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Fabrication and structural characterization of self-crosslinking hydrogel based on Vietnamese sources of chitosan and alginate

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Life ScienceS
Biomedical applications
Volume 64 Number 3
Hydrogels are unique materials with several desirable
properties and they have been applied to a wide range of
applications, especially those in the biomedical field [1].
Besides their practical uses as contact lenses and wound
dressings, hydrogels have also received considerable attention
as a promising scaffolding material for tissue engineering.
This area of research aims to create an alternative source
of functional grafts to overcome the current gap between
transplantation supply and demand [2]. Specifically, hydrogels
are formed by crosslinking hydrophilic polymer chains in
water, thus, they not only possess an aqueous environment
resembling a native extracellular matrix, but also a porous
structure for nutrient and waste diffusion during cell culture.
Furthermore, control over the transformation from a polymer
solution into a gel structure enables, first, minimally invasive
injection into complicated defects, secondly, homogeneous
delivery of cell and bioactive factors, and, lastly, its potential
use as a specialized ink for developing 3D bio-printing
technology [3].
Although synthetic polymers are reproducible and
exhibit high mechanical stability, only a few of them satisfy
the requirements of biocompatibility and appropriate
biodegradation, such as poly(ethylene glycol) and poly(N-
isopropylacrylamide) [4]. Moreover, synthetic polymer-
based hydrogels usually lack the necessary bioactivity
while their crosslinking nature, especially polymerization
reactions, might employ cytotoxic reagents. Therefore,
natural polymers have been extensively targeted as hydrogel
components alone or in combination with synthetic
polymers [5]. Different crosslinking methods could be
employed for natural polymer-based hydrogels, such as
the exposure to external stimuli [6], the conventional
use of small bi-functional crosslinking agents [7], or the
combination of reactive polymers [8]. In the last stated
method, two or more hydrogel components with reactive
functional groups are prepared independently and allowed
to react upon combination. This self-crosslinking approach
helps to control the intensity of external factors or the use of
additional cytotoxic cross-linkers. Among different types of
reactions, Schiff-base reactions stand out as they take place
Fabrication and structural characterization of self-crosslinking
hydrogel based on Vietnamese sources of chitosan and alginate
Tin Dai Luong
1, 2
, An Tran-My Le
1, 2
, Nhan Thien Vo
1, 2
, Thi Hiep Nguyen
1, 2*
School of Biomedical Engineering, International University, Ho Chi Minh city
Vietnam National University, Ho Chi Minh city
Received 22 April 2022; accepted 11 July 2022
Corresponding author: Email: [email protected]
Hydrogel materials have attracted extensive research over the last few decades, especially in tissue engineering,
due its many comparable properties with native tissue. This study proposes a new approach to hydrogel
fabrication that combines oxidized alginate (OA) into N,O-carboxymethyl chitosan (NOCC) and an oxidized
hyaluronan-based hydrogel system employing low cost, domestically sourced chitosan and alginate. Hydrogel
fabrication parameters including component ratio and hydrogel concentration were studied. Fourier transform
infrared spectroscopy (FT-IR) analysis was applied to confirm the chemical structure of the modified materials.
Fabricated hydrogel samples were assessed by cross-sectional surface morphology, equilibrium swelling
degree, and
in vitro
degradation behaviour. The results revealed NOCC and oxidized hyaluronic acid (OHA)-
OA component contributions toward hydrogel properties, a threshold of raising total polymer content within
the network, and a comparison with previous formulations using unmodified alginate. Using low cost domestic
resources is a promising way to reduce fabrication expenses, and further work should be performed to evaluate
the potential of this cost-effective hydrogel for the tissue engineering field.
carboxymethyl chitosan, oxidized alginate, oxidized hyaluronan, self-crosslinking hydrogel,
Vietnamese materials.
Classification number:
DOI : 10.31276/VJSTE.64(3).53-61
Life Science
september 2022
Volume 64 Number 3
under the physiological conditions with rapid kinetics [9].
This reaction requires one component with nucleophilic
amino groups (-NH
) and another with electrophilic aldehyde
groups (-CHO), both of which react with each other to form
covalent Schiff-base bonds (C=N).
Chitosan, a linear polysaccharide derived from natural
chitin by a deacetylation step, is a common material with amino
functional groups for Schiff-base reaction-based hydrogels
[10, 11]. Chitosan has demonstrated good biocompatibility
and low immunogenicity in previous studies. To overcome
its drawback of low solubility at neutral pH, chitosan can
be grafted with additional carboxylate anions (-COO
) or
quaternized to obtain permanently protonated amino groups
). NOCC belongs to the former modification technique
and is a common constituent for Schiff-base crosslinking
reactions since sufficient amino groups remain compared to
other grafting techniques targeting N positions. Following
chitosan, a second component with aldehyde groups can
be achieved by periodate oxidation. It is necessary that
the polymer possesses vicinal hydroxyl groups along their
chains for the oxidation to take place [9]. Hyaluronic acid
(HA), or hyaluronan, is a linear natural polysaccharide that
satisfies such a requirement. It exists in the extracellular
matrix of human connective tissues, especially cartilage and
synovial fluid [12]. Short HA chains have been hypothesized
to mediate many biological functions related to proliferation
and differentiation of chondrocytes and pro-inflammatory
response during wound healing [13]. Modified chitosan
has been crosslinked with OHA, such as succinyl chitosan
for chondrocyte encapsulation [14], or NOCC for tissue
adhesive and dermal wound healing [15, 16]. Despite good
healing results, most of these hydrogel formulations exhibit
rapid degradation, especially under
in vivo
conditions due to
the enzymatic hydrolysis of HA [15]. Therefore, improving
the stability of hydrogel containing HA is indispensable to
apply this potential biomaterial for tissue engineering field.
Alginate is another linear polysaccharide derived
from brown algae with desirable biocompatibility,
biodegradability, and low-immunogenicity [17]. It can
also be oxidized to crosslink with modified chitosan and
has been further combined with bioactive compounds such
as albumin for soft tissue engineering [18] and curcumin
for dermal wound healing [19]. As a strategy to improve
NOCC-OHA hydrogel formulation mentioned above,
unmodified alginate was blended into a hydrogel network
and an increase in overall stability and degradation time was
observed even though the hydrogel concentration remained
constant [20]. The given hypothesis was the creation of a
more balanced amount of charged groups for a synergistic
polyelectrolyte complexation. There is no follow-up study
on the effect of oxidizing alginate, which might promote
overall crosslink density inside the network and let OA form
stronger covalent bonds with NOCC instead of electrostatic
Herein, a self-crosslinking hydrogel was fabricated based
on NOCC, OHA, and OA (Fig. 1). Besides investigating
the potential of incorporating OA into the NOCC-OHA
network, domestic sources of chitosan and alginate were
also targeted to make use of their abundant resource in
Vietnam. Different parameters in the hydrogel fabrication
process were evaluated including the component ratios and
the concentration of polymer content. Modified structures
were analysed by FT-IR and viscosity measurements while
fabricated hydrogel samples were characterized by scanning
electron microscopy (SEM) observation, equilibrium
swelling degree, and
in vitro
degradation tests.
Fig. 1. Chemical structures of (A) NOCC, (B) OHA, (C) OA, and (D)
crosslinking mechanism of NOCC-OHA-OA hydrogel.
s and methods
Chitosan derived from shrimp shells with high, medium,
or low molecular weight were purchased from Vietnam
Food JSC. (Vietnam). HA was purchased from Shandong
Bouliga Biotechnology Co., Ltd. (China). Alginate derived
from brown seaweed
Sargassum mcclurei
was supplied by
Nha Trang Institute of Technology Research and Application
(Vietnam). Chloroacetic acid was purchased from HiMedia
Laboratories Pvt. Ltd. (India). Sodium metaperiodate

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