Micro Nano Bio Aspects

https://www.mnba-journal.com Online ISSN: 2980-8081

Advanced formulations of hyaluronic acid and its derivatives for antimicrobial, wound
healing, tissue engineering, and anticancer applications

Sayed Hussain Mosawi1 and Elham Rezaei Niaraki2*

1
Medical Sciences Research Center, Ghalib University, Kabul, Afghanistan
2
Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

ARTICLE INFO ABSTRACT

Mini-review paper The application of natural and synthetic polymers for improving quality of life has been investigated for
several decades. Polysaccharides, particularly hyaluronic acid as a non-sulphated glycosaminoglycan are
Article history: being employed in the improvement of novel pharmaceutical and therapeutic applications, specifically drug
Received: 11 Feb 2024 delivery systems. This biopolymer has suitable biocompatibility and biodegradability for novel therapeutic
Revised: 04 June 2024 formulations. The molecular weight of hyaluronic acid determines its biological activities as angiogenic,
Accepted: 04 June 2024 wound healing, and anti-angiogenic. By the bacteriostatic effect, this biopolymer can be employed in
ePublished: 05 June 2024 antibacterial formulations. In this review, a variety of micro and nanoformulations of hyaluronic acid with
antimicrobial and anticancer agents have been discussed by considering their main clinical limitations
Keywords: including side effects of inadvertent arterial occlusion, tissue necrosis, and infections resulting from
Polysaccharides, Non-sulphated unsuitable injection hyaluronic acid gel.
glycosaminoglycan, Anti-
angiogenic, Clinical limitations,
Tissue necrosis

DOI: https://doi.org/10.22034/mnba.2024.442816.1059 Copyright: © 2024 by the MNBA.

Introduction It should be noted that the molecular weight of
hyaluronic acid determines the biomedical effects as
Polysaccharides such as cellulose, chitosan, and
induction of heat shock proteins by 0.4–4.0 kDa,
hyaluronic acid are the main natural polymers being angiogenic (<60 kDa), wound healing (200–500 kDa),
employed in the progress of novel pharmaceutical, and anti-angiogenic (more than 500 kDa) [6]. In this
biomedical engineering, and therapeutic applications, review article, different formulations of hyaluronic
specifically drug delivery systems [1]. Hyaluronic acid acid with antimicrobial and anticancer agents have
(C14H21NO11)n or hyaluronan or hyaluronate has repeat been presented by considering their main clinical
units of β-1,4-d-glucuronicacid-β-1 linked to 3-N- limitations involving severe side effects of chronic
acetyl-d-glucosamine with important functional groups lymphoplasmacytic inflammatory reactions,
of hydroxyl and carboxyl (Figure 1) synthesized by inadvertent arterial occlusion, granulomatous foreign
hyaluronan synthase (HAS) (three isoenzymes in body, tissue necrosis, and infections resulting from
mammals including HAS1, 2, and 3) at the cell hyaluronic acid gel injection [7-9].
membrane without attachment with proteoglycans [2].
Hyaluronan is an anionic, nonsulfated
glycosaminoglycan biopolymer found in the
extracellular and pericellular matrixes of neural,
epithelial, and connective tissues in different molecular
sizes and concentrations [3]. This natural polymer is a
more suitable material for tissue engineering because
of its ability for cell migration and proliferation [4, 5].
Fig. 1. Chemical structure of hyaluronic acid.

*Corresponding author. E-mail: elham.rezaei.n@gmail.com

Micro Nano Bio Aspects, 2024, 3(2): 7-13
 Mosawi and Rezaei Niaraki / Advanced formulations of hyaluronic acid and its derivatives for therapeutic applications, 2024, 3(2): 7-13

Antimicrobial and medical implant applications commonly carried out by depositing oppositely
There is bacteriostatic activity for hyaluronic acid charged materials in alternating layers [15]) has been
owing to the saturation of the hyaluronidase enzymes exploited to suppress bacterial attachment. In this way,
as a virulence factor of bacteria by this biopolymer in loading of triclosan (2,4,4'–trichloro-2'-
the bacterial medium [2]. The antibacterial activity of hydroxydiphenyl ether) on hyaluronic acid/chitosan
hyaluronic acid may be effective for its application in polyelectrolyte multilayers was employed after acid
different surgical implants such as dental and bone hydrolysis of commercial titanium alloys (Ti-6Al-4V).
implants [10]. Pristine titanium has not shown This modified micro-patterned titanium surface
promising antibacterial activity leading to high hindered the adhesion and proliferation of
morbidity and augmenting expensive treatment. In this Staphylococcus aureus [16]. Ti-6Al-4V material was
way, bacteria adhesion followed by biofilm formations coated by hyaluronic acid via two crosslinking agents
at the first 24 hours after implantation is the major involving 1,4-butanediol diglycidyl ether and divinyl
cause of bacterial infections resulting from titanium sulfone. These modified Ti-6Al-4V biomaterials
implants [11]. It should be noted that four main steps showed accelerated cell differentiation, proliferation,
including primary reversible attachment, irreversible and mineralization with sustained drug release.
attachment (microcolony formation), maturation, and Furthermore, there was bactericidal activity for this
dispersion have been known for biofilm formation on implantable biomaterial against S. aureus and E. coli
titanium-based implant (Figure 2) [12, 13]. In with values of 82–119 % and 83–87 %, respectively
orthopedic implants, hindering the onset of bacterial [17]. In another study, titanium nails pre-coated
infections on peri-implant is a complicated affair for sulfated hyaluronic acid functionalized by dopamine
researchers. Ti-6Al-4V biomaterial is a titanium alloy were placed in the femoral medullary cavity. Local or
with Young’s Modulus of 100-110 GPa, commonly systemic bacterial infections were not observed in the
employed in bone support materials and dental groups treated with pre-coated nails after one week of
implants [14]. Implant surface modification by injecting 1 mL of bacterial suspension of methicillin-
polymers using the ―Layer-by-Layer‖ method (a thin resistant S. aureus (MRSA) [18].
film and multilayer formation method, which is

Fig. 2. Four major stages of biofilm formation on the implant surface (adopted with slight modification from [12]).

Wound healing and tissue engineering applications by biocompatible polymeric wound dressings. Four
Preparing an appropriate environment and protecting wound healing steps involving hemostasis,
chronic wounds, specifically diabetic foot ulcers inflammation, proliferation, and remodeling
(DFU) for accelerating wound healing can be possible (maturation) can be influenced by hyaluronic acid and
its derivatives [19]. As mentioned in the introduction

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section, a medium molecular weight of hyaluronic acid inflammatory activity, cell proliferation, and
in a range of 200–500 kDa is needed to stimulate vascularization at the subcutaneous implant edge [27].
wound healing [6]. High-molecular weight hyaluronic Bio-mimicking extracellular matrix (ECM) for
acid accelerated the osteogenesis-inducing functions in growing vascular cells in wound zone is a critical issue
bone via mesenchymal cell differentiation in bone for preparing effective wound dressings. Hydrogels
wounds wound healing after bone marrow ablation composed of hyaluronic acid and collagen I have been
[20]. In another study, Kawano et al., (2021) reported exploited to bio-mimic ECM and accelerate wound
that the increase of molecular weight up to 2290 kDa closure. These injectable porous hydrogels were
and concentration up to 0.1% emulsified into the synthesized using horseradish peroxidase enzyme for
purified lanolin and oily ointment base (Plastibase®) of in situ coupling of phenol moieties of hyaluronic acid-
hyaluronic acid enhanced migration ability and cell tyramine and collagen I-hydroxybenzoic acid.
proliferation of HaCaT cells, human keratinocyte cell Improved vascular regeneration and proliferation of
lines. In this cell line vascular endothelial growth fibroblasts and endothelial cells were the result of
factor (VEGF), interleukin (IL-1β), IL-8, matrix these porous hydrogels [28]. Cartilage tissue
metalloproteinase (MMP)-9, and MMP-13 were engineering by hyaluronic acid can be possible via the
upregulated under ointment with higher hyaluronic increase of chondrocytes (cartilage cells) attachment,
acid (2290 kDa) [21]. A hyaluronic acid gel containing proliferation, and differentiation. Poly(d,l-lactic acid-
5% benzocaine, 2% hyaluronic acid, 1% antioxidants, co-glycolic acid) (PLGA) scaffold with macroporous
vitamin E, and coenzyme Q10 was applied for treating property was modified by hyaluronic acid to enhance
palatal wounds in rats. After 21 days of treatment, the cartilage tissue formation by expression of collagen
number of inflammatory cells and fibroblasts was type II in chondrocytes [29]. Adipose tissue
reduced and augmented, respectively [22]. Various engineering based on biopolymers, particularly
micro- and nanocarriers have been made by hyaluronic hyaluronic acid and collagen is employed for tissue
acid to improve biocompatibility and control drug regeneration of the craniofacial region, specifically
release. For instance, epidermal growth factor (EGF) [30, 31]. In this regard, permeable and porous 3-D
was loaded by photo-responsive hydrogels composed collagen (15%) –hyaluronic acid (7.5%) scaffolds with
of azobenzene-hyaluronic acid and β-cyclodextrin. total porosity of ∼85% cross-linked by 1-ethyl-3-(3-
Results of this study exhibited that these dimethylaminopropyl)-carbodiimide hydrochloride
supramolecular hydrogels caused the controlled EGF improved the differentiation, proliferation of
release followed by significant angiogenesis, and preadipocytes, and proportion of cycling cells (Ki-
granulation tissue formation [23]. Among herbal 67+). Moreover, there was an increase level of adipsin
polyphenols, curcumin and its derivatives have gene expression for these 3-D matrices for 8 days
obtained more attention from researchers because of compared to the control group. Therefore porous 3-D
their antioxidant, anti-inflammatory, anticancer, and collagen–hyaluronic acid may be considered as 3-D
antimicrobial capacities. Low stability and solubility in model of the mammary gland for the development of
aqueous solution are the main hindrances to effective stromal tissue and adipose tissue engineering [32].
clinical formulations of curcumin [24, 25]. In this
communication, conjugation of curcumin with Anticancer formulations
hyaluronic acid can be regarded to improve Hyaluronic acid receptors are overexpressed on many
antioxidant, anti-inflammatory, and wound healing cancer cells [33]. Conjugation of oligomers of
activities in vitro and in vivo. Both in vitro and in vivo hyaluronic acid with polymeric hyaluronic acid-
assessments demonstrated improved cell migration in aldehyde (CHO) was prepared by imino connection of
the wound zone and augmented cell proliferation and bis-oxyamino or bis-hydrazido as spacers. This
antioxidant activity than pure curcumin and hyaluronic polymeric conjugation exhibited significant anticancer
acid alone [26]. A conjugate of hyaluronic acid- activity towards cancer HT-29 cells (a human
glycidyl methacrylate (an ester of glycidol and colorectal adenocarcinoma cell line) after 24 h [34].
methacrylic acid) cross-linked by photopolymerization Targeting specific receptors of tumor cells, particularly
exhibited desirable biocompatibility, anti- cancer stem cells and drug-resistant cells is a crucial

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 Mosawi and Rezaei Niaraki / Advanced formulations of hyaluronic acid and its derivatives for therapeutic applications, 2024, 3(2): 7-13

factor in drug delivery of cancer therapy. In numerous 2290 kDa and concentration of up to 0.1% absorbed
tumor cells, the CD44 receptor, a transmembrane into the purified lanolin and Plastibase® (a
glycoprotein, is highly expressed and regulates hydrocarbon gel ointment) improved re-
metastasis by the migration and invasion processes. epithelialization, the appropriate outcome for healing
These receptors are related to P-glycoprotein 1, chronic wounds. Hyaluronic acid and its derivatives
multidrug resistance protein 1 (MDR1) has three main impact four wound healing steps involving hemostasis,
domains including the intracellular, extracellular inflammation, proliferation, and remodeling. Future
domain, and transmembrane domain [35]. Conjugates studies should focus on overcoming the main side
of nanogel–drugs based on hyaluronic acid- effects of hyaluronic acid gel injection including
membranotropic cholesteryl were utilized to load three infections, tissue necrosis, chronic lymphoplasmacytic
drugs involving curcumin, etoposide, and salinomycin inflammatory reactions, and inadvertent arterial
by negative zeta potential with 6.98, 17.36, and 21.62 occlusion.
% drug content and sizes of 29.15, 32.17, and 36.48 Highlights
nm, respectively. Nanogel–etoposide and nanogel-
salinomycin conjugates displayed values of 3 and 0.9 Study Highlights
μM of half-maximal inhibitory concentration (IC50). In  As the bacteriostatic effect, hyaluronic acid can lead
addition, for nanogel-curcumin conjugate, there was 9 to the saturation of the hyaluronidase enzymes of
μM of IC50 more than other hyaluronic acid-based bacteria.
nanogels of etoposide and salinomycin [36]. Carbon-  Different molecular weights of hyaluronic acid
based micro- and nanomaterials can be decorated and exhibited different therapeutic effects, specifically
modified by biopolymers such as hyaluronic acid due in the case of the wound healing process.
to upgraded biocompatibility and drug release profile  Immobilized hyaluronic acid on PLGA showed
in physiological conditions [37]. Drug carriers with inducing cellular attachment, proliferation, and
pH-responsive property can target cancer cells because differentiation of chondrocytes.
of the low pH environment of tumors. Doxorubicin-  Conjugation of oligomers of hyaluronic acid with
loaded graphene oxide was decorated by hyaluronic polymeric hyaluronic acid-aldehyde exhibited
acid to specific target tumor cells. This nanohybrid significant anticancer activity towards cancer HT-29
exhibited the sustained doxorubicin-release in pH 5.3 cells.
and tumor inhibition rate against H22 hepatic cancer in  Reducing and overcoming the main side effects of
vivo than graphene oxide–doxorubicin and doxorubicin hyaluronic acid gel injection such as infections and
alone [38]. tissue necrosis should be regarded in future
investigations.
Conclusions
The saturation of the hyaluronidase enzymes as a Abbreviations
virulence factor of bacteria as bacteriostatic activity DFU: Diabetic foot ulcers
can result from hyaluronic acid treatment. As a critical ECM: Extracellular matrix
note, the deferent molecular weight of hyaluronic acid EGF: Epidermal growth factor
leads to different therapeutic effects such as inducing HAS: Hyaluronan synthase
heat shock proteins by 0.4–4.0 kDa, angiogenic (<60 IC50: Half-maximal inhibitory concentration
kDa), wound healing (200–500 kDa), and anti- IL: Interleukin
angiogenic (more than 500 kDa). Bacteriostatic MDR1: Multidrug resistance protein 1
activity for hyaluronic acid is results from the MMP: Matrix metalloproteinase
saturation of the hyaluronidase enzymes of bacteria by MRSA: Methicillin-resistant S. aureus
this biopolymer. Inducing cellular attachment, PLGA: Poly(d,l-lactic acid-co-glycolic acid)
proliferation, and differentiation of chondrocytes has VEGF: Vascular endothelial growth factor
been indicated for immobilized hyaluronic acid on
PLGA. In the case of wound healing activity, Funding
hyaluronic acid with a high molecular weight of up to Any institutes did not support this study.

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 Mosawi and Rezaei Niaraki / Advanced formulations of hyaluronic acid and its derivatives for therapeutic applications, 2024, 3(2): 7-13

7. Edwards PC, Fantasia JE. Review of long-term

Funding adverse effects associated with the use of chemically-
Any institutes did not support this study. modified animal and nonanimal source hyaluronic acid
dermal fillers. Clinical Interventions in Aging.
2007;2(4):509-19. doi:https://doi.org/10.2147/cia.s382
Conflict of interest 8. Schanz S, Schippert W, Ulmer A, Rassner G,
The authors declare that they have no conflict of Fierlbeck G. Arterial embolization caused by injection
interest. of hyaluronic acid (Restylane). British Journal of
Dermatology.2002;146(5):928-9.
Ethical approval doi:https://doi.org/10.1046/j.1365-2133.2002.04707.x
This article does not contain any studies with animals 9. Hirsch RJ, Lupo M, Cohen JL, Duffy D. Delayed
presentation of impending necrosis following soft tissue
or human participants performed by any of the authors.
augmentation with hyaluronic acid and successful
management with hyaluronidase. Journal of drugs in
Author contributions dermatology.2007;6(3):325-8.
All authors: conceptualization, preparing the first draft, doi:https://pubmed.ncbi.nlm.nih.gov/17373195/
and editing. 10. Chen X, Zhou J, Qian Y, Zhao L. Antibacterial
coatings on orthopedic implants. Materials Today Bio.
Acknowledgments 2023;19:100586.
doi:https://doi.org/10.1016/j.mtbio.2023.100586
Declared none.
11. Souza JGS, Bertolini MM, Costa RC, Nagay BE,
Dongari-Bagtzoglou A, Barão VAR. Targeting implant-
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HOW TO CITE THIS ARTICLE:

Mosawi SH, Rezaei Niaraki E. Advanced formulations
of hyaluronic acid and its derivatives for antimicrobial,
wound healing, tissue engineering, and anticancer
applications. Micro Nano Bio Aspects. 2024; 3(2): 7-
13.
doi: https://doi.org/10.22034/mnba.2024.442816.1059

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