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REVIEW
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A functional chitosan-based hydrogel as a wound
dressing and drug delivery system in the treatment
of wound healing
He Liu, a Chenyu Wang,ab Chen Li,
Zuhao Li*a and Jincheng Wang*a
a
Yanguo Qin,a Zhonghan Wang,a Fan Yang,a
Functional active wound dressings are expected to provide a moist wound environment, offer protection
from secondary infections, remove wound exudate and accelerate tissue regeneration, as well as to
improve the efficiency of wound healing. Chitosan-based hydrogels are considered as ideal materials for
enhancing wound healing owing to their biodegradable, biocompatible, non-toxic, antimicrobial,
biologically adhesive, biological activity and hemostatic effects. Chitosan-based hydrogels have been
demonstrated to promote wound healing at different wound healing stages, and also can alleviate the
factors against wound healing (such as excessive inflammatory and chronic wound infection). The
unique biological properties of a chitosan-based hydrogel enable it to serve as both a wound dressing
Received 20th December 2017
Accepted 12th February 2018
and as a drug delivery system (DDS) to deliver antibacterial agents, growth factors, stem cells and so on,
which could further accelerate wound healing. For various kinds of wounds, chitosan-based hydrogels
DOI: 10.1039/c7ra13510f
are able to promote the effectiveness of wound healing by modifying or combining with other polymers,
and carrying different types of active substances. In this review, we will take a close look at the
rsc.li/rsc-advances
application of chitosan-based hydrogels in wound dressings and DDS to enhance wound healing.
1. Introduction
As the largest human organ, skin reaches 10% of the total body
mass, and acts as a protective barrier against the environment.1
Besides this physical protective function, skin is also responsible for sensory detection, thermoregulation, uid homeostasis and immune surveillance.2 Normally, the human body is
able to restore skin integrity aer injury with a minimal scar via
a complex and interactive process. The various processes of
acute tissue repair are divided into a sequence of four timedependent phases: coagulation and hemostasis, inammation, proliferation and remodeling.3 The normal and chronic
wound (such as in diabetes) healing processes are presented in
Fig. 1.4,5 However, the healing process could be interrupted by
a series of factors, such as local factors (oxygenation, wound
infection, foreign body, venous sufficiency, wound area, depth,
local tension and pressure) and systemic factors (age and
gender, sex hormones, stress, ischemia, diseases, obesity,
medications, alcoholism, smoking, immunocompromised
conditions and nutrition).6–9 As a series of factors affect wound
healing, medical treatment is necessary.10 In fact, the number of
Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun
130041, P. R. China. E-mail: heliu@ciac.ac.cn; cathwang0111@hotmail.com;
evanlee1357@163.com;
qinyanguo@hotmail.com;
wangzhjlu@outlook.com;
531040439@qq.com; lizuhao1992@163.com; jinchengwang@hotmail.com
a
b
Hallym University, 1Hallymdaehak-gil, Chuncheon, Gangwon-do, 200-702, Korea
This journal is © The Royal Society of Chemistry 2018
diseases resulted from wounds related to infection has
increased in the past few years. Therefore, a wide range of
wound care products have been developed to improve the life
quality of those who suffer from wounds.
Before the 1960s, wound dressings were just considered as
so-called passive products with a minimal role in healing
process. The pioneering research of Winter et al. initiated the
concept of an active involvement of a wound dressing in
establishing and maintaining an optimal environment for
wound repair.11 This awareness resulted in the development of
wound dressings from traditional passive materials to functional active dressings. Through interacting with the wound
where they cover, functional active dressings create and maintain a moist environment for wound healing. Regardless of
trauma, burns, diabetic foot or postoperative incision, the
application of efficient wound dressings is an important therapeutic method. An ideal wound dressing is expected to provide
a moist wound environment, offer protective role in secondary
infections, remove wound exudate and promote tissue regeneration, and to improve the quality of wound healing.5,12 Taking
above factors into consideration, hydrogel has great potential as
wound dressings.13,14
Hydrogel is made up of a three-dimensional (3D) network of
hydrophilic polymers.15 The network confers an insoluble
behavior to the polymeric system and allows the hydrogels to
absorb from 10–20% (an arbitrary lower limit) to up to thousands of times their equivalent weight in water until the process
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Fig. 1
Review
Differences in the normal and diabetic wound healing phases (Reprint with permission from L. I. F. Moura et al.5).
reaches an equilibrium state.10,16 They are mainly employed to
dry to-moderately draining wounds, to promote autolytic
debridement in necrotic wounds and in granulating wounds.
Fully swollen hydrogels have a number of common physical
properties in living tissues, such as so, elastic, and low interfacial tension. The elastic properties of the hydrogel can reduce
the stimulation of the surrounding tissues. Low interfacial
tension between the hydrogel surface and body uid can
decrease the absorption of proteins and cell adhesion to
a maximum, thereby ameliorating the chance of a negative
immune response.12,13,17 Many polymers hydrogels, such as
poly(acrylate acid) (PAA), poly(ethylene glycol) (PEG), and
poly(vinyl alcohol) (PVA), can increase the retention time of the
drug and the permeability of the tissue.17 Due to the composition and mechanical aspects, the properties of the hydrogel are
similar to the natural extracellular matrix (ECM), so the
hydrogel not only serves as the supporting material of the cells
in the tissue regeneration process, but also delivers a drug
payload.18,19
From another aspect, chitin is a natural biological macromolecule polymer and one of the most abundant polysaccharide in nature that exists in some of the shell of crab,
shrimp, insects, algae and bacterial cell walls.20,21 Extensive
sources and low cost make the chitin in the application of
biological materials to be valued.22 Chitin is insoluble in
7534 | RSC Adv., 2018, 8, 7533–7549
aqueous solution, so it is usually transformed into chitosan to
increase the solubility. The main difference between chitosan
and chitin is the content of acetyl group in C-2 position.23
Chitosan comprises copolymers of glucosamine and N-acetylglucosamine units linked by b-1,4-glycosidic linkages.24 Chitosan is generally considered to be a biodegradable, biocompatible, non-antigenic, non-toxic, biologically adhesive,
antimicrobial, biological activity, with a hemostatic effect.25–27
Chitosan and its derivatives have been widely used in the elds
of medicine, cosmetics, wound dressings, biochemical separation systems, tissue engineering and some other elds.28
These and other positive features, such as hydrophilic and
a net cationic charge, make chitosan a suitable polymer for the
delivery of other active ingredients like drugs, growth factors,
stem cells and peptides.12 Different formulations of chitosanbased hydrogel wound dressings can promote wound healing at different periods, and ease the unfavorable factors that
affect wound healing. Because of the ability to accelerate
wound contraction and healing, chitosan-based hydrogels are
regarded as an occlusive dressing for wound healing.29 The
commercially available wound dressings of chitosan are in the
form of non-wovens, hydrogels, lms and sponges. A briey
summary of some chitosan-based wound dressing trademarks
that are already commercially available are presented in
Table 1.30
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Table 1
RSC Advances
Some commercial chitin- and chitosan-based wound dressings
Trademarks
Characteristics
Chitipack P® Eisai Co
Chitin-based. Swollen chitin disperse in poly(ethylene terephthalate). Favors early granulation tissue
formation. For defects difficult to suture and large skin defects
Chitin-based. Sponge-like chitin obtains from squid. Favors early granulation tissue formation, no retroactive
scar formation. Suitable for traumatic wounds and surgical tissue defects
Chitosan-based. Containing chitosan particles will swell while absorbing exudate and forming a so gel. A
layer of waterproof Tegaderm® lm dressing covers the hydrocolloid. Suitable for leg ulcers, sacral wounds,
chronic wounds
Chitosan-based. Antibacterial and biocompatible. It combines strongly to tissue surfaces and forms a exible
barrier, which can seal and stabilize the wound. For stuffing into a wound track to control severe bleeding
Chitosan-based. Cotton-like chitosan. Repair body tissue completely, rebuild normal subcutaneous tissue and
regenerate skin regularly
Chitosan-based. Chitosan and polynosic Junlon poly(acrylate) for preparing antimicrobial wears. For
preventing dermatitis
Chitosan-based. Good biocompatibility and hemostatic function. For bleeding wounds
Chitipack S® Eisai Co
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Tegasorb® 3M
Chitoex® HemCon
Chitopack C® Eisai
Chitopoly® Fuji spinning
Chitoseal® Abbott
Application of chitosan-based hydrogel dressings. The unique biological properties of chitosan-based hydrogels enable it to serve both as
a wound dressing and as a drug delivery system to deliver active substances, which could further promote wound healing.
Fig. 2
In this review, we will analyze and summarize the various
classes of chitosan-based hydrogels, study their properties and
applications, and present recent advances in using natural
polysaccharide, chitosan, preparation of hydrogel for wound
healing and controlled drug delivery (Fig. 2).
2. Chitosan-based hydrogels for
wound healing
The characteristics of hydrogels critically depend on the
employed polymers and on their interactions within the
network. Hydrogels are known as either chemical when their
network is covalently cross-linked or physical when the network
is sustained by molecular entanglements and/or secondary
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attractions, including electrostatic interactions, hydrogen
bonding or hydrophobic forces. The reversibility of these
hydrogels comes from the disruption of the above network
interactions via modications in physical conditions such as
ionic strength, pH, temperature, stress or specic solutes.
Hydrogels can be generated from lots of polymers, and they are
classied according to the source of these macromolecules:
synthetic, natural or a combination of both.16,31
Chitosan is considered as an ideal material for hydrogels due
to its biodegradable, biocompatible, non-toxic, antimicrobial,
biologically adhesive, biological activity and hemostatic effect,
as well as its amino and hydroxyl groups can be easily reacted
and chemically modied, thus allowing a high chemical versatility. The conditions employed for amino group chemical
modication may interfere with the nal degree of
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deacetylation and therefore with the cationic nature of the obtained materials.32 The positively regulatory factors makes chitosan more susceptible to interact with negatively charged
molecules such as proteins, anionic polysaccharides and
nucleic acids in bacterial membrane, which is the key to antibacterial properties.33,34 Chitosan-based materials usually
exhibit a positive charge (at typical wound pH values), lmforming capacities, mild gelation characteristics and strong
wound tissue adhesive properties.35 Chitosan can interact with
mucus and epithelial cells, and nally result in opening of
cellular tight junctions thus increasing the paracellular
permeability of the epithelium. Besides, other structural
elements of this polymer are likely to contribute to their
penetration-enhancing activity.36
Wound healing is a dynamic process involving many molecules and cells, such as mediators, ECM, blood cells and
parenchymal cells.37 Chitosan-based hydrogels play a positive
role in various stages of wound healing. (i) Coagulation and
hemostasis, beginning immediately aer injury, take place in
the wound, which can prevent exsanguination and provide
a matrix for invading cells that are needed in the later phases of
healing.38 Platelets are the most important component in blood
coagulation by releasing some cytokines to enhance the healing
process.39 Chitosan promotes surface-induced thrombosis and
blood coagulation and accelerates coagulation in vivo by inuencing the activation of platelets. Chitosan is a hemostat, which
helps in natural blood clotting and blocks nerve endings, thus
reducing pain.40 (ii) The inammatory phase of wound healing
starts shortly thereaer.41 This phase is dominated by inammatory reactions mediated by cytokines, chemokines, growth
factors, and their actions on cellular receptors. Intracellular
signaling cascades are activated, contributing to cell proliferation, migration, and differentiation. In addition, chemoattractant factors recruit different cell types, such as
granulocytes and macrophages, to the wound site, thus initiating wound repair.42 In this process, chitosan-based hydrogels
can regulate the activity of related cells and factors releasing,
thus forming an appropriate inammatory microenvironment
conducive for healing. Previous studies have shown that
chitosan-based dressings can accelerate different tissues
repairing and regulate secretion of the inammatory mediators
such as interleukin 8, prostaglandin E, interleukin 1b and
others.29 Other works also indicated that chitosan-based
hydrogels could enhance the inammatory functions of polymorphonuclear leukocytes, macrophages and neutrophils,
promoting tissue granulation to an appropriate inammatory
response.43 (iii) Proliferation, which starts from 2 to 10 days
aer the injury and encompasses the major healing processes,
is characterized by proliferation and migration in different
types of cells. The proliferative phase includes neoangiogenesis,
formation of granulation tissue and ECM, re-epithelialization.44
Chitin and chitosan could induce Platelet-Derived Growth
Factor (PDGF)-AB and Transforming Growth Factor (TGF)-b1
releasing from the platelets, particularly with a high concentration chitosan.39 Chitosan provides a non-protein matrix for
3D tissue growth and activates macrophages for tumoricidal
activity. Chitosan will gradually depolymerize to release N-
7536 | RSC Adv., 2018, 8, 7533–7549
Review
acetyl-b-D-glucosamine. As a result, chitosan-based hydrogels
could stimulate broblast proliferation, angiogenesis, regular
collagen deposition and increase level of natural hyaluronic
acid (HA) synthesis at the wound site. It helps in faster wound
healing and scar prevention.29,30,45 (iv) Remodeling: content and
arrangement of collagen bers in scar tissue are adjusted by the
action of various enzymes and stress, in order to adapt to
physiological work, and results in the development of normal
epithelium and maturation of the scar tissue. The N-acetyl
glucosamine (NAG) present in chitin and chitosan is a major
component of dermal tissue which is essential to the repair of
scar tissues.46 In particular, chitosan lms of low deacetylation
degree have already proved to be efficient in dressing supercial
wounds.47
Chitosan-based hydrogels can not only promote wound
healing at different wound healing stages, but also alleviate the
factors against wound healing. For the excessive inammatory
and chronic wound infection, chitosan-based hydrogels have
unique advantages. Inammatory response is the basis of
wound healing, but excessive inammation can lead to necrosis
of local tissue cells, which is a factor that hinders wound
healing. If it is not timely controlled, it may lead to a systemic
infection, which will make the wound healing delayed, and even
can be a threat to life. On the other hand, it is easy for bacteria
to settle and breed on the chronic wounds, such as diabetic foot
ulcer. The presence of infection, bacteria and inammatory
cells increased the consumption of oxygen and other nutrients,
broblast metabolism were damaged. The release of protease
and oxygen free radicals aer the neutrophil phagocytic
bacteria in the infected area will destroy the tissue, and thus the
collagen was dissolved other than deposited. The exudation and
the increased local tension make wound dehiscence, which
results in delaying wound healing.48,49 Chitosan-based hydrogels can exert its advantages on this situation, because of its
anti-inammatory and antibacterial properties, thus provide
a suitable microenvironment for healing, inhibiting the
inammatory reaction in the wound and controlling the infection.33,34 In addition, if loaded with antimicrobial agents, it can
further inhibit microorganisms, thereby accelerating wound
healing. As drug delivery system (DDS), chitosan-based hydrogels, which load with active substances (such as growth factors
or stem cells), can promote wound healing and it will be discussed as following. Besides the above mechanisms to promote
wound healing, chitosan-based hydrogels can also be as
a barrier to avoid microorganism proliferation and invasion,
and provide scaffold for cell growth, which is shown in Fig. 3.29
3.
Application
As described above, chitosan plays an important role in wound
healing, so it is widely used in wound dressings. Here, we will
describe its application of wound dressings in two aspects, as
wound dressings and DDS. As wound dressings, the physical,
chemical and mechanical properties of chitosan can be
enhanced by modication, as well as complexed or cross-linked
with other polymers and/or cross-linking agents. By this
approach, it is possible to design chitosan-based hydrogel
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The mechanisms of chitosan-based hydrogels to promote wound healing. Chitosan provides a non-protein matrix for three dimensional
tissue growth and activates macrophages for tumoricidal activity. It stimulates cell proliferation and histoarchitectural tissue organization.
Chitosan is a hemostat, which helps in natural blood clotting and blocks nerve endings reducing pain (Reprint with permission from R. Jayakumar
et al.29).
Fig. 3
dressings with improved healing properties. They include
increased exudate absorption capacity, enhanced adherent and
anti-bacterial capacity, stimulation of angiogenesis and reepithelialization of skin tissue and collagen deposition, and
sustained delivery of drugs.50,51 In addition, as DDS, due to its
unique properties, chitosan is a suitable polymer for the
delivery of other active ingredients, such as drugs, growth
factors, stem cells, peptides and etc., to provide a therapeutic
payload that can be more effective in the treatment of local
wounds.52 The main achievements obtained recently regarding
chitosan-based hydrogels as wound dressings or DDS for wound
healing will be discussed in the following part.
3.1. Chitosan-based hydrogels as wound dressing
In terms of wound healing, chitosan-based hydrogels could
provide a moist wound environment, offer protection from
secondary infections, remove wound exudate, be biocompatible, induce faster wound healing, and produce smoother
scarring. As a result, chitosan-based hydrogels are considered
advantageous in their application as a wound dressing material.
Especially, when the chitosan is modied and/or combined
with other polymers, chitosan-based hydrogel dressings will
have some better properties to promote wound healing. In
addition, these chitosan-based hydrogels as DDS, such as chitosan–PVA hydrogel,53 can deliver bioactive substances (drug,
grown factors or stem cells and etc.) and controlled release at
the wound.
3.1.1. Modied chitosan-based hydrogels. Chitosan could
enhance drug absorption due to its mucoadhesive nature.
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However, the absorption of drugs decrease at higher pH attribute to chitosan's poor solubility at pH greater than 6.0.54
Modication of chitosan, through derivatization of the amino
and hydroxyl groups by quaternizing with carboxyalkyl,
hydroxyalkyl, and acyl derivatives, could increase water solubility at higher pH. As a result, we can improve the biodegradability and biocompatibility, enhance transfection efficiency,
and decrease toxicity. Modication has substantially enhanced
the biomedical applications of chitosan.55–57
There are several common modications to improve chitosan's properties associated with wound healing. N,N,N-Trimethyl chitosan, N-succinyl chitosan, N-carboxymethyl
chitosan, and thiolated chitosan, have been applied to the
preparation of chitosan-based hydrogels.58 Carboxymethyl chitosan is water-soluble when pH > 7.59 And its antibacterial
activity is superior than that of chitosan.60 N-Succinyl chitosan
(NSC), formed by the introduction of acyl groups into chitosan,
is an amphiprotic derivative containing amine, hydroxyl, and
carboxyl groups. The introduction of these groups bestow it
with excellent physical, chemical, and biological properties.58
NSC has better water retention properties, so it can be exploited
in wound dressings. Straccia et al. synthesized NSC/sodium
alginate hydrogel containing micro-cellulose. The composite
had antimicrobial activity against Escherichia coli (E. coli) and
Staphylococcal aureus (S. aureus), improved swelling degree,
stability and water vapor transmission rate. This chitosan-based
hydrogel was conducive to maintaining a moist environment in
the wound bed to enhance regeneration and epithelialization.61
In addition, N-succinyl chitosan-based hydrogels were studied
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in vivo. The result showed that they signicantly enhanced
wound healing and prevented wound infection.62,63 More chitosan modied studies were used in the hydrogel for wound
healing dressings are listed in Table 2.58,59,64–66
3.1.2. Combined with other polymers. In addition to
modication, chitosan could also be mixed with other polymers
to form a complementary and exert the advantages of each
component, thereby enhancing the therapeutic effect of wound
dressing.
Natural polymers are classied by obtaining from microbial,
animal, and vegetal sources that are usually of a protein or
polysaccharide nature. Although these naturally occurring
polymers can closely simulate the original cellular environment
and ECM, and these biomaterials are known to undergo naturally controlled degradation processes. Their large heterogeneity and batch-to-batch variations upon their isolation from
animal or vegetal tissues, as well as the poor stability and
mechanical performance are the main limitations for their
applications.25,67 Other concerns include the relatively high cost
(namely of protein-based materials) and the associated risk of
the transmission of infectious diseases due to the allogenic or
xenogenic origins of the original materials.68 Except chemical
synthesis and/or processing modications can overcome some
of above disadvantages, blending with other polymeric materials (including natural polymers and synthetic polymers) is
another viable alternative.19 Application of chitosan-based
composite hydrogels will be presented and discussed in the
following sections.
3.1.2.1. Natural polymers
3.1.2.1.1. Alginate. Alginate is abundant in nature, which
has been widely studied and applied in tissue engineering and
drug delivery applications,68 due to its high biocompatibility,
forming gel easily and rapidly under very mild conditions.69,70
However, alginate has low cell adhesiveness because of its poor
protein adsorption for the hydrophilic nature.71 Therefore,
alginates were blended with chitosan to enhance cell interaction, adhesion, and proliferation.72,73
Table 2
Coacervates of alginate and chitosan were prepared to
synthesis hydrogel. The dressing promoted the cell proliferation and accelerated the wound closure.74 In addition, Sukumar
et al. reported a new hydrogel containing silk, chitosan, alginate, dextrin, and recombinant human epidermal growth factor
(rhEGF). This hydrogel promoted the healing process of deep
diabetic wound in rats, and showed advantages in the context of
tissue engineering.75
Chitosan and alginate incorporated with curcumin and
honey (CHS) could be formulated by a simple mixing and situ
polymerisation method. The optimised CHS had a good
swelling capacity, tensile strength, drug diffusion, bioadhesion, and water vapour transmission. In vivo results indicated that the dressing induced tissue granulation and reepithelialisation rapidly. The wounds completely healed
within one week.76 The result was similar to the studies by Dai
et al., who reported the wound healing property of nonmedicated alginate-chitosan hydrogel.77
However, alginate-based hydrogels may present unpredictable and uncontrollable degradation resulting from the loss of
divalent cation cross-linkers.78 To overcome this issue, covalent/
ionic cross-linking with chitosan was employed. Han et al.
utilized carboxylate moieties on alginate and protonated
amines on chitosan to form polyelectrolyte complex (PEC),
which exhibited higher mechanical strength and better thermal
stability. This method is also used for chitosan and hyaluronic
acid (HA), which will be described in the next section.79
3.1.2.1.2. HA. HA is a natural polysaccharide, namely a nonsulfated glycosaminoglycan, which is also referred as hyaluronan due to it usually exists in vivo as a polyanion but not in the
protonated acidic form.80 HA presents many importantly physiological functions such as structure and space-lling properties, lubrication, and water sorption and retention abilities.81
HA is also an interesting biomaterial for wound dressing since it
is known to promote mesenchymal cells and epithelial cells
migration and differentiation, thus enhancing collagen
The common chitosan modification methods for wound healing dressings
Modication
Remarks
Carboxymethyl chitosan
Enhanced water solubility. The most fully explored derivative of chitosan; it is an amphoteric polymer,
whose solubility depends on pH, when pH > 7 is water-soluble
Very important as amphiphilic polymers based on polysaccharides. Improve the stability of the interfacial
lm, cationic surfactant adsorbed on the alkyl chain graed on chitosan, promotes its solubilization
This cationic derivative, water soluble over all the practical pH range, is obtained by quaternization of
chitosan. These polymers show good occulating and antistatic properties
Having good complexing efficiency for cations such as Ca2+, and transition metals (Cu(II), Zn(II) etc.). The
complexation provides corrosion protection for metal surfaces. These derivatives were also modied and
graed with alkyl chains to obtain amphiphilic properties
These derivatives are water soluble. Carbohydrates can be graed on the chitosan backbone at the C-2
position by reductive alkylation, which are important as they are recognized by the corresponding specic
lectins and thus could be used for drug targeting
When gra with different polymers have different properties. One of the most explored derivatives is PEGgraed chitosan, which has the advantage of being water soluble, depending on the degree of graing
Thiourea chitosan increases the antibacterial properties
N-Succinyl chitosan (NSC) is an amphiprotic derivative containing amine, hydroxyl, and carboxyl groups,
have excellent physical, chemical and biological properties, as required for biomedical applications
Alkylation chitosan
Trimethyl chitosan ammonium
N-Methylene phosphonic
chitosans
Carbohydrate branched chitosans
Chitosan-graed copolymers
Thiolated urea derivatives
Sugar derivatives
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deposition and angiogenesis.80,82,83 However, hydrogels formed
from natural materials are typically mechanically weak that
limits their applications.84,85 Therefore, it is necessary to
produce a material that retains the native conformation of
bioactive polymers while improving mechanical properties.
By taking advantage of the poly-anionic nature of HA and the
poly-cationic nature of chitosan in aqueous solution, a unique
hydrogel material comprised of poly-electrolytic complex (PEC)
bers was produced. It gave the matrix structural integrity and
elastic properties without chemical or ultraviolet cross-linking.
Each component remained its native and biological relevant
state.86 Beth et al. also used chitosan and HA for preparing PEC.
As a result, human mesenchymal stem cells (hMSCs) in the PEC
were induced to differentiate and form emergent tissue-like
features.87 In addition, studies involving the using of chitosan–HA hydrogels in wound healing have been reported. Novel
hydrogels, such as HA–poly(vinylphosphonic acid)–chitosan88
and aldehyded 1-amino-3,3-diethoxy-propane–HA–chitosan
hydrogel89 were fabricated and characterized. The results
showed these hydrogels enhanced wound healing by promoting
cell migration, proliferation, granulation formation, and
angiogenesis.
3.1.2.1.3. Cellulose and its derivatives. Cellulose is the
primary structural component of plant cell walls and is the most
abundant organic polymer on earth. Cellulose-based materials
are considered biocompatible due to their reduced inammatory response for foreign bodies.90 Microbial (or bacterial)
cellulose, different from plant-origin, is synthesized by various
bacteria and has already proved to have great potentials in
wound healing applications. Its high mechanical strength,
crystallinity, and capacity to retain water mostly arise from its
unique nanobrillar structure.90,91
Bacterial nano-cellulose (BNC), of which the biggest feature
is ber diameter, one percent of plant cellulose-only 3–300 nm,
is considered to possess incredible potentials in biomedical
applications due to its innate unrivaled nano-brillar structure
and versatile properties.92 However, its application is largely
restricted by inefficient production and insufficient strength
when it is in a highly swollen state. Zhang et al. fabricated
a fabric skeleton reinforced chitosan/BNC hydrogel, which
showed high mechanical reliability and antibacterial activity.93
Further in vivo study indicated that the wound covered with
chitosan/BNC hydrogel was completely lled with new epithelium within 2 weeks, without any signicant adverse reactions.94
3.1.2.1.4. Collagen and gelatin. Since collagen is one of the
major components of human ECMs, and usually considered as
an ideal biomaterial for wound dressings. But collagen is difficult to process and hard to control its degradation rate. Gelatin
is a collagen derivative, which is usually used to prepare
hydrogels for wound dressings.67
Collagen/gelatin and chitosan have been widely used to
develop scaffolds for skin engineering because of their cellrelated signaling properties, such as proliferation, migration
and survival. Sanchez et al. described the anti-inammatory
activity of chitosan–collagen type I hydrogel, which was
permissive for the culture of human adipose-derived
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RSC Advances
mesenchymal stem cells (hADMSC). The results indicated that
hADMSC cultured in the hydrogel were viable, proliferative, and
can secrete the anti-inammatory cytokine interleukin-10 (IL10), and showed good wound repairing potential.95 Xiao et al.
demonstrated that chitosan–collagen hydrogel with immobilized glutamine–histidine–arginine–glutamic acid–aspartic
acid–glycine–serine enhanced re-epithelialization and granulation formation, and signicantly accelerated diabetic wound
closure.96 In addition, chitosan scaffold loading with basic
broblast growth factor (bFGF) contained in gelatin microparticles was studied in chronic ulcers by aged mice. The results
suggested this hydrogel was an effective material for growth
factor delivery and accelerated healing.97 Chitosan–gelatin
hydrogels could not only effectively inhibit target microorganisms, but also showed a positive effect on promoting cell
proliferation and neovascularization, inducing granulation
tissue formation, delivering active substances, and accelerating
the wound healing.98–100
3.1.2.1.5. Other natural polymers. Many other natural polymers are also incorporated into chitosan-based hydrogels,
including brin, silk broin, dextran, elastin, apigenin, and
nerolidol etc. Fibrin is a protein produced from brinogen.
Polymerized brin is an important component in the coagulation process, which plays an important role in the wound
healing process.67,101 Kumar et al. developed a chitosan
hydrogel/nano-brin composite bandages, which enhanced
blood clotting, activated platelet activity, and accelerated
wound healing.102 Chitosan–dextran hydrogel was non-cytotoxic
and possessed antimicrobial efficacy, which would be a candidate for wound healing dressings.103,104 Chitosan–agarose
hydrogel provided an adequate wound healing environment,
with high cellular proliferation at hydrogels surface and
improved the wound repairing ability.105,106 In addition, chitosan mixed with apigenin,107 nerolidol108 or hemigraphis alternate109 also showed the potential for enhancing wound healing.
3.1.2.2. Synthetic polymers. Thanks to the large number of
available chemical monomeric entities of potential interest
and recent advances in polymer synthesis, many new synthetic
biocompatible polymers have been prepared in recent years.110
Some of these polymeric materials overcome the problems of
natural polymers, because they could be synthesized and
processed in a highly controlled way. In addition, some
synthetic polymers mainly degrade via chemical hydrolysis
and are quite insensitive to a number enzymatic processes,
hence, their degradation behavior will not vary greatly
individually.111
Although some studies have shown the potential for using
these biomaterials as wound dressings, in each material, individual limitation could be expected.112 For wound dressing,
naturally derived materials oen have desirable biological
properties and can inuence cell function, but they limited by
poor mechanical strengths and fast degradation proles.84,85 In
contrast, synthetic polymers provide appropriately 3D environments and have the desired mechanical strengths. However,
they lack the bioactive properties of natural material. Therefore,
it is necessary to produce hybrid materials by combining
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synthetic and natural polymers, and retain the desirable characteristics of both materials.
3.1.2.2.1. PVA. Chitosan–PVA hydrogels have been widely
used as wound dressing, and a series of studies have shown
these composite materials enhanced wound healing as well as
antibacterial activities.53,113–117 Related research also proved that
chitosan–PVA hydrogel exhibited a good bactericidal activity
against E. coli. The hydrogel with greater chitosan concentration (60% and 80%), had a better cell viability, proliferation,
and blood clotting ability.53,113 Khodja et al. used the chitosan–
PVA hydrogel to deal with deep second degree burn rats, and the
wound was healed earlier than those treated with paraffin gauze
dressing and cotton gauze.114 If honey or bee venom was added
into the chitosan–PVA hydrogel, it strengthened the antiinammatory effect and antibacterial activity, hence,
enhanced wound healing.115–117 All of these researches indicated
chitosan–PVA hydrogels have excellent potential as wound
dressings.
3.1.2.2.2. PEG/PEO. PEG is a polyether which is also known
as poly(ethylene oxide) (PEO) or poly(oxyethylene) (POE),
depending on its molecular weight.118 PEG can also be blended
with chitosan to improve its inherent solubility, erosion,
mechanical and thermal properties, crystallinity, and
viscosity.119 Chitosan–PEG hydrogel could release drug in
a sustained and controlled manner.120 Chitosan–PEO hydrogel
also could absorb exudate rapidly.121 Chen et al. indicated the
reinforced chitosan–PEG hydrogel has good mechanical property and appropriate degradation rates. Chitosan inhibited
inammatory cells inltration and enhanced broblast proliferation, and PEG promoted epithelial migration. Whether small
cuts or full thickness wounds, this reinforced chitosan–PEG
hydrogel could promote the wound healing with high quality.122
3.1.2.2.3. PVP. Like PVA and PEG, these hydrophilic and
biocompatible materials have been extensively studied as
wound dressings due to its water absorption and oxygen
permeability properties.5 Poly(vinyl pyrrolidone) (PVP) is usually
blended with other polymers to modify its solubility, delivery
property, soness, and elasticity.123 Sadiya et al. prepared
a chitosan–PEG–PVP hydrogel. The water vapour transmission
rate was in the range of 2000–3500 g per m2 per day, indicating
a moderate exudate absorption. When tetracycline hydrochloride was used as model drug within the hydrogel matrix,
showed a fast healing with minimum scarring.124
3.1.2.2.4. Poly(a-esters). Polylactide (PLA) is one of aliphatic
polyesters, which presents relatively high strength and an
appropriate degradation rate with regard to most drug delivery
and tissue engineering systems. Besides, PLA provides with
good mechanical characteristics, controlled degradability, and
excellent biocompatibility. However, its strong hydrophobicity
limits the applications.125 Chitosan–PLA hydrogel showed
a quick absorption capacity, high equilibrate water absorption,
and good air permeability, which helped the dressing absorbing
excessive exudates, provided a moist environment, and
exchanged oxygen in wound healing.126 Polyglycolic acid (PGA)
is another poly(a-esters) that presents a relatively hydrophilic
7540 | RSC Adv., 2018, 8, 7533–7549
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nature and degrades faster than PLA in aqueous solutions or in
vivo.127 Ching et al. presented a novel wound dressing consisting
of chitosan and PGA. The hydrogel signicantly enhanced the
wound healing by suppressing inammatory phenomena and
activating re-epithelialization, besides, easily stripping off from
the wound surface without damaging the newly regenerated
tissue.128
3.2. Chitosan-based hydrogels as a drug delivery system
The healing of acute wounds could be accelerated by chitosan
alone, however, chronic wounds must heal in a different way.
Therefore, the slow release of therapeutic payload may offer
a more effective treatment.12,129 Despite that a large number of
active compounds could serve as therapeutics for wound healing, the inammatory environment in the wound hinders the
drug to enhance healing, and only few candidates have shown
clinical effects.130 Chitosan-based hydrogels are suitable for the
intelligent delivery, which could load with antimicrobial agents,
growth factors, stem cells and peptides to balance the
biochemical events of inammation in the chronic wound and
enhance healing.
As a DDS, the performance of chitosan-based hydrogels
depend not only on the physical and chemical properties of the
gel, but also the loading ways between the therapeutic agents
and hydrogels. There are three main methods of drug loading:
permeation (diffusion), entrapment, and covalent bonding
(Fig. 4).12 Each method has its own advantages and disadvantages, and should take the hydrogel network and the properties
of drugs into consideration when choosing, which are
enumerated in Table 3.33,131–133 In this section, we will summarize chitosan-based hydrogels as DDS for accelerating wound
healing.
3.2.1. Deliver antimicrobial agents. The hydrogel provides
a moist environment for wound healing, but the hydrated
environment can also facilitate microbial infection, which will
prolong or impair the wound healing process.134 This is
a contradiction, especially in some of the more serious chronic
infection wounds. Therefore, hydrogels with antibacterial
properties have great potential for clinical application. Chitosan
hydrogels itself have antibacterial properties owing to the
positively charged amino groups in the chitosan molecule,
which could adsorb with negatively charged in bacteria easily.135
However, with the increasing of drug-resistant bacteria,
chitosan-based hydrogel as a DDS carrying other antimicrobial
agents has aroused great concern.
Usually antimicrobial agents are divided into two categories.
One is organic antibacterial agents, such as antibiotics, organic
mineral salts, and another is inorganic antibacterial agents,
such as silver, zinc, copper and metal oxide. Hence, the antimicrobial property of chitosan hydrogel has been developed
recently.
3.2.1.1. Organic antibacterial agents. Organic antibacterial
agents include a series of substances, such as antibiotics and
chemical synthetic drugs, can inhibit and kill bacteria and other
microorganisms. They have widely applications in preventing
infection, whether oral or injection administration. In recent
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Three main methods of drug loading. (A) The easiest drug loading method is to place the fully formed hydrogel into medium saturated
with the therapeutic. (B) In the case of larger drugs and bioligands, the payload must be entrapped during the gelation process. (C) In order to limit
the loss of the therapeutic reserve (and the risk of toxic exposure), drugs can be covalently or physically linked to the polymer chains prior to
gelation (Reprint with permission from N. Bhattarai et al.12).
Fig. 4
Table 3
Three different drug loading strategies for chitosan hydrogels
Permeation
Entrapment
Covalent bonding
Loadable drugs
Small molecules
Small molecules, peptides, proteins
Network formations
Physical, covalently cross-linked,
and IPN gels
NO
High
pH-Sensitive swelling, polymer
dissolution and degradation
Hours to days
High loading efficiencies for
hydrophilic drugs, low chance of
drug deactivation
Small molecules, peptides, proteins,
micro/nanospheres
Physical and covalently cross-linked
gels
YES
Moderate
pH-Sensitive swelling, polymer
dissolution and degradation
Days and weeks
Suitable for loading hydrophilic and
hydrophobic drugs, moderate
chance of drug deactivation, chance
of toxic material leaching
In situ gelation possible
Degree of burst release
Smart delivery mechanisms
Release durations
Comments
years, the application of organic antibacterial agent in local
wound has attracted the interest of researchers, because it can
increase drugs concentration in the wound locally, but not
produce a signicant antibiotic effect to other parts of the body.
It is important to load an antibacterial agent into the dressing,
in order to reduce the inammation caused by bacterial infection during the healing processes, since the wound bed is an
ideal environment for microbial growth.136
Nimal et al. prepared an injectable hydrogel consisting of
nanotigecycline and chitosan platelet-rich plasma. Tigecycline
was released in a sustained manner and inhibited bacterial
growth signicantly. This hydrogel was an effective medium for
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Physical and covalently cross-linked
gels
YES
None
Enzyme-sensitive release, polymer
dissolution and degradation
Days to months
Best suited for hydrophilic drugs,
possible drug deactivation during
polymer bonding
antibiotic delivery and prevented skin infections effectively.137
Sadiya et al. incorporated tetracycline hydrochloride into chitosan–PEG–PVP hydrogel as an antimicrobial and scar preventive dressing. The composite dressing showed good
antimicrobial properties against both type of bacterial strain.
Chitosan promoted wound healing with minimum scar and
tetracycline hydrochloride provided protection from bacterial
invasions.124 In addition, chitosan–PVA hydrogel was prepared
to delivery minocycline138 and gentamycin sulfate,139 and chitosan–polyacrylamide (PAM) hydrogel was fabricated to delivery
piperacillin–tazobactam.140 As well as amikacin,141 gentamicin/
ciprooxacin,142 ciprooxacin,143 noroxacin,144 sulfadiazine145
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were loaded into chitosan-based hydrogels to develop the antibacterial function. These studies have proved the efficacy of
antibacterial agents contained in chitosan-based hydrogel
dressings for decreasing infection, favoring granulation tissue
formation, and stimulating faster wound healing.
3.2.1.2. Inorganic antibacterial agents. Drug-resistant
bacteria in infected wound is a challenge to wound healing.146
Nano metals as inorganic antibacterial agents have good prospect against drug-resistant bacteria with a similar antibacterial
mechanism. Nano silver (nAg), for example, could be oxidized
on the wound surface when in contact with moisture or wound
uid. Then Ag+ ions are released and attached to the bacterial
cell membrane. Ag+ ions damage the membrane by interacting
with sulphur-containing proteins and enter inside the bacteria
to disrupt DNA.147,148 A large number of studies incorporated the
inorganic antimicrobial agents into chitosan-based hydrogels
as wound dressings.
3.2.1.2.1. Silver. nAg is a broad spectrum antimicrobial
agent via multiple mechanisms against microbes, which
signicantly reduces the chance of developing resistance. nAg
has a better effective antimicrobial than ionic silver due to their
better permeation and retention effects.149 A number of developed wound dressings containing silver (Acticoat™, 3M™
Tegaderm™, Bactigrass®, SilvaSorb®, Fucidin®, PolyMem®
Silver) have been approved by Food and Drug
Administration.150,151
Chitosan-based hydrogel containing silver nanoparticles
showed the maximum activity against the resistant bacteria
isolating from diabetic foot. This composite prevented the foot
infection with multidrug-resistant bacteria, and obviously
accelerated wound healing.152 In addition, topical formulations
based on chitosan/nAg hydrogels have been prepared and their
effects on wound healing were studied extensively. nAg were
incorporated into nanocomposite chitosan-based hydrogel
dressings for full-thickness skin wounds,153 bactericidal activity
of hydrogel beads based on N,N,N-trimethyl chitosan/alginate
complexes loaded with nAg,154 antibacterial chitosan/nAg bionanocomposite hydrogel beads as DDS,155 nAg-containing
antimicrobial membrane based on chitosan–tripolyphosphate
(TPP) hydrogel for the treatment of wounds.156 These results
indicated nAg played an important role in antibacterial aspect
and had a great application prospect in wound dressing.
The toxicity of nAg can kill microorganisms, but also have
the same effect on normal human cells. nAg shows a concentration dependent cytotoxic effect towards human dermal
broblast cells.157 Therefore, establishing a therapeutic window
to control nAg within a range can inhibit bacteria but not
produce toxicity to human cells, which is the key for the
application of chitosan–nAg hydrogel. The chitosan-based
hydrogels could release the nAg in a sustained way. At
a controllable concentration, silver incorporating into chitosanbased hydrogel show great potential for avoiding infection and
enhancing wound healing.
3.2.1.2.2. Zinc. As a necessary element of the human body,
zinc is effective on some antibiotic resistant strains due to its
complex antibacterial mechanism.151,158 Zinc oxide (ZnO) is the
7542 | RSC Adv., 2018, 8, 7533–7549
Review
main form to exert antibacterial effect. However, there also
some studies indicated that the zinc ion also had a signicant
antibacterial effect, weaker than the silver ion, though.158,159
Nair et al. reported that ZnO nanoparticles (nZnO) had
potent antibacterial activity without adverse effect on normal
cells at appropriate concentrations.160 To investigate the suitable concentration of zinc playing extensive antibacterial effect
with low toxic effects on the cells, a stable DDS was necessary.
Kumar et al. incorporated nZnO into chitosan hydrogel. The
result showed this composite dressing enhanced blood clotting
and inhibited bacterial growth without causing toxicity to cells.
Furthermore, in vivo researches revealed that the nanocomposite promoted re-epithelialization, collagen deposition,
and enhanced wound healing. These results indicated this
nanocomposite was a potential application for burn wounds,
chronic wounds and diabetic foot ulcers.161
3.2.1.2.3. Other metals. Titanium dioxide (TiO2) nanoparticles have been used in cosmetics and lters, which exhibit
potent bactericidal properties and the abilities of eliminate
odors.46 Slowly release of titanium ions from the nanoparticles
can inhibit microbial proliferation, and therefore accelerate
wound healing.162 The chitosan–TiO2 composite membrane had
excellent surface properties and bactericidal activities.163,164
Studies have indicated that gold (Au) also has a signicantly
antibacterial activity.165 Martins et al. successfully prepared
N,N,N-trimethyl chitosan/alginate complex-loaded with Au
nanoparticles had good biocompatibility and characterized by
wound dressing potential.166
3.2.2. Deliver growth factors. Growth factors are regulatory
peptides synthesized and secreted by broblasts, inammatory
cells, endothelial cells, epithelial cells, and platelets. Growth
factors can induce cell migration, proliferation, differentiation,
and promote the synthesis of ECM.37,42,167 Compared with
normal wound healing, chronic wound secrets less growth
factors in different stages.5 In the case of diabetic foot ulcers,
a series of multiple mechanisms decrease the peripheral blood
ow and local angiogenesis, all of which can hinder wound
healing.168 Growth factors are divide into several families based
on their characteristics. The most relevant growth factor families for wound healing are EGF, FGF, TGF-b, PDGF, and vascular
endothelial growth factor (VEGF). The sources and important
roles of these growth factors in wound healing are summarized
in Table 4.169–171
Exogenous growth factors enhancing wound healing were
initially promising. However, application of growth factors to
the wound directly has several limitations. The half-life is
generally short and need repeated administration. They also
degrade quickly because of the abundant proteolytic enzymes
in the wound environment. Furthermore, sequestration of
growth factors by the wound matrix may hinder its binding to
receptors at the surfaces of the cells.172 Therefore, it is necessary to develop an applicable system to deliver growth factors
in order to improve their clinical efficacy. Importantly,
chitosan-based hydrogels have unique advantage to become
an excellent choice to maximize the effectiveness of growth
factors.
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Table 4 Major growth factors in wound healing
Cell sources
Effects during wound healing
EGF
Platelets, macrophages, broblasts
FGF
TGF-b1,
TGF-b2
Macrophages, endothelial cells, broblasts
Platelets, keratinocytes, macrophages,
lymphocytes, broblasts
PDGF
Platelets, keratinocytes, macrophages, endothelial
cells, broblasts
VEGF
Platelets, neutrophils, macrophages, endothelial
cells, broblasts
Fibroblasts neutrophils, macrophages, hepatocytes,
skeletal muscle
Fibroblasts
Cell motility and proliferation, increased levels in the acute wound,
decreased levels in the chronic wound
Angiogenesis and broblast mitogen, keratinocyte mitogen and mitogen
Re-epithelialization and inammation, granulation tissue formation,
brosis and tensile strength, increased levels in the acute wound, decreased
levels in the chronic wound
Chemotaxis, inammation, granulation tissue formation, matrix
remodeling, increased levels in the acute wound, decreased levels in the
chronic wound
Angiogenesis, granulation tissue formation, increased levels in the acute
wound, decreased levels in the chronic wound
Stimulates wound re-epithelialisation and broblast proliferation
IGF
HGF
Suppression of inammation, granulation tissue formation, angiogenesis,
re-epithelialization
EGF incorporated into chitosan–albumin hydrogel microspheres could continuous release more than 3 weeks aer
subcutaneous implantation in rats.17 Pulat et al. prepared chitosan–polyacrylamide hydrogel loading with EGF, the
composite enhanced broblast cells proliferation for longer
periods than that of free EGF.140 Furthermore, as DDS, sodium
carboxymethyl chitosan hydrogel,172 chitosan–alginate beads75
and Pluronic–chitosan hydrogels173 were developed to carry
rhEGF and studied in diabetic rats. These results indicated that
the chitosan-based hydrogels released rhEGF at the wound sites
controllably, enhanced the healing rate, and improved the
healing quality signicantly.
FGF could stimulate angiogenesis by activating capillary
endothelial cells and broblasts.97 In order to maintain its
release stably at the wound site, FGF was incorporated into
chitosan-based hydrogels. A series of studies have indicated
that aFGF174 and bFGF97,175 incorporated into chitosan-based
hydrogels were effective material for enhancing chronic
wounds healing.
Rapid angiogenesis is crucial in skin regeneration, which
could promote regeneration, transmit oxygen and nutrients,
remove metabolic waste, and decrease the risk of infection.176
Incorporated VEGF into the dressing and released in a sustained way could improve angiogenesis and enhance wound
healing without signs of reactive or granulomatous inammatory response.177
3.2.3. Deliver stem cells. In recent years, stem cells in
wound repair have become a hot spot attributing to the fact that
stem cells can differentiate into epidermal cell phenotypes, upregulate cytokines and growth factors expression around the
wound site. Aerwards, increasing evidence has demonstrated
that the paracrine effect of stem cells play the key roles in
promoting wound healing.178–180 Both bone marrow mesenchymal stem cells (BMSCs) and adipose derived stem cell
(ADSCs) have been reported to enhance angiogenesis, promote
epithelialization, and affect recruitment or proliferation of
macrophages and endothelial progenitor cells during the
healing process.181,182 The differentiation and growth factors
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secretion of stem cells are regulated by the microenvironment.183,184 However, there is a large amount of cytotoxic and
inammatory mediators in the microenvironment of the
wound, which may cause the death of stem cells in the local
wound tissue.185 The mechanisms of stem cell-laden antiinammatory hydrogel enhancing chronic wound healing are
described in Fig. 5.186 Because chitosan-based hydrogels have
the biological advantages of biocompatible, biodegradable,
maintaining multipotency of the stem cells, and mimicking
ECM, they become excellent delivery systems to protect stem
cells in order to maximize the differentiation and paracrine
capacity.187 Currently, many researchers have focused on stem
cells-laden hydrogels to promote wound healing. Compared
with alginate hydrogel, stem cells in self-healing chitosan
hydrogel proliferated much faster.188 Here, we will discuss the
application of chitosan-based hydrogels loading with stem cells
in wound healing.
BMSCs are reported to enhance wound healing through
secreting a series of growth factors189 and differentiating into
effector cells, thereby accelerating wound closure, vascularization, granulation tissue formation, and re-epithelialization.190–192 Considering the aforementioned mechanisms, the
active role of BMSCs in wound healing establishes the foundation for their application in treating chronic wound healing.
A chitosan/dextran-based injectable hydrogel not only retained
BMSCs viability, but also maintained the differentiation
capacity and mesenchymal immune-phenotype. In the
chitosan/dextran-based hydrogel, BMSCs differentiated into
osteocytes and adipocytes successfully. In vivo study indicated
that the hydrogel was effective prevention of scar formation
aer surgery.193 In addition, hydroxypropyl–chitosan hydrogel194
and chitosan–collagen microbeads187 were also benecial to
BMSCs adhesion and proliferation, which were suitable materials to deliver BMSCs as wound dressings.
ADSCs have been used in wound healing since they have
immune-regulatory and multipotent differentiation capabilities.195 In vitro, chitosan-based hydrogels served as a scaffold
could promote ADSCs proliferation and differentiation with low
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Fig. 5 MSC-laden hydrogels can prohibit chronic inflammation and contribute to growth factor secretion, resulting in accelerated wound
contraction, ECM secretion, angiogenesis, re-epithelialization, hair follicle and sebaceous gland regeneration and reduced scar formation
(Reprint with permission from Chen et al.186).
cytotoxicity.196 ADSCs-encapsulated chitosan/gelatin hydrogel
promoted proliferation of broblasts and tube formation of
endothelial cells in vitro, and promoted wound angiogenesis in
vivo.197 Sanchez et al. developed a novel hydrogel with antiinammatory activity. Their study showed that the hADSCs
cultured in the collagen type I/chitosan/dexamethasone hydrogel were viable, proliferative, and secreted the antiinammatory cytokine IL-10 but not the inammatory cytokine tumor necrosis factor-a. This was for the rst time that
a native ECM molecule (collagen type I), a biocompatible
natural polymer (chitosan), and an inammation-controlling
molecule (dexamethasone) have been combined into a hydrogel that proved to be capable of sustaining mesenchymal stem
cells culture.95 Chang et al. reported an injectable chitosan–HA
hydrogel delivered ADSCs signicantly accelerated wound
closure. The composite hydrogel increased cell proliferation
and promoted keratinocyte migration, up-regulated mRNA
expressions of VEGF, chemotactic factors and ECM-remodeling
matrix metaloproteinases.198
In addition, synovial mesenchymal stem cells loaded into
hydroxyapatite–chitosan hydrogels. In vivo results indicated
that the composite hydrogel signicantly promoted reepithelialization, angiogenesis, and collagen maturity around
diabetic chronic wound surface.199
In general, chitosan-based hydrogels show great promise as
stem cells delivery vehicles for tissue regeneration. BMSCs have
a wide range of applications, and many studies have demonstrated its effectiveness and safety. Compared with other stem
cells, BMSCs have the advantage in terms of healing rate and
7544 | RSC Adv., 2018, 8, 7533–7549
blood ow of the limbs for ulcer patients.200 In comparison to
BMSCs, ADSCs acquired via liposuction are much easier to
access.201 In addition, the isolated cells can be cryopreserved
while maintaining all their properties intact for up to 6 months,
which provides a good potential for ADSCs to become an off-theshelf product.202 This convinced us that chitosan-based hydrogels loaded stem cells to promote wound healing is very
promising.
3.2.4. Deliver peptides. Although stem cells and growth
factors intend to improve angiogenesis and re-epithelialization,
cost and safety issues remain in their applications. Peptides
show similar effects with growth factors, but have lower cost
and controllable properties.203,204 Similarly, a stable delivery
system allows peptides to better promote wound healing. Chen
et al. reported a biomimetic fragment of the laminin mimetic
peptide, Ser–Ile–Lys–Val–Ala–Val-conjugated chitosan hydrogel.
This composite material signicantly promoted BMSCs adhesion and proliferation in vitro, and accelerated wound contraction in vivo. These results suggested that the peptide-modied
chitosan hydrogel signicantly improved the function of chitosan in angiogenesis and re-epithelialization of skin.205 Xiao
et al. presented that chitosan–collagen hydrogel with immobilized glutamine-histidine–arginine–glutamic acid–aspartic
acid–glycine–serine (an integrin-binding prosurvival peptide
derived from angiopoietin-1), treated the full-thickness excisional wounds in a diabetic mice. This composite hydrogel
signicantly enhanced wound closure via faster reepithelialization and granulation tissue formation.206
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3.2.5. Deliver other drugs. In addition to the above categories, chitosan-based hydrogels can also deliver some other
drugs, such as anti-inammatory drugs, antioxidants, amino
acids, vitamins, and nutrients, which can reduce the inammatory reaction, well-nourished wound tissue, and promote
wound healing.207
The inammatory phase starts within a few minutes of injury
up to 24 hours and lasts for about 3 days. This therefore
necessitates effective analgesic delivery during this inammatory period.208 Chitosan–PVA hydrogel containing bee venom
was developed, and exhibited anti-inammatory effect, which
could be comparable to that of diclofenac gel, a standard antiinammatory drug. Combination of chitosan and bee venom
signicantly accelerated wound healing in diabetic rats.116 In
addition, ibuprofen,207 betamethasone sodium phosphate,
streptomycin, and diclofenac208 also have the potential as antiinammatory drugs delivered in chitosan-based hydrogels.
These evidenced chitosan-based hydrogels have signicantly
potential to control the delivery of anti-inammatory drugs over
a period compatible with the wound healing progresses.
Antioxidants, such as nitric oxide, horseradish peroxidase,
and hydrogen peroxide were also studied in chitosan-based
hydrogels, which showed a stronger antibacterial activity,
stimulated broblast proliferation and collagen production,
exhibited fast contraction of incision, and accelerated epithelialization and wound healing eventually.209,210 In addition, Wu
et al. added vitamin C into chitosan–PVA hydrogel. Sustained
release of the vitamin provided a new system to enhance wound
healing in dermal tissue.211
4. Conclusion
Chitosan-based hydrogel is considered as an ideal material due
to its biodegradable, biocompatible, antimicrobial effects, and
these properties of chitosan-based hydrogels could be modied
by various natural or synthetic polymers. Relative to acute
wound, the chronic and complex wounds need to be treated
with functional wound dressing, possessing the capacity of
releasing therapeutic drugs or growth factors to offer a more
effective treatment. To address this, chitosan-based hydrogels
have been developed as wound dressings, which can deliver
antibacterial agents, growth factors, stem cells, peptides and
other active substances in a sustained release manner. The local
intervention can solve the problem of systemic toxicity and
maintain the effective concentration of the active material in
the wound to promote the chronic wounds healing. We believe
that as wound dressing and DDS, chitosan-based hydrogels
have great potential clinical application in wound healing.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This research was nancially supported by National Natural
Science Foundation of China (No. 81171681), Training Program
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RSC Advances
of Outstanding Doctoral Student by Norman Bethune Health
Science Center of Jilin University (No. YB201501), Scientic
Development Program of Jilin Province (No. 20160101109JC,
20150414006GH, 20150312028ZG and 20130206060GX), Graduate Innovation Fund of Jilin University (No. 2017032), Medjaden Academy & Research Foundation for Young Scientists
(Grant No. MJR20170016).
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