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Hyaluronic acid: A review on its biology, aspects of drug delivery,

route of administrations and a special emphasis on its approved
marketed products and recent clinical studies

Shyam Vasvani, Pratik Kulkarni, Deepak Rawtani

PII: S0141-8130(19)36547-X
DOI: https://doi.org/10.1016/j.ijbiomac.2019.11.066
Reference: BIOMAC 13847

To appear in: International Journal of Biological Macromolecules

Received date: 20 August 2019

Revised date: 25 October 2019
Accepted date: 7 November 2019

Please cite this article as: S. Vasvani, P. Kulkarni and D. Rawtani, Hyaluronic acid: A
review on its biology, aspects of drug delivery, route of administrations and a special
emphasis on its approved marketed products and recent clinical studies, International
Journal of Biological Macromolecules(2019), https://doi.org/10.1016/
j.ijbiomac.2019.11.066

This is a PDF file of an article that has undergone enhancements after acceptance, such
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© 2019 Published by Elsevier.

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Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations
and a special emphasis on its approved marketed products and recent clinical studies.

Shyam Vasvania* MS, Pratik Kulkarnia MS, Deepak RawtaniaPhD

a
Gujarat Forensic Sciences University, Nr. DFS Head Quarters, Sector 9, Gandhinagar, Gujarat
382007
Tel.: +91 9033072724, +91 9408276489
E-mail: pratik619prasad@gmail.com; rawtanid@gmail.com

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Corresponding author: Shyam Vasvani*

Mailing address: Gujarat Forensic Sciences University, Nr. DFS Head Quarters, Sector 9,
Gandhinagar, Gujarat 382007
Tel.: +91 7990372871,
E-mail: shyamvasvani123@gmail.com
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Highlights

 Hyaluronic acid-CD44 interaction leads to tissue regeneration and homoeostasis.

 Hyaluronic acid has an easy to modify chemical structure, is biocompatible and a
mucoadhesive agent.
 Hyaluronic acid plays a key role in mediating inflammation.
 HA can be used for the treatment of various diseases like asthma, cancer, wound healing,
dry eyes, arthritis etc.

Abstract:

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Hyaluronic Acid (HA) is a large non-sulphated glycosaminoglycan that is an important component

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of extracellular matrix (ECM) and a biodegradable polymer. Due to a variation in its molecular

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weight, HA derivatives can be utilized to make different formulations like fillers, creams, gels and
drops. HA based drug research has seen a recent surge largely due to some properties like
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mucoadhesion, biocompatibility and ease of chemical modification. Such properties of HA have
led to applications in tissue regeneration, anti-aging and anti-inflammatory medications. HA can
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be conjugated, functionalized or used as a nanocarrier supplement with a definite increase in its

cellular uptake and efficiency. HA when encapsulated in a nanocarrier may help to improve the
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ECM growth and provide a sustained release of agents. This review discusses the mechanistic
behavior of HA pertaining to its biological synthesis and degradation. It also discusses the
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administration of some noteworthy and recent HA based formulations through different routes for
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application in various physiological conditions along with their ongoing clinical trial updates and
approved marketed products.

Keywords: Hyaluronic acid; Tissue regeneration; Drug delivery; Inflammation; Clinical trials
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1. Introduction

Hyaluronic acid (HA) conjointly termed as Hyaluronan, is an anionic, non-sulfated

glycosaminoglycan (GAG) unfold wide throughout the connective and epithelial tissues.
Mucopolysaccharide, which is amongst the foremost elements of extracellular matrix (ECM) [1]
contributes considerably to cell propagation and migration, and is accountable for the enlargement
of some malicious tumors. A person with an average 70-unit weight has approximately 15 g HA
within the body, 33rd of which is spun over daily (degraded and synthesized) [2].

Works citing HA gained attention when the first medical specialty product of HA was developed

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during the 1970s and 1980s by Pharmacia and approved to be used in ophthalmic surgery.

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Subsequently, alternative corporations also released brands of HA medications for eye surgery.
Native muco-polysaccharide has comparatively a short half-life (shown in rabbits) [3] and

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therefore varied techniques for production were systematized for improving the chain length and
molecule stability for applied medical uses [4]. Stabilization of HA chains with chemical agents
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like NASHA (non-animal stabilized hyaluronic acid) were used in various diseases. In the late
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1970s, lens implantation typically followed a severe membrane swelling, due to epithelial tissue
damage during the surgery [4]. This made it highly evident that a viscous, clear and a physiological
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molecule was required, presumably HA to forestall the scraping of the epithelial tissue cells [5].

The name was modified to "HA" in 1986, which forms as a result of the carbohydrate synthesized
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by class cells and bound species of microbes that could be a salt, not associated with different
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acids. Since then, use of the name HA has become quite popular [6]. HA is built of an energetically
stable oligosaccharide that is composed of D-Glucuronic acid and N-acetyl glucosamine groups
through interchanging β-1, 4 and β-1, 3 glycoside bonds [Fig.1]. These individual disaccharides
bind along to form a coiling chain structure of varied length and relative molecular mass ranging
from 10-1000 kDa with length up to 10 nm. With such a large range in its molecular weight, HA
has acquired different elastic properties which can be employed for various medicinal uses [7].

Figure 1: Chemical structure of Hyaluronic acid

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2. HA synthesis, properties and degradation

2.1 Synthesis

HA is synthesized by a class of integral membrane proteins known as HA synthases [Fig. 2], from
which vertebrates have 3 types: HAS1, HAS2, and HAS3. They lengthen HA by repeated addition
of glucuronic acid and N-acetyl-D-glucosamine groups to the growing sugar and are extruded via
ABC-transporters through the cell wall into the cells [7]. HA synthesis is reversed by
4-methylumbelliferone (hymecromone, heparvit), a 7-hydroxy-4-methylcoumarin derivative. This
selective inhibition (without inhibition of alternative GAGs) might prove helpful in preventing

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metastasis of tumor cells. In a proprietary based method, Bacillus subtilis was genetically changed

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to yield HAs for manufacturing human-grade products [8]. Although any of the HAS proteins are
enough for HA production, the three forms of HA synthases have different kinetic characteristics

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which ultimately affects the size of HA. HAS1 and HAS2 proteins are responsible for the synthesis
of high molecular weight HA (HMWHA) and are moderately active, whereas HAS3 protein
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possesses the highest activity and polymerizes into low molecular weight HA (LMWHA) [9].
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In humans, the half-life of HA in tissues ranges from about 1 day in the skin layer [10] to up to 70
days in the vitreous body of the eye [11]. In animals, especially in horses, HA is employed for
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treating body part ailments. It is indicated for carpal and joint dysfunctions, however not once any
significant joint infection or fracture was suspected [12]. It is particularly useful for inflammatory
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disorders related to equine degenerative joint diseases. It is inoculated right into the affected joint
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for localized disorders causing gentle heating of the joint without deterring its clinical outcome.
Intra-articular administration of the medication is metabolized periodically. As per Canadian
regulation, HA in HY-50 preparation shouldn't be administered to animals that are to be
slaughtered for horse meat. However, in Europe an equivalent preparation didn’t yield such
results, inferring its edibleness.

Figure 2. Degradation of HA. Interaction of HA with CD44 receptor has been shown.
Internalization of HA via endocytosis leads to its degradation.
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2.2 Properties of HA

HA plays several structural tasks throughout the ECM by specific and non-specific interactions. It
is useful to proteins, and vital for cellular communication transduction with particular molecules
and receptors. Some examples of the receptors and molecules are: Neurocan, CD44, Receptor
for Hyaluronate-Mediated Motility (RHAMM), GHAP (Glial HA binding protein), LYVE-1
(Lymphatic Vessel Endothelial Hyaluronan Receptor 1), Versican, Aggrecan, and TSG6
(TNF-stimulated gene 6) [14]. However, current analysis denotes that CD44 is the one with prime
significance, because of its multifunctional cell surface conjugated protein present on several cell
varieties. HA is additionally helpful for the growth of epithelial tissue cells, eosinophil,

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macrophages, and a few animal tissues cells. Solely low relative molecular mass HA particles

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plays an important role in growth, ranging from size 20 kDa to 450 kDa [15]. HA is also essential
in healing and scar formation. Higher relative molecular mass molecules are known to aid in

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healing wounds. Less scarring tissue was determined in the presence of lower molecular weight
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HA. These results highlight the importance of relative molecular mass for the effectiveness of the
healing and scaring process. It has been found that HA with a higher molecular mass supports
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tissue integrity by developing tiny fragments to initiate links that nurses an inflammatory response
throughout an injury [16].
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Till the late 1970s, muco-polysaccharide was represented as a "goo" molecule or a supramolecule
which is a constituent of ECM [17]. HA is a key element of animal tissues, and acts as a coating
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around every cell (chondrocyte). Aggrecan monomers are known to form large aggregates due to
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their HA binding in the presence of HAPLN1 (Hyaluronan and Proteoglycan Link Protein 1).
These leads to a considerable water absorption, making HA responsible in imparting flexibility to
the animal tissue. While the mass (size) of HA in animal tissue decreases with age, the quantity of
HA increases [18]. HA provides lubrication in muscular connective tissues to increase the
slipperiness between the in-line tissue layers. A type of fibroblasts, embedded in dense facial
tissues, specialized to produce the HA-rich matrix has been reported to control the lubricating
ability between adjacent muscular connective tissues [19]. HA is also a significant element of skin,
with respect to tissue repair [20]. An exposure of skin to extensive ultra-violet beam rays causes
reddening (sunburn) making the cells within the derma to stop sufficient HA production and
thereby increases the speed of its degradation (Fig. 2) [21]. HA degradation machinery then starts
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accumulating within the skin. While it is abundant in ECM, HA additionally provides tissue with
better hydraulics, movement and proliferation of cells that contributes in variety of cell surface
receptor interactions, predominantly with its primary receptors, CD44 and RHAMM [22].
Regulation of CD44 is well-known as an indicator of lymphocyte cell stimulation. Interaction of
HA with CD44 is responsible for its role in growth. CD44 contributes in cell adhesion interactions
necessary for cell growth. Although HA binds to CD44, there is a proof that HA degradation
machinery changes over inflammatory signals through toll-like receptors TLR2, TLR4, or each
TLR2 and TLR4 in macrophages and nerve fiber cells [23]. TLR and HA play a vital role in innate
immune system [24].

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2.3 HA-receptor interaction and Degradation

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Thus far, there are 3 main groups of the cell receptors that are known for HA: CD44, RHAMM and

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intracellular adhesion molecule-1 (ICAM-1). CD44 and ICAM-1 are already well-known as cell
adhesion molecules with alternate ligands prior to HA binding [Fig 3] [25]. The formal
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demonstration of HA-CD44 binding was projected due to a diverse presence of CD44 in the body
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[26]. It is recognized because of a HA cell surface receptor. CD44 mediates its cell interaction with
HA and therefore the binding of the two functions as a vital half in varied physiological events like
endocytosis of HA etc. [27]. CD44 also plays a supporting role to HA binding in events such as
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cell aggregation, proliferation, migration, and activation, along with cell-cell and cell-substrate
adhesion.
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HA is degraded by an enzyme family referred to as hyaluronidases. In humans, there are minimum

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seven kinds of hyaluronidase-like enzymes, most of which are tumor suppressors.

Oligosaccharides (HA degradation products) and low-molecular-weight HA, exhibit
pro-angiogenic properties [28]. The primary structure of HA is degraded under several conditions
such as pH, temperature, thermal, mechanical, free radical, ultrasonic, and enzymatic stresses [29]
Also, recent studies have revealed that HA fragments and not the native high-molecular weight
HA are responsible for inducing inflammatory responses in macrophages, nerve fiber cells in skin
transplant and tissue injuries [30]. HA can also be degraded via non-enzymatic reactions which
includes acidic, alkaline hydrolysis and oxidant decomposition. The degradation of HA prompted
by stresses has pointed out its therapeutic importance i.e. HA is not susceptible to
depolymerization upon freeze-drying. After freeze-drying, the samples retain the same molecular
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weight as they had before the treatment [31]. HA’s turnover within a tissue occurs either by local
degradation or through release from the tissue into the lymphatic systems [32].

Figure 3- Important roles of HA and its receptors. RHAMM, CD44 and ICAM-1 acts with
HA with a specific function related to cell-tissue mechanics.

Two vital roles of CD44 in skin are projected. First one is the regulation of keratinocyte
proliferation in response to change in stimuli, and the second one is related to the maintenance of
native HA [33]. ICAM-1 is considered as a metabolic cell surface receptor for HA. This
supramolecule could also be accountable for the clearance of HA from body fluid and plasma that

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accounts for most of its turnover in the whole body. Binding to this receptor triggers a finely

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coordinated cascade of events that nurtures endocytotic vesicles. Fusion with primary lysosomes,
catalyzes its digestion to monosaccharides, their active transmembrane transport, phosphorylation

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and catalyst deacetylation [34]. ICAM-1 in addition may also function as a cell adhesion molecule,
and the binding of HA to ICAM-1 might therefore contribute to regulate ICAM-1-mediated
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inflammatory activation [35].
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HA owing to its biocompatibility and common presence within the ECM of tissues is gaining
reputation as a quality biomaterial scaffold in tissue engineering. Many researchers have found
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that HA's properties considerably improve by crosslinking in the form of a gel for tissue
engineering and as a regenerative drug [36]. HA is often cross-linked by attachment with chemical
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groups such as (a) tyramines (trade name: Corgel) [37], (b) thiols (trade names: Extracel, HyStem)
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[38], (c) methacrylates, hexadecylamides (trade name: Hymovis) [39], and also with gas (trade
name: Hylan-A) or with divinylsulfone (trade name: Hylan-B) [40].

This cross-linking ability of HA helps in stimulating epithelium cells to proliferate which are often
needed to produce hydrogels to review tube-shaped structure ontogenesis [41]. These hydrogels
resemble properties with human soft tissues, and are easily adapted to control and change, making
HA a good candidate for tissue engineering studies [42]. As an example, HA hydrogels are known
for creating vasculature from epithelium primogenitor cells via exploitation of growth factors-
VEGF and Ang-1 to start proliferation and form a network of tube-shaped structures. The ability to
form such tube-shaped structure networks by extensive use of HA hydrogels has offered some
prospects for in vivo analysis and clinical applications [43]. In an in-vivo study, HA gels were
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applied and epithelium colony forming cells were planted into mice up to 3 days. Hydrogel
formation showed that the host and built vessels joined within 1-2 weeks of implantation,
indicating viability of the built vasculature [44].

3. Route of administrations- under research

From late 1970s, various routes of HA based formulation are being administrated as shown in
Table 1 with a specific role of HA involved [45-48]. Currently some new routes are under picture
for more drug delivery applications which are discussed herein. Table 2 shows some registered
products containing HA along with their basic indications and composition [49-68].

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Table 1: Various (approved) routes of administration of HA.

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Table 2: Examples of registered HA based formulations along with their composition and
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3.1 Cutaneous administration
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An oral drug with some predetermined quantity may have some limitations like low
bioavailability, short half-life of the drug and multiple doses per day. HA thus can be an
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appropriate moiety, since this carbohydrate is incorporated well within the stratum [69]. HA is
able to improve the dermal delivery of various molecules, together with high relative molecules
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that can be easily encapsulated within the pores. In certain cases, the molecules can even
physically adsorb onto the surface of the gel particles [70]. Such systems help in the controlled
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release of the molecules, thereby reducing dose-dependent toxicity and increasing the
bioavailability [71].

However, the attachment of HA on the surface of vesicles could cause a major stiffening of the
bilayer, thereby neutering the general flexibility properties of the drug delivery systems [72]. A
recent work showcased the potential of HA-decorated liposomes for enhancing the connective
tissue administration of lidocaine. The presence of the carbohydrate on the cyst surface resulted to
be essential for efficient penetration of the liposomes into the skin [73].

As mentioned earlier, HA due to its ease of chemical functionalization can be used to modify its
structure to tailor specific demands. To prove the same, an octenyl succinic acid anhydride
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functionalization was done on the HA surface rendering it hydrophobic. This change helped it to
self-assemble in the form of multiphasic cross-linked nanogels, because of which entrapment of a
model hydrophobic agent (peptide) was possible. The administration of this nanogel was able to
reduce the toxicity of the DJK-5 peptide without affecting the efficacy of the non-formulated one
in comparison [74, 75]. A case study reporting subsequent administration of high dosed pulses of
hyaluronidase showed a significant improvement in vascular complications related to intra-arterial
injections that causes impending skin necrotic changes and vascular obstruction [76].

A prominent example of a marketed product named Bionect® is a HA based cream composed of

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sodium hyaluronate as the main constituent. It acts as a lubricant on the skin by restoring moisture
and thus preventing abrasion [49] (Table 2).

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3.2 Ocular administration

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Based on some recent studies, low viscosity ophthalmic preparations of HA are capable of
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enhancing the bioavailability of ocular components due to their bio adhesive properties. Findings
of these shows the mucoadhesive properties of HA salts like sodium hyaluronate [77].
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Cross-linked and thiolated HA hydrogels showed a significant improvement in the ocular surface
health due to bio-adhesion aided by the formulation. As a surgical aid in eye surgery, implantation
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of artificial lenses in elastic gel form replicates physicochemical characteristics of the drug and eye
[78]. HA in turn binds to many water molecules through non-covalent bonds leading to gel
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formation which is 97 % by weight made up of water giving the assembly a vitreous jelly-like,
semi-solid consistency. Although it may seem that replacing the vitreous using protein-based
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materials would be optimal, these have not been clinically successful yet [79].

Usage of tea polyphenols such as catechins especially Epigallocatechin gallate (EGCG) have
found uses in diseases ranging from bacterial infection to cancer. In a case here, gelatin-EGCG
nanoparticles decorated with HA were employed as ocular drops for the treatment of dry eye
syndrome using a rabbit model. HA due to its mucoadhesive properties helped to retain the
formulation for a longer time, directly increasing the retention of the drug in contact with the
ophthalmic layer. This treatment was achieved specifically by an inflammatory relief mechanism
as tea polyphenols like EGCG possess both anti-inflammatory and antioxidant properties. EGCG
along with HA due to its combinatorial action was able to achieve the inhibition of
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pro-inflammatory cytokine levels as usually evident during dry eye syndrome [Fig 4] [80].

Figure 4- A schematic diagram showing administration of HA based ocular drops for dry
eye syndrome treatment. HA-CD44 interaction allows retention of water in the ocular space
due to its high-water binding capacity.

Hyalistil® is a well-known example of a marketed product which are HA based ocular drops given
for the symptomatic treatment of dye eye syndrome and conjunctivitis. It is also given as an OTC
product for relief in cases of ocular discomfort. It provides lubrication and hydration to the ocular
surface [62] (Table 2).

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Treatment of eye complications in the form of ocular inserts can be discussed here as a unique

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approach. Recently, HA based ocular inserts with cyclosporine’s combination along with

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HP-β-CD complex helped to increase the overall levels of the drug compared to its free
counterparts. Again, HA providing mucoadhesion was responsible for increasing the drug
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retention time and providing a controlled release [81, 82].
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3.3 Topical administration:

HA as a topical formulation offers a robust and distinctive potential for the delivery and
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localization of medication to the skin [83]. The size of HA molecule is one of the most crucial
aspects to consider its topical delivery. HA, due to its uniqueness and a large polymeric structure,
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makes it challenging to obtain from outside as it cannot pass from the digestive system to the blood
circulation. As a result, most exogenous formulations of HA have been in the form of an injection
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or topical systems. Within its presence, HA permits the drug to penetrate the outer skin barrier and
insert within the stratum, restricting its general absorption which is advantageous particularly for
the delivery of cytotoxic agents in the treatment of cancer [84].

To enhance the antibacterial properties of the topical film, HA in combination with nanoparticles
(e.g. AgNPs) as bioactive agents were incorporated in a rat model leading to a more effective
dressing for restoration of the skin tissue homeostasis after 14 days [Fig 5] [85]. HA, topically
have also demonstrated that smaller the molecular weight of the active agent, the greater is the skin
penetration and skin hydration as observed in a controlled setting to assess the anti-wrinkle
efficacy of a cosmetic product [86].
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Figure 5- A schematic diagram of HA-AgNP topical cream. Application of the HA-AgNP

cream to the damaged skin layer leads to improvement in skin tissue homeostasis.

Connettivina® cream can be discussed here as it is prescribed for the treatment of skin disorders
and dehydration caused during radiotherapy treatments and in the prophylaxis of bacterial
infections of traumatic lesions, skin sores and burns. It stimulates the repair and regeneration of the
skin. Its hydrophilic properties provide a hydrated space in the cell environment thus aiding in cell
migration [50] (Table 2).

In an interesting study, topical administration of HA was employed for the treatment of some

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upper airway diseases with positive outcomes. Here HA was administered topically via a nasal

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douche (nebulized and micronized). Otolaryngolocial disorders are caused mainly due to the
inflammation of nasal tissues leading to infection in the nasal passageways. HA showed its

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potential to reduce the inflammation with substantial improvement in mucociliary clearance and
nasal respiration [87].
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Topical administration of hyaluronate gel is one prime example which illustrates the use of HA in
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diverse applications. Here an HA based topical gel was employed for the treatment of
muco-cutaneous oral lichen plexus which is caused predominantly due to an imbalance in the
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T-cell lymphocytic cascade leading to a basal cell layer damage [88]. The formulated HA gel
significantly improved the symptoms than the conventional corticosteroid treatment.
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3.4 Nasal administration

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HA has been used as a tool for the nasal delivery of small molecular drugs to enhance their
bioavailability and bio adhesion [89]. The increases conferred by HA were found to be
molecular-weight dependent with the HMWHA fractions (>300 kDa) promoting an increase in
bioavailability whereas LMWHA (55 kDa) showing no effect. With the enhancement in
bioavailability and penetration induced by HA in vitro, the ciliary beat frequency of rabbit nasal
mucosal membranes was not affected by the presence of HA in solution. Bioavailability is known
to increase due to mucoadhesion, prolonged retention time, and increased permeability of mucosal
epithelium. The mucoadhesive formulation significantly exhibited a more prolonged clinical
effect than the non-mucoadhesive product [90].
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A striking recent example of a nasally administered HA based formulation can be given here. As
discussed earlier, HA provides a gap to easily modify its chemical structure without compromising
its basic properties and remaining non-toxic. Similarly, in this study a pH responsive alloy-drug
nanoconjugates were used in the treatment of glioblastoma. Here HA was attached to
functionalized drug loaded nanoparticles and were further coated with lactoferin moiety in order to
increase the uptake of the nanoconjugates [91]. HA in this case was used as a CD-44 specific
marker for a better targeting of the tumor vasculature and delivery of the nanoconjugates.

In another study, intranasal HA spray and HA nasal drops were able to treat the complications

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related to chronic rhinosinusitis with nasal polyposis [Fig 6]. The patients showed a significant
improvement in their symptoms, more specifically the endoscopic appearance of the nasal mucosa

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and nasal burning. HA being a part of the GAG found in the ECM, plays a crucial part in the repair
of mucosal tissue. The same was demonstrated effectively in this study [92]. HA has also been able
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to help patients with chronic bronchitis where concomitant administration of nasal HA with a
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prescribed antibiotic therapy helped them recover fast [94]. Patients with such therapy needed a
lesser dose of antibiotics compared to the one without HA. There was a significant improvement in
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gas exchange measurements and lung mechanics [93, 94].

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Figure 6- A schematic diagram showing the administration of HA via nebulization or as a

dry powder for inhaler form for nasal rhinosinusitis treatment. HA reduces inflammation
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and nasal burning.

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Hyaneb® is also a nasal aerosol product given along with a nebulizer. It is used in loosening or
dissolving thick mucus making it easier to cough up. It is composed of hypertonic saline and
sodium hyaluronate. The salt in the water helps in attracting water molecules from the
surroundings and thinning the mucus. HA was added to mask the salty taste [65] (Table 2).

4. Recent applications of HA in drug delivery

4.1 Wound repair

Skin acts as a mechanical barrier to the external setting to stop the ingress of infectious agents,
failure of which makes the skin exposed to infection. Thus, fast and effective healing is
fundamental to reconstruct a barrier of the skin layers [95, 96]. Skin wound healing could be an
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advanced method, and includes several processes originated due to hemostasis of platelet-derived
factors. The subsequent stages are inflammation, granulation formation, re-epithelialization and
transformation. HA probably plays a multifaceted role in mediation of those cellular and matrix
events.

The strategic roles of HA based formulations for skin wound healing are elaborated here. HA has
been employed in the synthesis of biological scaffolds for wound-healing applications. These
scaffolds generally have proteins like fibronectin connected to HA to facilitate cell migration into
the wound due to its viscoelastic property. HA is under use as a primary dispersion agent but may

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also be considered for use in conditions like muscle stiffness where altered viscosity of the fascia is
desired [97]. This is often notably vital for people with polygenic disease affected by chronic

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wounds [98].

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As a wound healing agent, HA is expressed within the wound margin, the animal tissue matrix,
and is joined with CD44 for keratinocyte migration [99]. One of the studies found suppression of
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CD44 expression by epidermis-specific antisense transgene that resulted in faulty HA
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accumulation within the superficial corium [100]. A weakened native inflammatory response, and
diminished tissue repair were additionally determined. These observations powerfully corroborate
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the important roles of HA and CD44 in skin physiology and tissue repair [101]. Fetal wound
healing and lack of fibrous scarring is the prime feature of wound healing found in vertebrates
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[102]. Even for extended periods, HA content in vertebrate wounds continues to be more of that in
adult wounds suggesting that HA could partially cut back albuminoidal deposition resulting in
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reduced scarring. This suggestion lies in agreement with the analysis of WHO which stated that the
removal of HA leads to fibrotic scarring (showed in adult and late gestation vertebrates) [102-105].

Hyalofill® is a fleece and rope format product containing HA ester (HYAFF®). In the contact of
wound exudate, it converts itself into a soft gel that helps to maintain a most environment. This
leads to the promotion of granulation tissue formation and easy removal of the dressing [54] (Table
2).

HA has a substantial role in the inflammation cascade and granulation phase of healing. This
eventually helps in maintaining a moist environment around the wound where cell migration (for
e.g. fibroblast and endothelial cell migration) to the wound bed can take place. This also reduces
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the overall bacterial load [104-106]. For instance, Staphylococcus aureus is known to be one of the
main culprits behind wound formation. This property arises mainly due to its virulence factor
which produces the exoenzyme hyaluronidase, responsible for breaking down HA. In this case, the
wound healing effect of HA was demonstrated by administering it along with a systemic antibiotic.
Correspondingly, earlier studies have hypothesized that the hyaluronidase present in the S. aureus
may degrade the extra HA present without interfering with the amount in that of host’s body. This
may thus help in preventing S. aureus dissemination and promote wound healing. Such a property
can be foreseen as a viable treatment option in wound healing cases [107].

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HA in combination with adipose stem-cell derived exosomes were recently used for wound
healing application. In this pilot study carried out on nude mice, HA along with the exosomes

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helped in enhancing the re-epithelialization and vascularization of the cells leading to a faster
repair and healing of acute cutaneous wounds. Here, HA was used specifically to immobilize and
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thus increase the residence time of exosomes within the tissue vasculature [108].
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Full thickness wounds lead to severe tissue damage of dermal layers often causing the failure of
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normal wound healing process. As a damaged tissue usually needs a dermal matrix for repair of
tissues, HA can be used for this purpose as it is compatible and is known to stimulate wound
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healing process. Recently, HA in an esterified form was used to shorten the healing time and
reduce the recurring scar hypertrophy in deep dermal wounds. Moreover, the biopsy studies up to
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12-month post reconstruction showed neodermis growth that was histologically larger and
comparable to normal skin [109].
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4.2 Cancer

In recent times, the application of nanotechnology in medicine has garnered much attention.
Various nanomaterials have been widely used in nanomedicine as potential diagnostic and
therapeutic agents for cancer imaging and treatment. Compared to organic lipids or polymeric
nanoparticles, the inorganic counterparts exhibit unique properties such as ease of
functionalization, inertness and stability [110].

For an efficient treatment, it has been well documented that a targeted delivery is of utmost
importance as most anticancer drugs distribute throughout the body and are detrimental to normal
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healthy cells as well. To minimize the side effects, a target specific action of drugs is intended to
increase its concentration at the sites. Nanoparticles with small sizes (1–200 nm) preferably
accumulate at tumor sites caused by the enhanced permeability and retention (EPR) effect, also
called passive targeting. The active targeting action together with the EPR effect could further
enhance the cellular uptake of the drug or nanoparticles leading to a significant improvement in
cancer therapy [111, 112].

In some cancers, mucopolysaccharide levels correlate well with malignancy and poor prognosis.
HA here finds its use as a tumor marker for prostate and carcinomas and can also be used to

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monitor their progression due to its mucoadhesive property. HA and its derivatives can
specifically bind to some cell surface receptors, that are widely present in regions such as liver,

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kidney, body fluid, vessels, and most tumor tissues. This specific binding functions as a potential
for targeted drug delivery of HA [113]. HA and its derivatives may be used as carriers for proteins,
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peptides, nucleic acids, and various anticancer agents [112, 114].
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To demonstrate this HA was conjugated with folic acid for a tumor targeted delivery of the
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anticancer agent Doxorubicin. The micellar formulation showed an improvement in its

cytotoxicity and CD-44 mediated cellular uptake in comparison to blank micelles. This again
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showed the potential of HA as a structural assist in the formation of an amphiphilic molecule that
could be used for targeting [115].
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An ability to target tumors and site-specific drug release are some key factors for effective cancer
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therapy. Poly (ethylene glycol) (PEG)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) were
investigated as carriers for anticancer drugs including Doxorubicin and Camptothecin (CPT)
[116]. The advantage of HA formulations is well appreciated in cancer therapy since HA
specifically binds to the overexpressed CD44 receptor in several tumors [117, 118]. Stable
hydrophilic nanoparticles with HA, while using the recognition of CD44 receptors could enhance
the targeting of tumor cells.

Cancer cells expressing CD-44 on its surface can be used as a target for HA based formulation. For
example, HA decorated liposomes were successfully prepared for targeting cancer cells. In the
study, the prepared liposomes were complexed with HA via an aminoxy coupling reaction,
providing a great opportunity for visualizing the internal mechanics of the HA-CD44 interaction.
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The HA-decorated nanoliposomes showed a greater interaction with the cells with elevated CD44
expression compared to the downregulated cells which showed a negligible uptake citing the
possibility of tumor targeting in the future [119].

In addition to the targeting function, HA modified delivery systems can enter the cells more
efficiently via the HA receptor medicated endocytosis pathway. Utilizing the specific affinity of
CD44–HA is therefore an attractive strategy for cancer targeting treatments. However, to the best
of our knowledge, there are only fewer reports on HA conjugated nanoparticles for targeting
over-expressed CD44 cancer cells. HA coated on the outer surface of drug can be hydrophilic or

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hydrophobic showing that the nature of the drug may also have an influence on the cytotoxicity.
For example, a targeted drug delivery system based on HA modified mesoporous silica

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nanoparticles (MSNs) is under development. HA-MSNs possess a specific affinity to
over-expressed CD44 on specific cancer cell line surfaces. Therefore, it is hypothesized that in
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order to show the advantage of HA-NP delivery systems, both the target cell lines and suitable
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drug agents should be carefully designed for the study [120].
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In a recent work based on anti-cancer composites, HA decorated nanocomposites (Laponite®

nanodisks) were used for targeted delivery of Doxorubicin to CD44 overexpressed cells. The
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nanodisks were able to release the drug in a sustained release manner along with pH
responsiveness and specific internalization by the cells. The HA decorated nanocomposites also
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showed good biocompatibility and cytotoxicity against HeLa cells with overexpressed CD44
receptors [121].
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In a theranostic approach, dual targeted HA based nanorods showed a triple stimuli responsiveness
for photothermal breast cancer therapy. In the study, gold nanorods were decorated with
conjugated HA with an antibody for photodynamic therapy, better internalization and active
targeting. The nanorods were able to show a significant improvement in the targeting and
cytotoxicity. The combination of photodynamic and photothermal therapy proved to be beneficial
over individual therapy. Upon NIR radiation, the MCF-7 cells were able to generate reactive
oxygen species (ROS) and heat efficiently for a better cytotoxic effect [122].
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4.3 Inflammation

In the early stages of wound repair, the tissues are overabundant in HA. HA acts as a promoter of
early inflammation which is involved in whole skin wound healing [123]. In a murine air pouch
model of carrageenan/IL-1 induced inflammation, HA showed a dose-dependent increase of
inflammatory cytokines (TNF-α, IL-8) level. This was due to the CD44-mediated mechanism by
female reproductive organ fibroblasts at appropriate HA concentrations (10 µg/mL to 1 mg/mL).
Synthesis of HA as a result of combination with epithelium cells, in response to TNF-α like
inflammatory cytokines and microorganism LPS (lipopolysaccharide) have been shown to assist

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in primary adhesion of cytokine-activated lymphocytes that express HA-binding variants of CD44
present within the stratified and static flow conditions [124].

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HA has some contradictory functions within the inflammatory process. It doesn’t solely promote

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the inflammation but can also moderate the inflammatory response, which can contribute in the
stabilization of connective tissue matrix. A connective tissue in initial stages has a high amount of
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tissue intermediates produced by matrix degrading enzymes and reactive oxygen metabolites that
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are byproducts of inflammatory cells. Balance of a nearby joint tissue matrix can be attained by
tissue inflammation [125]. HA works here as a vital moderator that contradicts its role in
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inflammatory stimulation, as represented above. It also defends against any free-radical injury to
the cells. This attributes to its free-radical scavenging property, a characteristic that is shared by
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such giant polyionic polymers. In a recent rat model, HA showed to reverse the injury caused to
the connective tissue [125, 126]. In addition to that role, HA may also function within the response
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loop of inflammatory activation by specific interactions with the biological inflammatory

constituents. TNF-α, a vital protein produced during inflammation is known to stimulate the face
of TSG-6 in fibroblasts and inflammatory cells. TSG-6 is a HA-binding macromolecule which
combines with IgI to form a stable complex giving a synergistic impact on the latter's
plasmin-inhibitory activity [127, 128]. This enzyme acts to activate a chemical change cascade of
matrix metalloproteinase and alternative proteinases that results in inflammatory tissue injury.

The complex formation between TSG-6-IgI complex and its subsequent binding to HA within the
ECM may thus provide a potent feedback loop to moderate inflammation. This might ultimately
help in stabilizing the healing of connective tissues. In a murine air pouch model of
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carrageenan/IL-1 induced inflammation, HA has been shown to have a pro-inflammatory property

that reduces inflammation when TSG-6 is administered. Hence, the results are comparable to
general anti-inflammatory treatment [126, 127].

Recently, HA has been approved for treating degenerative knee arthritis via intra articular
injections directly into the joint [128] [Fig 7]. Also, intra articular injections of HA based
formulations have been studied for some beneficial effects in obese rat models. As discussed
above, HA exerts its anti-inflammatory action by suppressing pro-inflammatory cytokines and
chemokines [125,129]. For example, Orthovisc®, Healon® etc. are some well-known products

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composed of HA indicated for relief from knee pain and inflammation (osteoarthritis). They work
by acting as lubricants and shock absorbers in the joint which helps the knee to move smoothly,

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thereby lessening pain [51] (Table 2). In another instance, HA-NPs were demonstrated to show
beneficial effects on a diet-induced obese mice model for evaluating anti-inflammatory actions. In
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the study, the HA-NPs were able to suppress macrophage infiltration into adipose tissues and
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subsequently reduce their inflammation. This led to an improved insulin sensitivity and glycemic
control further revealing its practicability as a treatment option for type-2 diabetes [130].
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Enhancive therapy for arthritis was recently demonstrated by employing the use of HA based
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bilosomes for targeted delivery of triterpene (a phytomedicine). Here, the HA functionalized

bilosomes were administered intra-articularly for increasing the efficacy of triterpene.
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Ligand-receptor interaction was devised as the mechanism for an efficient uptake of the drug. The
use of HA helped in increasing the drug circulation and improvement in its intra-arthritic
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bioavailability [131].

In one more example, HA-CD44 interaction was induced causing the increase of collagen ratio
upon HA administration. Here, HA was used with platelet-rich plasm and was given in the form of
Extracorporeal Shock Wave Therapy (ESWT) for human chondrocyte regeneration in vitro. The
study demonstrated that due to ESWT, in-vitro susceptibility of human chondrocytes to HA for
cartilage repair was increased along with migration onto the cytokine rich cells leading to
anti-inflammatory actions and tissue regeneration [132].

Figure 7- A schematic diagram of intraarticularly injected HA. HA injection directly to the

knee leads to repair of the damaged tissue thereby lessening pain and inflammation.
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4.4 Respiratory disease

Asthma is a chronic disease of the airways and the lungs characterized by their transformation,
which incorporates changes within the ECM. But the role of ECM in mediating these changes is
poorly understood. HA, a significant part of the ECM, has been known to play a part in respiratory
illnesses and also in several alternative biological processes [133]. The assembly of HA has been
viewed as an essential marker of inflammation; however, an additional agent might have some
pathological significances like modification of the tissue mechanism, increase in the propagation
of single molecular chains, augmentation in the production of the remodeling growth factor-beta

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(TGF-ß) and modulating its consequences [134].

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HA is abundantly found within the lungs that shields the respiratory organ scleroprotein (that has a
mucoadhesive property) from inflammation [135]. As per a study, HA may be well utilized in the

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distribution of a drug to the respiratory organ and nose and may prolong its retention time by
providing sustained release [136, 137].
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Endogenous HMWHA plays an imperative role within the physiological state of the higher and the
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lower airways [138]. It is a crucial part of the conventional airway secretions that employs a
medicinal drug to cause anti-angiogenic actions, promoting cell survival and mucociliary
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clearance. This organizes complex matrix, stabilizes connective tissues, sustains healing processes
and regulates tissue association [139]. Exogenous HMWHA thus represents a promising
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therapeutic agent for treating nasal and respiratory organ diseases that involve inflammation,
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aerophilous stress and animal tissue regeneration, like allergic and non-allergic inflammation,
asthma, chronic preventive pneumonic malady and fibrosis [140].

hysan® Pflege spray is one such example of a marketed product which utilizes HA (moisturizer)
along with dexpanthenol (regeneration supporting). This product helps in the regeneration of a
stressed nasal mucosa. It helps in restoration of the natural protective barrier after a cold. HA coats
the nasal mucosa in the form of a film and dexpanthenol ensures a proper regeneration owing to an
extra moisturizing effect as a combinative effect [64] (Table 2).

An HA based medical device named Broncalt® is used for acute otorhinolaryngological disorders.
The device is composed of HA, thermal water and grapefruit seed extract. This class II device was
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able to exert safe and effective anti-inflammatory, antimicrobial and washing activities along with
faster symptom relief related to upper airways diseases. The 2-week treatment showed a
significant and safe reduction of clinical features in all patient sub-groups [141].

Employing HA along with a complexing agent or a drug for treating respiratory inflammation was
demonstrated recently. Here, HA was formulated as dry powders for inhalation by complexation
with novel urea crosslinks and sodium ascorbyl phosphate (SAP). A significant improvement was
seen over plain HA administration. The novel formulation showed non-toxicity and a significant
reduction in the interleukin-6 and reactive oxygen species levels. This property was imparted due

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to a combined use of HA along with SAP [142].

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Tolerability of HA can be difficult when inhalational therapy is considered. To demonstrate this, a
recent study showed an improvement in the tolerability of HA formulation for the treatment of

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bronchiectasis patients. This disease is characterized by excessive retention of sputum in the
airways which leads to life-threatening infections. A 7% hyaluronate saline (HS) solution is often
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prescribed for this particular disease, however not all patients are tolerable to this. An addition of
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0.1 % HA to this therapy (HS+HA) was able to improve the tolerance and helped in removal of
sputum from the airways and an overall increase in the adherence to the therapy [143].
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Targeted gene silencing by RNA interference technology is currently gaining a lot of attention. In
a novel study, PEG and HA modified lipoplexes were used for local delivery of siRNA to the
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lungs. With the mucopenetration ability of PEG along with selective targeting provided by HA, the
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modified lipoplexes were used to deliver siRNA to the CD44 overexpressed lung tumor cells. The
PEG-HA decorated lipoplexes were able to penetrate the cells more efficiently than the
non-decorated ones, showing the capability of HA for selective cell targeting owing to its
interaction with CD44 [144].

4.5 Anti-aging

HA plays a crucial role within the stratum with essential functions in the re-epithelialization
process because of its unique properties [145]. It is an integral part of the basal keratinocyte ECM
(major constituents of the epidermis). Its free-radical scavenging activity plays a role in
keratinocyte proliferation and migration [146]. In older skin, HA is found to grow in higher
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concentrations in the abundance of proliferating keratinocytes within the basal layer of the stratum
[147]. It is also reported that CD44 combines with HA for regeneration [148].

Provision of an open and a hydrous structure for nutrient transport are regarded as the most
important functions of HA in stratum. A recent report stated an increase in the content of HA in the
presence of retinoic acid (vitamin A) [149]. A rise in skin content of HA is related with some of the
effects against skin photo damage and aging which provides tissue extension. HA as a free-radical
scavenger helps in protection against radiation. This is in accordance with the role of CD44 acting
as an HA receptor within the stratum [150]. Epidermal HA moreover functions as a moderator for

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keratinocyte proliferation and is also essential in cuticle formation and tissue re-epithelialization.
For which, HA accelerates and stimulates an altered protein expression in vivo in human deep

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dermal skin wound [151]. Usage of HA loaded skin patches have recently seen prominence in the
sector of anti-wrinkle products [152]. Beauty Pie’s TM HA microneedle patch is a good example of
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HA based anti-wrinkle product. This HA microneedle patch is loaded along with anti-aging agents
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like Acetyl Hexapeptide-8, which stimulates collagen production and improves skin elasticity and
firmness. Here, HA plumps fine lines and madecassoside (triterpene) is also added to soothe
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inflammation [66] (Table 2).

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Skin aging is one of the causes for a decrease in the skin tone and volume causing firming due to
the degradation of ECM components like collagen and HA, leading to wrinkling and sagging
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[153]. To cite an example, HA was formulated in the form of a skin patch for studying its
anti-wrinkle efficacy. The objective of the study was to offer a solution to the reduced efficacy in
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relation to the corneal penetration and hydration and the reports of the method being invasive
[154]. To counter this, HA fillers are normally used in order to maintain the above issues. But the
method of application remains invasive as it employs the use of a needle making the patient opt for
alternatives. Recently, use of a novel synthesized tripeptide in combination of other anti-aging
agents like sodium hyaluronate, carnosine etc. were used to stimulate the synthesis of HA, both in
dermal fibroblasts and keratinocytes. This study presented a substantial improvement in skin
features related to skin firmness and spot removal [155].

Centella asiatica, a medicinal herb is well known as an alternative therapeutic remedy option for
various diseases like psoriasis, eczema, cancer etc. Recently, extract of this herb containing
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asiaticoside was entrapped in niosomes for efficient dermal delivery. Here, HA was used to coat
the outer surface of the niosomes to provide sustained release of the constituent. The HA coated
asiaticoside niosomes provided enhanced penetration of the transdermal layer compared to the
extract without HA coating. This strategy could be well applied in the future for better skin
therapeutics [156, 157]. Dry, scaly skin resembling to that caused by dermatitis is also treated with
skin lotion consisting of metal hyaluronate as an active ingredient [158] HA may be a common
ingredient in skin-care products [159] and this mucopolysaccharide has been employed as a
dermal filler in plastic surgery [160].

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4.6 Tissue and regenerative medicine

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In tissue engineering applications, hydrogels play a vital role in cell attachment and proliferation.
Recent advances in biomaterials provides a different approach to formulate scaffolds for tissue

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engineering, which includes HA like mucoadhesive materials. Hydrogels like HA have a
capability to modify a three-dimensional and a natural ECM like structure which can deliver
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growth factors for easy surface modification and a versatile design for tissue regeneration [161].
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Here, HA helps to initiate a new cell layer for anti-aging purposes and to enhance the therapeutic
effectiveness of the scaffold or matrix. This also improves the cell adhesion, viability and tissue
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regeneration capabilities [161, 162]. Regenerative medicine targets the methods to replace
damaged or diseased cells or tissues based on integrated strategies from tissue engineering [163].
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Hylase Wound Gel® can be given as an example here. It is an HA based gel used for wound
dressing and management. HA acts to contribute in the maintenance and support of healing
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process [68] (Table 2).

In a novel study, an injectable HA based in-situ gel composed of a polymeric blend of HA and
carboxymethyl hexanoyl chitosan was used for sustained release of berberine. The gels formed
were found to be cytocompatible, bio adhesive and biodegradable. The gels were efficient to
protect the chondrocytes from sodium nitroprusside (SNP) induced apoptosis. The LMW-HA used
to formulate gels was simply mixed with carboxymethyl hexanoyl chitosan without the need for
any crosslinkers or any thermal treatments. The gels thus proved to be a fruitful prospect for
intra-articular drug delivery and cartilage tissue engineering [164].

Tendinopathy is a peculiar disease usually characterized by debilitating musculoskeletal injury

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and tissue damage. In a recent study, application of HA loaded hydrogels to the site of damage
provided the patients with better recovery of the tissues and faster healing. The HA hydrogels was
proposed to act by arresting the degenerative process at an early stage thereby promoting healing
process and oxidative stress mitigation. Furthermore, addition of an anti-oxidative agent like
EGCG provided an additive effect for the healing process [165].

The regeneration of brain tissue is particularly limited by an extremely low permeation rate of
nanomedicine (<1%) through the blood brain barrier (BBB). Depending on their characteristics,
small molecules can cross the BBB by three main routes to reach the brain parenchyma under

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physiological conditions. First, paracellular transportation through an aqueous pathway; second,
by entry of small lipophilic molecules into the brain tissue by transcellular diffusion and third, by

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entry of small molecules in the brain through a substrate-specific process, the endogenous
transporter- or carrier-mediated pathway. This barrier is formed by tight junctions between blood
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vessels and endothelial cells (ECs), which restrict the passage of solutes and HA based drug
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delivery could demonstrate their possible use in crossing the BBB. Cells can be adhered to proteins
located in the nanofibrous ECM by their nanoscale receptors to fabricate biomimetic scaffolds
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which can be used for tissue regeneration. Nanomaterials such as nanoparticles, nanotubes, and
thin films have been developed to mimic the composition and structure of tissues at nanoscale
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level [166].

One of the examples is an ECM peptide derived hydrogel (HA) for promoting endogenous cardiac
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repair and growth factor-releasing hydrogels for an improved recovery from injury. Hydrogels are
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typically used in two different forms: First, bulk or conventional hydrogels and second, injectable
hydrogels or gels. Bulk hydrogels or interchangeably known as hydrogels, which are preformed
ex-situ as a semi-solid or gel structure are typically implanted at the site. On the other hand,
injectable hydrogels, are hydrophilic materials, in a liquid form before injection that transforms
into a gel in the infarct region in response to a change in physiological stimuli such as temperature
or pH [167]. Other types of natural polymers widely used so far for hydrogel preparation are
polysaccharides including HA, chitosan and cellulose. In particular, the natural biomaterials that
have generated the most promising results for hydrogel production in cardiac tissue engineering
are de-cellularized ECM constructs for biomimicking the native biochemical and structural matrix
composition and alginates that presents a structure similar to the ECM [168].
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The intermediate molecular weight HA (100−300 kDa) showed tissue regeneration by promoting
keratinocyte proliferation and the self-defense of skin epithelium by inducing β-defensin known as
skin antimicrobial peptide. In contrast, HMWHA over 1000 kDa showed anti-inflammatory
responses and immunosuppressive properties [169]. To cite one example, a recent study showed
the effect of HA on cartilage tissue repair mechanics. In the study, HA composite was prepared
and transplanted along with human umbilical cord blood-derived mesenchymal stem cells into the
defects of an experimental knee model. The combination proved to be superior in terms of overall
cartilage repair in comparison with HA alone or no treatment [170]. Appropriate molecular weight
of HA should be selected for each specific application. Nowadays, it is strongly required to select

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an adequate target disease and optimize the delivery system in terms of therapeutic efficacy and

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safety. Thus, HA should be produced to have a diverse molecular weight and a narrow molecular
weight distribution with well-defined characterization [171].

5. Clinical Trial updates -p

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The earliest therapeutic use of HA has been reported to be in 1968, where a burn was treated with
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pure HA [172]. Since then, it has found applications in nearly every field of medicine. Clinical
applications of muco-polysaccharide products cover many areas: Joint diseases, Ocular diseases,
Wound healing, and in Cosmetic industry [173].
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Medical technologies can be made use of smaller devices which are less invasive and can perhaps
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be implanted in the body, as their biochemical reaction times are much shorter. As compared to
conventional drug delivery, nanomedicine devices are much faster and offer more sensitivity
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[174]. A table displaying some noteworthy clinical updates in various diseases have been shown
with a prospective outcome for HA based products. Due to a large scope of including examples of
phase wise clinical trial, only the ones with a completed status, clinically significant results and
reported publications have been cited in this article [175-192] (Table 3). The safety and efficacy of
some different HA based products will be discussed here.

Table 3: Clinical trial updates for HA based products intended for different diseases.

In a trial for correction of moderate to severe nasolabial folds (NLF), the HA based crosslinked gel
showed a significant improvement. The patients also reported high satisfaction with the product
throughout the study. For the study, a validated photo numeric NLF severity scale was employed
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[175]. In another study, HA crosslinked gel was used for the correction of nose features of Asian
patients. There was a 96.6% clinically meaningful correction (≥1 grade improvement on the
Assessment of Aesthetic Improvement Scale) at the end of study. The patients also reported high
satisfaction throughout the study (12 months) [177].

Similarly, crosslinked HA hydrogel have been tested for the prevention of postoperative adhesions
like myomas and ovarian cysts. In this randomized controlled trial, the gel was found to be safe
and reported to be significant in reduction of adnexal adhesion formation and global adhesion
formation after gynecologic laparoscopic surgery. There was also a very low incidence of
postoperative incidence of moderate to severe adhesions in the case of the HA gel (5.9% vs

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14.9%). The safety profile of the HA gel was comparable to that of saline gel [192].

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Bacillus Calmette-Guerin (BCG) is considered as the most effective treatment for recurrence and

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progression of non-muscle invasive bladder cancer (NMIBC). However, it can also induce local
side effects leading to treatment failure. In a recent trial, intravesical administration of HA with
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BCG or BCG alone were tested to evaluate their efficacy in reducing the local side effects. Post vs.
pretreatment differences in visual analog scale (VAS) for pain, International Prostate Symptom
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Score (IPSS) and number of daily micturitions were all significantly lower in the group with HA
and BCG combination (4.2 of HA+BCG vs 5.8 of BCG alone) [186].
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For inflammatory conditions, a multicenter, randomized, double blind, placebo-controlled study

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was performed for a HA based product (hylan G-F 20) now in market. The primary objective of the
trial was to compare a single intra-articular injection of the product with placebo in patients with
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symptomatic knee osteoarthritis. The safety and efficacy of repeat injection was also assessed. The
results indicated no risk of local adverse effects and the product was found to be safe and effective
during the study period (26 weeks post injection). The pain scores evaluated during the study
showed significantly greater improvements and there was no difference between the groups
studied (single and repeat) [185].

In a recent proof of concept trial, HA based film was studied for a potential use in trauma open
abdomens. Here, carboxymethylcellulose sodium hyaluronate adhesion barrier (CMHAB) was
used to evaluate abdominal adhesions and wound characteristics in trauma open abdomens. The
patients had a shorter duration of stay in intensive care units (15 vs 22 days). There was no
difference in the intraoperative adhesion scores for initial operations. However, a 67%
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improvement was seen on the 5th operation compared to the CMHAB group. This study failed to
eliminate adhesions but limited their severity especially in abdomens (i.e. left open >9 days or
requiring > 5 operations) [188].

6. Human exposure and toxicity of HA

HA has intra-articular, cosmetic, and topical uses etc. It is used in the treatment of pain in patients
with knee osteoarthritis. Cosmetically, it is used for mild to deep dermal implantation aimed at
rectifying moderate to severe facial wrinkles and nasolabial folds, and also in submucosal
implantation for lip augmentation in patients older than 21 years [193]. Its topical uses comprise of

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the dressing and management of partial to full thickness dermal ulcers, wounds including cuts,

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abrasions, donor sites and postoperative incisions, irritations of the skin, first- and second-degree
burns [194]. HA, its degrading enzymes and products can be considered as biomarkers for

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detecting a recurrent disease in earlier stages and also an effective therapeutic follow up of some
cancer patients [195].
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Adverse effects of cosmetic use may include the following: hypoesthesia, vasovagal reactions,
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allergic reaction, anaphylactic shock, hypersensitivity, abscess, blanching, bruising, device

dislocation, discoloration, erythema, extrusion of device, injection-site numbness or tingling,
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ischemia, mass formation, necrosis, pain, scarring, swelling, vascular accidents, capillary
disorders, granuloma, herpetic eruptions, inflammatory reactions, presumptive bacterial infections
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and telangiectasias. Common adverse reactions reported for Hyalgan (intra-articular) treated
subjects were GI complaints, injection-site pain, knee swelling or effusion, local skin reactions
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(ecchymosis, rash), pruritus, and headache [196]. Adverse effects were not observed in animal
reproduction studies in rats and rabbits. Epidurally-administered HA did not produce any sign of
neurotoxicity in rabbits. Results of a study of LMWHA in vivo and in vitro suggested that
LMWHA might be a potential natural immune-modulatory agent. HA also acts chemically to
achieve its anti-inflammatory, analgesic and chondroprotective effects. These effects are believed
to allow HA for achieving its primary intended purpose as they act to mitigate the underlying
condition under FDA guidelines which intend to be safe [197, 198].
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7. Future Aspects and Challenges:

HA is a remarkable molecule that provides a fine potential for tissue engineering and other areas of
medical research. Researchers have used the properties of this linear GAG for applications ranging
from scaffold and tissue design to the carriage of drugs [199, 200]. HA shows distinctive
biophysical properties that provides potential functionalities. In terms of structure, HA is a huge
unmodified GAG (molecular mass between 103 and 104 kDa, extended length 2–25 mm)
consisting of a linear chain of continuing disaccharides of glucuronic acid and N-acetyl
glucosamine (Fig. 1) [201, 202]. Because of a sufficient electric charge, HA attracts positive ions,
making a diffusion imbalance that pulls in water, a property that has proved to be ideal for creating

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hydrogels and different ECM surrogates. Due to its hydration, HA has a great compressive

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strength in tissues and joints in vivo and provides lubrication to articulating surfaces. In vitro form
of HA has facilitated cell migration and pericellular matrix formation [203]. In addition, HA-drug

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conjugates could increase cellular uptake and cytotoxicity in vitro, decrease tumor weight, and
prolong the survival time of tumor-bearing mice compared to free drug [204]. The CD44-mediated
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internalization occurs quickly when HA based nanoparticles bind with tumor cells. Even the
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fragments of HA are known to bind with CD44. Therefore, the hyaluronidase degradation may not
significantly influence the targeting capacity of HA based nanoparticles [205].
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Figure 8: Key properties of HA in treatment of various diseases.

Figure 9- Current trends in HA based research.

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HA is used in the treatment of mouth sores, dry eyes, and aging of skin and many other diseases
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[Fig 8]. Awareness related to anti-aging treatment and consideration of alternatives like plastic
surgeries can possibly favor its market growth. HA as a biodegradable polymer, may well be used
as a sustained release and a targeted drug delivery agent [Fig 9] [206, 207]. HA based products are
currently undergoing clinical trials catering to the treatment of various diseases. The use of implant
technology can be viewed as a worthy prospect in the future. In situ gelling features of cross-linked
HA have been tested for implantable and depot drug formulations. This approach presents an
alternative to pre-formed gels. The sol–gel transformation allows complete filling of irregular
surgical defects, reduces implant migration and enables implantation of extemporaneously
prepared formulation using a less aggressive surgical procedure [205, 208]. Although there are
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several concerns to be addressed in the future, HA is still one of the most impressive nanomaterials
for constructing various drug delivery systems [207-209].

As discussed, HA due to variation in its MW can provide different biological actions. This
however is responsible for changes in its metabolism, receptor affinity and clustering which needs
to be explored more. Also, how HA works as a nanocarrier itself or as an additive, its exact role in
signaling with respect to its size and localization can be studied further. Synthesis of HA from
different sources need to be made more economical and time savvy. Use of strategies like one-pot
synthesis, solvent free methods, and click chemistry approaches etc. needs to be employed for
optimizing the preparation of HA derivatives [210]. While various biological fields are

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developing, HA in the form of a useful formulation with desired properties such as robust stability,

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reduced dosage frequency, wide options for its delivery etc. can be envisioned which can improve
its market in a broad sense [211].

8. Conclusion
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HA based materials depict a wide variety of features, such as cellular permeability, site-specific
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functionalization of molecules, tunable chemical structure, biocompatibility, and the ability to

respond to external stimuli. This in turn makes them excellent candidates for use in vast medicinal
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applications. Despite advantages, there are some limitations which need to be addressed. For
example, lab synthesis of HA can be an arduous process and time consuming. This can make the
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final product quite expensive when other costs such as inclusion of nanocarriers, chemical
conjugates or any other biological agents are involved. Therefore, an economical approach needs
Jo

to be developed which can make it more feasible as a drug delivery agent or product. This review
presented the possible benefits of HA in different fields such as tissue regeneration, respiratory,
neurological, topical, retinal and inflammatory diseases. In future, more intensive experimental
and clinical studies are needed to explore the diagnostic and therapeutic potential of HA as a
combinative agent with encapsulation of different drugs and biomolecules or in the form of a
nanocarrier itself. Carefully designed studies on the intracellular behavior, biocompatibility and
regulatory aspects of HA should be carried out as they have so far displayed some significant
advantages over other biomaterials for drug delivery applications.

Declaration of interest
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The authors report no conflicts of interest. The authors alone are responsible for the content and
writing of this article.

Acknowledgements

The authors would like to thank Maithri Tharmavaram for proofreading our manuscript.

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Route Role of HA Reference

Ocular Minimal effects on visual acuity and minimal resistance to blinking [45]

Nasal Mucoadhesion, prolonged retention time [46]

Pulmonary Absorption enhancer and dissolution rate modification [47]

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Parenteral Drug carrier and facilitator of liposomal entrapment [48]

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Table 1: Various (approved) routes of administration of HA
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 Journal Pre-proof
Commercially available Indication
product
Bionect® Removes harmful chemicals (free
radicals) and restores skin integrity.
Connettivina® Treatment of localized skin
irritations caused by physical agents
such as sun, cold, wind, diaper rash,
irritation and dehydration resulting
from radiotherapy treatments.
Jossalind® , HA cream Treatment of joint dysfunction
0.2% (Ialugen®),
Hyalgan®, Orthovisc®,
(surgery), Osteoarthritis
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Opegan®,and Opelead®,
lP
na
HA gel (Solaraze®) Pain in infectious and inflammatory
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diseases of ENT organs.
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Inflammatory eye non-infectious
nature, post-traumatic inflammation
in penetrating and non-penetrating
wound of the eyeball.
Composition References
Hyaluronic acid sodium salt [49]
(Hyalastine®)
Each mL contains 10 mg [50]
Connettivina sodium (hyaluronate
sodium), 8.5 mg sodium chloride,
0.223 mg sodium phosphate
of
dibasic and 0.04 mg sodium
phosphate monobasic.
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Each mL contains 10 mg [51]
hyaluronate sodium, 8.5 mg
sodium chloride, 0.223 mg sodium
[52], [56,57]
phosphate dibasic and 0.04 mg
sodium phosphate monobasic.
A derivative of phenylacetic acid, [53]
Solaraze containing hyaluronate
sodium.
 Journal Pre-proof

Hyalofill® Hyalofill® is an absorbent, soft and HA ester containing product [54]

conformable dressing composed of available in fleece and rope
HYAFF® (hyaluronic acid ester) formats.
that provides a moist hyaluronic acid
enriched wound environment.

Laserskin® To reduce the appearance of An epidermal autograft composite [55]

wrinkles and scars, even skin made of autogenous keratinocytes

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pigmentation, tightens skin, and grown on a biodegradable matrix

ro
remove lesions, both benign made of 100% esterified HA (i.e.,
(non-cancerous) and malignant. benzyl ester)
Monovisc A Single Injection, Lightly
Cross-linked High Molecular
-p Partially cross-linked sodium
hyaluronate (NaHA) in a phosphate
[58]
re
Weight Hyaluronic Acid for buffered saline solution. Maximum
lP

osteoarthritis management. dose of HA is 88 mg.

Cystistat® Cystistat® temporarily replaces the Each mL contains 10 mg Cystistat [59]
na

deficient GAG layer on the bladder sodium, 8.5 mg sodium chloride,

wall, helping to relieve the pain, 0.223 mg sodium phosphate
ur

frequency and urgency of interstitial dibasic and 0.04 mg sodium

cystitis. phosphate monobasic
Jo

iAluRil™ Interstitial cystitis or painful bladder iAluRil contains two of the natural [60]
syndrome, Radiotherapy-induced GAGs that form this barrier; HA
cystitis, Recurrent urinary tract and chondroitin sulfate (CS)
infections
Gelclair® Bioadherent oral protective gel for Water, Maltodextrin, Propylene [61]
mucositis relief, irritation due to oral Glycol, Polyvinylpyrrolidone
surgery, traumatic ulcers caused by (PVP), Sodium Hyaluronate,
braces or ill-fitting dentures, or Potassium Sorbate,
disease. Sodium Benzoate,
Hydroxyethylcellulose, PEG-40
 Journal Pre-proof

Hydrogenated Castor Oil,

Hyalistil® It is indicated in all cases of ocular
discomfort; in particular, it relieves
irritation and dryness due to
quali-quantitative alterations of the
Disodium Edetate, Benzalkonium
Chloride,
Flavoring, Saccharin Sodium,
Glycyrrhetinic Acid.
Sodium hyaluronate, sodium [62]
chloride; potassium chloride,
monobasic sodium phosphate
monohydrate, disodium phosphate

of
tear film or to environmental factors dodecahydrate, purified water.

ro
such as pollen, dust, glare, pollution
and the use of video terminals.
Juvéderm Ultra Plus JUVÉDERM VOLUMA® XC
-p Cross-linked HA produced by
injectable gel is for deep injection in Streptococcus species of bacteria,
[63]
re
the cheek, facial tissue, lips, perioral formulated to a concentration of 24
lP

area to correct age-related volume mg/mL and 0.3% w/w lidocaine in

loss in adults over 21. a physiologic buffer.
na

Yabro® and hysan® Recurrent upper or lower respiratory 0.3% HA [64]

tract infections,
ur

prolonged cough, dry or damp,

Hyaneb® Hyaneb is a product that is used to Hyaneb contains hypertonic saline [65]
Jo

loosen or dissolve thick mucus in the and HA.

airways
111 Skin® meso infusion Self-dissolving mesoporous mask Hydrolysed HA and ascorbic acid [66]
overnight micro mask and for anti-aging applications
Beauty Pie’s TM
DROPSTAR ® Treatment of dry eyes or lacrimal 0.4 % of hyaluronic acid sodium [67]
insufficiency. Also, as a lubricant salt per 10 ml.
and humectant.
 Journal Pre-proof

Hylase Wound Gel® Wound care dressing and Sodium Hyaluronate (2.5 %), [68]
management. Hydroxyethyl cellulose, Methyl
paraben, Polyethylene Glycol,
Water.

Table 2: Examples of some registered HA based formulations along with their composition and

of
indications.

ro
-p
re
lP
na
ur
Jo
 Journal Pre-proof

Application Disease or Condition Use of HA alone or in combination Outcome

Number with another compound.
NCT01559064 Age-related Volume Crosslinked HA gel JUVÉDERM  Smooth and easy t
Deficit in the Mid-face VOLUMA®  Well tolerated

NCT02312154 Aging Restylane Vital  Skin elasticity and

improved significa

of
ro
NCT01846039 Asian Nose Enhancement Cross-linked HA gel  Safety and efficacy

-p reported for specif

procedures in selec
re
lP
na

NCT01029535 Mid-face Volume Cross-linked HA gel  Safe and effective

Deficiency
ur

severe facial volum

Jo

NCT01240382 Dry Eye 3% DE-089 ophthalmic solution, 0.1%  Sodium hyaluronat

sodium hyaluronate ophthalmic efficacy in improv
solution scores of dry eye p
DE-089 ophthalmi
NCT02117687 Dry Eye Carboxymethylcellulose  HA was non inferi
0.5%/glycerin 0.9%| sodium objective signs of d
hyaluronate 0.18%
 Journal Pre-proof

NCT00918736 Osteoarthritis (OA) Sodium hyaluronate  Sodium hyalurona

effective option fo
ankle OA

NCT00669032 OA of the Knee HA,  Improvement in kn

Other: Placebo symptoms was rep

of
NCT00379236 OA EUFLEXXA, Placebo  Safe, effective, we

ro
 Not associated wit
as synovial effusio

-p
re
NCT01586312 OA Allogenic mesenchymal stromal cells  A valid alternative
(MSC) injection, HA chronic knee osteo
lP

 Logistically more
autologous MSC tr
na
ur
Jo

NCT00131352 OA, Knee, hylan G-F 20, Phosphate Buffered  Statistically signifi
Musculosskeletal Saline relevant pain relief
Diseases

NCT02207608 Poisoning by BCG HA, BCG (Immucist®)  Reduction in the lo

Vaccine
 Journal Pre-proof

NCT01970397 Patients With Moderate JUVEDERM®  Higher response ra

to Severe Perioral Lines Ultra XC, Belotero Balance®  Greater improvem
than CPM-22.5

NCT01594385 Trauma or Wounds and Seprafilm  Although CMHAB

Injury adhesions in this p
limited their severi

of
NCT00477152 Dehydration Hyaluronidase (human recombinant)  Subcutaneous hydr


ro
or rehydration fluid Safe and effective
mild or moderate d

-p
re
lP

NCT01935531 Actinic Keratoses 3% diclofenac in 2.5% HA gel  Reduced lactate an

na

(precancerous skin AK, especially in r

lesions)  Infiltration of derm
IFN-γ mRNA expr
ur

improved T cell fu
Jo

NCT02773251 Prostate cancer HA-carboxymethylcellulose  Reduction in bowe

abdominal wall aft
surgery.
 Good clinical safet
 Journal Pre-proof

NCT02166554 Postoperative adhesions Cross-linked Hyaluronan Hydrogel  Safe and significan

(Myomas, Ovary Cysts, adhesion formation
Endometriotic Cysts, formation througho
Adhesions) cavity.

Table 3: Clinical trial updates for HA based products intended for different diseases.

of
ro
-p
re
lP
na
ur
Jo
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9