(4 Suppl):s35–s39.
Dermatol Surg 2008;34(Suppl 1):S64–7.
58. Cohen JL. Understanding, avoiding, and managing dermal filler
38. Vleggaar D. Soft-tissue augmentation and the role of poly-L-lactic acid. complications. Dermatol Surg 2008;34(Suppl 1):S92–S99.
Plast Reconstr Surg 2006;118(3 Suppl):46s–54s.
59. Sadashivaiah AB, Mysore V. Biofilms: their role in dermal fillers. J
39. Vleggaar D. Facial volumetric correction with injectable poly-L-lactic Cutan Aesthet Surg 2010;3:20–2.
acid. Dermatol Surg 2005;31:1511–7; discussion 1517–8.
60. Ceri H, Olson ME, Stremick C, Read RR, et al. The Calgary Biofilm
40. Andre P, Lowe NJ, Parc A, Clerici TH, et al. Adverse reactions to Device: new technology for rapid determination of antibiotic
dermal fillers: a review of European experiences. J Cosmet Laser Ther susceptibilities of bacterial biofilms. J Clin Microbiol 1999;37:
2005;7:171–6. 1771–6.

41. Champion JA, Mitragotri S. Role of target geometry in phagocytosis. 61. Anwar H, Strap JL, Chen K, Costerton JW. Dynamic interactions
Proc Natl Acad Sci U S A 2006;103:4930–4. of biofilms of mucoid Pseudomonas aeruginosa with tobramycin
and piperacillin. Antimicrob Agents Chemother 1992;36:
42. Christensen LH, Nielsen JB, Mouritsen L, Sørensen M, et al. Tissue 1208–14.
integration of polyacrylamide hydrogel: an experimental study of
periurethral, perivesical, and mammary gland tissue in the pig. 62. Watnick P, Kolter R. Biofilm, city of microbes. J Bacteriol 2000;182:
Dermatol Surg 2008;34(Suppl 1):S68–S77; discussion S77. 2675–9.

12 DERMATOLOGIC SURGERY

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 HERRMANN ET AL

63. Wang Y, Leng V, Patel V, Phillips KS. Injections through skin colonized 68. Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M,
with Staphylococcus aureus biofilm introduce contamination despite et al. Foreign body granulomas after all injectable dermal
standard antimicrobial preparation procedures. Sci Rep 2017;7:45070. fillers: part 1. Possible causes. Plast Reconstr Surg 2009;123:
1842–63.
64. Fitzgerald R, Vleggaar D. Facial volume restoration of the aging face
with poly-L-lactic acid. Dermatol Ther 2011;24:2–27. 69. Lam SM, Azizzadeh B, Graivier M. Injectable poly-L-lactic acid
(Sculptra): technical considerations in soft-tissue contouring. Plast
65. Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all
Reconstr Surg 2006;118(3 Suppl):55s–63s.
injectable dermal fillers: part 2. Treatment options. Plast Reconstr Surg
2009;123:1864–73.

66. Lemperle G, Morhenn V, Charrier U. Human histology and persistence Address correspondence and reprint requests to: Rachel K.
of various injectable filler substances for soft tissue augmentation. Hoffmann, MD, MSEd, Department of Dermatology, New
Aesthet Plast Surg 2003;27:354–66; discussion 367.
York University School of Medicine, 240 East 38th Street
67. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers: 11th Floor, New York, NY 10016, or e-mail:
review. Dermatol Surg 2005;31:1616–25. RachelKHoffmann@[Link]

[Link]MONTH 2018 13

© 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.