Review Article

Journal of Cosmetic Dermatology, 15, 520--526

Physiochemical properties and application of hyaluronic acid: a

systematic review
_ z dło, MD,3 & Dominika L
Natalia M Salwowska, MD,1 Katarzyna A Bebenek, MD,2 Dominika A Za
4
Wcisło-Dziadecka, MD, PhD
1
Department of Dermatology, Andrzej Mielez cki Memorial Independent Public Clinical Hospital in Katowice, Katowice, Poland
2
Department of Medicine, Adventist Hinsdale Hospital, Hinsdale, IL, USA
3
Department of General and Endocrine Surgery, School of Medicine in Bytom Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
4
Department of Skin Structural Studies, Chair of Cosmetology, School of Pharmacy with Division of Medicine in Sosnowiec, Medical University of Silesia,
Sosnowiec, Poland

Summary Background Hyaluronic acid is a widely available, biocompatible, polysaccharide with

distinguishing physiochemical properties which inspire its application throughout
several fields of medicine.
Objective We aim to investigate the application of hyaluronic acid and its effectiveness
throughout several fields of medicine, including several therapies administered and
prescribed by general health practitioners.
Methods We conducted a systematic review on randomized controlled trials about the
physiochemical properties of hyaluronic acid and its application through primary
care. Studies included in this review were peer reviewed and met our inclusion
criteria.
Findings Factors were clustered into the following: uses throughout several fields of
medicine, physiochemical properties, bioavailability, tolerance, effectiveness, and
adverse effects. Therapies with hyaluronic acid provided long-lasting, pain relieving,
moisturizing, lubricating, and dermal filling effect. Tissue hydration, elasticity, and
durability improved.
Conclusions Adjunct therapy with hyaluronic acid provides longer-lasting therapeutic
effect when compared to the use of glucocorticosteroids and NSAIDs in osteoarthritic
chronic diseases, is well-established in ophthalmology due to its lubricating properties
for the corneal endothelium, and improves tissue hydration and cellular resistance to
mechanical damage in aesthetic dermatology, and has marginal adverse effects.
Several trials indicated its role in tumor markers, liver diseases, and in
pharmaceuticals, but further research would be necessary to draw conclusive results
in those fields.
Keywords: hyaluronic acid, bioavailability, tolerability, wound healing, adjuvant
therapy, long-lasting effect

Correspondence: Dominika L Wcisło – Dziadecka PhD, M.D., Department Introduction

of Skin Structural Studies, Chair of Cosmetology, School of Pharmacy with
Division of Laboratory Medicine, Medical University of Silesia, 41-200 Although many years have passed since the discovery
Sosnowiec, ul. Kasztanowa 3, Poland. E-mail: ddziadecka@interia.pl of hyaluronic acid (HA), its popularity has not
Accepted for publication May 9, 2016 decreased throughout primary care and several other

520 © 2016 Wiley Periodicals, Inc.

 Properties and application of hyaluronic acid
fields of medicine. The widespread use of hyaluronic
acid results from its biocompatibility and/or ease of
processing.
The name of this compound is derived from the
Greek word hyalos meaning “glass” which refers to its
physical properties. In 1934, Karl Meyer and John Pal-
mers first extracted the substance from bovine vitreous.
Hyaluronic acid (HA) is a biopolymer composed of
repeating units of disaccharides, which include mole-
cules of D-glucuronic acid and N-acetylglucosamine
molecules linked by b- (1–4) and b- (1–3)glycosides. It
belongs to a group of substances called mucopolysac-
charides belonging to the glycosaminoglycans (GAGs)
family. Representatives of this group also include other
commonly known compounds, such as chondroitin
sulfate, keratan sulfate I and II, heparin, heparan sul-
fate, and dermatan sulfate.
Hyaluronic acid is the only one of mucopolysaccha-
rides which is not synthesized in the Golgi apparatus.
There are three HA synthases which are responsible
for its formation (Has1, Has2, and Has3). All of which
located in the cell membrane with the active end fac-
ing the inside of the cell. Synthesis takes place on the
inner side of the cell membrane and keeps the individ-
ual portions of the polymer emerging outside of the
cell.1 This is different from the synthesis of other poly-
mers, as it correlates with the length of the HA mole-
cules and their viscosity. The difference between the
results noted from several synthases is in the chain
length of the HA they produce. Depending on the
chain length, we may distinguish small, medium, and
large polymers. The first two forms have pro-angio-
genic and anti-apoptotic properties which stimulate the
synthesis of heat-shock proteins (HSP) and are potent
immunostimulants. Large polymers mainly operate in
immunosuppressive and anti-angiogenic function.2
Hyaluronic acid catabolism may occur by enzymatic
or chemical means. We differentiate the following hya-
luronidases: HYAL1- is an enzyme associated with
lysosomes, which degrades the HA into tetrasaccha-
rides, HYAL2- degrades HA of high molecular mass
into products 20 kDa in size,3 HYAL3- is an enzyme
we do not know much about,4 PH-20 is present in
sperm5 and HYALP1.6,7 The enzymatic processes
involve b-glucuronidase, N-acetyl-glucoaminodase, and
exoglycosidases. Late research on the enzymes can be
attributed to their specificities, as emphasized by Vopli.
This is why even though they are present in very small
quantities, they have a high level of activity. In addi-
tion, they require special conditions during extraction
and research on them takes extensive amount of time.8
In turn, chemical degradation is associated with
© 2016 Wiley Periodicals, Inc.
. N M Salwowska et al.
reactive oxygen species. The products are smaller,
being 4–6 saccharide chains in length. Reactions asso-
ciated with the formation of the smaller fragments of
HA prevent superoxide dismutase.
Occurrence
HA is widely used in aesthetic medicine due to its
specific properties which allow it to bind a large num-
ber of water molecules. It improves tissue hydration
and their resistance to mechanical damage. The inter-
est in this compound in this branch of medicine is also
apparent from the fact that it is widely available, fully
resorbable, and biocompatible. The compound can also
be used as a marker in the diagnosis of certain cancers
and liver diseases.
The human body weighing 70 kg contains 15 g of
HA. The greatest amount of the compound is present
in the skin (about half of the total HA),9 synovial
fluid,10 the vitreous body,11 and the umbilical cord.12
It can also be found in the places where friction
occurs: the joints, tendons, sheaths, pleura, and the
pericardium.
This compound is involved in numerous processes
occurring in the body. Besides rheological and deprecia-
tive properties, getting rid of free radicals also plays an
important role in wound healing, ovulation, fertilization,
signal transduction, and tumor physiology.10,13 In both
vertebrates and bacteria, its structure is identical.1,14
From this standpoint, there is an advantage in obtaining
this compound; however, the presence of a hyaluronan
coating around some bacteria makes them invisible to
the human immune system making it less desirable.14
The biocompatibility and thus negligible side effects make
it one of the more readily available compounds used
throughout many fields of medicine in the 21st century.
Despite many studies on new techniques of acquiring
hyaluronidase, the main sources are rooster combs
and shark skin, for it is these structures which contain
the greatest amount thereof. HA isolated from animal
tissues that contain proteins and DNA which may
potentially cause adverse immune reactions. For this
reason, interest in animal sources has decreased. HA
can also be obtained from fermentation by bacteria.
The risk of mutations or infection by exogenous prod-
ucts or endobacterial toxins, although small, may limit
the role of this method.
Oncology
Further direction in which HA may be more widely
used is in the field of oncology. Many tumors show an
521
Properties and application of hyaluronic acid . N M Salwowska et al.
increased HA content in the stroma of the tumor and
the surrounding tissue matrix which presents an obsta-
cle. An especially significant increase in the level of
HA can be observed in tumors of epithelial origin (as
stated by Kultti, as many as 87% cases of adenocarci-
nomas of the pancreas have a high expression of HA).
In most cases, this process is associated with poor
prognosis. This is due to the fact that an increase in
the synthesis of HA is responsible for apoptosis, resis-
tance of drugs, and invasiveness. The increase in HA
in the tumor environment is associated with increased
interstitial pressure, which can lead to the constriction
of the lumen of the supplying blood vessels. This phe-
nomenon leads to hypoxia and drug resistance. Besides
the above-mentioned physicochemical properties, HA
has an extremely important role in tumor physiology,
especially its effect on the receptors of tumor cells.15–17
HA acts on cells by binding to receptors CD44 and
RHAMM. The first of these is involved in inflammatory
processes, atherosclerosis, and carcinogenesis.17 The
second receptor is responsible for the motility of cells,
tissue healing, and carcinogenesis.18 Most cancer,
besides the standard receptor CD44 + neoplasm, pro-
duces various isoforms. Their production depends on
the progression of the disease. The interaction between
HA and receptor CD44 affects proliferation, survival,
motility, invasiveness, and the chemoresistance of cells.
On the other hand, overexpression of the receptor
RHAMM is associated with the promotion of tumor
growth and metastasis. It has been proven that HA of
a low molecular weight promotes motility of tumor
cells through interactions with CD44 receptors. It is
known that CD44 + tumors are rich in receptors for
HA and are more invasive.15,19,20
It is also noted that HA promotes tumor progression
by recruiting stromal cells and angiogenesis.2 It is
believed that the HA of high molecular molar mass is
responsible for the migration, cell differentiation, and tis-
sue collection of progenitor cells. The process of angio-
genesis is one of the fundamental processes necessary
for the survival of cancer. Due to the abundant supply of
blood, tumors can grow and metastasize. Tumor cells
stimulate neovascularization by interaction with vascu-
lar endothelium. According to studies, HA oligomers
can also stimulate endothelial proliferation and migra-
tion. It is not completely known whether tumor cells are
responsible for producing ready-made oligomers of HA,
which may lead to degradation of macromolecular HA
with ECM. It is common knowledge, however, that the
relationship between HA and carcinogenesis exists.13
Many authors emphasize the role of hyaluronidases
in supporting the development of neoplasms through
522
HA. This knowledge has resulted in the use of these
enzymes in numerous studies. Among the results
reported, a reduction of tumor growth and DNA syn-
thesis in cancer cells was noted. The administration of
hyaluronidase in adjunction with antineoplastic agents
allows them to more readily penetrate the cell which
results in a better response to treatment and the possi-
ble use of lower doses of pharmaceuticals. These prop-
erties have been used for some time in chemotherapy.
Excess hyaluronidase leads to inhibition of the pro-
oncogenic action of HA which in this case was
obtained by exogenous administration. In addition, the
formation of small oligomers of HA has a positive effect
on drug resistance and suppression of tumor growth. It
should be noted that both the HA and its counterpart
hyaluronidase have pro- and antitumor effects which
are concentration and origin dependent (endogenous
or oncogenic).7,15,21,22
Orthopedics
Due to the natural occurrence of HA in the synovial
fluid, joint capsule and articular cartilage, it is widely
used in orthopedics. This compound is used mainly
among joint diseases such as osteoarthritis or rheuma-
toid arthritis. Osteoarthritis is the most common dis-
ease of the joints, which leads to substantial disability
and decline in quality of life. In this disorder, an imbal-
ance between the process of formation and destruction
of articular cartilage occurs, in favor of the latter.23
The intra-articular changes which may be observed
in this disease include a decrease of GAG, an increase
in proteoglycans and collagen degrading enzymes, as
well as, an increase in accumulated water. Changes in
endogenous HA are dependent on the reduction of its
molecular mass and concentration.24,25 As a result of
inflammation, there is an increased production of reac-
tive oxygen species which are responsible for the
degradation of collagen, laminin, and HA.26 The
resulting fragments of HA due to this mechanism per-
petuate a vicious cycle of increased inflammatory
responses.
Physiologically occurring HA in synovial fluid is a
compound of high molecular mass that has properties
which neutralize free radicals.27 The commercially
available intra-articular injections containing HA differ
among themselves by molecular mass and sterility, but
unfortunately none of them contain HA with a molec-
ular mass identical to endogenous sources which
means their realistic effects are uncertain.
HA of a high molecular mass reduces the chemotaxis
and migration of inflammatory cells which acts as a
© 2016 Wiley Periodicals, Inc.
 Properties and application of hyaluronic acid
good barrier to the inflammatory process and protects
against the effects of free radicals.24,25 The important
viewpoint pertaining to the etiopathogenesis of OA is
the inhibitory action of HA on apoptosis of chondro-
cytes and the stimulatory action on proteoglycan syn-
thesis. HA takes part in the direct analgesic
effect.24,25,28–30
Intra-articular HA preparations are characterized by
good tolerability and therapeutic effects (reduction of
pain) which are confirmed in randomized trials.25,31 A
very important advantage of intra-articular injections
is the lack of systemic adverse reactions.32 As we
know, osteoarthritis affects mainly the elderly, who
often have other illnesses. In these patients due to their
age and the amount of medications, they are taking,
interactions are likely to occur between preparations.
Moreover, increasing the number of medications, as
studies show, significantly worsens compliance.
Studies on HA have shown that it promotes the syn-
thesis of cartilage matrix, prevents its degradation,
reduces inflammation, stimulates the synthesis of
endogenous HA, and improves the resilience and mois-
ture of cartilage.24,25
The impact of applied intra-articular HA has been
proven in many studies in animals, which were
observed in the repair processes of articular cartilage.
Of course, HA itself does not lead to a complete regen-
eration of articular surfaces, but it does lead to benefits
by reducing pain and thereby reducing the administra-
tion of nonsteroidal anti-inflammatory agents which
provides a more than acceptable result. The future
direction of these therapies would be to introduce cul-
tures of autologous chondrocytes, for which HA could
be the ideal substrate.24,25,33,34
The effect felt by the patient occurs some time after
the application and lasts for an extended period of time
when compared with use of glucocorticosteroids. It is
therefore particularly worth noting Stern’s view on the
sequential treatment involving the use of glucocorticos-
teroids prior to therapy with HA. In truth, glucocorti-
costeroids provide relief faster but for a shorter length
of time. For this reason, these two substances may be
supplementary to one another.
Besides injections containing HA, patients show an
increased interest in oral preparations of HA. In oppo-
sition, oral formulations lack documented therapeutic
effect on OA. From the available studies of oral formu-
lations of HA, we see that oral supplementation may
have beneficial effects on level of pain and quality of
life. The weaknesses of these findings are due to the
inadequate size of the studied groups. Meaning, the
results of these studies are bias. While some did not
© 2016 Wiley Periodicals, Inc.
. N M Salwowska et al.
obtain statistical significance, none of the studies com-
pared the effect of HA with morphological changes. In
a randomized study, Kalman’s DS et al. reported
reduced consumption of acetaminophen in the study
group. In truth, there were no serious adverse effects
but the lack of risks and the uncertain results as per-
taining to the effectiveness, does not allow for exclusive
opting for oral formulations of HA. All authors empha-
size that more research is needed. In the literature, you
can also find ideas that HA orally administered is not
absorbed. In 2008, studies were revealed by Balogh
et al.35, whose aim was to evaluate the absorption, dis-
tribution, and elimination of orally administered HA in
rats and dogs. This was confirmed with the use of
technetium-labeled HA of high molecular mass to mea-
sure the uptake of HA by connective tissue. After a sin-
gle dose of labeled HA, scintigraphic examination
revealed concentrations of the compound in the joints,
salivary glands, ribs, and others. On this basis, it is
highly likely that HA behaves similarly when adminis-
tered orally to humans.
Ophthalmology
HA has multiple applications in ophthalmology, both
in the conservative and in operational aspect. It is fre-
quently used as the “lubricant” component, due to its
viscoelastic properties and often constitutes as the
main ingredient in artificial tear formulations, and is
used in the relief of dry eye. It reduces irritation, mois-
turizes the eye, and replenishes the deficiencies of
sodium hyaluronate in the tear film.
The compound is often present in a form that con-
tains no preservative. Eye drops are used by those who
wear contact lenses. Its distinctive properties, such as
tear film stabilization, reduction of friction during
blinking, and the prevention of harmful substances
binding to the eye greatly, reduce the symptoms of dry
eye. More than 50% of people cite dry eye the main
reason for resignation from wearing contact lenses. We
can differentiate preparations containing HA from
other eye drops due to the fact that most ophthalmic
solutions deposit residues onto the surface of the eye
because the formula contains artificial substances and
preservatives. In addition, the fluid often does not dis-
tribute uniformly on the surface of the eye, which may
cause noticeable blurring and blurred vision. In turn,
HA has viscoelastic and hydrophilic properties thus
reducing friction and slowing down the evaporation of
tears. It is also significant that the products in which
water is replaced with HA does not dilate conjunctival
blood vessels, so they can be safely used in winter.36,37
523
Properties and application of hyaluronic acid . N M Salwowska et al.
In 2008, Van Beek et al.38 discovered that HA may
be safely used in the structure of silicone or silicone
hydrogel contact lenses without affecting the optical
properties. Its action involves the gradual release from
the lens preventing the formation of a protein layer on
the contact lens (through the reduction of adsorption
or uptake by the lysozyme), which could potentially
reduce its transparency and degrade visual acuity.
Work on these formulations continues.
HA also plays an important role in ophthalmic sur-
gery. Its effects are mainly based on the establishment
and maintenance of comfortable conditions to promote
healing of the postsurgical area. This is obtained
through the stabilization of the tear film, the decreased
duration of healing, the minimized risk of adhesions,
decreased formation of free radicals, and the normal-
ization of intra-ocular pressure. It is widely used during
operations of the anterior segment of the eye, such as
trabeculectomy, cataract removal, glaucoma treat-
ments, refractive surgery, and corneal plastic surgery.
Aesthetic dermatology
Sodium hyaluronate (KH) is currently the most com-
monly used cosmetic filler. The function of which is to
fill and plump up the extracellular tissue space. In liq-
uid formulations, it is used to fill small, superficial
wrinkles, giving the skin elasticity and flexibility, while
cross-linked preparations are used for the correction of
facial contours, modeling the breast in women, thorax
in men and buttocks.
Excellent effects can be achieved with the correction
of nasolabial folds and wrinkles, mitigating horizontal
forehead wrinkles, raising eyebrows, positioning the
nose, changing the shape and volume of the lips, mod-
eling the cheeks, chin, body contouring (enlargement
and modeling of breasts, thighs, buttocks, and calves),
and recently improving the shape of the labia (labi-
aplasty). Small volumes of HA are injected intrader-
mally or subcutaneously to give approximately
6 months of fill effect. The drugstores also sell many
creams and oral formulations containing KH but so far
no randomized studies have confirmed a positive, long-
term smoothing effect on skin wrinkles using these
methods.A formulation composed of high molecular
mass HA is used in preparations for the care of the
eyes, face, neck, and body, as well as, in anticellulite,
and antistretch mark cosmetics by forming a protective
layer making skin appear softer and feel smoother to
the touch. KH, however, does not penetrate into the
deeper layers of the skin, but only covers the
stratum corneum, maintaining the moisture of the
524
skin.37–41Pharmaceuticals. Antibody–polymer conju-
gates are a type of connection between antibody IgG1
which are directed against TNF-a and IL-1b with HA.
Accordingly, as a commercial drug polymer compound
is linked to an antibody depends permanent and long-
term effects of drugs (in this case antibodies against
TNF and IL-1b) at the site of inflammation process.
Presently, a new form of drug testing based on the rat
model is taking place. Application of the new dosage
form will reduce the dose necessary for a desired effect
and thereby reduce, to a minimum, the effects of the
antibodies on the whole body. Along with this, it is
expected that the number and severity of adverse
events will be reduced. According to authors, HA com-
pared to other polymers (CMC-carboxymethylcellulose,
sodium alginate ALG-alginate sodium) is very valuable
from the viewpoint of the biochemical characteristics
including its significant biological activity. Of course, a
combination of antibodies to a polymer requires
painstaking research. Whether the local neutralization
of the inflammatory process will be effective in the
human model is at this time unknown but at the same
strategy is what makes this fascinating.42
Discussion
The distinct physiochemical properties of hyaluronic
acid which were interpreted in this review clearly elu-
cidate its practicable application throughout several
fields of medicine. It is widely available, biocompatible,
and fully resorbable with few adverse affects. Based on
the results described in the trials referenced in this
review, it is suggestive that a dynamic maintenance of
the utilization of HA in medicine is essential for its pro-
gression. Hyaluronic acid binds a large number of
water molecules and improves tissue hydration and
cellular resistance to mechanical damage which was
reported in trials as a beneficial characteristic in the
specialty of aesthetic dermatology. Trials show remark-
able effects can be achieved with sodium hyaluronate
in the correction facial folds, wrinkles, and in body
contouring. The polysaccharide can also be used as a
marker in the diagnosis of certain cancers due to its
binding capability with the surface of the cell. Hyaluro-
nic acid acts by binding to receptors CD44 and
RHAMM. Interaction between hyaluronic acid and
receptor CD44 affects proliferation, survival, motility,
invasiveness, and the chemoresistance of cells, and it is
known that CD44 + tumors that are rich in receptors
for hyaluronic acid are more invasive. In pharmacolog-
ical trials, hyaluronic acid has been conjugated to an
antibody (in this case antibodies against TNF and
© 2016 Wiley Periodicals, Inc.
 Properties and application of hyaluronic acid
IL-1b) to ensure steady and prolonged drug action at
the site of the inflammation. However, further study of
antibody–polymer conjugates would require extensive,
time-consuming research. Patients with osteoarthritis
see delayed analgesic affect but longer-lasting results
when compared to treatment with glucocorticosteroids
and should be considered as adjunct to therapies. The
greatest amount of the compound is present in the
skin, as well as in synovial fluid, the vitreous body,
and the umbilical cord. It can also be found in the
places where friction occurs: the joints, tendons,
sheaths, pleura, and the pericardium which indicates
its notable bioavailability. These notably distinctive
physiochemical properties of hyaluronic acid encour-
age future study of this polysaccharide for the
advancement of the field of medicine in several spe-
cialties and indicate its advantageousness throughout
medicine.
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