Received: 30 January 2018 Accepted: 8 May 2018

DOI: 10.1111/dth.12623

SPECIAL ISSUE ARTICLE

Aesthetic dermatology: What’s new, what’s true?

Uwe Wollina1 | Piotr Brzezinski2,3

1
Department of Dermatology and Allergology,
Academic Teaching Hospital Dresden, Abstract
Dresden, Germany Aesthetic dermatology (AD) is a rapidly growing subspecialty of dermatology. The acceptance of
2
Faculty of Mathematics and Natural Sciences, AD in scientific community and the society is associated with its competence, efficiency, and
Institute of Biology and Environmental
seriousness. This review highlights some recent developments toward new tools, techniques,
Protection, Pomeranian Academy, Slupsk,
Poland and understanding in the field of AD. Analyzing the specific needs of patients and assessing the
3
Department of Dermatology, 6th Military effect by objective measurements is important for further progress. For long time ignored, white
Support Unit, Ustka, Poland adipose tissue has gained increasing interest in biology and rejuvenation. Characterization of
Correspondence dermal and subcutaneous white adipose tissue has made progress. The interaction of hyaluronic
Uwe Wollina, Department of Dermatology and acid and calcium hydroxyl apatite (CaHA) fillers with adipocytes could be responsible for clinical
Allergology Städtisches Klinikum Dresden,
Academic Teaching Hospital of the Technical
efficacy. New developments of oral collagen treatment and highly diluted CaHA to contour the
University of Dresden, Friedrichstrasse body outside the face will be discussed. Submental contouring using purified desoxycholic acid
41, Dresden 01067, Germany. is another new development.
Email: wollina-uw@khdf.de

KEYWORDS

adipose tissue-derived stem cells, aesthetic dermatology, body contouring, calcium hydroxyl
apatite, deoxycholic acid, hyaluronic acid, oral collagen nutrients, scores, society, white
adipose tissue

1 | I N T RO D UC T I O N
Aesthetic Dermatology (AD) has a historical background with roots
dating back to antiquity. Beauty was seen as an expression of health
(perfectissima et absolutissima sanitas), whereas exaggeration was
opposed (Gadebusch Bondio, 2005). AD is based on principles not
different from other medical specialties and can provide a serious
adjunct to medical and surgical treatments (Sahan & Tamer, 2017;
Wollina & Goldman, 2017).
AD is a rapidly developing part of dermatology in science and
clinical practice. Concerns have been raised that AD might be a
frivolous specialty, guided by the market that is aimed primarily at
profit. The focus, however, needs to be patient-centered and the work
scientific to avoid the ethical dilemma (Wiesing, 2009).
The acceptance of AD in the general population varies with tradi-
tions, cultural background and education. As AD has the potential of
being preventive medicine at its best, the attitude to AD may also
reflect the position to prevention, life style, and quality of life (QOL).
The Aesthetic Dermatology and Emotional Well-Being (DEBIE)
scale is a tool to assess the perception that the general population
has in relation to AD and its contribution to their emotional well-
being (Martínez-González, Martínez-González, & Guerra-Tapia, 2014).
DEBIE was performed in 770 Spanish adults for two dimensions, that
is, emotional well-being and perception of AD. A statistically signifi-
cant and directly proportional relationship has been found between
the degree of emotional well-being (self-esteem, assertiveness,
optimism, and motivation) and the knowledge about AD and their
attitude toward AD (Martínez-González, Martínez-González, &
Guerra-Tapia, 2017).
A French online, observational trial investigated the motivation
and attitude of 1,000 adult women aged between 25 and 70 years
toward AD. The study identified natural look, self-confidence, and
attractive skin as major criteria for beauty. Confidence in the medical
doctor, good post-procedure follow-up, efficacy, safety, and cost are
important in decision making in AD (Ehlinger-Martin, Cohen-Letessier,
Taïeb, Azoulay, & du Crest, 2016). AD significantly contributes to the
attempt of aging gracefully.
2 | S C O RE S A N D M E A S U R E M E N T S
To establish reliable tools to measure the effects of AD procedures,
validated and standardized scales are mandatory. For a long time,
photography has been the gold standard. In recent times, a number of

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https://doi.org/10.1111/dth.12623
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scales for facial aging and hand aging have been developed
(Carruthers & Carruthers, 2010; Cohen et al., 2015; Jdid, Latreille,
Soppelsa, Tschachler, & Morizot, 2018).
Automated objective measurements may become more accepted
in the near future in daily practice. A summary of validated assess-
ment tools is listed in Table 1 (Cohen et al., 2015; Carruthers et al.,
2012; Flynn et al., 2012; Geister et al., 2013; Kane, Lorenc, Lin, &
Smith, 2012; Narins, Carruthers, Flynn, & Smith, 2012; Niforos et al.,
2017; Rzany et al., 2012; Sattler et al., 2012).
Although these efforts are useful to measure signs of aging and
success to correct them, they are arrested in static tidiness. They are
unable to mirror dynamic function. In the future, we need other
measures to describe our efficacy.
3 | FACIAL ADIPOSE TISSUE
HA is found in various human tissues and organs including skin.
Dermal fibroblasts express a specific receptor for HA, CD44.
Therefore, filler injections have been linked to the stimulation of fibro-
blasts (Girardeau-Hubert, Teluob, Pageon, & Asselineau, 2015;
Landau & Fagien, 2015). The very long half-life of mature collagen,
however, raised doubts that neo-collagenesis is relevant for the
observed beneficial effects (Kruglikov, 2012, 2013).
Investigations with imaging techniques and cadaveric studies
argue for specifically targeting deep midfacial fat pads for rejuvena-
tion and volumizing effects. Clinical experience supports the use of
HA fillers deeply injected into facial fat pads to gain best results
for midfacial rejuvenation (Wollina, 2016; Wollina, Goldman, &
Tchernev, 2017).
Based on investigations in vitro and in vivo, Wollina and Kruglikov
developed the concept of HA as a non-specific modulator of
adipogenesis (Wollina, 2015; Kruglikov & Wollina, 2015).

Facial adipose tissue is different from abdominal adipose tissue in sev-

eral regards. It consists of subcutaneous fat pads (sWAT) and dermal
white adipose tissue (dWAT) (Kruglikov et al., 2016). A remarkable
modulation of dWAT content can be observed during the aging pro-
cess. Extrinsic aging by exposure to ultraviolet light (UVL) causes a
replacement of dWAT adipocytes by fibrotic structures, probably by
adipocyte-myofibroblast transition (AMT) (Kruglikov & Scherer, 2016).
Reduction in the amount of sWAT and changes in the stability of
5 | VOLUMIZING AND ADIPOSE TISSUE-
D E R I V E D ST E M C E LL S
Adipose tissue-derived stem cells (ATDSC) have a great potential in
regenerative medicine and AD. HA is a potential matrix for expansion
of ATDSC in vitro and in vivo. in vitro HA is biocompatible with
ATDSC. Scanning electron microscopy revealed that ATDSC main-

the boundaries between fat compartments are hallmarks of the aging
face (Gerth, 2015). Superficial fat becomes increased during aging,
whereas the deep fat in the same compartment become reduced
(Le Louarn, Buthiau, & Buis, 2007). These modifications also impact
the mechanical properties of the facial soft tissue, as the fibrotic
content of sWAT decreases with age (Kruglikov, 2014).
4 | HYALURONIC ACID FILLERS TARGET
FAT PADS
Today, the most common used fillers are based on hyaluronic acid
(HA). By tailoring size, HA content and cross-linking HA fillers for
various applications have been marketed (Wollina & Goldman, 2011).
tained intact structures in HA and develop abundant cell attachments
(Guo, Guo, Wang, & Yu, 2017). HA may serve as a vehicle for ATDSC
transfer into human tissue (Lequeux et al., 2015).
Human ATDSC injected into subcutaneous pockets of the back of
immunodeficient (BALB/cAnNCrj-nu/nu) male mice were capable to
produce new adipose tissue in the presence of HA gel. Histological
studies indicated that all newly formed adipose tissue samples were
viable adipocytes of human origin with large, intact, and highly uni-
form vacuole-like lipid droplets with very small cell nuclei. Neovascu-
larization was notable between HA gel and new adipose tissue (Huang
et al., 2015).
An injectable tissue-engineered mixture of ATDSC with HA has
been suggested by Korean researchers. They used abdominal
adipose tissues obtained by liposuction washed with Dulbecco's

TABLE 1 Validated assessment scores in aesthetic dermatology (a selection)

Score Explanation and target Reference

Global face scale
Upper face scale
Allergan Infra-oRbital Scale
Mid face scale
Lower face scale
Medicis Lip Fullness Scale
Neck volume scale
Platysmal bands scale
Décolleté wrinkling and
pigmentation scale
Merz hand grading scale
20 grading scales and global face assessment scales to rate age and outcome of aesthetic Rzany et al. (2012)
treatments
Four 5-point photonumeric scale that describes lines and brow position Flynn et al. (2012)
Photonumeric scale that describes volume loss in the infraorbital region Niforos et al. (2017)
Three 5-point rating scales to assess infraorbital hollow and upper and lower cheek fullness Carruthers et al. (2012)
Four 5-point rating scales to assess upper and lower lip wrinkles, oral commissures, and the Narins et al. (2012)
jawline
Separate 5-point scales for the upper and lower lips Kane et al. (2012)
5-Point rating scale to assess neck volume Sattler et al. (2012)
5-Point photonumeric scale for platysmal bands Geister et al. (2013)
Three photonumeric grading scales to assess décolleté wrinkles (at rest and dynamic) and Landau et al. (2016)
décolleté pigmentation
5-Point scale to grade appearance of the dorsum of the hand Cohen et al. (2015)
WOLLINA AND BRZEZINSKI
phosphate-buffered saline (DPBS) and then incubated in Dulbecco's
Modified Eagle Medium/Ham's F-12 containing 0.075% collagenase
type I for 2 hr at 37  C followed by centrifugation to enrich the
ATDSC fraction. The resulting pellet rid of red blood cells was
re-suspended in 5 ml of DPBS and filtered through a 100-μm nylon
mesh. Resulting ATDSC-enriched fraction was diluted in HA for sub-
cutaneous injection for tissue augmentation (Rhee, You, & Han,
2014). The study was limited by the low number of patients treated.
6 | ORAL HA
Oral HA has been suggested as an alternative to injection therapy for
reducing facial wrinkles. All published studies have been performed in
Asian people. There are three published trials.
A placebo-controlled Korean trial included females aged
>30 years with crow's feet. HA of a molecular weight of 75 kDa was
given at a dose of 240 mg/day for 8 weeks. The HA group presented
with significantly less wrinkles compared with the placebo group
(p < .05) (Kim, Moon, & Kim, 2007).
In a Japanese placebo-controlled trial, 28 females aged
30–49 years with crow's feet were analyzed. HA with a molecular
weight of 38 kDa was given at a dose of 240 mg/day for 8 weeks.
The verum group presented with a significantly decreased maximum
wrinkle mean depth (p < .01) (Watanabe, Matsui, & Kondo, 2015).
In a second Japanese trial, HA of a molecular weight of either 2 or
300 kDa was treated with 120 mg/day for 12 weeks and compared
with a placebo group. Sixty patients with crow's feet of both genders
aged 22–59 years were analyzed. After 12 weeks, the winkle parame-
ters improved in both HA groups compared to the placebo. The
300 kDa HA worked somewhat faster (Oe et al., 2017).
As HA is easily digested, the technology to protect HA from
gastric acid and hyaluronidase seems to be crucial. It seems to be
questionable that oral application can achieve similar effects as HA
injections.
7 | C A L C I U M H Y D R O X YL A P A T I T E O U T OF
THE F ACE
Calcium hydroxyl apatite (CaHA) constituted by microspherules of
25–45 μm in a carrier gel (Radiesse®) is considered as a biostimulatory
filler for midfacial rejuvenation and facial contouring with longer last-
ing effects that HA fillers (Dallara et al., 2014; Moers-Carpi et al.,
2007; Wollina, 2014). However, CaHA seems to be effective on other
body parts as well.
In an open, prospective trial, 30 women (45–65 years) who have
age-related flaccidity and loss of volume of upper arms were treated
with 1.5 ml of CaHA mixed with 0.5 ml of lidocaine solution per arm
per session, 1 month apart. The total volume injected was 8 ml.
Results were rated at a follow-up visit 4 months after the second
treatment. Flaccidity and the volume were improved. At the end of
the study, 43.3% of subjects described the improvement as a “great
improvement.” No adverse reactions were noted (Anselem, 2015).
3 of 6
To correct the flaccidity of thighs, the abdomen or CaHA (3 mL)
was diluted with 0.6 ml of lidocaine (2% without epinephrine). In this
open trial, 20 women, aged 28–67 years, were evaluated by cut-
ometer and 22 MHz ultrasound for skin density, thickness, and flac-
cidity before and 5 weeks after treatment. The CaHA solution was
administered into deep dermis with a 27-G needle and multiple
injections—each 0.05 ml—to a total volume of 3 ml per thigh, 1.5 ml
per hemiabdomen, and 1.5 ml per brachial zone. Bruising and injection
pain were the only adverse effects. Skin density was improved (best
results on abdominal skin), skin thickness was increased (best results
on thighs), and flaccidity reduction was most pronounced in the
brachial area (Cogorno Wasylkowski, 2015).
Dilution of CaHA does not result in the loss of efficacy for body
contouring. Ten female patients were treated for the flaccidity of
upper arms and abdominal skin using a dilution of CaHA 1:2 (arms) or
1:4 (abdomen) with 2% lidocaine in linear threading technique.
Seventy days after the procedure, all patients demonstrated an
improvement in skin elasticity (cutometer) and a mean increase in
dermal thickness by 26.7%. At the end of this study, 90% of patients
rated the outcome much or very much improved (Lapatina &
Pavlenko, 2017).
Recently, further diluted CaHA has been introduced for skin tight-
ening as a novel technique not restricted to the face. The final mixture
is composed of 3 ml of CaHA, 8 ml of physiological saline, and 1 ml of
lidocaine. The treatment is used to improve contours and firmness in
age-associated upper arm and elbow skin changes. Injection can be
realized by crosshatching technique with retrograde threads using a
long 25-G cannula or by vertical retrograde linear threads and multiple
entry points (Fabi et al., 2017).
Diluted CaHA is also used in the neck and décolleté with multiple
(0.025 ml per pass) and retrograde linear threading (0.5 cm apart).
Here, dilutions are used to vary between 1:2 and 1:6 with lidocaine.
Injection is followed by a gentle massage (Yutskovskaya &
Kogan, 2017).
The optimum results are seen after 3–4 months and last between
1 year (upper arms) and 2 years (neck and décolleté) (Fabi
et al., 2017).
CaHA was used to improve red and white stretch marks in 35 indi-
viduals. CaHA was diluted 1:1 with 2% lidocaine. The solution was
injected at multiple points with a 23-G needle with a maximum vol-
ume of 3 ml followed by microneedling and topical application of 20%
ascorbic acid. Microneedling with ascorbic acid was repeated twice
after 1 and 2 months. At the end of treatment, 62.9% of patients were
“very satisfied” (Casabona & Marchese, 2017).
It has been supposed that CaHA stimulates neocollagenesis, elas-
tin, and angiogenesis (Yutskovskaya & Kogan, 2017; Yutskovskaya,
Kogan, & Leshunov, 2014).
The temporary increase in collagens I and III does however not
explain the long-term improvement obtained by CaHA as mature
collagen incorporated into extracellular matrix has a half-life of
>200 years in bone, cartilage, and tendons and of about 15 years in
skin (Heinemeier, Schjerling, Heinemeier, Magnusson, & Kjaer, 2013;
Libby, Berger, Mead, Alexander, & Ross, 1964; Verzijl et al., 2000).
Indeed, the study of Holzapfel, Mangat, and Barron (2008) could not
find any evidence of mature collagen formation by CaHA (Holzapfel
4 of 6
TABLE 2ATX-101 for submental contouring; randomized, placebo-controlled trials (cClinician- and pPatient-rReported SMF rRating sScales -
CPRSMFRS)
Trial n Outcome (CPRSMFRS)
NCT01305577 363 ≥1-Point improvement in 59.2% (1 mg/cm2) and 65.3% (2 mg/cm2) versus 23.0% (placebo)
NCT01294644 360 ≥1-Point improvement in 58.3% (1 mg/cm ) and 62.3% (2 mg/cm ) versus 34.5% (placebo)
REFINE-1 (NCT01542034) 506 ≥1-Point improvement in 70.0 versus 18.6% (placebo)
REFINE-2 (NCT01546142) 516 ≥1-Point improvement in 66.5 versus 22.2% (placebo)
Note. The dosage used was 2 mg/cm2 unless otherwise indicated.
et al., 2008). Another investigation using light and electron microso-
pies described a well-represented Golgi apparatus in fibroblasts in
vicinity to CaHA (Zerbinati, D'Este, Parodi, & Calligaro, 2017). Golgi
apparatus is involved in the protein glycosylation and in the synthesis
of ground substance of the extracellular matrix, such as proteoglycans,
glycosaminoglycans, and glycoproteins. Therefore, the stimulation of
ground substance could contribute to the volumizing and sculpturing
effects of CaHA. Unfortunately, no investigations on CaHA in SWAT
have been performed. This is crucial importance for the improvement
of mechanical properties of soft tissue.
Mechanical stress to the skin by fillers causes the reorientation of
collagen fibers leading to a limited reinforcement while reinforcement
of sWAT can induce additional fibrotic structures around adipocytes
with effective reduction of the average adipocyte size (Kruglikov &
Scherer, 2017). Reinforcement of sWAT appears to be the most suc-
cessful target in AD aiming correction of age-related soft-tissue
changes such as sagging and ptosis.
8 | I N J E C T I O N LI P O L Y S I S W I T H A T X - 1 0 1
Facial contouring by injection lipolysis has a long history. Recently,
compound ATX-101 – a proprietary formulation of purified synthetic
deoxycholic acid (DCA) for pharmacological submental contouring –
has been evaluated in trials in Europe and the United States
(Wollina & Goldman, 2015). Purified synthetic DCA 1 or 2 mg/cm2
was injected in the target area monthly for four to six treatment ses-
sions. Improvement in submental contour was evaluated by validated
scales as well as skin caliper measurements and magnetic resonance
imaging.
Injection lipolysis with DCA acts on adipocytes causing cytolysis
and mild panniculitis. Postganglionic sympathetic nervous system is
attached to adipocytes in a fat pad-specific pattern. Signals for WAT
can be transferred into the brain known as adipose afferent reflex.
This raises the possibility of another mechanism of action by the mod-
ulation of sensory signals of adipose tissue. It has been demonstrated
that injection lipolysis sensation by sWAT afferent nerves triggers
brown fat thermogenesis in animal models (Garretson et al., 2016).
Several phase III, multicenter, randomized, placebo-controlled,
double-blinded clinical trials with >1,700 patients have demonstrated
the dose-dependent efficacy of ATX-101 (Table 2). Adverse events
were very common but transient and localized to the treatment area
such as injection pain, swelling, bruising, numbness, and induration
(Ascher et al., 2014; Dunican & Patel, 2016; Humphrey et al., 2016;
Jones, Carruthers, et al., 2016; Rzany et al., 2014).
WOLLINA AND BRZEZINSKI
Reference
Rzany et al. (2014)
2 2
Ascher et al. (2014)
Jones et al. (2016)
Humphrey et al. (2016)
An additional observational study with 100 patients and up to six
treatments and ≥1 month treatment interval was published recently.
The clinician-reported submental fat rating scale improved at least by
one point in 88% of patients. A marginal mandibular nerve paresis was
observed in two patients (Shridharani, 2017). Another very rare
adverse effect is alopecia, but the mechanism behind is unknown
(Souyoul, Gioe, Emerson, & Hooper, 2017).
To reduce adverse events, exact injection technique and some
preventive measures are recommended. Pretreatment with oral
nonsteroidal anti-inflammatory drugs an hour before treatment and
preinjection with epinephrine-containing buffered lidocaine 15 min
before treatment reduces pain and bruising. Cold application to the
treated area before and immediately after the procedure reduces
swelling and pain. When possible, anticoagulant or antiplatelet drug
therapy should be discontinued about 1 week before ATX-101
treatment to reduce the risk of bruising (Fagien, McChesney,
Subramanian, & Jones, 2016; Jones, Kenkel, et al., 2016).
9 | CONCLUSIONS AND OUTLOOK
AD has become a medical and surgical subspecialty targeting the aging
process and preventing age-related conditions. The basics for further
development of AD lie in the better understanding of environmental
and genetic factors contributing to aging and illness. Individually tai-
lored protection from environmental hazards is a promise to the
future. Ongoing research on the role of adipose tissue to tissue
homeostasis and its interaction with the immune defense will change
the paradigms of AD treatments. AD has become a dynamic part of
preventive medicine.
CONFLIC T OF INT E RE ST
No conflicts of interest.
ORCID
Uwe Wollina http://orcid.org/0000-0001-5933-2913
Piotr Brzezinski http://orcid.org/0000-0001-6817-606X
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How to cite this article: Wollina U, Brzezinski P. Aesthetic
dermatology: What’s new, what’s true? Dermatologic Therapy.
2018;e12623. https://doi.org/10.1111/dth.12623