NEO- COLLAGENOGENESIS IN

AESTHETIC DERMATOLOGY WHAT’S

NEW, WHAT’S TRUE
Mar 27, 2020 | Aesthetic Feature | 0  |     

Alexander Turkevych, Marta Turkevych, and Danylo

Turkevych take an in-depth look at how treatments can affect
collagen levels in the skin
 Alexander Turkevych
MD, PhD, Assoc. Prof; Marta Turkevych, MD; Danylo Turkevych,
MD

Aesthetic dermatology (AD) has roots dating back to antiquity.

Aesthetic dermatology is based on principles no different from other
medical specialties and can provide a serious adjunct to medical and
surgical treatments. It is a rapidly developing part of dermatology in
science and clinical practice. Concerns had been raised that AD might
be a frivolous specialty, guided by a market that is aimed primarily at
generating a profit. The focus, however, needs to be patient-centred
and the work scientific to avoid any ethical dilemma. The acceptance
of AD by the general population varies with traditions, cultural
backgrounds and education. As AD has the potential of being
preventive medicine at its best, the attitude toward AD may reflect
the individual’s position to prevention, lifestyle, and quality-of-life
(QOL)1–5.
Skin rejuvenation using procedures based on different injectables
(HA, PDRN, PLLA, CaHA, PMMA), light sources (laser, IPL, LED),
radiofrequency (monopolar, bipolar, fractional), and ultrasound, as
well as combinations of these, have become popular in aesthetic
medicine. Almost all treatment modalities based on these methods
claim the main effect of their application to be the stimulation of
neocollagenesis. This inspires the feeling that physiological
neocollagenesis is a non-specific process, which can be stimulated
through completely different ways. 

Modulation of the dermal ECM via non-invasive or minimally-invasive

aesthetic treatments, especially the stimulation of the collagen
production de novo, should be arranged in a safe and physiological
fashion. The ECM, with its insoluble scaffold — consisting mainly of
stiff, mature fibrillar collagen — provides the structural support for the
tissue and significantly determines its characteristic shape and
dimensions. It is understood that collagen levels in the dermis
continuously diminish with progressing age and can be further
reduced as a result of photodamage or from the repeated initiation of
remodelling processes. 
The hypothesis that the injections of biological (PDRN, HA), chemical
(PLLA), or mechanical/physical (CaHA, PMMA) substances or
application of radiofrequency, ultrasound, or light sources can locally
improve collagen levels in the dermis — consequently demonstrating
some level of skin tightening and skin rejuvenation — appears to be
reasonable. Indeed, the effect of neocollagenesis is generally
considered to be long-term compared to the impact of other
processes, such as hyaluronan and, consequently, water
accumulation in a treated area. Such a long-term result is required in
order to give credibility to the treatment methods that claim to
improve the condition of the skin weeks and months after their
application. This natural assumption contradicts, however, modern
knowledge about the connective tissue structure and especially
insight into its turnover, thus making the proclaimed results
sometimes controversial and even theoretically impossible 6–9. 
HYALURONIC ACID: WHAT DO WE KNOW?
Hyaluronan (HA) has high cross-species structural homology, which
makes HA synthesized in bacteria or other species non-antigenic and
non-immunogenic in humans. This property enables its widespread
application for cosmetic uses. In fact, HA plays a central role in the
dermal filler industry. By itself, it is the agent of choice for wrinkle
fillers, preferred over collagen or other categories of smaller synthetic
wrinkle fillers. 

HA is a non-sulfated linear glycosaminoglycan polymer consisting of

repeating disaccharide units of β-1,4 linked D-glucuronic acid (GlcUA)
and β-1,3 linked N-acetyl-D-glucosamine (GlcNAc). HA is secreted to
the extracellular matrix in most mammalian tissue. It is synthesized
by three plasma membrane-bound hyaluronan synthases, HAS1,
HAS2 and HAS3. During their synthesis, the nascent HA chains are
extruded through pore-like structures into the extracellular space.
Newly synthesized HA can be processed by hyaluronidase (HYALs) or
broken down non-enzymatically by reactive oxygen species.
Hyaluronidase hydrolyzes the hexosaminidic β (1–4) linkage between
GlcNAc and GlcUA of the HA chain and releases small HA fragments.
The half-life of HA varies in different organs. The turnover of HA is
extremely high in circulation. In humans, the plasma half-life of HA is
estimated to be about 2–6 min, resulting in a total turnover of 10–100
mg per day, the HA turnover in the whole body is estimated to take
place within 3 days with a turnover of about 5 g per day. HA synthesis
and degradation is also very dynamic at the cellular level. In cells,
normal HA synthesis is activated transiently for cell division or
motility, after which HA is rapidly cleared from the site by endocytic
uptake and hyaluronidase-catalyzed hydrolysis 10. 
White adipocyte tissue (WAT) grows via cellular hyperplasia and
volume expansion during development and a calorie surplus.
However, the origin of white adipocytes and their developmental
process, especially in adulthood, are complicated and remain to be
completely understood; however, much progress has been made in
recent years11. The prevailing hypothesis is that a perivascular
population of cells, which are large in number and resemble mural
cells (pericytes and vascular smooth muscle cells), give rise to new
adipocytes under proadipogenic conditions, such as a high-fat diet.
During maturation of preadipocytes, they progressively change their
shape and accumulate lipid droplets, a process that needs to be
coordinated with the remodelling of the extracellular matrix (ECM) to
accommodate the expanding cellular volume and intercellular
space12. So, adipogenesis is spatially and temporally regulated by the
ECM.
Recent progress in genetics and the development of serum stable
hyaluronidase enzymes have advanced our understanding of HA in
the metabolism, especially the role of HA in adipogenesis and adipose
tissue metabolism. Future studies should leverage the advancement
in genetically engineered animal models, in which tissue specifically
overexpresses an HA synthase or a hyaluronidase to carefully dissect
the roles of HA in the adipose tissue and other metabolic organs 10.
CAVEOLAE, CAVINS AND CAVEOLINS
Role in the ECM regulation and dermal adipose tissue
reversible dedifferentiation
Skin ageing leads to various macroscopic and mesoscopic alterations
within the structure of the individual skin layers as well as in the
interactions between these layers, thereby affecting their mechanical
stability and resulting in the appearance of the typical signs of
ageing. These alterations affect both the composition of the skin cell
population as well as the interactions between the skin cells and the
extracellular matrix (ECM)13, 14.
Plasma membranes of eukaryotic cells have spatially heterogeneous
structures containing lipid clusters enriched in cholesterol and
sphingolipids, which are referred to as lipid rafts. Lipid rafts can
appear in the form of planar structures or caveolae — plasma
membrane invaginations forming nanodomains with a typical size of
50–100 nm, which are especially prevalent in mechanically stressed
cells. They are involved in rapid adaptation to cellular volume
changes, in various signal transduction processes, and in the
processes of endo- and exo-cytosis. 

Caveolae are enriched with a number of characteristic proteins, such

as cavins and caveolins (Cav’s). The presence of caveolin-1 (Cav-1),
which is the principal structural component of caveolae, is necessary
for their characteristic appearance. Cav-1 is not exclusively localized
to the plasma membrane, but is also found in different intracellular
compartments, and can be transported in extracellular vesicles,
providing a long-range mechanism of communication inside tissues or
even between adjacent tissues. 

Caveolin-1 (Cav-1) appears to be both a pathophysiological

contributor and a target in different inflammatory and
hyperproliferative skin conditions as well as in skin ageing. Skin
fibroblasts demonstrate an up-regulation of Cav-1 expression both in
chronological and UV-induced ageing, and such an up-regulation was
observed both in vitro and in vivo. 
CAV-1 EXPRESSION
Typical alterations in ageing skin involve a reduction of the dermis
thickness, a significant expansion of the dermal white adipose tissue
as well as modifications to the distribution of hyaluronan, impairment
of autophagic flux, a reduction of collagen expression and an increase
in tissue inflammation. All of these phenomena can be connected to
changes in Cav-1 expression in the ageing skin. Modified expression
of Cav-1 can also significantly influence the mechanical properties of
individual skin layers, thus changing the total mechanical stability of
the layered composite skin/WAT, leading to structural modifications to
the surface of the ageing skin. Selective reduction of Cav-1
expression has the potential to exert anti-ageing effects on skin
changes under pathological conditions as well as over the course of
the ageing process and can be affected by different external chemical
and physical factors. Cav-1 demonstrates a stratified pattern of
differential expression in various skin layers. High expression of Cav-1
is seen at the stratum granulosum/stratum corneum interphase and
in the stratum basale as well as in the dermis, especially in
association with connective tissue and endothelial cells.

“In the presence of HA, the majority of the TGF-β receptors

are partitioned into Cav-1 lipid raft-associated pools, which
significantly attenuates TGF-β1 signalling. As a result,
collagen synthesis in response to TGF-β1 must be modulated
by the presence of HA. “

Cav-1 expression correlates with ageing both in vitro and in vivo. It is

strongly up-regulated in human diploid fibroblasts displaying a
senescent phenotype in vitro. Overexpression of Cav-1 leads to a
higher density of caveolae in the plasma membrane as well as
morphological modifications of these cells, mainly concerning their
focal adhesion and formation of actin stress fibres. Human corneal
epithelial cells also demonstrate a continuous increase of Cav-1 levels
with ageing, and in aged subjects, these cells display almost five
times more caveolae than in young subjects15. 
In the presence of HA, the majority of the TGF-β receptors are
partitioned into Cav-1 lipid raft-associated pools, which significantly
attenuates TGF-β1 signalling. As a result, collagen synthesis in
response to TGF-β1 must be modulated by the presence of HA. It was
proposed that the availability of exogenous HA leads to a co-
localization of CD44 and TGF-β into Cav-1 lipid raft-associated pools.
This effect was observed only with high molecular weight HA (HMW-
HA) of 2 × 106 Da. In contrast, low molecular weight HA (LMW-HA) of
65,000 Da was unable to antagonize the effect of TGF-β1. This
demonstrates how not only the content but also the sub-type of HA
can influence the local collagen production in the tissue. Also,
stimulation with TGF-β1 commonly enhances the total amount of HA
in skin fibroblasts through an enhanced expression of hyaluronan
synthase, whereby the molecular size of newly produced endogenous
HA is dependent on the expression levels of a hyaluronan-binding
protein involved in hyaluronan depolymerization (HYBID). In intact
human skin, the content of TGF-β1 receptors positively correlates
with HAS2 and negatively correlates with HYBID expression. This
mechanism works only for HMW-HA, but not for depolymerized HA (as
in the case of inflammation or aged skin)15–17.
Caveolae are flask-shaped plasma membrane specializations. A 22-
kDa protein, caveolin, is a principal component of caveolar
membranes in vivo. As recent evidence suggests that caveolae may
participate in G-protein-coupled signalling events, the potential
interaction of caveolin with heterotrimeric G-proteins was
investigated. Using cell fractionation techniques, it was discovered
that mutational or pharmacologic activation of G-proteins prevents its
cofractionation with caveolin. In a second independent approach, the
interaction of G-proteins with caveolin was directly examined. For this
purpose, caveolin as a glutathione S-transferase fusion protein was
recombinantly expressed. Using an in vitro binding assay, it was
found that caveolin interacts with G-protein α subunits (Gs, Go, and
Gi). Mutational or pharmacologic activation (with guanosine 5′-O-
(thiotriphosphate)) of G-proteins subunits prevents this interaction,
indicating that the inactive GDP-bound form of G-proteins subunits
preferentially interacts with caveolin. This G-protein binding activity is
located within a 41-amino acid region of caveolin’s cytoplasmic N-
terminal domain. Further functional analysis shows that a polypeptide
derived from this region of caveolin effectively suppresses the basal
activity of purified G proteins, apparently by inhibiting GDP/GTP
exchange. This caveolin sequence is homologous to a region of the
Rab GDP dissociation inhibitor, a known inhibitor of GDP/GTP
exchange for Rab proteins. These data suggest that caveolin could
function to negatively regulate the activation state of heterotrimeric
G-proteins18.
FAT CELLS
White adipose tissue evolved as the principal site for energy storage
for vertebrate animals. White adipocytes, or ‘fat cells,’ are
characterized by the presence of a single large lipid droplet
(‘unilocular’ adipocytes). Their classical function is to serve as a
storage compartment for excess energy; however, we now recognize
that adipocytes are dynamic endocrine organs that secrete various
hormones and cytokines (adipokines) to control nutrient homeostasis,
energy balance, and immune cell regulation. White adipocytes arise
through the process of adipocyte differentiation, or ‘adipogenesis’. In
rodents and humans, most adipocytes arise pre- or perinatally, with
fat cell numbers largely established by the adolescent period. In
adulthood, there is relatively little fat cell turnover in the major, well-
characterized, subcutaneous and intra-abdominal WAT deposits. In
response to certain challenges (e.g. caloric excess, cold exposure,
injury), de novo fat cell differentiation can occur, through the
recruitment of resident adipocyte precursors (preadipocytes).
However, physiological changes in subcutaneous or intra-abdominal
WAT mass are largely driven by alterations in lipid content
(lipogenesis and lipolysis). Upon various challenges, the de-
differentiated cells proliferate and re-differentiate into adipocytes. In
addition, manipulation of dWAT highlighted an important role for
mature dermal adipocytes for hair cycling and wound healing.
Altogether, these observations unravel a surprising plasticity of
dermal adipocytes and provide an explanation for the dynamic
changes in dWAT mass that occur under physiological and
pathophysiological conditions, and highlight the important
contributions of dWAT towards maintaining skin homeostasis 19–22.
The model of dermal adipose tissue reversible dedifferentiation was
described by Zhuzhen Zhang and is shown in Figure 1.
An upregulation of Cav-1 demonstrates a strong correlation with
ageing phenotypes, both in chronological and UV-induced ageing in
vitro and in vivo (Figure 2). The modification of Cav-1 content
significantly affects collagen production and inflammation in the
ageing process. The age-dependent modulation of Cav-1 also leads to
modifications of the content and distribution of hyaluronan in the
skin, and contributes to an impairment of the autophagic flux in
ageing cells. Recent results reported in areas such as skin ageing,
fibrosis and psoriasis suggest that the above-mentioned interactions
are not merely correlations. Rather, Cav-1 is a pathophysiological
factor and should be a target for different inflammatory and hyper-
proliferative skin conditions, as well as in skin ageing. The modulation
of Cav-1 expression can significantly influence the mechanical
properties of single skin layers, as well as the adhesion between
adjacent layers. This will affect the mechanical stability of the layered
composite skin/WAT. As such, scientists propose that selective
targeting of Cav-1 expression should lead to relevant anti-ageing
effects in the skin15.
COLLAGEN-INDUCING TREATMENTS IN AD
Every treatment modality that claims the modification of dermal
collagen levels is the main effect of its application comes up against
at least three problems. One is that the upregulation of multiple
stages of collagen production is not necessarily an indication of
increased levels of mature collagen in the skin. While procollagen can
be easily overexpressed after the application of different physical
modalities, it can also be easily degraded, which results in a very slow
net remodelling of mature collagen. The second problem is connected
with the type of induced collagenesis — physiological (with a regular
collagen network structure) or pathological (scar-like, with typical
hyalinised collagen regions). Strengthening of the natural structure of
the collagen network in ECM would be the ideal solution,
guaranteeing that physiological processes are retained, but this
structure is not necessarily in equilibrium and can be reduced
relatively rapidly. Pathological neocollagenesis (fibrosis) is connected
to the application of higher intensities and results in the production of
scar-like, intra-tissue structures. These structures can significantly
improve the skin rigidity; they are, however, pathologic in their
nature. The areas with hyalinised collagen, which is the typical
hallmark of keloid scars, will not be refilled with fibroblasts, making
later remodelling in this area difficult or even impossible. And the
third problem is the dynamic nature of the ECM remodelling, with
different characteristics of the dynamic processes involved. Especially
important here is the very slow remodelling dynamic of mature
collagen that cannot be significantly modified under quasi-
physiological conditions, thus almost elevating the ‘wounding’ of ECM
to the status of effective non-invasive treatment23.
The degradation of collagen is a very sophisticated process, which
has both extracellular and intracellular pathways. Extracellular
degradation is mediated by some MMPs and is specific to rapidly
growing or damaged tissue. Under physiological conditions, collagen
degradation is primarily connected to an internal pathway, which is
often named collagen phagocytosis. This process is independent of
MMP-1 activity, but can be significantly modulated by MT1-MMP. It
has been shown that the same subjects can have a very different
relationship with the synthesis of procollagen and the expression of
MMPs in different regions of the body. The areas with low sun
exposure (chronological skin ageing) in older people demonstrate
significantly decreased production of procollagen I mRNA and the
increased expression of MMPs, when compared to the same body
areas in younger people. In the areas of strong sun exposure
(photoageing), the procollagen I mRNA production was, however, on
average 2.9 times higher and the MMPs were more strongly
overexpressed than in the areas with pure chronological ageing in the
same subjects. Both processes (chronological and photo-induced
ageing) led to the same endpoint—total collagen deficiency23–25.
PATHOLOGICAL NEO-COLLAGENOGENESIS — 
MECHANICAL OR PHYSICAL STIMULATION OF
COLLAGEN PRODUCTION
The significant migration and production of new fibroblast does not
usually take place under non- or pathophysiological conditions. What
we typically describe as a pathophysiological condition for
collagenogenesis is a ‘foreign-body reaction’ as a result of the
presence of permanent or semi-permanent particles in the tissues,
injected for so-called ‘new collagen stimulation’ and causing fibrosis
at the end. Among them, CaHAP and PMMA are two substances that
play a central role in the market. It’s necessary to mention that
commercialized CaHAP’s come in two different forms — 8–12 mcm
particle size, branded on the market as PEG HA filler with 1% CaHAP,
and at least three brands with >25 mcm particle size, branded as
30% CaHA fillers from Germany and Israel. Calcium hydroxyapatite
(CaHAP) has bibliographic evidence of its capability to stimulate
collagen synthesis in fibroblasts. 
We need to mention that the biosafety of the 8–12 mcm particle size
1% CaHA has been tested with at least three different methods: MTT
test, NRU test, and Kenacid Blue assay. Moreover, any possible effect
on the structure, morphology, and viability of cells has been
evaluated. The results obtained show that the 8–12 mcm particle size
1% CaHA does not cause any cytotoxic effect and does not affect the
correct structure and morphology of cell cultures. Non-cytotoxic
concentrations of the product with 8–12 mcm particle size with 1%
CaHAP has been used to treat human fibroblasts to evaluate any
possible increase in the collagen production. Due to this, we can tell
that there are two different types of CaHA in AD: scientifically-
evident, small, non-cytotoxic concentrations of CaHA with small
particles, and concentrations of CaHA with larger particles, which are 
likely cytotoxic for the surrounding tissue and human fibroblasts with
a lack of scientific, marketing-free evidence. We have searched the
medical and biological literature and found some interesting data:
recently, a proliferation-suppressive effect of HAPs nanoparticles
against various cells, also cancer among them was reported. This
study was aimed at assessing the translational value of HAPs both as
a bone-regenerating material and as an anti-tumour agent27,28.
Inhibition of tumour growth, prevention of metastasis, and
enhancement of the survival rate of tumour-bearing rabbits treated
were demonstrated. Activated mitochondrial-dependent apoptosis in
vivo was confirmed and was it was also observed that a stimulated
immune response was involved in the induced anti-tumour effect.
With the HAPs rising concentration, the percentage of early and late
apoptotic cells increased from 8.99 ± 1.4% to 13.08 ± 1.6%.
Meanwhile, it was found that genes expressed by different types of
immune cells were also up-regulated in the HAPs group (TNF,
DCSTAMP, MRC1, CLEC7A, TLR4, RLA-DR-ALPHA, and GZMK),
revealing that HAPs might have stimulated the innate immune
system and recruited numerous immune cells, including
macrophages, dendritic cells, mononuclear cells, and lymphocyte
cells, to the tumour microenvironment. In addition, genes involved in
cellular calcium transport (ATP2A1, SLC8A1, TRDN, SRL, CACNB1,
RYR1, CASQ2, CALB1, STC1, and CACNA2D1) were also expressed
differentially, suggesting that intracellular calcium homeostasis might
be disturbed by HAPs26,27. There is also data that compares the
cytotoxicity of HAPs on tumour and healthy cells. Due to the degree
of difference between the inhibition of human cancer cells and
healthy cells from HAPs treatments. The cancer cells (MGC-803, Os-
732, and Bel-7402) and healthy cells (L-02, MRC-5, and HaCaT) were
treated with low (0.14 g L−1) and high (0.56 g L−1) concentrations of
HAPs for 3 days. The data represents that the inhibition of cancer
cells was from 54.3 +/- 1.5 to 88.0 +/- 3.5, but inhibition of the
healthy cells was also up to 29.0 +/- 4.0 [28]. 
So, the more we know about the positive anti-tumour effect of HAPs,
the more we understand that it should be studied in AD much more
than it has in the past, taking into account particle size, shape and
concentration. On the other hand, we have to understand that
changing the viscosity, elasticity, plasticity or concentration of the
injectable by the practitioner means that it is off-label and can’t be
used safely in the majority of the civilized countries around the
world. 

QUASI-PHYSIOLOGICAL NEO-
COLLAGENOGENESIS
The net amount of procollagen I protein in the dermis of photo-aged
skin, which demonstrated a higher synthesis of procollagen I mRNA, is
much lower. This apparently paradoxical result, which is mainly
connected with the different expression of MMPs, allows some
authors24 the opportunity to write about the potentially different
pathophysiologies of chronological and photo-induced skin ageing 23.
The significant migration and production of new fibroblasts does not
normally take place under quasi-physiological conditions, such as RF,
lasers and chemical substances, as well as topical (TCA) or injectables
(PLLA) procedures. These phenomena can, however, be of significant
importance in moderate to severe tissue damage, for example, in
wound healing or in skin resurfacing procedures, where quick and
strong repair is required. What becomes apparent is the significant
difference between the processes involved in skin rejuvenation and in
wound healing, which are often considered to be very similar. Under
quasi-physiological conditions, the connective tissue remodelling is in
a dynamic balance between the production and destruction of its
matrix components. Each instance of overproduction of collagen or
other ECM components will, in the short-term, initiate the feedback
mechanism, causing the stimulation of their enzymatic degradation
and thus undoing a large part of the stimulatory effect. For example,
the 532 nm KPT and the 1064 nm Q-switched Nd:YAG laser at
intensities of 1.5 J/cm2 can increase the expression of pro-collagens I
and III mRNAs and simultaneously decrease the expression of MMP-1
and MMP-210, consequently suppressing the cleavage of collagen. At
the same time, the ablative application of Er-Yag or CO2 laser could
significantly increase the induction of procollagen I (by up to 7.5
times the original value, 21 days after the procedure) and III mRNAs
and MMP-1 mRNA (by up to 40,000 times, seven days after the
procedure), which also correlates with the dynamical change of MMP-
1 protein levels. Whereas the net amount of procollagen I protein was
also increased, up to six months after CO2 laser treatment, its
increase was much lower than that of procollagen I mRNA, clearly
demonstrating the balancing effect. The qualitative difference
between the dynamic processes in the dermis after the application of
these two treatment modalities may be connected with much
stronger amplitudes of dynamic changes after applying the CO 2 laser.
It has even been assumed that different laser applications can cause
different mechanisms of collagen destruction.
Let us estimate how realistic the changes actually are to the skin’s
appearance through the quasi-physiological remodelling of the
mature collagen network. We will assume the physiological half-life
time of the mature collagen in the dermis to be 15 years. The
increase of the procollagen I protein in the dermis will be taken to be
2.4, as, for example, the maximum value measured after one skin
rejuvenation treatment with photodynamic therapy recorded seven
days after the procedure. Assuming the whole procollagen I protein
will be utilised to replace the mature protein and that the procollagen
upregulation is constant during the whole time after the treatment
(which is surely wrong and will cause us to significantly overestimate
the results), the proportion of the mature collagen network that will
be replaced during the first seven days after the treatment can be
calculated to be approximately 0.15% (the upper limit of the
estimation). Realistically, this value has to be reduced at least twice.
It is absolutely unrealistic that such a modification can significantly
improve the skin appearance and explains why mentioned
procedures need to be repeated to maintain the visible results 23, 29–31.
PHYSIOLOGICAL NEO-COLLAGENOGENESIS VIA
A2A RECEPTORS STIMULATION AND CAV-1
REGULATION
Chronic inflammation and inflammatory cells and cytokine networks
play a pivotal role in one of the leading theories of ageing –
inflammaging. Several cytokines are significantly elevated, including
early proinflammatory factors (tumour necrosis factor-a (TNFa),
interleukin-1 (IL-1), and IL-6), late proinflammatory factors (e.g., anti-
inflammatory molecules (e.g., IL-10, IL-1 receptor antagonist, and
transforming growth factor b). Also, one of the key facts is the role of
adenosine— a purine nucleoside that is released from a variety of
cells in response to several types of stress32. It has been suggested
that adenosine regulates inflammation via interaction with one or
more of its four known receptors (A1, A2A, A2B, and A3)33. Stimulation
of adenosine A2 and A3 receptors has been shown to alter the
cytokine network by decreasing inflammatory cytokine secretion by
macrophages in vitro34–36. In animal models of acute and chronic
inflammation, non-selective adenosine receptor antagonists reverse
the anti-inflammatory effects of methotrexate (MTX), a ‘gold
standard’ of therapy in acute inflammation37–39.
It has been shown by many authors40 that a particular extract of DNA
from the gonadic tissue of wild male sturgeons possesses cell renewal
effects with possible anti-ageing benefits for skin moisture, thickness,
elasticity and a reduction in skin wrinkles. In addition to inhibiting the
early and late inflammatory cytokine cascade, PDRN increased
circulating levels of IL-10 and IL-10 expression in the tissues. Taking
into account all mentioned before and the fact, that the majority of
injectables in aesthetic dermatology should be injected in the
superficial fat pads (sWAT) we propose another model for the possible
interactions (Figure 3) to explain how and why collagen can be
stimulated; moreover, why some methods induce physiological, while
others quasi-physiological or even pathological collagenogenesis.
We want to appeal to all our practitioner colleagues with the following
message: not all of the rejuvenation methods currently offered on the
market have a sufficient evidence base, especially regarding their
safety. This does not mean that they are certainly dangerous, but it
does mean they should be further studied. Again, we urge colleagues
to understand the fact that any self-made changes to the officially
recommended way of administering of the substances (HA, PLA,
CaHa) — for example, mixing with other products or dissolving— is the
responsibility of the doctor, who in this situation, knowingly or
unconsciously, violates the official recommendations and, therefore,
in cases of complications, can find themselves isolated in terms of
legislation and patient safety. And last, but not least, beauty and
youth also have a price, and it is our job to ensure it is not too high.

  Declaration of interest None

  Figures 1–3 © Dr Turkevych redrawn by Prime Journal