Keywords
Hyaluronic acid - Humans - Mesenchymal stem cell transplantation - Necrosis
INTRODUCTION
The use of facial fillers to provide adequate volume on depressed areas of the skin
and maintain a youthful rejuvenating appearance has been increasing remarkably in
recent years. Fillers have become very popular due to their safety profiles and the
low invasiveness, reversibility, and easy-to-handle characteristics.
When administered by experienced and licensed professionals, filler injections rarely
result in complications. Frequently, patients who experienced acute and chronic complications
have been treated by unlicensed individuals, and these complications, such as vascular
compromise and skin necrosis, are often significant and permanent. Patients with skin
necrosis referred to our department for treatment after filler injection have been
treated with skin grafts, local flaps, surgical debridement, and dressings with different
materials. However, the treatments have often resulted in unsightly skin loss, scarring,
and asymmetry.
Stem cells are known to self-renew and differentiate in order to regenerate multiple
tissues [[1]]. They have also been known to promote angiogenic processes and wound healing by
secreting angiogenic factors, differentiating into different cells contributing to
neovascular formation and stimulating cells that perform significant roles in wound
healing through mechanisms not yet fully understood.
We herein report 2 patients treated with adipose-derived stem cells (ADSCs) for skin
necrosis and acute inflammatory reaction after receiving filler injections for soft
tissue augmentation in the nose. To the best of our knowledge, there are no published
reports on the use of ADSCs for the treatment of acute complications after a filler
injection.
CASES
Case 1
A 25-year-old female received filler injection (Restylane, Q-med, Uppsala, Sweden)
on her forehead, glabella, and nose by a non-medical professional. She reported tenderness
and redness on the injected areas the day after the injection, which were treated
with intravenous antibiotics and hydrocolloid dressings. However, the wound continued
to aggravate, and when she was referred on the fifth day after injection, her wound
exhibited pus-like discharge, severe inflammation, and a 3×3 cm skin necrosis over
her nasal tip, lateral wall, and dorsum. Following her hospital admission, she underwent
an empirical intravenous antibiotic therapy and a debridement of necrotic tissues.
On the third day of admission, she received adipose-derived stem cell therapy on her
nose. Her postoperative course was uneventful, and she was discharged on postoperative
day 8. Her wound was completely re-epithelialized 10 days after injection and during
6 months of follow-up; there remained an unnoticeable linear scar on the skin and
soft tissue defect site without evidence of asymmetry or disfigurement due to scar
contraction on the nasal tip and nostril ([Fig. 1]).
Fig. 1 Case 1
(A) A 23-year-old female patient. Inflammation and necrosis with swelling, erythema,
and pus-like discharge in the nose dorsum and tip area. (B) After foreign body and
necrotic tissue removal. The nasal tip shows skin necrosis. (C) View 6 months postoperatively
after adipose-derived stem cell therapy. A linear scar remains only in the nose tip
area without scar contracture deformity.
Case 2
A 30-year-old woman underwent filler hyaluronic acid (HA) injection (Juvederm, Allergan,
Irvine, CA, USA) on her nasal dorsum and tip at a private clinic. Erythema and painful
swelling developed on the injected area from the nasal tip to the dorsum and lateral
wall on the day after injection, for which she received hyaluronidase (1,000 U) and
a steroid injection by the physician who had performed the original filler injection.
When she was referred to us on the fifth day after filler injection, the wound showed
multiple pustules, eschars, and regional necrosis on the nasal tip and dorsum. Debridement
of the necrotic tissue was performed and intravenous empiric antibiotics were administered.
On the eleventh day after the filler injection, she was admitted to our hospital and
adipose-derived stem cell therapy was administered to the wound. She was discharged
4 days after the stem cell treatment and the wound was completely reepithelialized
8 days after the injection without any evidence of complications. On follow-up, the
wound had healed with satisfactory results and only a slightly noticeable scar remained
(Pictures of this case were not included because the patient did not want them to
be publicly available).
Method
Adipose tissues were harvested from the patients' abdomens by using a Lipokit (Medikan
Inc., Seoul, Korea) for the lipotransplant and centrifuge. Fat tissues harvested by
liposuction were divided into 50 mL syringes and centrifuged for 4 minutes at 3,500
rpm. They were subsequently mixed with collagenase type II (Worthington industries,
Columbus, OH, USA) and liquefied by saline (20 mL) in the syringe. A mixture of harvested
fat and enzymes was incubated for 30 minutes at 37℃ with Maxstem (Medikan Inc.) and
centrifuged for 3 minutes at 3,500 rpm. After mixing the washing solution composed
of gentamicin, Hartmann solution, and 5% dextrose saline, the syringe was centrifuged
again for 3 minutes at 200 relative centrifugal force. The centrifuging and washing
procedure was repeated 3 times and the solution containing adipose-derived stem cells,
which amounted to 3 mL, was divided into 1 mL syringes ([Fig. 2]). Two mL of the solution were injected into the lesion at the subcutaneous and dermis
levels, and a wet dressing with the remaining 1 mL of solution was performed. Four
days after the procedure, the first dressing was applied with foam material and repeated
every 2 days.
Fig. 2 Schematic procedure showing isolation of adipose-derived stem cell
DISCUSSION
Paraffin was the first injectable material used by Gersuny in 1899 as a testicular
prosthesis in a man whose testicles had been resected [[2]]. Since then, many different materials such as paraffin, silicone, collagen, and
more recently HA products have been developed for soft tissue augmentation. Ideal
facial augmentation materials should be host-compatible to avoid inflammation and
easy to handle in order to avoid additional scars, thereby maintaining healthy and
natural skin. Among all the materials for soft tissue augmentation, HA fillers have
become the most popular.
HA was first named by Karl Meyer, who isolated an unknown substance from a cow's vitreous
in 1934, and it was subsequently demonstrated to exist in all species of animals,
including humans. HA is a naturally existing glycosaminoglycan that constitutes the
extracellular matrix of the connective tissues, supports structures, and provides
volume while binding water. Injecting HA fillers into the skin immediately suppliess
volume and rejuvenates the appearance of the skin. Moreover, they have good safety
profiles and reversibility, and do not require allergy tests. Complications of injectable
fillers are known to be uncommon clinically, but mild complications such as erythema,
swelling, tenderness, bruising, and lumps can develop temporarily. More serious complications,
which are rare, include the Tyndall effect, allergic reaction, nodule and granuloma
formation, and skin necrosis [[3]]. Skin necrosis is recognized as the most severe complication, and occurs secondary
to vascular compromise in the areas with direct or indirect interruption of blood
vessels. Hydrophilic actions of HA fillers can sometimes compress the facial artery,
angular artery, supratrochlear artery or branches that supply the nasal tip, alar,
and glabellar area. Hydrophilic actions are thought to be the main cause of skin necrosis
of the nasal area [[4]]. Although skin necrosis is very rare, it results in scarring, asymmetry, and permanent
disfigurement. In the early stage of necrosis, conservative management including topical
nitroglycerin and a heat lamp can be applied to stimulate vasodilatation. Hyaluronidase
is also known to be able to resolve HA with successful outcomes [[5]]. If not managed properly, necrosis can be aggravated, making wounds wider and deeper
without showing any improvement with conventional dressings. They may require more
invasive treatment modalities, such as surgical debridement and different types of
local flaps or grafts.
Stem cells are known to undergo self-renewal and can differentiate into multiple cell
phenotypes. Due to their reproducibility and multi-potency, they have been considered
to play a significant role in many clinical and preclinical fields. Stem cells can
be harvested from various mesenchymal sources, most commonly bone marrow, but harvesting
stem cells from the bone marrow causes pain and discomfort to patients and only a
relatively small number of cells can be harvested. In 2002, Zuk et al. [[6]] isolated stem cells from human adipose tissues capable of differentiating into
adipogenic, chondrogenic, myogenic, and osteogenic cells as an alternative source
to bone marrow-derived stem cells. ADSCs leave less donor site morbidity, yield a
greater number of mesenchymal stem cells, and are relatively easier to harvest than
bone marrow-derived stem cells.
Among the diverse properties of adipose-derived stem cells, many studies are focused
on their angiogenic effects in ischemic models. These include models of myocardial
infarction, heart failure, limb ischemia, diabetic foot, and arteriosclerosis obliterans.
Local injection and topical administration of ADSCs are also found to be effective
in enhancing the healing of ischemic skin flaps in animal models. ADSCs are thought
to affect ischemic tissues by secreting angiogenic factors that stimulate angiogenesis,
differentiation of ADSCs into vascular cells as functional components of neovasculatures,
and secretion of factors that enhance progenitor cell availability [[7]]. These angiogenic effects are thought to improve necrosis and inflammation of wounds
that are believed to be caused by vascular compromises after filler injection into
the nasal area. In addition to these angiogenic properties, Kim et al. [[8]] suggested that ADSCs promote human fibroblast proliferation via direct cell-to-cell
contact and paracrine activation of secretory factors that result in significant reduction
of the wound size and acceleration of re-epithelialization. The potential of ADSCs
that differentiate into multiple cell phenotypes, promote angiogenesis, and secrete
growth factors that have been thought to enhance wound repair could be applied to
acute complications of skin necrosis by vascular compromise developed after filler
injection.
In rare cases, dermal filler injection produces skin necrosis that leads to undesirable
results if not treated in a timely manner. The cases we present herein describe acute
complications of skin necrosis on the nasal area after filler injection. Usually,
skin defects developed after debridement of necrotic and inflammed tissues can be
reconstructed with different grafts or flaps, but donor site morbidity and scarring
can remain a permanent problem.
We herein report 2 cases of patients who achieved satisfactory results with successful
reconstruction of the inflamed and necrotized area. Following treatment with adipose-derived
stem cells, they healed with barely noticeable linear scars without complications
like, asymmetry, disfigurement, or pigmentation that would require further management.
This report suggests a potential therapeutic use of ADSCs for managing skin necrosis
that may occur after filler injection.
