ORIGINAL ARTICLE

Complications Associated With Injectable

Soft-Tissue Fillers
A 5-Year Retrospective Review
Steven M. Daines, MD; Edwin F. Williams III, MD

Importance: Even when administered by experienced

hands, injectable soft-tissue fillers can cause various unintended reactions, ranging from minor and self-limited
responses to severe complications requiring prompt treatment and close follow-up.
Objectives: To review the complications associated with
injectable soft-tissue filler treatments administered in the
Williams Rejuva Center during a 5-year period and to
discuss their management.
Design and Setting: Retrospective medical record review in a private practice setting.

1, 2007, and December 31, 2011, and identified as having a treatment-related complication.
Results: A total of 2089 injectable soft-tissue filler treatments were performed during the study period, including 1047 with hyaluronic acid, 811 with poly-L-lactic acid,
and 231 with calcium hydroxylapatite. Fourteen complications were identified. The most common complication was nodule or granuloma formation. Treatment with
calcium hydroxylapatite had the highest complication rate.

Participants: Patients receiving injectable soft-tissue fillers and having a treatment-related complication.

Conclusions and Relevance: Complications are rare

following treatment with injectable soft-tissue fillers. Nevertheless, it is important to be aware of the spectrum of
potential adverse sequelae and to be comfortable with their
proper management.

Interventions: Injectable soft-tissue filler treatments.

Level of Evidence: 4.

Main Outcome Measures: A retrospective medical record review was conducted of patients undergoing treatment with injectable soft-tissue fillers between January

JAMA Facial Plast Surg. 2013;15(3):226-231.

Published online March 28, 2013.
doi:10.1001/jamafacial.2013.798

Author Affiliations: Dr Daines

is in private practice at Daines
Plastic Surgery in Newport
Beach, California. Dr Williams
is in private practice at the
Williams Center Plastic Surgery
Specialists in Latham,
New York.

OLUME ENHANCEMENT HAS

long been recognized as a

means to achieve facial rejuvenation. Various softtissue fillers have gained
popularity among aesthetic surgeons and
patients alike for their rapid and predictable results, relative ease of delivery, and
favorable safety profiles. Over the years,
as patients have developed an almost insatiable appetite for soft-tissue augmentation with injectable fillers, the pool of
providers has expanded from aesthetic surgeons and dermatologists to include health
care practitioners with little or no formal
training in aesthetic medicine.
A recent study 1 conducted by the
American Society of Plastic Surgeons revealed a 190% increase in the number of
soft-tissue filler treatments performed by
plastic surgeons between 2000 and 2011.
This astounding number does not reflect
the explosion in filler treatments admin-

JAMA FACIAL PLAST SURG/ VOL 15 (NO. 3), MAY/JUNE 2013

226

istered by noncore physicians and other

medical practitioners.
Even when administered by experienced hands, injectable fillers can cause
various unintended reactions, ranging from
minor and self-limited responses to severe complications requiring prompt treatment and close follow-up. The aesthetic
surgeon should not only have a firm understanding of the potential complications caused by injectable fillers but also
know when to intervene and be confident in managing the entire spectrum of
adverse sequelae.
In this study, we review 5 years of injectable filler treatments administered in
the Williams Rejuva Center to determine
the number and types of complications that
occurred and how they were managed. We
also searched the literature to provide treatment options for the more commonly observed adverse reactions.
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Author Aff
is in private
Plastic Surg
Beach, Cali
is in private
Williams C
Specialists i
New York.

Table. Breakdown of Injectable Soft-Tissue Filler Types and Their Associated Complications
No. (%) of Complications

Filler Type (Total No.

of Treatments)
Hyaluronic acid (n = 1047)
Poly-L-lactic acid (n = 811)
Calcium hydroxylapatite (n = 231)
All fillers (N = 2089)

Cellulitis

Nodule or Granuloma Formation

Skin Necrosis

Other

Total

0
0
4 (1.7)
4 (0.2)

1 (0.1)
5 (0.6)
1 (0.4)
7 (0.3)

0
0
1 (0.4)
1 (0.05)

1 (0.1)
1 (0.1)
0
2 (0.1)

2 (0.2)
6 (0.7)
6 (2.6)
14 (0.7)

METHODS

other 2 cases of nodules were palpable but not visible,

although the nodules were associated with a generalized induration of the midface in one of these patients.
Hyaluronic acid injections were the least likely to result in a complication in this series. One patient developed an inflammatory granuloma after treatment of her
lips with hyaluronic acid. A second patient experienced
the Tyndall phenomenon after injection of hyaluronic acid
to treat a tear trough deformity.

We queried the billing database to determine the total number

of soft-tissue injectable filler treatments administered in the Williams Rejuva Center between January 1, 2007, and December
31, 2011. Neurotoxin injections were not included in our analysis. The treatments were further categorized as hyaluronic acid,
poly-L-lactic acid, and calcium hydroxylapatite. In practice, we
routinely see all patients treated with hyaluronic acid or calcium hydroxylapatite 2 weeks after treatment for reassessment, whereas patients undergoing treatment with poly-Llactic acid are seen approximately 8 to 12 weeks after they are
treated. Any adverse reactions noted at a follow-up visit or reported at any other time by the patient are documented in their
clinic medical record, as well as in a monthly quality assurance report. To determine the total number of complications
associated with injectable soft-tissue fillers during this interval, we reviewed the medical records of all the patients identified in the quality assurance reports as having a filler-related
complication.

Injectable soft-tissue fillers offer patients noticeable and

immediate results, without the downtime associated with
traditional facial rejuvenation surgery. Whereas mild pain,
swelling, and bruising at the injection site are common
and expected consequences of these treatments, true complications arise less commonly.

RESULTS

VASCULAR OCCLUSION AND SKIN NECROSIS

Between January 1, 2007, and December 31, 2011, a total

of 2089 soft-tissue filler injections were performed in the
office for volume augmentation. These injectable treatments consisted of the following: 1047 hyaluronic acid,
811 poly-L-lactic acid, and 231 calcium hydroxylapatite. Complications were defined as adverse events not
considered expected sequelae of the injection itself (ie,
swelling, bruising, pain, and others). During the 5-year
period reviewed, 14 complications were identified: 2 involved treatment with hyaluronic acid, 6 with poly-Llactic acid, and 6 with calcium hydroxylapatite. The filler
type and number of complications are summarized in the
Table.
Calcium hydroxylapatite was the filler most commonly associated with complications in this series. Three
patients developed cellulitis at the treatment site, one of
whom developed cellulitis on 2 separate occasions following treatments administered 7 months apart. One patient developed a submucosal nodule visible beneath the
buccal mucosa, and another patient experienced partialthickness necrosis at the alar-facial junction following injection of calcium hydroxylapatite into her melolabial
folds.
Patients treated in the office with poly-L-lactic acid
experienced 6 total complications, including 5 cases of
subcutaneous nodules and 1 case of perioral dermatitis.
In a patient with a history of sarcoidosis, the nodules were
visible at rest, while in 2 other patients the nodules were
barely perceptible with extreme facial animation. The

Although rare, skin necrosis is a potentially devastating

complication of treatment with injectable fillers. Necrosis is caused by vascular compromise resulting from arterial or venous obstruction.2 The occlusion of blood flow
can be due to trauma to the vessel wall, inadvertent intravascular injection of the product, or a direct pressure
effect of the filling agent on the vessel causing obstruction of the vessel lumen.3,4 Furthermore, injectionrelated edema can compromise blood flow by contributing an external force on the vessel wall.
Arterial compromise is typically heralded by immediate-onset blanching and severe pain, whereas venous
obstruction frequently manifests with a delayed reticulated, violaceous appearance.2 If untreated, injectablerelated vascular compromise (IRVC) will progress to a
partial-thickness or full-thickness injury to the skin, leading to necrosis, skin slough, and scarring.
Various algorithms have been described to manage
IRVC, although none are supported by more than anecdotal evidence.2-8 If IRVC is recognized during the treatment session, the injection should immediately be
stopped, and an attempt should be made to aspirate the
product. Measures should then be implemented to improve blood flow and dissipate the agent. These include
aggressive massage, warm compresses, and the application of nitroglycerin to the affected area.6-8 When the culprit filler is hyaluronic acid, hyaluronidase can also be
administered to digest the offending product.9 A course
of aspirin has also been advocated in these circum-

COMMENT

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Figure 1. Superficial necrosis of the cheek and ala following calcium

hydroxylapatite injection to the left melolabial fold.

stances because of its anti-inflammatory and antiplatelet effects, and some authors have promoted the use of
topical oxygen therapy to facilitate an enhanced rate of
epithelialization.5
In cases of IRVC, prompt recognition and swift intervention can potentially prevent progression to necrosis.
If the IRVC cannot be reversed, local wound care should
proceed in the usual fashion, and the resultant mature
injury can be dealt with using traditional scar mitigation techniques.
In this series, 1 of 2089 injections (.05%) was complicated by IRVC. The sole instance occurred in a 43year-old woman who underwent calcium hydroxylapatite filler injection to the melolabial folds. Three days after
treatment, she developed an area of painful swelling
and gray to purple discoloration along the ala and superior portion of the nasolabial fold (Figure 1). Initially
presumed to be cellulitis, she was treated with multiple
courses of antibiotics. The acute presentation ultimately evolved into a small violet-hued patch of skin
that eventually resolved with topical hydroquinone, as
well as treatment with the pulsed dye laser. In retrospect, what was initially thought to be infectious in nature was likely an instance of IRVC resulting in superficial epithelial necrosis and prolonged postinflammatory
hyperpigmentation.
CELLULITIS AND BIOFILMS
Cellulitis can occur following treatment with soft-tissue
fillers due to inadvertent inoculation of bacteria into the
skin or entry of pathogens following temporary disruption of the skins barrier function. The head and neck
usually represents an anatomical safe haven against
postprocedural soft-tissue infections owing to its excellent blood supply and high rate of metabolism. However, cellulitis, abscess formation, and other infectious
complications can be seen following treatment with injectable fillers.
Biofilms are a potential mechanism in injectable filler
related complications and have been implicated in infections involving a diverse array of organ systems, especially in the setting of indwelling prosthetic devices or

Figure 2. Cellulitis of chin and jawline following treatment of the prejowl

region with calcium hydroxylapatite filler.

other foreign bodies.10 A biofilm typically consists of a

living bacterial colony that adheres to a foreign implant
and self-encapsulates with a complex extracellular matrix principally consisting of polysaccharides. Biofilms
are able to alter gene expression and change their microenvironment to evade the host immune system and
become antibiotic resistant. A common denominator for
the development of an injectable fillerrelated biofilm is
the need for bacterial or other infectious contamination
as an inciting event.11
Chronicity and recurrence of infection are hallmarks
of biofilms.11 Implants, especially those that are permanent (silicone), may become contaminated by a biofilm,
yet activation may not occur until hematogenous seeding or local trauma introduces a new load of bacteria, leading to an active infection. Although antibiotics and drainage may suppress an active infection, complete resolution
is rare (if not impossible) without removal of the implant and its associated biofilm. Some authors propose
a 2-week window during which bacterial contamination can occur and lead to biofilm formation.12 Avoiding additional injections in the region of the implant, as
well as dental procedures and facial trauma, will mitigate the risk of biofilm formation.13 Given the potential
for biofilm formation and the significant morbidity that
can result, a topic of future investigation should be
whether periprocedural prophylactic antibiotics offer an
improvement in infection rates.
In this series, 3 patients developed early postprocedural cellulitis, with all cases occurring following treatment with calcium hydroxylapatite in the perioral region or midface. In each instance, oral antibiotics were
promptly initiated, and complete resolution of symptoms ensued. Figure 2 shows a female patient who un-

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derwent treatment of the prejowl region with a calcium

hydroxylapatite filler. One day later, she developed an
area of erythema and swelling along the chin and lower
cheek that was indurated and warm to the touch. She was
diagnosed as having cellulitis and oral antibiotics were
started. The affected area blistered and desquamated and
was then treated with topical emollients until healing was
complete. The cellulitis completely resolved, with no longterm sequelae.
One patient developed 2 distinct episodes of cellulitis of the cheek after treatment sessions with calcium hydroxylapatite separated by 7 months. The second episode was more fulminant, with extensive erythema and
numerous small pustules. Given the recrudescence of her
infection during such a lengthy interval, the specter of
bacterial biofilm formation was considered. Fortunately, both infections resolved with conservative medical management.
NODULES AND GRANULOMAS
Subcutaneous nodules are a known complication of injectable fillers. Fibrotic nodules may arise from stimulatory products such as poly-L-lactic acid and calcium
hydroxylapatite. They tend to be painless, appear weeks
to months following treatment, and can last for years. In
most cases, they are palpable but cannot be seen. Although the nodules usually remain localized to the site
of treatment, a degree of migration can also occur. In extreme cases, they can become visible and are a source of
significant anxiety for the affected patient.14
Subcutaneous nodules have been reported in 0% to
40% of patients receiving poly-L-lactic acid.15,16 Localized accumulations of product are the most common cause
of nodules in patients receiving calcium hydroxylapatite or hyaluronic acid, whereas fibrotic nodules are usually seen with stimulatory products, such as poly-Llactic acid.17 Furthermore, certain anatomical sites are
known to present a higher risk for nodule formation, particularly the lower eyelid. Overall, a decrease in nodule
formation may be seen with subdermal injection, postinjection massage, a higher reconstitution volume, and a
longer latency between reconstitution and injection.18,19
In this series, one instance occurred of an accumulation of calcium hydroxylapatite visible beneath the buccal mucosa due to an inadvertent depot delivery of filler
in this region. Five cases of apparent fibrotic nodule formation also occurred in patients receiving poly-L-lactic
acid. One patient, a 66-year-old woman with a history
of sarcoidosis, underwent a series of 3 treatments during 5 months to the midface, melolabial folds, and prejowl regions. Six months after her final treatment, she
was noted to have diffuse beadlike nodules throughout
her treatment areas (Figure 3). Unlike the other 4 patients in the series who developed fibrotic nodules that
were only apparent on palpation, hers were visible at rest.
Although the bumps were not painful and demonstrated no other inflammatory characteristics, we surmised that the sarcoidosis may have had a role in her developing such an extensive distribution of nodules. She
was followed expectantly and showed no further nodule progression.

Figure 3. Diffuse visible subcutaneous nodules following treatment with

poly-L-lactic acid.

Although the prescribing information provided by the

manufacturer of injectable poly-L-lactic acid recommends reconstitution of 1 vial of product with 5 mL of
sterile water,20 we prefer an off-label 8:1 dilution. In addition, we reconstitute the product 48 hours before injection and use a laboratory vortex to agitate the mixture before its transfer for injection. We believe that these
simple measures in conjunction with meticulous injection technique are responsible for our very low rate of
nodule formation (0.6%).
Nodules can also represent an infectious, immune, or
inflammatory process resulting in granuloma formation.21 A granuloma can be differentiated from a fibrotic
nodule by its later onset, tenderness, swelling, possible
erythema, and occasional suppuration. Proposed causes
include biofilms, protein impurities, and irregularities of
surface microspheres.13 Histologically, these nodules show
a foreign-body response with epithelioid granulomas and
an inflammatory infiltrate surrounding the inert product.22 With poly-L-lactic acid, it is possible that processes resulting in localized inflammation, such as sunburn, trauma, or treatment of the skin with a laser, could
stimulate inflammatory nodule formation.
Hyaluronic acid fillers can also form intradermal granulomas that are characterized by abundant multinucleated giant cells surrounding the basophilic product.23 Hyaluronidase injections are the initial treatment of choice.9
One patient in this series developed an inflammatory
granuloma after undergoing augmentation of the upper
and lower lips with hyaluronic acid filler. Approxi-

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Figure 4. Inflammatory nodule of the left lower lip after treatment with
hyaluronic acid filler.

mately 2 months after injection, she noted painful swelling of the lower lip and was found to have nonfluctuant
swelling and induration confined to the left side of the
lower lip (Figure 4). She was treated with a course of
antibiotics and a tapering course of oral corticosteroids,
and the swelling completely resolved during the next few
weeks. Because of the delayed presentation, this was
thought to be an inflammatory granuloma, with biofilm
formation a possible culprit.
During the 5-year study period, a patient with chronic
inflammatory granulomas was managed who had undergone perioral silicone injections in another city. She was
seen in the office intermittently reporting pain, redness,
and swelling around her mouth and chin (Figure 5) and
was treated on each occasion with oral and intralesional
corticosteroids. This chronic waxing-and-waning inflammatory response is a hallmark of granulomas resulting
from soft-tissue injection of silicone. Because of the potentially devastating consequences associated with injectable silicone, we strongly recommend against its use
for volume augmentation.
CONCLUSIONS

A significant shortcoming of this study was the retrospective nature of its design. Furthermore, despite a policy
to see all patients treated with injectable soft-tissue fillers for scheduled follow-up visits and to document all
complications in the quality assurance reports, it is possible that we were unable to capture every adverse event
that occurred during the study period. Some patients may
have failed to recognize an adverse event, did not return
for their follow-up visits, or sought care for a complication with another physician.
Volume loss, an integral component of the facial aging process, is responsible for some of the telltale signs
of senescence. Therefore, volume restoration, alone or
in conjunction with other procedures, has become an important focus of most facial rejuvenation strategies. Softtissue injectable fillers have been and will continue to be
popular because of their minimal downtime, favorable
safety profile, and rapid and reproducible results. Nevertheless, injectables are not without risk. Todays ex-

Figure 5. Inflammatory nodules in the prejowl region due to silicone

injection.

panding population of patients seeking injectable softtissue fillers may be vulnerable to complications that go
underrecognized and undertreated due to physician shopping, limited follow-up care, and the lack of training
among many practitioners performing filler treatments.
Infection, fibrotic nodules, granuloma formation, and vascular compromise are possible sequelae that must be recognized and managed properly to prevent potentially permanent disfigurement.

Accepted for Publication: November 18, 2012.

Published Online: March 28, 2013. doi:10.1001/jamafacial
.2013.798
Correspondence: Steven M. Daines, MD, Daines Plastic
Surgery, 180 Newport Center Dr, Ste 158, Newport Beach,
CA 92660 (dainesmd@gmail.com).
Author Contributions: Dr Daines had full access to all
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Daines and Williams. Acquisition of data: Daines. Analysis and interpretation of data:
Daines. Drafting of the manuscript: Daines. Critical revision of the manuscript for important intellectual content:
Daines and Williams. Statistical analysis: Daines. Administrative, technical, and material support: Daines. Study supervision: Williams.
Conflict of Interest Disclosures: None reported.

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