Carbohydrate Polymers 227 (2020) 115349

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Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol

An overview on antimicrobial and wound healing properties of ZnO T

nanobiofilms, hydrogels, and bionanocomposites based on cellulose,
chitosan, and alginate polymers
⁎ ⁎
Mehran Alavia, , Ali Nokhodchib,c,
a
Department of Nanobiotechnology, Faculty of science, Razi university, Iran
b
Professor of Pharmaceutics and Drug Delivery, Arundel Building (Room 407), School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK
c
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Release of Zn2+ ions from zinc oxide nanoparticles (ZnO NPs) is a major mechanism for oligodynamic activities
Antibacterial of these metal oxide NPs against eukaryotic and prokaryotic microorganisms. In addition to this mechanism, ZnO
Wound healing NPs can form reactive oxygen species (ROSs) resulted from electron-hole formation under certain light wave-
ZnO NPs length. These properties with suitable biocompatibility and biodegradability of ZnO NPs compared to other
Chitosan
metal NPs have caused higher applications of these nanomaterials in therapeutic and cosmetic fields. Recently,
Cellulose
Alginate
natural polymers including cellulose, chitosan, and alginate polymers have gained more attention as safe and
cost-effective scaffold for wound healing. Both ZnO NPs and these polymers have not been able to satisfy related
patients. In this way, the coupling of these materials and nanomaterials as nanocomposites (NCs) is an alter-
native way to increase the mechanical and antibacterial properties of wound-healing tissue scaffolds.
Controllable release of Zn2+ ions in physiological medium should be considered as an indispensable factor to
obtain appropriate industrial formulation. Therefore, in this review, attempts were made to highlight particu-
larly important antibacterial results of these NCs in recent investigations.

1. Introduction Wang, Gong et al., 2019). As demonstrated in Fig. 1, lipid peroxidation,

Engineering of new materials having therapeutic applications is a
major issue in biomedicine engineering. In this way, nanotechnology
has introduced nanomaterials with excellent physicochemical proper-
ties including higher aspect ratio and large surface area to volume
compared to bulk one. These nanomaterials may be divided into two
groups, organic and inorganic types, according to their derived sources.
For example, metal and metal oxide nanoparticles (MNPs/MONPs) such
as Ag, Cu, CuO, ZnO, TiO2, Fe3O4, MgO NPs are located in inorganic
nanoparticles (Alavi & Karimi, 2019; Hassabo, El-Naggar, Mohamed, &
Hebeish, 2019; Taran, Rad, & Alavi, 2016; Taran, Rad, & Alavi, 2017).
Recently, medicinal and industrial importance of these NPs has ob-
tained more consideration. In this regard, antimicrobial, anticancer,
antidiabetic and wound healing activities of ZnO NPs were indicated by
abundant studies. In this way, antibacterial and wound healing prop-
erties of ZnO NPs are objective of this review. These properties of ZnO
NPs can be resulted from their photocatalytic abilities and reactive
oxygen species (ROSs) production (Alavi, Karimi, & Salimikia, 2019;
protein oxidation, and nucleic acids damage are common results of ROS
formation under ultraviolet or visible light wavelengths (Kadiyala,
Turali-Emre, Bahng, Kotov, & VanEpps, 2018). Changes of gene ex-
pression in bacteria under NPs are indicator factor to evaluate precise
antibacterial activities of NPs at biomacromolecule level (Shokoofeh
et al., 2019). For instance, down-regulation and up-regulation of re-
spectively amino acids and pyrimidine biosynthesis were observed in
the case of Staphylococcus aureus under ZnO NPs (Kadiyala et al., 2018).
In addition, the safety of bulk materials of ZnO was approved by food
and drug administration (FDA). The function of more mammalian en-
zymes (about 300) contributing in nucleic acid repair and cell cycle
progress is completed by Zinc element as co-factor (Bisht & Rayamajhi,
2016). In contrast, biocompatibility and biodegradability of these NPs
in the human physiological condition is a major problem. Due to sol-
ving this hindrance, various methods were used recently by in-
vestigators. Encapsulation, incorporation, and loading of MNPs may be
a helpful solution. Hydrogels, composites, and films are related for-
mulations for these performances. For these purposes, different

⁎
Corresponding authors.
E-mail addresses: mehranbio83@gmail.com (M. Alavi), A.Nokhodchi@sussex.ac.uk (A. Nokhodchi).

https://doi.org/10.1016/j.carbpol.2019.115349
Received 28 July 2019; Received in revised form 3 September 2019; Accepted 18 September 2019
Available online 21 September 2019
0144-8617/ © 2019 Elsevier Ltd. All rights reserved.
M. Alavi and A. Nokhodchi
Fig. 1. Several antibacterial mechanisms of ZnO NPs under light condition.
materials and biomaterials were applied as a complementary part.
Natural and synthetic polymers are emerging materials with various
properties. Among natural polymers, polysaccharides such as chitosan,
cellulose, and alginate have obtained more attention compared to other
polymers because of their high availability, biocompatibility, and bio-
degradability (Lv et al., 2019; Rasool, Ata, & Islam, 2019; Sajjad et al.,
2019). Coupling of these polymers with ZnO NPs may be improved its
therapeutic effects. It is worth emphasizing that in order to heal wounds
at appropriate period, considering materials having suitable roles in
four sequential stages of wound healing including hemostasis, in-
flammation, proliferation, and remodelling is vial affair (Prasanna
et al., 2018). Keeping the above argument in mind, this review has
explained recent progress and challenges about antibacterial and
wound healing ability of micro/nanoformulations of ZnO NPs complex
with cellulose, chitosan, and alginate.
2. MNPs/MONPs
Unique properties such as large surface area to volume ratio of NPs
particularly MNPs and MONPs compared to bulk materials are major
reasons for wide applications of NPs in various technologies and science
fields (Hu et al., 2019). In the case of infectious diseases remedy,
MNPs/MONPs such as Ag, Cu, TiO2, and ZnONPs have been illustrated
significant antibacterial activities against drug-resistant bacteria. Ions
release of these MNPs/MONPs is a main antibacterial mechanism which
can lead to free radicals stress in bacteria (Alavi, Karimi, & Valadbaeigi,
2019). In addition to this mechanism, TiO2 and ZnONPs can generate
ROSs under specific light wavelength which can damage biological
macromolecules of bacteria in the photodynamic way (Pathak et al.,
2019). In spite of these advantages, the important drawback for MNPs/
MONPs applications in the pharmaceutical industry is high cytotoxicity
effects (Fahmy et al., 2019). For this purpose, coating and encapsula-
tion of MNPs/MONPs by accessible, biodegradable, and biocompatible
materials such as natural polymers may be efficient. In this regard,
cellulose and chitosan having accessible functional groups of hydroxyl
and amine can be suitable options owing to low cytotoxicity in phy-
siological conditions (Jatoi, Kim, & Ni, 2019; Liang et al., 2019).
3. ZnO NPs
Several synthesis methods involving precipitation, wet chemical,
2
Carbohydrate Polymers 227 (2020) 115349
sol-gel, solid-state pyrolytic, and green synthesis have been applied by
many investigators (Mishra, Mishra, Ekielski, Talegaonkar, & Vaidya,
2017; Taran, Rad, & Alavi, 2018). For example, in a comparative study,
ZnO NPs and modified ZnO NPs with (3-glycidyloxypropyl) tri-
methoxysilane (GPTMS) were prepared by sol-gel method. Heat treat-
ment (up to 600 C°) of ZnO NPs and GPTMS-ZnO NPs (with approxi-
mately 5 nm) for 24 h resulted in decreased antibacterial activities
compared to 3 h treatment against Escherichia coli (da Silva, Caetano,
Chiari-Andréo, Pietro, & Chiavacci, 2019). Inhibition 50% of bacterial
growth as MIC50 for Enterococcus faecalis and E. coli were 95.21 and
90.9 μg/mL for biomodified ZnO NPs by Punica granatum fruit peels
extract followed thermal decomposition under 700 °C (Mohamad Sukri
et al., 2019). In this case, thermal decomposition has a determinative
role in ZnO NPs formation and their antibacterial activities. As other
thermal treatment at 600 °C temperature showed 22.09 and 64.53 μg/
mL values of MIC50 for respectively E. faecalis and E. coli. Higher an-
tibacterial activity against E. coli and S. aureus was reported compared
to Salmonella Paratyphi bacteria. Electron-hole formation in ZnO NPs as
semiconductor under light wavelength (≥ 3.2 eV) was a supposed
mechanism for these results (Fig. 2) (Raja et al., 2018). As illustrated in
various studies, this bandgap can be improved by coupling metal
sources with ZnO NPs. For instance, Cu and Sn metals were used to
reduce bandgap as amount as 0.54 eV (3.22 to 2.68 eV). For this regard,
antibacterial activities of Sn-Cu-ZnO nanocomposites (NCs) at 50 μg
concentration showed inhibition zone diameter (IZD) values of 19 ± 1
and 19 ± 0.5 mm for E. coli and S. aureus respectively. As a com-
parative way, IZD results were lower for pure ZnO NPs as well as Sn-
ZnO and Cu-ZnO NCs (Shanmugam & Jeyaperumal, 2018). Increased
antibacterial activities against S. aureus and E. coli resulted from the
reduction of bandgap from 2.2 to 1.8 eV were reported for doping of
La3+ ions in biosynthesized ZnO NPs by Gymnema sylvestre leaves ex-
tract (Karthikeyan, Ahamed, Karthikeyan, & Kumar, 2019).
Production of ZnO NPs on large scale can be possible via physical
approaches such as high energy ball milling (Das et al., 2019). Sim-
plicity, reproducibility, and control of size and shape are important
advantages of this method. For instance, sizes of 50, 40, and 20 nm
were generated after milling up to 7, 10, and 15 h (Verma et al., 2018).
In this way, higher antibacterial effects against S. aureus and E. coli were
observed for the smaller size of ZnO NPs (20 nm) compared to larger
sizes. It is worth noting that interaction in molecular level between
metal NPs and bacterial macromolecules such as proteins and nucleic
M. Alavi and A. Nokhodchi
Fig. 2. Electron-hole formation in ZnO NPs under photon energy (Bomila, Suresh, & Srinivasan, 2019).
acids is an important issue to understand antibacterial activities of ZnO
NPs. Molecular docking, as one of the computational molecular tools,
has been able to be helpful in this case (Wang, Zhang et al., 2019). E.
coli express BamA as beta-barrel protein in the outer membrane which
can be targeted by ZnO NPs. Based on molecular docking results, this
interaction may have resulted from hydrogen bond between Asparagine
residue of BamA and ZnO NPs (Verma et al., 2018). In wet chemistry
method as a subtype of the chemical approaches, several factors such as
type of metal salt and other precursors, concentrations of each reactant
as well as temperature value can change physicochemical properties
(shape and size) of MNPs (Rad, Taran, & Alavi, 2018). In addition,
antibacterial abilities of MNPs may be influenced by changing these
properties. In a comparative study, effects of sodium hydroxide (NaOH)
and potassium hydroxide (KOH) as hydrolyzing agents and three Zn
salts involving zinc nitrate, zinc acetate, and zinc chloride were eval-
uated on morphology and antibacterial activities of ZnO NPs against E.
coli and Staphylococcus epidermis pathogens. Results of this investigation
demonstrated lower minimum inhibition concentration/minimum
bactericidal concentration as 32/64 and 128/256 μg/mL respectively
against E. coli and S. epidermis for prepared ZnO NPs via zinc chloride
and KOH (Shankar & Rhim, 2018). In another study, as green com-
bustion method, Artocarpus gomezianus fruit extract was used to prepare
ZnO NPs with spherical shape and size in the range of 10–30 nm. Higher
antibacterial effect on S. aureus as IZD of 16.0 ± 0.66 mm was ob-
served for 5 mL concentration of fruit extract compared to 10 and 15
amounts (Anitha, Ramesh, Ravishankar, Kumar, & Ramakrishnappa,
2018). In this work, fruit extract concentration had a determined role in
NPs formation and antibacterial results. As mentioned above, type of
precursor reagents can impact on antibacterial abilities of ZnO NPs.
Graphene oxide (GO) is another nanomaterial which has antibacterial
activities related to its shapes and surface functionalization. For this
purpose, loading ZnO NPs (spherical shapes and mean diameter size of
50 nm) on GO (spindle shape) showed MIC values of 31.25, 31.25,
15.62, and 15.62 μg/mL for respectively E. coli, Salmonella typhimurium,
B. subtilis, and E. faecalis pathogens. In contrast, higher MIC amounts
were observed in the case of ZnO NPs and GO alone (Zhong, Liu, Samal,
& Yun, 2018). As mentioned in introduction section, NCs of ZnO with
natural polysaccharides of cellulose, chitosan, and alginates have
gained more attention because of acceptable feedbacks of these poly-
mers in physiological conditions. Therefore, in the following sections,
recent investigations related to antibacterial activities and wound
healing of ZnO/cellulose, ZnO/chitosan, and ZnO/alginate NCs were
comparatively presented.
4. Cellulose
Frequency of cellulose particularly in herbal and bacterial sources
has created this natural polysaccharide as more accessible polymers in
3
Carbohydrate Polymers 227 (2020) 115349
the biosphere. D-glucose units are linked by glycoside bonds of β(1→4)
to produce cellulose with the formula (C6H10O5)n having three hy-
droxyl groups for each unite. In order to improve biomedical applica-
tions such as wound dressing production, these functional groups are
targeted purposely for modifications of cellulose. For instance, en-
hanced fibroblast cell attachment and proliferation were observed in
the case of modified bacterial cellulose/keratin nanofibrous mats via a
hydrogel of tragacanth natural gum (Azarniya, Tamjid, Eslahi, &
Simchi, 2019). Due to obtaining appropriate physicochemical proper-
ties, nanotechnology facet of this polysaccharide should be considered.
However, there are two common nanoforms of cellulose including na-
nofibrillated (NFC) and nanocrystalline cellulose (NCC) which could be
modified by several biochemical methods (Alavi, 2019).
4.1. ZnO/cellulose
Acceptable crystallinity and tensile strength are two superior
properties of bacterial cellulose (BC) than to other natural celluloses.
Contribution of BC in production of artificial blood vessels, skin, dental
implant, and wound dressings may be important applications of this
type of cellulose in the tissue engineering field. For this purpose, wound
healing abilities including cytotoxicity, antibacterial, and antifungal of
loaded ZnO NPs on BC biofilm (with 2D and 3D configuration) were
evaluated compared to BC alone as a control. In a period of 72 h, the
proliferation of human dermal fibroblast cells on ZnO-BC biofilm illu-
strated a slight reduction compared to both BC and ZnO NPs alone. This
result was accompanied by higher preventing effects on surface ad-
herence of E. coli, B. subtilis bacteria and C. albicans fungi (Dincă et al.,
2018). Similarly, synthesized ZnO NPs (20% w/v of Zn(NO3)2)/BC
pellicle by solution plasma method showed IZD values of 5.33 ± 0.29
and 3.33 ± 0.29 mm against S. aureus and E. coli respectively
(Janpetch, Saito, & Rujiravanit, 2016). Also, average wound areas were
234.6 ± 5.7, 98.3 ± 7.6, 143 ± 7.5, and 66.6 ± 5.7 mm2 for re-
spectively negative control, BC-ZnONPs, BC, and 1% silver sulfadiazine
cream after 15 days treatment (Khalid, Khan, Ul-Islam, Khan, & Wahid,
2017). Electrospun NCC-ZnO NCs (5%)-poly(3-hydroxy-butyrate-co-3-
hydroxy-valerate) (PHBV) matrix illustrated 2.9 and 3.6 mm of IZDs for
respectively E. coli and S. aureus (Abdalkarim, Yu, Wang, & Yao, 2017).
As discussed in the introduction section, haemorrhage control is a
crucial step of wound healing. Biofilm composed from TEMPO-oxidized
NFC and polyethylene glycine (PEG) with different porosity (100 μm for
5% PEG than to 200 μm for 10% PEG) was used to loading ZnO NPs
(less than 100 nm). Results demonstrated less bleeding time in the case
of mentioned biofilm with 5% PEG compared to 10% PEG as well as
each component alone. In addition, antibacterial activities against S.
aureus were more than S. epidermidis and E. coli for this biofilm with 3%
ZnO NPs (Shefa et al., 2019). Considering components of extracellular
matrix (ECM) for the healing of wounds specifically in infected chronic
M. Alavi and A. Nokhodchi
wounds at an appropriate time is critical. In this way, heparin as sul-
fated glycosaminoglycan of the basement membrane ECM can enhance
wound healing via binding to growth factors (GFs) including vascular
endothelial cell growth factor (VEGF-A165) and platelet-derived
growth factor (PDGF-BB) (Ishihara et al., 2018). In this regard, hepar-
inized ZnO NPs-Poly vinyl alcohol (PVA)-carboxymethyl cellulose bio-
nanocomposite hydrogels showed cell viability value up to 83% for
human dermal fibroblast (HDF) and mouse fibroblast cells (L-929)
(Joorabloo, Khorasani, Adeli, Mansoori-Moghadam, & Moghaddam,
2019). Suitable oxygen permeability in the wound area is another
factor which should be considered in wound dressing production. Me-
soporous silica NPs such as MCM-41 is one choice to loading wound
healing agents. Impregnation of ZnO NPs in MCM-41/carboxymethyl
cellulose hydrogels had prominent results involving 500% gas perme-
ability, 100% swelling, and antibacterial activities against E. coli and S.
aureus (Rakhshaei & Namazi, 2017).
5. Chitosan
After cellulose, chitosan polysaccharide is the most abundant
polymer in nature. A number of publications about antibacterial and
wound healing applications of chitosan in recent years showed con-
siderable importance of this polymer (Fig. 3). This polymer can be
generated via deacetylation treatment (60% up to 98%) of extracted
chitin from exoskeleton and cell wall-related to crustaceans and fungi
respectively. It is worth mentioning that only natural source of chitosan
is fungi of Mucoraceae family (Sahariah & Masson, 2017). In the case of
antibacterial activity, positive charge related to amine (NH2) functional
group of chitosan can interact with the negative charge of bacterial
membrane containing phospholipids and proteins. This process is im-
portant for antibacterial effects in acidic conditions. Therefore, to im-
prove this ability in neutral solution, functionalization of chitosan such
as quaternization and cationic groups is required (Cheah et al., 2019).
Admissible biocompatibility and antimicrobial results for both ZnO NPs
Fig. 3. Publication number related to antibacterial (a) and wound healing abilities (b) of chitosan in 2015–2019 years (SCOPUS®database).
4
Carbohydrate Polymers 227 (2020) 115349
and chitosan were approved by several investigations. In this regard, a
combination of these materials for therapeutic purposes particularly
infected wound treatment may be an appropriate alternative compared
to conventional products.
5.1. ZnO/chitosan
There are several studies about chitosan applications as a stabilizer
and antibacterial agents. In this regard, diameter size in the range of
50–70 nm with antibacterial effects on E. coli and S. aureus were ob-
served for ZnO/chitosan (Yusof, Zain, & Pauzi, 2019). IZD values for of
ZnO/chitosan NCs (the average size of 20–150 nm with rod shape)
against E. coli, K. pneumoniae, S. aureus, and B. subtilis were 25.5, 24.5,
22.5, and 21 mm respectively (Bharathi, Ranjithkumar, Chandarshekar,
& Bhuvaneshwari, 2019). It can be used other MNPs specifically silver
NPs to enhance antibacterial results. Ag/ZnO NCs (0.1. 0.2, 0.5, and
1 mg/mL) loaded on chitosan demonstrated 88% porosity as well as
striking antibacterial activities against drug-resistant P. aeruginosa,
methicillin-resistant S. aureus (MRSA), and drug-resistant E. coli. In
addition, wound closure after 7 days and cell viability of human normal
hepatocyte for 0.5 mg/mL of Ag/ZnO solution were 100% and 94%
respectively (Lu et al., 2017). ZnO/chitosan biofilms may be prepared
by using polyvinyl alcohol (PVA) having appropriate properties in-
cluding biocompatibility, biodegradability, water solubility, emulsi-
fying, film forming, and adhesive. Significant wound healing was ob-
served for chitosan/PVA/ZnO after 7 days compared to chitosan,
chitosan/PVA, and phosphate-buffered saline (PBS) samples. Also, S.
aureus and E. coli showed sensitivity to chitosan/PVA/ZnO NPs with
respectively IZDs of 20 and 19 mm (Gutha, Pathak, Zhang, Zhang, &
Jiao, 2017). Similarly, heparinized chitosan/PVA/ZnO NPs hydrogels
showed cell viability in the case of fibroblast cells (L-929) as the value
of 89% after 48 h with antibacterial activities against E. coli and S.
aureus (> 70%). Keratin proteins can activate keratinocyte cells and
production of proteins collagen IV and collagen VII in the wound
M. Alavi and A. Nokhodchi
healing process (Kelly, 2016). Preparation bandages composed of ker-
atin-chitosan hydrogel and ZnO NPs 92% after 14 days (Zhai, Xu, Zhou,
& Jing, 2018).
6. Alginic acid
Pseudomonas aeruginosa bacteria can produce alginic acid (con-
sisting of β-D-mannuronate and α-L-guluronate unites with (1–4)
bonds) in their biofilm structure. Also, this polysaccharide is available
in the cell wall of brown algae such as Sargassum muticum seaweed
(Flórez-Fernández, Domínguez, & Torres, 2019). Hydrogel formation is
a prominent property of this polymer which can be useful to generate
novel drug delivery systems. Also, wound moisture preservation and
exudates absorption are crucial factors to heal quickly wounds which
alginate can provide this condition by significant properties of liquid
maintain and absorption (Shi et al., 2019). Three major forms of algi-
nate including sodium alginate (NaC6H7O6), calcium alginate
(C12H14CaO12), and potassium alginate (KC6H7O6) are produced by
respectively sodium, calcium and potassium salts of alginic acid
(Shahzad et al., 2019; Trevisol, Fritz, de Souza, Bierhalz, & Valle,
2019).
6.1. ZnO/alginate
Biomedicine applications of various types of natural gum such as
acacia, karaya, and tragacanth gums are majorly related to hydrogel
formation and higher viscosity of these polysaccharides (Bashir, Teo,
Ramesh, & Ramesh, 2018; Parwani, Bhatnagar, Bhatnagar, Sharma, &
Sharma, 2019; Rao, Kumar, Rao, Haider, & Han, 2018). In this regard,
hydrogel based on sodium alginate-acacia gum was used to load ZnO
NPs. This hydrogel with 90.35 nm showed higher antibacterial effects
on Bacillus cereus and Pseudomonas aerigunosa at a concentration of
1000 μg/well (Raguvaran et al., 2017). As explained in the above
paragraph, fabricated wound dressings by alginates have the appro-
priate ability to absorb wound exudates. This characterization in the
case of infected wounds such as diabetic foot ulcer (DFU) and infected
pressure ulcers can be helpful (Satish, Aswathi, Maria, & Korrapati,
2019). Using cellulose fibre has improved the effect on mechanical
properties such as Young modulus in nanocomposites formation. In this
way, 379 MPa value of Young modulus was indicated for ZnO NPs-
cellulose fibre with 1.5% sodium alginate (Varaprasad, Raghavendra,
Jayaramudu, & Seo, 2016). It is worth noting that the biodegradability
of chitosan is better than alginate. Therefore, the compound of these
two polymers is an appropriate approach to produce hydrogels. In this
way, biofilm-based chitosan/alginate and ZnO NPs showed reduced
wound dehiscence via significant antibacterial, biodegradability, and
biocompatibility (Gong, Luo, & Pan, 2019). Prominent mechanical
properties and antibacterial activities against E. coli and S. aureus were
illustrated for carboxymethyl chitosan-sodium alginate-ZnO NPs com-
pared to each component alone (Wang, Shi, Fu, & Zhu, 2019). Also,
composite bandage was prepared by chitosan-sodium alginate with
different concentrations of ZnO NPs (0.05%, 0.1%, 0.25%, 0.5%,
0.75%, and 1% w/w). Results of this investigation showed meaningful
hemostatic ability, biocompatibility, and antimicrobial effects on S.
aureus, E. coli, and Candida albicans pathogens for these nanobiofilms
(at 1% ZnO NPs) compared to commercial KALTOSTAT® Alginate
Dressing (Mohandas, Kumar, & Raja, 2019).
7. Overview
Based on this review, to increase antibacterial activities of ZnO NPs,
improving bandgap by adding other metals for the production of ap-
propriate NCs is an essential affair. Application of cellulose, chitosan,
and alginate alone as a scaffold to heal infected wounds is not practical,
because lower mechanical properties and solubility are two major
limiting factors of these polymers. To overcome these hindrances, ZnO
5
Carbohydrate Polymers 227 (2020) 115349
NPs having antibacterial activities and wound healing can be a suitable
choice. In addition, ZnO NCs based on these polymers have higher
mechanical strength. Uncontrollable release of Zn2+ ions in physiolo-
gical conditions may be an important hindrance to obtain appropriate
industrial formulation. Therefore, the need for a high dose of NPs can
neutralize the therapeutic effects of formulation and increases side ef-
fects and preparation costs. In the case of hydrogel formulations, smart
and sustained release of Zn2+ ions should be considered. In this way,
appropriate selection of initiator and cross-linker materials in hydrogel
preparation can cause a smart response to physiological conditions of
wound area such as pH and temperatures. For this purpose, there are
four common types of polymers including pH-responsive basic, pH-re-
sponsive acidic, pH-responsive neutral, and multi-responsive polymers.
In order to get a better effect, application of multi-responsive polymers
such as poly[(2-N-morpholino)ethyl methacrylate] (PMEMA) and poly
[(2-dimethylaminoethyl) methacrylate] (PDMA) as complement poly-
mers may be helpful (Kocak, Tuncer, & Bütün, 2017). Therefore, based
on mentioned advances in this review, future viewpoint in the case of
usage of multi-responsive polymers and antibacterial materials in in-
fected wound healing cannot ignore these types of formulations.
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