Hindawi

BioMed Research International

Volume 2020, Article ID 8159047, 9 pages
https://doi.org/10.1155/2020/8159047

Research Article
Safety Assessment of High- and Low-Molecular-Weight
Hyaluronans (Profhilo®) as Derived from Worldwide
Postmarketing Data

Daniel Cassuto,1,2 Mara Delledonne,3 Giovanna Zaccaria,2 Immacolata Illiano,4

Andrea Maria Giori,3 and Gilberto Bellia 3
1
Private Practice, Jerusalem, Israel
2
Private Practice, Milan, Italy
3
IBSA Farmaceutici Italia Srl, Lodi, Italy
4
IBSA Institut Biochimique SA, Lugano, Switzerland

Correspondence should be addressed to Gilberto Bellia; gilberto.bellia@ibsa.it

Received 9 September 2019; Revised 30 March 2020; Accepted 21 May 2020; Published 22 June 2020

Academic Editor: Sheldon Lin

Copyright © 2020 Daniel Cassuto et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. At present, dermal fillers based on hyaluronic acid (HA) represent the most popular intervention of dermoesthetic
medicine for the treatment of skin aging. Recent studies have shown that the combination of HA chains of different lengths and
molecular weights improves tissue repair and regeneration through a synergistic mechanism. Profhilo® is a product available that
has been on the market since 2015 and is based on stable, hybrid, and cooperative complexes (HyCoCos) produced by means of
NAHYCO® Hybrid Technology, which is an innovative thermal process that rules out the use of any chemical reagents. The result
is a filler with high biocompatibility and low viscosity that favors optimal diffusion at the tissue level to obtain the target
bioremodeling of the facial contour. The objective of this review is to provide data from the overall postmarketing experience after
3 years of use and more than 40,000 patients treated with the medical device. Methods. All spontaneous postmarketing adverse
event (AE) reports received from physicians and healthcare professionals worldwide between February 9, 2015, and February 8,
2018, associated with the use of the studied medical device and sent to the IBSA global safety database were analyzed. Results. In
total, 12 adverse event reports were logged in the global database, and none were considered serious. Early-onset injection site
reactions, i.e., swelling, edema, redness, ecchymosis, and erythema, were the most frequently observed. Late-onset local reactions
(e.g., swelling, nodules) followed. The genesis of these reactions was considered, both by the reporting physician and IBSA, as being
local reactions of hypersensitivity and/or due to inappropriate injection techniques. In no case was the product held liable for
direct damage. All events resolved without any complications according to the treatment guidelines. Two late-onset reactions were
collected. Conclusions. Although underreporting of minor events cannot be ruled out, the overall number of reports is very low,
thereby supporting the high tolerability and safety of the product. After 3 years of postmarketing experience, the safety profile of
the studied medical device is favorable and consistent with the product information.

1. Introduction volume loss in the aging face, as well as improvement of

damaged and scarring tissues, and has contributed to the
Minimally invasive procedures have revolutionized the treat- increasing success of cosmetic surgery. The ideal soft tissue
ment paradigm for both facial and body rejuvenation and the filler is effective, nonimmunogenic, nontoxic, noncarcino-
recent history of cosmetic surgery. Initially, developed exclu- genic, nonmigratory, easily applied, nonpalpable, painless,
sively for the treatment of fine lines and wrinkles, the concept and long lasting [1]. Moreover, it should be low cost, provide
of dermal fillers has expanded to include the correction of lasting results and, while showing an acceptable persistence,
2 BioMed Research International

Table 1: HA dermal filler AEs.

Early-onset AEs (<72 hrs) Late-onset AEs (>72 hrs)

(i) Late infection: biofilm and fibrosis
(i) Injection site reactions: edema, pain, erythema, itching, bleeding, ecchymosis
(ii) Inflammatory nodule or granuloma
(ii) Displacements: lumps, asymmetries, contour deformities (iii) Noninflammatory nodule
(iv) Altered pigmentation
(iii) Hypersensitivity reaction
(v) Scarring
(iv) Early acute infection: HSV, abscess, cellulitis
(v) Tyndall effect
(vi) Thromboembolism

ought to be easy to remove if necessary. Hyaluronic acid der- larger volumes and layering techniques, new classes of prod-
mal fillers have most of these ideal characteristics [2]. ucts, and repeated treatment will most likely result in an
As a linear polysaccharide composed of repeated disac- increase in the number of complications, even with an expe-
charide units of glucuronic acid and N-acetylglucosamine, rienced physician.
hyaluronic acid (HA) forms an integral part of the natural Many factors may lead to AEs after dermal injection with
extracellular matrix and is found in high amounts in sev- hyaluronans [10–17]:
eral connective tissues, including the skin, vitreous humor
of the eye and synovial fluid [3]. Due to its hygroscopic (i) HA is obtained from the fermentation of bacteria,
property, biocompatibility, and reversibility, HA is cur- which may be a source of impurities
rently the most popular dermal filler used to replace vol-
ume loss due to aging. Therefore, over the past decades, (ii) The breakdown products of HA crosslinked fillers
various forms of HA fillers have been developed, each hav- in vivo could likewise elicit hypersensitivity
ing different characteristics, such as the type and degree of reactions
crosslinking, gel viscosity, gel hardness, gel consistency,
(iii) Differences in water-binding capacity among prod-
extrusion force, total HA concentration, and duration of
ucts could be relevant to localized reactions such as
presence in the skin [4]
pain and swelling
A role for HA chains of different lengths has been
reported in wound repair, especially considering the simulta- (iv) Patient history and anatomical characteristics repre-
neous occurrence of both high- (H-HA) and low- (L-HA) sent predisposing factors in the occurrence of AEs
molecular-weight hyaluronan at an injury site in vivo. The
effect of H-HA, L-HA, and the HHA/L-HA HyCoCos on (v) Complications may be the consequence of relevant
wound closure was tested in keratinocyte cell monolayers, product-related factors, such as the concentration
where these compounds provided faster regeneration and and rheologic properties of the filler, as well as the
wound closure that was achieved in half the time of H-HA manufacturing processes (e.g., purification)
stimulated-cells and 2 [5] fold faster than the control. The (vi) A key role is played by the clinician, who has full
outcomes of this research showed that, at both high and control over the injection technique, as well as
low concentrations, hybrid complexes performed better than procedure-related factors, specifically, the depth,
HA alone, thus suggesting their potential as medical devices volume, speed, and accuracy of the injection. HA
in both esthetic and regenerative medicine [5]. In the US, filler complications can be divided into early (which
esthetic procedures with HA dermal fillers were rated as the typically appear within hours to days post proce-
second most popular nonsurgical procedure in 2017 by The dure) and delayed onset complications (which usu-
American Society for Esthetic Plastic Surgery, and statistics ally develop weeks to years post HA filler injection),
worldwide confirm its medical use globally as well as the dra- as shown in Table 1
matic expansion of this market [6].
The advantages of HA dermal fillers are their ease of (vii) The most common side effects associated with HA
administration and rapid achievement of the desired esthetic injection are site reactions, including edema, pain,
improvement. When correctly performed, the safety profile erythema, itching, bleeding, and ecchymosis, which
of hyaluronic acid fillers is favorable, and the injection proce- normally last less than one week
dure is relatively safe [7]. (viii) Placing HA fillers too superficially might result in
The experience gained to date shows that the frequency the so-called Tyndall effect, which appears as a blu-
of AEs is currently relatively low compared to other kinds ish discoloration of the skin
of dermal fillers. However, other rare AEs can lead to severe
complications requiring monitoring, early detection, and (ix) Displacement of the filler material is mainly a con-
treatment [8, 9]. sequence of wrong technique or lack of experience
As the usage of HA dermal fillers is increasing due to of the physician and can lead to the early appear-
expanded indications and types of procedures, the use of ance of lumps, asymmetries and deformities
BioMed Research International 3

(x) Hypersensitivity reactions to HA injections PROFHILO® is indicated for the treatment of the face and
reported since the 1990s are now believed to have body, in particular for the treatment of the malar-zygomatic
been related to protein contaminants that were and submalar areas. An initial cycle of two sessions at 30-day
present in the first-generation HA preparations. intervals is recommended, followed if necessary by mainte-
As a matter of fact, the introduction on the market nance procedures every 2 months. However, it is suggested
of a hyaluronic raw material with a protein content to evaluate the specific PROFHILO® protocol according to
that is six times lower than the raw material previ- the patients’ degree of aging.
ously used has led to a reduction in the frequency of The product shows unique characteristics, such as a
hypersensitivity reactions high HA concentration (64 mg/2 mL), ideal manageability,
optimal tissue diffusion and low viscosity, and with a pre-
(xi) Infections can result from the breach in skin surface dominance of fluidity over elasticity (tan delta > 1). More-
integrity, and they can range from reactivation of her- over, several features provide HyCoCos with a high
pes simplex infection to the formation of an abscess biocompatibility profile. First, HyCoCos are produced by
and cellulitis, which may be caused by the late-onset means of the biosynthesis of a natural substrate without
formation of a biofilm, which is a collection of bacte- any further chemical modification; second, their thermally
ria surrounded by a protective and adhesive matrix. stabilized natural HA has a duration similar to that of a
Bacteria present in biofilms use the implanted filler weak crosslinked gel. Compared to other native HA formu-
as a surface on which to attach and excrete their lations, HyCoCos show the potential for a more effective
own matrix, which gives them the ability to survive, global bioremodeling performance, and the simultaneous
develop and resist antibiotic treatment. Long-lasting presence of high- and low-molecular-weight hyaluronan
biofilms can eventually lead to tissue fibrosis makes it a medical device that can be used in both esthetic
(xii) Foreign body granuloma is a chronic inflammatory and regenerative medicine. As proven by the research car-
reaction that entraps an alien element into the ried out by D’Agostino et al., the hybrid complex formed
body, preventing its migration and/or elimination. by H-HA and L-HA promotes wound healing of human
Even small amounts of residual protein contami- keratinocytes in vitro better than HA alone.5 Moreover, this
nants, after HA filler purification, potentially carry particular combination increases the expression levels of
a risk for hypersensitivity reactions and formation type I and type III collagens as well as elastin [18]. Finally,
of granulomas. The incidence of foreign body gran- Stellavato et al. proved that HyCoCos enhance adipogenic
uloma formation after the injection of HA fillers differentiation and proliferation of adipose-derived stem
ranges from 0.02% to 0.4%; cells (ASCs), which are used for recovery from local tissue
ischemia and scar remodeling and potentially improve fat
(xiii) The most severe complication regarding filler injec- tissue renewal [19].
tions is vascular occlusion due to unintentional Over the last 3 years, these in vitro data have been vali-
intravascular injection or embolization. Some ana- dated and integrated by clinical studies, which have con-
tomical areas, such as the glabella, alar base, nose, firmed both the efficacy and tolerability of the studied
and temple, are known to be associated with higher medical device [20–23].
risks for vascular complications In vitro and clinical trials have confirmed the innovative
characteristics of the product. Therefore, after 3 years of mar-
1.1. Profhilo®. Launched in 2015, Profhilo® is a novel HA keting use, the manufacturer has reviewed the postmarketing
preparation by IBSA that is based on stable hybrid coopera- safety data to provide a full and extensive description of the
tive complexes (HyCoCos), which is the first product devel- product profile.
oped by NAHYCO® Hybrid Technology, an innovative
thermal production process patented by IBSA. 1.2. Injection Technique. IBSA recommends 2 sessions with a
Package includes 1 prefilled syringe with 2 needles one-month interval by means of the BAP (Bio Esthetic
29 G × ½ (0.33 x 12 mm) in the following available Points) Techniques to minimize the risks and maximize the
volume:−2 ml prefilled syringe − 32 mg ðH − HAÞ + 32 mg product’s flowability.
ðL − HAÞ of hyaluronic acid sodium salt in 2 ml of buffered Five points for intradermal administration of PROF-
sodium chloride physiological solution. The prefilled syrin- HILO® must be identified as follows:
ges are sterilized by moist heat, and the needles are ster-
ilized with ethylene oxide. (1) Zygomatic Protrusion. It is recommended to stay at
The production process starts with a simple mixture of least 2 cm away from the lateral canthus (external
32 mg of high-molecular-weight HA (1100-1400 kDa) and corner) of the eye.
32 mg of low-molecular-weight HA (80-100 kDa). The mix-
(2) Nasal Base. A line connecting the nostril and tragus
ture is then stabilized by the abovementioned thermal process,
and a perpendicular line starting from the pupil must
which does not use crosslinking agents and consists of, first, a
be drawn to locate the injection point at the intersec-
high-temperature step, followed by a low-temperature step. tion of the 2 lines.
The result is a product that boosts both remodeling and
repair processes of tissues, even when scarring has occurred. (3) Tragus. It is recommended to stay at least 1 cm ante-
It also improves skin laxity of the face, neck, and body. rior to the inferior margin of the tragus.
4 BioMed Research International

Table 2: Sales details referring to the number of syringes sold (in EU and non-EU countries) and estimated patient exposure.

Period No. of syringes sold worldwide No. of patients exposed

2015-2016 46,943 (42,982 EU countries; 3,961 non-EU countries) 6,706
2016-2017 91,613 (80,162 EU countries; 11,451 non-EU countries) 13,088
2017-2018 158,201 (131,548 EU countries; 26,653 non-EU countries) 22,600

(4) Chin. A vertical line at the center of the chin and a 3. Results
perpendicular line one-third of the distance from
the top of the vertical line have to be drawn. From Table 2 shows the estimation on a yearly basis along with
the point of intersection, it is indicated to move worldwide sales data; the sales (and therefore the patient
1.5 cm towards the oral commissure to locate the exposure) almost doubled in the first and second periods
injection point. and increased again by almost twice between the second
and third periods. This reflects a general upward trend in
(5) Mandibular angle. The fifth point is located 1 cm the use of dermal fillers on a global scale.
above the mandibular angle. All reports received were assessed from quality and safety
points of view.
Then, 0.2 ml of product with the bolus technique must be Routinely, IBSA Farmaceutici Italia carried out investi-
injected in the deep dermal/subcutaneous levels. gations and analysis of the samples or batches available to
Injections should be followed by a gentle massage. identify the possible causes of the malfunction or of the
occurrence of any AEs. Table 3 reports the list of all AEs
2. Methods following the injection of the medical device, with their
From February 9, 2015, to February 8, 2018, IBSA Farmaceu- description and evaluation from a safety perspective.
tici Italia received spontaneous reports from physicians who 3.1. Quality Complaints. Overall, 18 quality complaints
used the studied medical device on their patients. The safety related to the use of the medical device were reported to IBSA
data were evaluated on an annual basis in relationship with Farmaceutici Italia. No adverse events or incidents were
sales data for the product worldwide. Therefore, three associated.
periods were identified for the analysis: February 9, 2015-
February 8, 2016; February 9, 2016-February 8, 2017; and 3.2. Safety Cases: Adverse Events. During the 3-year interval
February 9, 2017-February 8, 2018. period, 12 AE reports were received by IBSA Farmaceutici
Furthermore, all the adverse events were assessed based Italia, as shown in Table 3.
on their time to onset from the injection: All safety cases were received from Italy, Spain, and
Germany, which were the first, third, and fourth country
(i) Early onset, including ranked for sales, respectively, in the period 2017-2018.
All events were described by the reporting physician as
(i) immediate onset-within 24 hours nonserious and resolved with no sequelae, generally with
(ii) delayed onset: <=72 hours the use of a topical treatment (mainly corticosteroids and/or
antibiotics). In one case only, the outcome was unknown due
(ii) Late onset: >72 hours to loss to follow-up, despite the manufacturer’s numerous
attempts to contact the physician. No anomalies were
As reported in the product information, the current detected after sample investigation (when available).
posology for the use of the medical device is “an initial cycle In 3 out of 12 reports, the medical device was not consid-
of two treatment sessions at 30-day intervals, followed if nec- ered related to the AE description. In the other nine cases, the
essary by maintenance treatments every 2 months. However, injection of the product was regarded as a contributory ele-
it is suggested to evaluate the specific Profhilo® protocol ment, similar to other factors that may have likely played a
according to the patient’s degree of aging.” role in the onset of AE, e.g., administration procedure and
An estimation of the patient’s exposure was calculated the patient’s predisposition.
assuming that the highest number of syringes that could be
used by a patient for a cycle of treatment (of a year) was 4. Discussion
seven, i.e., 7. two during the first two months and then one
every two months. Accordingly, the number of patients Postmarketing safety data are very reassuring and confirm
exposed = number of syringes sold/7: the excellent safety profile of the studied medical device
Based on this assumption, the global cumulative patient resulting from its quality and manufacturing characteristics
exposure has been estimated to be 42,394 patients. and clinical trials. It is known that the results do not reflect
With the exception of one male patient (54 years of age), any of the percentages and the figures that could be described
all the other cases reported were female patients, aged in standard clinical trials. Therefore, these data should be
between 40 and 63 years. No cases were reported outside interpreted in this context taking into account the following
the European continent. points:
 Table 3: Detailed individual listing of AEs associated with Profhilo® 3.2% injection.

PT
Time Other suspect
demographic, AE description & medical evaluation Outcome
interval product
country
Edema at the injection site (zygomatic arch+suborbital area)→resulted
1-F, 63 yrs,
— from too hard massage after injection rather than from device itself; Topical treatment with a corticosteroid-recovering
Italy
medical device possibly related
Swelling localized at the cheekbones+submalar area 20 days after the 2nd
injection, followed by thickening of tissue→alternative causes, i.e., depth of
injection, amount of filler administered, location of the implant, process and Oral and topical steroid treatment+radiofrequency
2-F, Italy —
BioMed Research International

degree of degradation of the implant, subject’s predisposition & risk factors +azithromycin 500 mg for 2 wks-lost to follow-up
(i.e., anatomy, prior surgery, and/or filler treatment in the area); medical
device possibly related
Year 1
Edema of the face + periocular area after the 2nd injection→sensitization after
the 1st injection, diagnosed as an allergic reaction by the patient herself (a
nurse); the reporting physician supposed that the patient had been sensitized
3-F, Italy — 4 mg Bentelan IM-resolved
to the product during the first injection and therefore, she suggested the
occurrence of an allergic reaction during the second injection; a medical
device was possibly related
Hypertensive crisis+vertigo+wavelike nausea 5-6 hours after the
4-F, Germany injection→histamine intolerance: the patient ate fish before treatment. A Resolving
reaction reoccurred after another seafood meal, not related to the MD
Ecchymosis at the injection site with areas of telangiectasia Topical treatment with Kelarion cream–resolved. Only few
5-F, 57 yrs,
(with no pain, no swelling, and no dermal lesions) after the 2nd capillaries remained more visible in that area without the
Italy
injection→medical device possibly related appearance of depressed, hardened or inflamed areas
Maculopapular erythema+itching at the injection site subsequently diagnosed
6-M, 54 yrs, as an allergic reaction-15 days after injection→pretreatment with
Topical treatment with mometasone-resolved
Year 2 Spain chlorohexidine possibly causing precipitation with HA and hypersensitivity;
medical device possibly related
Swelling at the injection site (lateral side of the eyes + forehead) 6 days after
Botulinum
the injection of both products→BotToxA presumably blocked some
7-F, Germany neurotoxin A 3 ultrasound treatments-resolved
lymphatic vessels. The medical device was not related according to both the
subcutaneous
physician and IBSA
Mild and transitory hematoma at the injection
8-F, Italy — Topical treatment with arnica cream-resolving
site→medical device possibly related
Edema, intense red skin, marked hardening, mainly at the chin and malar
9-F, 59 yrs,
— level on the right side and nodular/granular at the cheek level→medical Azithromycin+deltacortene-resolved
Italy
Year 3 device possibly related
10-F, 40 yrs, Bilateral swelling more evident on the right side of the face→medical
— Ice+massage-resolved
Italy device possibly related
11-F, 54 yrs,
— Topical treatment with antinflammatory drug+laser-resolved
Italy
5
 6

Table 3: Continued.

PT
Time Other suspect
demographic, AE description & medical evaluation Outcome
interval product
country
Injection site reaction with redness→according to physician and IBSA, not
related to Profhilo® but to patient’s underlying disorder (couperose) and to
the concomitant cold weather
Skin eruption with redness, erythema and swelling at the injection site twice
after Profhilo® injection→the physician initially considered the AE to be
12-F, 47 yrs, After an AE at the 2nd injection: zamene
related to the topical application of Auriderm (vitamin K oxide) cream;
Spain 2 tbls (corticosteroid)-resolved
however, when the same reaction occurred after the 2nd injection the causal
role of Profhilo® could not be ruled out
F: female; M: male; yrs: years; IM: intramuscular; wks: weeks; tbls: tablets.
BioMed Research International
BioMed Research International 7

(i) First, cases reported to the manufacturer were a Patient exposure

25000
spontaneous initiative of the physician and/or other
users; therefore, underreporting of AEs cannot be 20000
ruled out. This is plausible for mild and expected
15000
AEs and much less likely for serious or severe AEs
following the awareness of the importance of report- 10000
ing AEs for the interest of both patients and doctors,
5000
as this contributes to better knowledge for the med-
ical community; moreover, in case of litigation, the 0
Period 1 Period 2 Period 3
reporting of AEs protects doctors
AE reporting
(ii) Second, because most AEs were successfully treated 6
by the medical doctor himself or herself and were 5
sometimes considered to be a consequence of an 4
inadequate injection technique, these events were
3
not promptly reported to the Manufacturer (failure
to report also occurred because certain AEs were 2
already described in the product instructions for 1
use); 0
Period 1 Period 2 Period 3
(iii) Finally, it is likely that in many cases, the patient is
properly informed by the physician on how to act Figure 1: Patient exposure and AE reporting.
in cases of the appearance of mild and transient AEs
Hence, our results cannot be compared with those
described in the context of any traditional research. According to the consensus statement by Philipp-
Furthermore, at the time this paper is being written, sim- Dormston et al. in 2017, preventing most AEs is possible by
ilar publications have not been identified in the context of adhering to a series of recommendations [25]. The cosmetic
dermo-esthetics; therefore, it is not possible to make any real surgeon should
comparisons with other similar products currently in use.
The decision to publish the results of this review is based (i) have a detailed knowledge of important anatomical
on the willingness to provide doctors with all data available to structures and vessels of the specific target injection
improve the knowledge of this medical device. sites, as well as of the injectable material and its
Despite an important increase in sales data, there is no properties
direct proportional number of AEs reported over the 3 years (ii) ensure formal sterile surgical preparation to prevent
considered, as shown in Figure 1. the introduction of bacteria and potential subse-
Twelve (12) case reports were collected; many of them quent biofilms
described the occurrence of AEs falling into the “early onset”
classification; only two cases reported two late-onset adverse (iii) administer injections slowly and react quickly to
events. patient pain or the occurrence of any unexpected
The events have been mainly described as “swelling, reactions
edema, redness, ecchymosis, and erythema”, particularly in (iv) use aspiration if possible and a blunt cannula in
the malar and submalar areas, which are notoriously the high-risk zones to lower the risk of intravascular
most prone to show such AEs due to their peculiar anatom- injection
ical features. In some other cases, the event occurred after
the second injection as a probable result of a “sensitization” On the other hand, the quality complaints reported
phenomenon that took place after the first treatment. In over the 3 years were more numerous than the safety cases
one case, the simultaneous administration of Botulinum (18 versus 12, respectively) but always in a very limited num-
Neurotoxin A was regarded as a contributing factor, even ber when compared to the number of products that have
though the combination of the studied medical device and been sold worldwide. Regarding this aspect, the manufac-
botulinum is considered suitable in particular as a treatment turer identified possible causes for some of the quality com-
for wrinkles localized in the forehead and in the neck, and it plaints which received (e.g., the breakage of some of the
has proven to be successful and well tolerated in some case components of the medical device during its use) a possible
reports [24]. However, all the reported cases were resolved incorrect technique of handling by the physician, which
in a short time following the recommendations that have could have emerged as a consequence of a not entirely ade-
been drawn up by panels of experts over the last few years. quate description on how to handle the components of the
This has been simplified and summarized in Table 4. product. In fact, during the reference period, the manufac-
Rare AEs and complications, other than those already turer has therefore decided to improve and make clearer
listed in the product instructions for use, were not reported and more complete this section of the information leaflet to
to the manufacturer. minimize these inconveniences.
8 BioMed Research International

Table 4: Recommendations in case of AEs occurring after dermal filler injection, according to the most recent guidelines.

AEs Treatment
Early onset (<72 hours)
(i) Bruising, edema, bleeding, redness, swelling Cold compresses, no exercise for 24 h
(ii) Tyndall effect Hyaluronidase ∗ and massage
(iii) Lumping, superficial placement Hyaluronidase ∗ and massage
(iv) Abscess Antibiotic (amoxicillin+clavulanate; cephalexin; ciprofloxacin); incision and drainage
Late onset (>72 hours)
(i) Displacement Hyaluronidase ∗
Hyaluronidase ∗ ; antibiotic therapy (clarithromycin+moxifloxacin; ciprofloxacin;
(ii) Nodule
minocycline) and steroid (in case of infection); excision
(iii) Biofilm Antibiotic therapy after culture
Hyaluronidase ∗ ; antibiotic therapy (clarithromycin+moxifloxacin; ciprofloxacin;
(iv) Granuloma
minocycline) and steroid (in case of infection); incision and drainage
(Adapted from Signorini et al. 2016 and W.G. Philipp-Dormston et al. 2017). ∗From 10 to 20 U single injection up to four injection points according to the
extension of the area.

Regarding published clinical data, four trials have investi- The numbers analyzed should therefore be taken with all
gated the efficacy and tolerability of the studied medical due caution, as it is likely that not all doctors reported all
device since 2015. the possible adverse events that their patients presented. In
addition, some patients who experienced mild symptoms
(v) Laurino et al. treated 11 women with two injections probably overcame them without consulting the physician.
of 2 mL of the product once a month for 2 months: Furthermore, not all reports have detailed the patient’s med-
mild AEs such as localized hematomas followed ical history or tracked subjects in the long term.
12.1% of procedures, and they disappeared after These elements undoubtedly represent limitations to the
2-3 days [20] data reported in this study. It is reasonable to assume that
there were mild symptoms that were successfully treated in
(vi) Abascal and Fernandez treated 30 women with
a higher number of cases. Therefore, the data presented in
64 mg/2 mL doses administered 30 days apart:
this study are likely to be underreported [26].
overall, three cases of ecchymosis and three cases
of pain of mild intensity were recorded; [21]
(vii) Beatini et al. evaluated 15 subjects who underwent 5. Conclusions
two treatments 4 weeks apart: two cases of bruising
and one case of swelling at the injection site, which The data presented herein validate the excellent safety char-
resolved within 2 days, were reported [22] acteristics of the studied medical device, which were already
highlighted in the clinical trials conducted so far. However,
(viii) Sparavigna and Tenconi monitored 64 women who it cannot be excluded that some AEs may not have come to
were injected with two doses using the BAP (Bio the attention of the manufacturer for different reasons. The
Esthetic Points) technique a month apart for 16 number of reports was fairly low, and there was no significant
weeks: 23% of subjects presented local minor and variation over the three-year period considered. Further-
temporary skin reactions [23] more, it can be assumed that the cases, which were not
reported, fell within the events listed in the product instruc-
Safety results seem to be consistent when compared with tions for use, and therefore, it can be stated with relative cer-
existing data in the literature. Stojanovič et al. carried out a tainty that use of the product did not lead to any unforeseen
systematic review of published medical literature on the or serious events, since in this case, the manufacturer would
effectiveness and safety of different HA fillers used to have been directly involved. It is important to emphasize that
enhance overall lip fullness. Twenty-two studies were the safety cases have remained steady despite the global sharp
included in the qualitative synthesis, with a total of 3965 sub- rise in product sales and consequently in the number of peo-
jects included. Hyaluronic acid fillers turned out to be an ple exposed. In the opinion of the physicians involved and of
effective and safe treatment. The most common adverse the manufacturer, no AEs were directly and exclusively
events were local reactions at the injection sites (swelling, related to the administration of the product itself but rather
contusion, bruising, pain, redness, and itching), and the were related to the injection technique used and some pecu-
majority of included subjects were satisfied with the results liar and unforeseeable characteristics related to the anatomy
and their physical appearance [26]. and physiology of the subjects. The facts that all cases had a
positive outcome (successfully resolved or resolving at the
4.1. Study Limitations. The study was based on spontaneous moment of the report), that only one patient was lost at fol-
reporting by the specialists who carried out the treatment. low-up, and that no quality complaints resulted in any AEs
BioMed Research International 9

give conclusive evidence of the biocompatibility, tolerability Journal Clinical Aesthetic Dermatology, vol. 3, no. 5, pp. 32–35,
and safety of the product. 2010.
[14] D. Cassuto, O. Marangoni, G. D. E. Santis, and L. Christensen,
Data Availability “Advanced laser techniques for filler-induced complications,”
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If requested, the safety database can be shared with [15] J. M. Lee and Y. J. Kim, “Foreign body granulomas after the use
editor/reviewers. of dermal fillers: pathophysiology, clinical appearance, histo-
logic features, and treatment,” Archives of Plastic Surgery,
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Conflicts of Interest
[16] A. P. Sclafani and S. Fagien, “Treatment of injectable soft tissue
MD, AMG & GB are employees of IBSA Farmaceutici Italia filler complications,” Dermatologic Surgery, vol. 35, Suppl 2,
Srl. II is an employee of IBSA Institut Biochimique SA. The pp. 1672–1680, 2009.
other authors declare that they have no conflicts of interest. [17] C. DeLorenzi, “Complications of injectable fillers, part 2: vas-
cular complications,” Aesthetic Surgery Journal, vol. 34, no. 4,
pp. 584–600, 2014.
Acknowledgments [18] A. Stellavato, L. Corsuto, A. D’Agostino et al., “Hyaluronan
hybrid cooperative complexes as a novel frontier for cellu-
The authors are grateful to Marta Castano for her help in
lar bioprocesses re-activation,” PLoS One, vol. 11, no. 10,
writing the manuscript. Medical writing has been supported p. e0163510, 2016.
by IBSA Farmaceutici Italia.
[19] A. Stellavato, M. L. Noce, L. Corsuto et al., “Hybrid complexes
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