Acsnano 1c04206

Review
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Functional Hydrogels as Wound Dressing to

Enhance Wound Healing
Yongping Liang,# Jiahui He,# and Baolin Guo*
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ABSTRACT: Hydrogels, due to their excellent biochemical and

mechnical property, have shown attractive advantages in the
field of wound dressings. However, a comprehensive review of
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the functional hydrogel as a wound dressing is still lacking. This

work first summarizes the skin wound healing process and
relates evaluation parameters and then reviews the advanced
functions of hydrogel dressings such as antimicrobial property,
adhesion and hemostasis, anti-inflammatory and anti-oxidation,
substance delivery, self-healing, stimulus response, conductiv-
ity, and the recently emerged wound monitoring feature, and
the strategies adopted to achieve these functions are all
classified and discussed. Furthermore, applications of hydrogel
wound dressing for the treatment of different types of wounds such as incisional wound and the excisional wound are
summarized. Chronic wounds are also mentioned, and the focus of attention on infected wounds, burn wounds, and diabetic
wounds is discussed. Finally, the future directions of hydrogel wound dressings for wound healing are further proposed.
KEYWORDS: multifunctional hydrogel, bioactive wound dressing, wound healing, tissue engineering, bioactive biomaterials,
wound regeneration, skin repair, wound closure, collagen deposition
T he skin is a very important organ that covers the surface

of the human body and directly contacts the external
environment, and it has the effects of feeling external
stimuli and regulating body temperature, protecting the human
body from external damage.1−3 Due to the characteristics of
significant effect on wound healing. An ideal skin wound
dressing needs to meet the following requirements: (1) good
tissue compatibility, without causing toxicity or inflammation;
(2) good moisture retention, which can maintain the moist
environment of the wound and promote cell hydration and have
direct contact with the outside world, the skin has also become certain absorption for wound exudate; (3) sufficient physical
one of the most vulnerable tissues. Although most of the and mechanical strength to ensure its integrity and avoid the
common injuries of skin can be basically restored to their intrusion of external bacteria caused by materials’ breakage; and
original appearance within a period, it is difficult for adult skin (4) appropriate surface microstructure and biochemical proper-
damage to restore 100% of skin functions like babies.4,5 This is ties to promote cell adhesion, proliferation, and differ-
often accompanied by the formation of scar tissue and the entiation.15 Many wound dressings have been developed to
critical absence of skin appendages such as hair, sweat glands, promote wound repairs, such as semipermeable membranes,
and sebaceous glands.6 The repair of skin wounds is divided into semipermeable foams, hydrocolloids, and hydrogels.16,17
four continuous and coordinated processes, including hemo- Among them, hydrogels have become the most competitive
stasis, inflammation, proliferation, and remodeling.5,7 However, candidates for wound dressings due to their good hydrophilicity,
the process of wound healing generally cannot be followed biocompatibility, and three-dimensional (3D) porous structure
perfectly and orderly. The impact of various factors at any stage like extracellular matrix (ECM), and it also has aroused the
may cause abnormal wound repair,8 such as excessive
inflammation,9 burns,10 or an accident caused by large area Received: May 17, 2021
skin tissue loss,11 infection,12 diabetes,13 and others. Accepted: August 4, 2021
Wound dressings can cover the wound and provide a Published: August 10, 2021
temporary barrier against external infections14 and serves as an
induction template to guide the reorganization of skin cells and
subsequent infiltration and integration of host tissues, showing a
© 2021 American Chemical Society https://doi.org/10.1021/acsnano.1c04206

12687 ACS Nano 2021, 15, 12687−12722
ACS Nano www.acsnano.org Review
Figure 1. Four stages in wound healing: (a) hemostasis, (b) inflammation, (c) proliferation, and (d) remodeling. Reprinted with permission
from ref 20. Copyright 2018 Elsevier.
interest of many researchers.18 The research on hydrogels as elaborated. Finally, the future development trends are also
wound dressings also shows a trend of increasing especially in further prospected.
the past decade. Many hydrophilic polymers, including natural
ones such as chitosan,19 gelatin, hyaluronic acid, alginate, and THE PROCESS OF SKIN REPAIR AND EVALUATION
dextran as well as synthetic hydrophilic polymers such as PARAMETERS
poly(ethylene glycol) (PEG) and poloxamer, poly(vinyl Before discussing the process of skin repair, we must understand
alcohol), olefin-containing polymerized monomers such as the structure of normal skin at first. It involves the physiological
polyacrylamide (PAM), poly(acrylic acid), and polypeptides structure of the skin, which is usually divided into an epidermal
have been used to construct hydrogels through various chemical layer and a dermal layer. The epidermal layer directly relates to
or physical cross-links.20,21 Among them, dynamic chemical the outside world, mainly including the keratinocyte layer and
bonding, photo-cross-linking in situ polymerization, dual the germinal layer, which can prevent the outflow of tissue fluid,
network, semi-interpenetrating network, and 3D printing all antifriction, and anti-infection. Therefore, the reconstruction of
show good advantages.22 In addition, the function of hydrogel the integrity of the epidermal layer is critical to the repair of skin
has also changed from a single physical coverage or a single tissue, and it is generally possible. The dermis layer is composed
function to a combination of multiple functions now and shows of dense connective tissue, and from shallow to deep is the
a trend toward further intelligence. However, a comprehensive papillary layer and the reticular layer, respectively. The papillary
review of the functional hydrogel as wound dressing still has not layer is rich in capillaries, lymphatic vessels, nerve endings, and
been reported. tactile corpuscles, and other receptors. The reticular layer
In this review, the process of skin wound healing and enriches in collagen fibers, elastic fibers, and reticular fibers,
parameters to evaluate the process are first discussed. Second, which mainly provide mechanical strength to the skin.23
the advanced functions of hydrogel dressings including The regeneration of wounds is divided into four continuous
antimicrobial activity, adhesion and hemostasis, anti-inflamma- processes, that is, hemostasis, inflammation, proliferation, and
tory and anti-oxidation, substance delivery, self-healing, stimulus remodeling7 (Figure 1). Almost within a few minutes after
response, conductivity, and wound monitoring feature are all trauma, platelet aggregation and fibrin clot formation will
classified and discussed. Third, the applications of these produce a hemostatic effect, and the process of wound healing is
functional hydrogel wound dressings in various wounds, such rapidly transferred into the inflammatory stage. At this stage,
as incisional wound and excisional wound as well as chronic inflammatory cells such as neutrophils (a kind of white blood
wounds like infection, burn, and diabetic wounds, are cell) and monocytes are recruited to the wound site and
12688 https://doi.org/10.1021/acsnano.1c04206
ACS Nano 2021, 15, 12687−12722
Figure 2. Advanced functions appeared in hydrogel wound dressing.
differentiate into macrophages.24 The resulting inflammatory Given the complexity of the wound healing process and the
response can not only remove foreign bodies, bacteria, and number of cells and cytokines involved, there are many factors
damaged endogenous tissues but also secrete chemokines and affecting wound healing. Therefore, evaluation parameters in
growth factors (GFs) to further attract cells. The number of wound healing are also numerous. At first, the wound closure
neutrophils usually reaches a peak within 24 to 48 h after injury rate is the most intuitive parameter to show the speed of wound
and decreases significantly after 3 days. As white blood cells healing.
leave, macrophages continue to clear debris and secrete GFs and In the inflammatory stage, appropriate inflammation is
proteins, attracting immune system cells to the wound to conducive to the recruitment of inflammatory cells.26 There
promote tissue repair,25 thereby guiding the healing process into are also some studies to further confirm the anti-inflammatory
the proliferation phase. In the proliferation phase (within 2 to 3 properties of hydrogel dressings in promoting wound healing
days after the wound generated), fibroblasts and keratinocytes at through some inflammation-related cytokines such as TNF-
the wound surface generate some light pink tissue to fill the α,27−30 TGF-β, IL-1,27 IL-6,31,32 and CD 68.33
defect, which is called granulation tissue because its shape is The formation of granulation tissue is also used as an indicator
similar to granulation. The granulation tissue mainly contains to evaluate wound healing. Most literature believes that thicker
inflammatory cells, fibroblasts, and some new capillaries. granulation tissue will transport more nutrients and build a
Simultaneously with the formation of granulation tissue, the larger volume frame for subsequent repair,34−37 but some
basal cells around the defected tissue continue to proliferate and reports state that the thicker granulation tissue shows the
migrate to the wound surface to form new epithelial cells. When precursor of partial scar healing. However, granulation tissue
the whole wound was covered with the epithelial cells, it marked changes dynamically during wound healing, and different
the completion of re-epithelialization, while the scar epithelium thicknesses may exist at different times, so proper thickening
will be formed if the epithelialization is completed after the should be beneficial, but excessive thickening may lead to poor
granulation tissue completely fills the defect. On the other hand, healing.
collagen will be deposited because the production of collagen Since the completion of re-epithelialization means that wound
(mainly type III collagen) at the wound site is higher than the healing enters the next stage, the remodeling phase, it is also a
decomposition. Meanwhile, the endothelial cells of the vascular particularly important indicator in the healing process. A large
wall break through the basement membrane to split into vascular number of studies have revealed that the hydrogel dressing
buds and further develop into microvessels or capillaries, which achieves a better healing effect by promoting re-epithelializa-
exist in the granulation tissue. Subsequently, the wound repair tion.34,38,39 Some cytokines such as epidermal growth factor
process turns to the final remodeling stage, collagen production (EGF) are also used to further evaluate epidermal production.28
and decomposition gradually tend to balance, and gradually The metabolism of collagen participates in the whole process
changes from type III collagen to type I collagen. The of wound repair and the regenerated collagen constitutes an
arrangement of collagen also tends to be more consistent, important part of the repaired wound, so its importance is
resulting in increased strength of the new tissue. The number of obvious. On the other hand, the strength of the repaired tissue
capillaries also reduced, and a few capillaries are converted into mainly depends on the orientation of the regenerated collagen.
small arteries and veins. Some skin appendages such as hair, Therefore, a large number of reports suggest that more collagen
sweat glands, and sebaceous glands may regenerate. The deposition35,40−42 during the proliferative phase, and a more
previously formed matrix slowly shifts toward the formation of consistent collagen trend43 in the remodeling phase indicates
functional skin or semi/nonfunctional scar tissue. better wound healing efficiency.
ACS Nano 2021, 15, 12687−12722
Table 1. Functional Classification of Hydrogel Wound Dressings
function functional components
ACS Nano
antibiotics and other amoxicillin,30,51 ampicillin,52,276,277 tetracycline,53−55,278−280 doxycycline,35,56,57 gentamicin,58,59,281−283 neomycin,284 ciprofloxacin,60−62 moxifloxacin,63,64 chloramphenicol,65
antibacterial drugs sulfadiazine,66 linezolid,67 povidone-iodine,68,285 chlorhexidine acetate,42,69,70 triclosan,71 simvastatin,72 salicylate73
inorganic metals and Ag,92−101 Au,80,81 zinc,82−86,104 copper,87−89 Ag/curcumin,102 Ag/graphene,103 Ag/sulfadiazine,66 Ag/Au,81 Ag/zinc,85 Ag/iron,84 ZnO/CS,86 Zn-penicillin,52 ZnO/mesoporous
metal oxides silica,53 ZnO/GO,83 CuS/CuO,105 Cu/metal organic framework,88 CuS/mesoporous silicon88
antibacterial photothermal CNTs,57,107 GO,35,49,108 PDA,60 grape seed extract,45 cypate106
property antibacterial
photodynamic MoS2,111 g-C3N4@AuNPs,110 Fe3O4@MoS2-Ag,112 tannic acid/Ag,116 selenoviologen/polythiophene286
antibacterial
cationic polymer CS/gelatin,118 CS/konjac glucomannan,119 CS/lignin/PVA,120 CS/PVP/agar,121 CS/carbon dots,122 CS/PF127,123 CS/PEG,125 poly(aminoethyl),127 antimicrobial
peptides106,128−131
cationic polymer CS,50,119,137 quaternized CS,36,125 EPL138
aldehyde group oxidized dextran,137 aldehyde-terminated PF-12750 and PEG139
adhesion polymers containing SA,136 N-acryloyl 2-glycine,150 HA147
carboxyl groups
polyphenol dopamine,35,49,57,74,143,144,104,148,149 3,4-dihydroxybenzaldehyde,144 dihydrocaffeic acid,51 pyrogallol147
others sulfydryl,140 long-chain alkyl groups,124,137,141 gum arabic,58,151 hydrogen bonding287
cationic polymer CS,86,152 cationic polypeptides,132 quaternization CS,155 quaternized hydroxyethyl cellulose/mesoporous silicon foam153
anion SA,136 hyaluronic acid,288 montmorillonite289
hemostasis
metal Ca2+,159 Fe2O3,290 ZnO,291 Ag NPs292
silicon-based materials zeolite,293 mesoporous silicon foam,153 montmorillonite,289 kaolinite290
natural polyphenols tea polyphenols,161 resveratrol,162 anthocyanins,163 flavonoids164
curcumin curcumin/2-hydroxypropyl-γ-cyclodextrin,175 nanocurcumin,176 curcumin NPs/gelatin microspheres,177 curcumin/PF127 micelles50
12690
antioxidant, anti-
inflamm-atory DA gelatin-DA/CS/CNT,57 HA-DA/GO,35 gallic acid43
others honey,165 aloe vera,166,167 acacia gum,168 sericin,169,170 ferulic acid,38 quercetin,171 bletilla striata polysaccharide,28,172 astragaloside IV,173 Hippophae rahmnoides L. extract,174
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Polyaniline,36 aniline tetramer,30 SOD,179 prostaglandin E2,26 thrombin-derived peptide TCP-25,131 citrate,89 povidone-iodine180
controlled delivery cells ADSCs,147,167,183−186 BMSCs,187−190 umbilical cord mesenchymal stem cells,27 L929 fibroblast,191 keratinocytes/fibroblasts,192−194 endothelial progenitor cells,195,196 human
microvascular endothelial cells48
cytokines FGF,32,198−202 FGF-2,37,204,205 FGF/EGF,203 EGF,39,67,206,207 EGF/VEGF,208 VEGF,124,147,162 KGF,210 platelet-derived GF BB,90 interleukin-8/macrophage inflammatory protein-
3α,211 SDF-1,212 rhGM-CSF213
gas NO,44,214−216 O2217−219
others miR-223-microRNAs,31 feather keratin,220 neurotensin,221 laminin mimetic peptide SIKVAV,41 boron,223 proline hydroxylase inhibitor224
self-healing hydrogen bond tannic acid,230 COOH294
Schiff base carboxymethyl CS/oxidized cellulose nanocrystal,236 hydrazide-modified HA/benzaldehyde terminated F127,237 quaternized CS/benzaldehyde-terminated PF12750
metal coordination phosphate/Ag,238 Ag-SH coordination,77 Fe3+/COOH,90 Fe3+/DA29,295
host−guest interaction tripeptide Phe-Gly-Gly ester derivative (FGG-EA)/cucurbit[8]uril,232 cyclodextrin/amantadine,234 cyclodextrin/silk fibroin235
others electrostatic interaction,231 acylhydrazone bonds,42 phenylboronate ester,191 dopamine35,74
stimulus response thermoresponse NIPAM,32,61,89,189,190,204,212,240 NIPAM/Ag@rGO,79 PEG-PCL-PEG,243,244 PLGA-PEG-PLGA,245 PEG-PLGA-PEG,246 PF127,50,80,177,202,210 polyisocyanopeptide,247
ethylcellulose,95 hydroxybutyl CS67
pH response tannic acid/metal ions,251,252 schiff base,191,253 electrostatic interaction, hydrogen bonds and π−π stacking,106 carboxyl/metal ions133,254
photoresponse photothermal and photodynamics antibacterial, GO/malachite green carbinol base255
multiresponse PDA/glycol chitosan (photo/thermoresponse),60 PDA/cellulose (photo/pH-response),55 Schiff base/phenylboronate ester (pH/glucose response)191
conductivity organic polymer polyaniline,36 aniline tetramer,30,269 polypyrrole,270,296 polythiophene,271 Ag/polyaniline74
inorganic nanomaterials CNT,57,107 GO35,108,178
wound monitoring pH responsive color-changing mesoporous resin beads (pH monitoring),272 temperature sensor (infection diagnosis),273,274 phenol red/glucose oxidas/horseradish peroxidase (pH/
glucose monitoring)275
Review
ACS Nano 2021, 15, 12687−12722

https://doi.org/10.1021/acsnano.1c04206
Figure 3. Antibacterial hydrogel in wound healing application. (A) Ag-Au NPs composite chitosan-based hydrogel for bacteria-infected wound
repair. Reprinted with permission from ref 81. Copyright 2017 American Chemical Society. (B) A conductive self-healing adhesive
nanocomposite hydrogel dressing based on Schiff base of N-carboxyethyl chitosan and PF127 and CNTs was encapsulated for photothermal
antibacterial. Reprinted with permission from ref 107. Copyright 2020 Elsevier. (C) A hydrogel dressing containing PDA nanoparticles loaded
with ciprofloxacin not only exerts near-infrared-induced photothermal effect of PDA but also realizes the synergistic antibacterial effect by
photothermal response release of drugs. Reprinted and modified with permission from ref 60. Copyright 2019 Elsevier. (D) Cationic short
peptides-functionalized amino acid-derived pseudoprotein-based hydrogel for antibacterial wound repair. Reprinted and modified with
permission from ref 132. Copyright 2019 American Chemical Society.
The regeneration of blood vessels mainly involves the Besides, perfect wound healing often involves the regener-
proliferation and remodeling stage of wound healing. When ation of some dermal appendages during the remodeling phase.
granulation tissue is produced, the microvessels or capillaries In addition to blood vessels, the regeneration of hair follicles is
present in it were responsible for transporting oxygen and also an indicator of better repair.27,43
nutrients to the wound site. On the other hand, local blood
supply also plays an important role in the absorption of necrotic ADVANCED FUNCTIONS IN HYDROGEL WOUND
substances and the control of local infection. It can be stated that DRESSINGS
the regeneration of blood vessels is essential for wound healing.
Among most wound healing research, blood vessel regeneration As a wound dressing, hydrogels initially only play a role of simple
is mentioned.26,44−47 There are also some studies to further physical isolation and creating a moist environment, but with the
confirm the properties of materials to promote angiogenesis increasing clinical requirements for wound repair, more and
through some cytokines related to angiogenesis such as vascular more requirements for material performance were proposed,
endothelial growth factor (VEGF)48−50 and CD31.29,30,33 and with the deepening of basic research, more hydrogel
ACS Nano 2021, 15, 12687−12722
dressings with enhanced single/multiple biological functions are properties. Besides, some other metallic elements are also used
beginning to appear (Figure 2). In this section, we discuss the in wound dressings as antimicrobial ingredients. Copper sulfate
recent advances in hydrogel wound dressings from the and copper oxide105 have been shown to promote healing in
perspective of functional modification, and the related content healthy and diabetic BALB/c mice.89 But at the same time, the
is summarized in Table 1. toxicity level of copper ions is class 3 (moderately toxic), so
Antibacterial Hydrogel Wound Dressing. Bacterial some methods were developed to reduce the potential toxicity of
infections are the most common and inevitable challenge to copper ions, such as compounded copper into metal organic
wound healing. When a wound becomes infected, the bacteria framework nanoparticles (HKUST-1 NPs) or use mesoporous
may cause a continuous inflammatory response in the infected silicon dioxide to modify CuS nanoparticles.88
site, which will further delay the healing process during the The resistance of antibiotics and the biological toxicity or the
inflammatory phase. For severe inflammation, it often leads to potential for long-term retention of inorganic metal antimicro-
unsuccessful wound healing and can even result in complica- bials has prompted researchers to try to find better antimicrobial
tions, including sepsis. Although antibiotics can be used strategies. Photothermal therapy is a therapeutic method by
clinically to achieve good infection control, the problem of converting light energy into heat. The common materials that
bacterial resistance is becoming increasingly serious. Therefore, can possess photothermal ability mainly include metal materials
the search for better antibacterial strategies has become a topic such as gold, Ag, tungsten, and copper87,88 as well as carbon-
of great concern. Thus, the following section will focus on based materials such as carbon nanotubes (CNTs) and GO.35,49
describing the research progress of various antibacterial Besides, photothermal agents such as polydopamine (PDA),60
hydrogel dressings on wound healing by category. grape seed extract,45 and cypate106 have also been reported
So far, antimicrobial drugs remain the preferred strategy for recently. Our research group has prepared a series of
clinical treatment of infected wound, and a large number of multifunctional hydrogels with photothermal antibacterial
drugs have been reported to be encapsulated into hydrogels for activity based on CNTs,57,107 and GO,35,108 respectively. And
preparing antimicrobial wound dressing, including antibiotics it is worth noting that the hydrogels in both systems also contain
like amoxicillin,30,51 ampicillin,52 tetracycline,53−55 doxycy- the photothermal component PDA. As shown in Figure 3B, we
cline,35,56,57 gentamicin,58,59 ciprofloxacin,60−62 moxifloxa- developed a multifunctional nanocomposite hydrogel with good
cin,63,64 chloramphenicol,65 sulfadiazine,66 linezolid67 and photothermal antibacterial properties based on N-carboxyethyl
some other antibacterial drugs such as povidone-iodine,68 chitosan (CEC), benzaldehyde-terminated Pluronic F-127
chlorhexidine acetate,42,69,70 triclosan,71 simvastatin,72 and (PF127-CHO) and CNTs, which has been proved to have
salicylate.73 great potential as photothermal therapy for infected wounds
Inorganic metal NPs, including silver (Ag),74−79 gold,80,81 through in vivo animal tests.107 Furthermore, Gao et al. recently
zinc,82−86 copper,87−89 and other metal-containing NPs,90,91 developed a strategy that combines near-infrared (NIR) light-
have been widely explored for potential antibacterial applica- induced antibiotic release with photothermal effects (Figure
tions. Although some of the biotoxicity problems associated with 3C).60 In addition, by mimicking the way in which biological
the use of metal as biomaterials and some of the potential risks of enzymes (such as peroxidase, oxidase) generate ROS to achieve
long-term retention have not been addressed, it still cannot stop sterilization, while avoiding the disadvantages of high cost and
them from being one of the most used antimicrobials agents complex conditions in production and poor catalytic stability of
except for antibiotics. Ag has been known for many years to be a biological enzymes, nanozymes have become promising
useful antimicrobial agent with broad-spectrum activity and alternatives to fight against bacteria. Metal-based compounds,109
compatibility with mammalian tissues, and numerous proposals carbon-based nanomaterials,110 transition-metal dichalcoge-
have been made to incorporate Ag into wound dressings to nides/peroxides/oxides,111,112 single-atom nanozymes (SA-
obtain bactericidal properties. Early Ag wound dressings were zymes),113 and metal−organic frameworks (MOFs)-based
mostly physical coating hydrogel systems of silver nanoparticle compounds114 have been widely developed.115 Some of them
(Ag NPs), which was based on a range of natural or synthetic have been applied to skin wound repair. For example, hydrogels
polymers such as chitosan (CS),92,93 gelatin,94 cellulose,95 containing MoS2 nanoenzymes have been shown to convert
xylitol,96 κ-carrageenan,97 poly(vinyl alcohol) (PVA),98 poly- H2O2 into ·OH with higher bactericidal efficiency, which can
(vinyl pyrrolidone) (PVP),99 PAM,100 and 2-acrylamide-2- realize antibacterial and repair of infected wounds.111 Besides, in
methylpropanesulfonic acid sodium salt,101 and others. In addition to generating hydroxyl radicals, Au nanoparticles
addition to exerting antibacterial properties alone, Ag is also integrated ultrathin graphitic carbon nitride (g-C3N4@
used in combination/synergy with various substances such as AuNPs),110 Fe3O4@MoS2-Ag,112 tannic acid chelated Ag
curcumin,102 graphene,103 sulfadiazine,66 and other metal such nanoparticles (TA-Ag NP),116 and others also exert long-term
as gold,81 zinc,85 or iron84 to achieve better antibacterial effects. antibacterial activity due to the release of Au, Ag and other
For example, Li et al. prepared a CS-based hydrogel particles. However, PDT and nanozymes antibacterials also have
encapsulated with Ag−Au composite NPs, showing good some problems such as low catalytic activity, limited specificity,
antibacterial activity (Figure 3A).81 After Ag, zinc is the most and long clinical conversion time.
widely studied metal particle used in antibacterial wound Some cationic substances have also been shown to have
dressings. Kumar et al., respectively, applied zinc oxide in CS and antibacterial activity, because the positive charges among them
chitin to obtain a series of freeze-dried hydrogels with easily attract bacteria with surface negative charge and then kill it
antibacterial properties.86,104 Then, Ag/Ag@AgCl/ZnO hybrid by damaging bacterial cell membrane.117 As the only natural
nanostructures,85 Zn-penicillin complex, ([Zn(pin−G)(Cl)]· cationic polysaccharide, CS has been used to combine with
6H2O),52 zinc oxide impregnated mesoporous silica (ZnO- gelatin,118 konjac glucomannan,119 lignin/PVA,120 PVP/
MCM-41),53 and zinc oxide quantum dots (ZnO QDs)- agar,121 carbon dots,122 PF127,123 four-armed benzaldehyde-
modified thin-layer graphene oxide (GO)83 have all been terminated PEG,124 and other natural or synthetic polymers as
extensively studied and demonstrated to have good antibacterial antimicrobial excipients. There are also some methods to
ACS Nano 2021, 15, 12687−12722
Figure 4. Hydrogel wound dressing with tissue adhesion function. (A) An Mfp5-mimetic polymer (dopamine-modified ε-poly-L-lysine-
polyethylene glycol) hydrogel dressing prepared by the inspiration of Mfp-5, an important component of mussel adhesion protein in the plaque
of mussel. Reprinted and modified with permission from ref 146. Copyright 2017 Wiley-VCH. (B) An adhesive hydrogel dressing based on
gelatin-grafted dopamine via oxidative coupling of catechol groups with polydopamine coated CNTs. Reprinted and modified with permission
from ref 57. Copyright 2019 Elsevier. (C) A bioadhesive hydrogel prepared by skin secretion of Andrias davidianus and the difference in
adhesion between the hydrogel and cyanoacrylate and fibrin glue were studied by (g) edge-to-edge adhesion test, (h) standard lap shear test,
and (i) three-point bending test. Reprinted and modified with permission from ref 141. Copyright 2019 Wiley-VCH.
enhance the antibacterial effect by further grafting cations such that surface peptide modification can enhance the antibacterial
as quaternary ammonium,125,126 and poly(aminoethyl)127 onto ability of hydrogel (Figure 3D).132 Beside, hydrogel dressings
the main chain of CS. In addition, for example, polyethylenimine with protamine nanoparticles,133 and silk sericin134 have also
(PEI), cationic peptides were also added into the hydrogel been proved to possess antibacterial properties through the
dressing to exert antibacterial effect.106,128−131 Zhu et al. also cationic role.
developed an amino acid-derived pseudoprotein hydrogel Adhesive and Hemostatic Hydrogel Wound Dressing.
dressing consisting of polyester amide and three cationic short Hemostasis occurs at the earliest stage of wound healing.
peptides (RGDK, RRRFK, and RRRFRGDK) and confirmed Therefore, hydrogel dressings with the hemostatic property have
ACS Nano 2021, 15, 12687−12722
Figure 5. Hydrogel wound dressing with hemostatic function. (A) (a) Illustration of the hemostasis and antibacterial process of the quaternized
hydroxyethyl cellulose/mesocellular silica foam hydrogel sponge (QHM); (b) composite hydrogels promotes adhesion and aggregation of
blood components; and (c) schematic image of the hemostatic effect of this QHM hydrogel sponge in a model of fatal liver defect. Reprinted and
modified with permission from ref 153. Copyright 2019 American Chemical Society. (B) An injectable antimicrobial conductive cryogel based
on CNTs and glycidyl methacrylate functionalized quaternized CS for lethal noncompressible hemorrhage hemostasis and wound healing. (a)
Schematic diagram of cryogel preparation; (b) schematic diagram of cryogel triggering hemostasis; (c) statistical chart of quantitative
experimental data of hemostasis time and amount of bleeding in mice with liver injury; and (d) in rabbits with lethal incompressible
hemorrhage. Reprinted with permission under a Creative Commons Attribution 4.0 International License from ref 155. Copyright 2018
Springer Nature.
positive significance in promoting wound healing. Studies have through electrostatic interaction. Furthermore, the cationic
shown that the hemostatic property of hydrogels is not only quaternary ammonium group was grafted on the backbone of CS
supported by the physical sealing but also the enrichment of to achieve better adhesion.36,125 ε-Polylysine (EPL) is also a
coagulation factors through the absorption of wound cationic polymer at physiological pH value, showing excellent
extract.70,132 But as a basic function, hemostasis is often used biological adhesion to various biological surfaces.138 It has also
in combination with other functions. For example, combining been reported that free radical-induced covalent bonding during
with the adhesiveness of bioadhesive hydrogels, the wound can the formation of in situ hydrogels by photo-cross-linking can also
be sealed to provide hemostasis, and the adhesive hydrogels can provide a certain degree of tissue adhesion.31,129
also be seamlessly attached to the wound site for a long time, In addition, a common method for preparing adhesive
avoiding the potential risk of infection caused by the contact hydrogels is to incorporate functional groups with adhesive
between the wound and the external environment.135 Therefore, properties to their structures, which can interact and bind with
adhesive hydrogels were first discussed. In the following section, the surrounding tissues. The aldehyde group can be cross-linked
a review of hydrogels that perform hemostatic effects by other with the amino group on the tissue via a Schiff base reaction,
means is summarized. resulting in strong tissue adhesion. A variety of adhesive
Adhesive hydrogels based on dextran,125 sodium alginate hydrogels based on the oxidized SA and dextran, aldehyde-
(SA),136 and CS50,119,137 have been reported because bio- terminated PF-127 and PEG have been prepared.50,137,139 The
polysaccharides show a certain adhesion. CS with a certain enhancement of tissue adhesion by mercapto-tissue reactions
positive charge can enhance the adhesion to biological tissues has also been reported.140 Besides, grafting some long-chain
ACS Nano 2021, 15, 12687−12722
alkyl groups on the main chains of macromolecules can produce quaternary ammonium and blood cells that can trigger
hydrophobic interactions with the alkyl groups in subcutaneous hemagglutination and platelet aggregation, a moderate amount
adipose tissue, thus achieving adhesion effect.124,137,141 of mesoporous silicon foam (9.82 w/w %) was testified to
Inspired by the super adhesion of marine mussels in the activate FXII further. Thus, QHM hydrogel can significantly
humid environment, the underwater wet adhesion theory based reduce the in vitro plasma clotting time to 59 ± 4% by these
on dopamine is widely known, and a large number of dopamine- synergistic effects (Figure 5A).153 In response to the irregular
based biological tissue adhesive hydrogels have been devel- shape and incompressible bleeding, our group reported an
oped.49,74,104,142−145 For example, an in situ formed biomimetic multifunctional cryogel based on glycidyl methacrylate function-
dopamine-modified EPL-PEG-based hydrogel (PPD hydrogel) alized quaternization CS enhanced by CNT. These cryogels
was developed by using horseradish peroxidase (HRP) cross- have been proved to have good mechanical capacity, rapid blood
linking. Due to the synergistic effect of catechol-Lys, the PPD trigger shape recovery, and high blood uptake ability. In
hydrogel has a good wet tissue adhesion property (Figure addition, the cryogel showed excellent hemostatic performance
4A).146 Shin et al. also prepared catechol/pyrogallol grafted in mouse liver injury and lethal incompressible hemorrhage
hyaluronan (HA) hydrogel patches, serving as drug-loaded model of rabbit liver (Figure 5B).155 Furthermore, porous
ready-made tissue tape for promoting wound healing.147 In the cryogels formed by low-temperature oxidative cross-linking of
past two years, our research group has also made progress in the dopamine with chitosan,156 quaternary ammonium chitosan,157
direction of dopamine-based adhesive hydrogels.35,51,57 For and gelatin158 have been proved not only to have an excellent
example, Figure 4B shows a gelatin-grafted dopamine-based hemostatic effect but also to promote the final tissue repair.
CNT-loaded hydrogel, which not only possesses good adhesion As a blood coagulation factor, calcium ion can promote blood
performance but also has multiple functions such as injectable, clotting. Therefore, Zhou et al. prepared an acetate CS/CaCO3
antibacterial, conductive, hemostatic, and antioxidant, showing hydrogel. The H+ of acetate CS reacted with CaCO3 to release
great potential to promote better healing of infected full- Ca2+ after absorbing water, which not only enhanced the
thickness skin wounds.57 At the same time, Lu’s group reported strength of the hydrogel but also participated in hemostasis.159
a series of adhesive hydrogels based on the adhesion properties Anti-Oxidant and Anti-Inflammatory Hydrogel
of dopamine.39,148,149 By comparison, the average shear Wound Dressing. Inflammatory, the second stage of wound
adhesion of dopamine-enhanced tissue adhesive hydrogels can healing, focuses on the destruction of bacteria and the removal of
be increased by 10−30 kPa. debris. Proper inflammation is essential in wound repair, so
Besides, other bioinspired adhesive hydrogels were also controlling inflammation is an important feature of wound
prepared. For example, Deng et al. used the skin secretion of dressings. Excessive inflammation can lead to high oxidative
Andrias davidianus to prepare a bioadhesive hydrogel. The test stress, and a sharp increase in reactive oxygen species (ROS,
results showed that the shear adhesion of the adhesive hydrogel including superoxide anions, hydrogen peroxide, hydroxyl
(26.66 ± 8.22 kPa) was equivalent to cyanoacrylate synthetic radicals, and nitric oxide), will destroy cells by triggering chain
glue (40.71 ± 3.71) and was significantly higher than fibrin glue reactions, such as lipid peroxidation, or the oxidation of DNA
(3.76 ± 0.16 kPa) (Figure 4C).141 A kind of hydrogel based on and proteins. Antioxidants are substances that help to trap and
poly(N-acryloyl 2-glycine) and hydroxyapatite showed adhesion neutralize free radicals, thereby eliminating their damage to the
strength that up to 105 kPa, which is because of the synergistic body. Therefore, hydrogels with antioxidant properties can
interactions between carboxyl and the substrate surface and the obviously promote wound healing.160
enhanced contraction of poly(N-acryloyl 2-glycine) chains to As the most widely used natural antioxidant, polyphenol
adherent surfaces facilitated by hydroxyapatite nanoparticles.150 antioxidants exhibit better stability and are better able to bear
Inspired by the Sundew, a carnivorous plant, gum arabic was also prolonged storage. Common natural polyphenols such as tea
used in the hydrogel to play a role of adhesion.58,151 polyphenols,161 resveratrol,162 and anthocyanins,163 and some
In addition to relying on the adhesive properties of the flavonoids164 have been loaded into hydrogels to exert an
hydrogels to seal the wound for hemostatic effect, several other antioxidant role in promoting wound healing. In addition,
hemostatic hydrogels have also been reported. In 2012, Kumar et honey,165 aloe vera,166,167 acacia gum,168 sericin,169,170 ferulic
al. prepared a series of nanocomposite hydrogel bandages based acid,38 quercetin,171 bletilla striata polysaccharide,28,172 astraga-
on CS or chitin, demonstrating that cationic CS interacts with loside IV,173 and Hippophae rahmnoides L. extract174 also
negatively charged blood cells and activates platelets to promote showed an anti-inflammatory effect during wound healing.
clotting.86 Subsequently, Fan et al. prepared CS/gelatin/PVA Curcumin, a low molecular weight polyphenolic compound
composite hydrogel and further elaborated on the hemostatic isolated from ginger plants, has been shown to possess anti-
mechanism of the activation of platelet by CS to produce inflammatory activity comparable to steroid or nonsteroidal
coagulation factor and physical sealing of hydrogel.152 Further drugs. However, curcumin has poor water solubility and
studies have shown that grafting positively charged components stability, which greatly limit its further application in vivo. A
on the hydrogels can improve the interaction between hydrogels variety of strategies have been developed to overcome these
and platelets, blood cells, and plasma fibronectin through shortcomings and to capsulate curcumin into hydrogel dressings
electrostatic attraction, induce platelet activation and blood cell in recent years.33 For example, Wathoni et al. prepared curcumin
aggregation, and thus achieve the effect of promoting composite 2-hydroxypropyl-γ-cyclodextrin hydrogel, which
coagulation. In addition to CS, such cationic constituents also showed enhanced water solubility and stability of curcumin.175
include quaternary ammonium groups153,154 and cationic Li et al. prepared nanocurcumin and loaded it into
polypeptides.132 Wang et al. prepared a quaternized hydrox- carboxymethyl CS/SA hydrogel, which greatly improved the
yethyl cellulose/mesoporous silicon foam hydrogel sponge bioavailability of curcumin.176 Liu et al. loaded curcumin NPs
(QHM) for hemostasis. QHM hydrogel with hydrophilic and into gelatin microspheres and further develop an efficient and
high-water absorbability can induce blood cells to enter its safe system for promoting skin wound healing in diabetic
network. In addition to electrostatic interaction between patients (Figure 6A).177 Qu et al. prepared curcumin micelles
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Figure 6. Antioxidant and anti-inflammatory hydrogel dressings. (A) Schematic representations of curcumin NPs/gelatin microspheres
(CNPs@GMs) loaded hydrogel dressing for diabetic wound repair. Reprinted and modified with permission from ref 177. Copyright 2018
American Chemical Society. (B) Schematic diagram of the preparation of the electroactive and antioxidative PDA-reduced GO (rGO)-
encapsulated chitosan and silk fibroin (SF) (rGO-CS/SF) scaffold. Reprinted with permission from ref 178. Copyright 2019 American
Chemical Society. (C) Synthesis scheme of oxidized HA-grafted-aniline tetramer/CEC hydrogel and its application in full-thickness skin
wound. Reprinted with permission from ref 30. Copyright 2019 Elsevier.
and combined them into hydrogels, which significantly biocompatible polymer CEC and oxidized HA-grafted-aniline
improved the drug loading and encapsulation ratio of curcumin, tetramer (OHA-AT) polymer are mixed and constructed the
while the sustained release effect also provided sustained conductive antioxidant OHA-AT/CEC hydrogel through the
antioxidant effect of curcumin in vivo (Figure 8C).50 Schiff base reaction between amino and aldehyde (Figure 6C).
Due to the presence of catechol structures, dopamine The hydrogel shows a suitable gelation time, stable rheological
molecules show good antioxidant activity. Inspired by the self- properties, high swelling ratio, and suitable in vitro biode-
polymerization of dopamine in the hydrogen peroxide/HRP gradation and electrical activity. When stable DPPH free radicals
system and the ability to form a coating on any surfaces under are used as compounds for testing the oxidation resistance of the
alkaline conditions, our research group prepared a series of dressings, aniline tetramer (AT) with good redox properties
multifunctional antioxidant hydrogel dressings based on gelatin/ exhibits excellent DPPH scavenging ability.30
CS/CNT and HA/GO, respectively. Good antioxidant activity In addition, some endogenous factors were also added to the
of hydrogel was verified by the usually used α,α-diphenyl-β- hydrogel to make the dressing have anti-inflammatory ability.
picrylhydrazyl (DPPH) free radical capture experiment. At a For instance, SOD can catalyze the decomposition of superoxide
concentration of about 5 μg/mL of lyophilized hydrogels, a free free radicals into H2O2 that was then converted into water and
radical scavenging ratio of more than 90% can be achieved.35,57 oxygen. Therefore, Zhang et al. developed a SOD contained
At the same time, Tang and Gao et al. also prepared dopamine- wound dressing that could remove excessive O2− and promote
based antioxidant hydrogels and verified the positive role of their the healing process of chronic wounds.179 Prostaglandin E2 is a
antioxidant properties in wound repair (Figure 6B).60,178 lipid signaling molecule that acts as both an inflammatory
Dopamine-like phenolic compound gallic acid has also been mediator and a fibroblast regulator. So, Li et al. prepared a CS/
shown to have a good antioxidant effect.43 Moreover, based on prostaglandin E2 hydrogel, which prolonged the release of
polyaniline36 (Figure 10A) and aniline tetramer,30 our research Prostaglandin E2, and demonstrated that the hydrogel achieved
group prepared different antioxidant hydrogel systems. The better repair by balancing inflammation, angiogenesis, and
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Figure 7. Hydrogel with controlled delivery property for wound dressing. (A) A schematic diagram of preparation for an ADSC-loaded
ultravior-induced in situ forming hydrogel based on methacrylated gelatin and methacrylated HA. Reprinted and modified with permission
from ref 184. Copyright 2017 Elsevier. (B) The preparation of a biomimetic CS/alginate (CS-SA) self-assembling microcapsule hydrogel
encapsulated with bFGF and EGF. Reprinted and modified with permission from ref 203. Copyright 2019 Elsevier. (C) Illustration of the
preparation process for NO-carried prussian blue nanocubes and the use of NIR responsive NO-release for wound healing. Reprinted and
modified with permission from ref 44. Copyright 2019 American Chemical Society. (D) Schematic illustration of the formation for GelMA
hydrogel contained miR-223 5p mimic and hyaluronic acid nanoparticles. Reprinted and modified with permission from ref 31. Copyright 2019
Wiley-VCH.
fibrosis remodeling during the healing process.26 TCP-25 is a (NIPAM)), verifying the antioxidant properties of citrate by
thrombin-derived peptide with antibacterial property, and it can free radical scavenging experiments of 2,2′-azino-bis(3-ethyl-
lead to decreased downstream immune activation. Puthia et al. benzthiazoline-6-sulfonic acid),89 and also confirmed that
developed a TCP-25-based hydrogel scaffold that mimics the povidone-iodine shows obvious anti-inflammatory effect due
endogenous role of host defense peptides derived from to the free radical scavenging effect.180 Another study also
trauma.131 demonstrated that WO3 can achieve anti-inflammatory effects
Besides, Xiao et al. prepared a hydrogel containing poly- during wound healing by inhibiting tumor necrosis factor α
(polyethylene glycol citrate-co-N-isopropylacrylamide (TNF-α).181 The positively charged amino acid residues of
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chemokines can also bind to the negatively charged sulfate group Growth factors are a class of important bioactive proteins,
of GAGs through electrostatic interaction, thereby reducing which play an important role in regulating cell function and
chronic wound inflammation during the treatment.182 maintaining tissue homeostasis. Numerous studies have shown
Hydrogel with Controlled Delivery Property for that topical treatments such as EGF, fibroblast growth factor
Wound Dressing. The porous structure of hydrogels makes (FGF), keratinocyte growth factor (KGF), and nerve growth
them naturally suitable for loading a wide variety of substances factor enhance wound healing in primate models and clinical
and releasing them slowly at specific locations. Of course, drug trials.197 Conversely, the absence of relevant cytokines often
delivery should be the first one among the substances that results in delayed repair or even failure to heal the wound.
hydrogels can support. But most of the drugs delivered are Among all the GFs, EGF and FGF are the most commonly used
antibiotics, which we have covered in the antibacterial section. factors that encapsulated in hydrogel dressings for wound
Wound healing also requires cellular interactions among various healing. FGF plays an important role in angiogenesis, nerve
cell types, including keratinocytes, fibroblasts, endothelial cells, regeneration, bone regeneration, anti-inflammatory, wound
neutrophils, and macrophages, and is also regulated by the healing, and other aspects. However, a short half-life seriously
endogenous release of GFs, cytokines, and chemokines at the limits its application. So, many FGF encapsulated hydrogel
wound site. Therefore, local delivery of exogenous cells or wound dressings have been reported.32,198−200 For example,
cytokines showed a good advantage in promoting wound heparin-functionalized polymer hydrogel was prepared by
healing. combining positively charged bFGF with negatively charged
Among various types of stem cells, adipose-derived stem cells heparin through electrostatic interaction. Test results also
(ADSCs) are an effective source of cell therapy and have demonstrated that bFGF dose dependently accelerates wound
properties similar to mesenchymal stem cells. ADSCs can be healing (Figure 9B).201,202 After loading bFGF with thermo-
performed through simple minimally invasive surgery and are sensitive CS hydrogel, Kong et al. also double-loaded EGF with
less affected by the age of the donor. In addition, ADSCs can hydrogel and microsphere, which better simulated the differ-
secrete some necessary factors conducive to wound repair to ential release of bFGF and EGF, and achieved rapid healing
stimulate angiogenesis and re-epithelialization, so as to promote while avoiding the scar hyperplasia due to fibroblast
tissue regeneration. As a result, ADSCs have become the most proliferation caused by bFGF overexpression in the later stage
commonly used hydrogel-loaded cells.147,167,183 For example, (Figure 7B).203 Besides, FGF-2 is also loaded into different
Eke and coworks achieved in situ loading of ADSCs via photo- hydrogels and has been shown to promote wound healing by
cross-linking between methacrylate anhydride functional gelatin increasing the formation of dermal and granulation tissue,
(GelMA) and methacrylate HA, demonstrating that the vascular
angiogenesis, and re-epithelialization.37,204,205
regeneration of the stem cells contained hydrogel group
EGF is a polypeptide consisting of 53 amino acid residues that
increased three times compared to the stem cells-free hydrogel
promote the proliferation of epithelial cells and the synthesis of
group (Figure 7A).184 Wang et al. prepared different ADSCs
ECM, which is the basis for accelerating wound healing. It has
encapsulated hydrogels and detected significant increases in pro-
also been adopted by many reports.39,67,206 For example, semi-
angiogenic GF proteins such as PIGF, VEGF, and TGF-β.185,186
interpenetrating network hydrogels were synthesized from PAM
Bone marrow mesenchymal stem cells (BMSCs) have also been
shown to secrete TGF-β1 and bFGF, which can further and CS by free radical polymerization, and EGF is embedded to
differentiate into effector cells like keratinocytes, fibroblasts, increase the mitotic activity of hydrogels. The synthesized CS-
and endothelial cells, to accelerate wound healing and PAM hydrogel shows a successfully sustained-release effect on
strengthen vascularization,187 granulation tissue formation188 EGF for more than 5 days.207 There have also been studies that
and re-epithelialization.189 For example, Chen et al. prepared an encapsulate VEGF at the same time as EGF loading, and the
BMSCs loaded in situ forming hydrogel composed of PNIPAM common control release of them can also improve the effect of
and poly(amidoamine).190 Besides, hydrogel dressings loaded angiogenesis and re-epithelialization compared with the control
with human umbilical cord mesenchymal stem cells have also group or the group with a single GFs loading.208 VEGF is a
been reported.27 multifunctional molecule that has strong effects on the vascular
Fibroblasts play an important role in wound repair because system, including the ability to stimulate the growth of new
they produce extracellular matrix molecules (such as collagen I) blood vessels and increase vascular permeability and has been
and secrete essential GFs (such as VEGF). These fibroblast- widely used in hydrogel dressings in recent years.124 For
derived factors are necessary for endothelial cells to germinate, example, by combination with resveratrol, VEGF can simulta-
making the epithelium move toward the center of the wound neously inhibit the inflammatory response and promote
and promote wound healing. Zhao et al. prepared an L929 microvascular formation in burn wounds.162 Strong covalent
fibroblast loaded self-healing hydrogel.191 Hydrogels loaded interaction between catechol and various nucleophilic compo-
with human epidermal keratinocytes and dermal fibroblasts nents in the protein resulted in the sustained release of VEGF
were also reported to synergistically promote better wound from the hydrogel patch for 9 days and significantly increased
repair.192−194 microvascularization in the related tissues.147 Cyclic adenosine
Skin-derived extracellular matrix bioinks have been used for phosphate has long been recognized as a second messenger and
3D cell printing of simulated skin hydrogels, and it has been regulator of human keratinocyte proliferation. Therefore, one of
demonstrated that hydrogels combined with endothelial its lipophilic analogues, which has been shown to promote
progenitor cells195 can accelerate wound healing by accelerating wound healing, was also added to the hydrogels and showed
hemostasis, epithelialization, and angiogenesis.196 It was also significantly faster re-epithelialization.209 In addition, in the
found that the human microvascular endothelial cells (HMEC) process of wound healing, KGF,210 platelet-derived GF BB,90
loaded hydrogel possessed an obvious proliferative behavior. interleukin-8 and macrophage inflammatory protein-3α,211
More importantly, certain levels of VEGF were observed in stromal-derived factor-1 (SDF-1),212 and recombinant human
HMEC hydrogels, which led to the possibility of angiogenesis.48 granulocyte/macrophage colony stimulating factor (rhGM-
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Figure 8. Self-healing hydrogel wound dressing. (A) A self-healing hydrogel based on host−guest interaction, and cross-linkable
supramonomers. Reprinted and modified with permission from ref 232. Copyright 2017 American Chemical Society. (B) A double-cross-linked
hydrazide-modified HA (HAAD) and benzaldehyde terminated F127 (BAF127) hydrogel with dynamic acylhydrazone bonding and
micellization cross-linking. Reprinted and modified with permission from ref 237. Copyright 2018 American Chemical Society. (C) Self-healing
properties of quaternized CS/benzaldehyde-terminated PF127 hydrogel: (a) Schematic illustration of Cur-QCS/PF hydrogel and TEM image
of PF127-CHO micelles. Scale bar: 200 nm. (b) The mechanical property of QCS/PF hydrogel. Scale bar: 1 cm. (c−j) Self-healing property of
the hydrogels and (k) the rheological properties of the hydrogel when alternate step strain switched from 1% to 200%. Reprinted and modified
with permission from ref 50. Copyright 2018 Elsevier.
CSF)213 etc. also showed promoting effects by angiogenesis and hydrogel dressings improves the quality of granulation tissue and
re-epithelialization. increases the strength of healed wound by upregulating the
Studies have long confirmed that the vasodilatory action of deposition of the collagen.214 Schanuel et al. also verified that
NO can increase the blood flow of microvessels in wound when s-nitrosoglutathione (GSNO), the most commonly used
healing process, thus promoting the transport of nutrients and NO carrier, was loaded into PVA/PF127 hydrogel, the release of
cells to the injured site. The production of NO by macrophages NO increased the differentiation of myofibroblast.215 In
and other cell types can also promote wound healing by Champeau’s study, more than 5 days’ NO release from
increasing the expression of VEGF. In addition to the PAA:PF127/GSNO hydrogels in addition to leading the
antibacterial action we discussed above to promote wound increased angiogenesis, also increased the expression of TGF-
healing, studies also demonstrated that NO released from the β, insulin-like GF-I, SDF-1, and IL-10 genes in damaged
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tissue.216 In addition to GSNO, Su et al. successfully prepared a hydrogel dressings during wound healing. Therefore, the
hemin-modified Prussian blue nanocubes recently, which concept of self-healing hydrogels is proposed as a “smart”
possesses a strong affinity for NO gas. The thermal-induced material that can repair its own functional and structural
release of NO was realized due to the photothermal properties of damage.225,226 Most self-healing hydrogels are prepared based
Prussian blue (Figure 7C).44 on the strategy of constitutional dynamic chemistry, which
The availability of oxygen gets a profound effect on the repair involves dynamic and reversible chemical bonds in the
process. In addition to the role of superoxide free radicals in formation of a cross-linking network of hydrogels.227−229
preventing bacterial infections, oxygen also regulates angio- Although self-healing hydrogels have been reported in large
genesis, promotes cell proliferation and migration, and interacts numbers, their use in the repair of damaged skin tissue has only
with a variety of cytokines. It is also a prerequisite for the been developed in the last 5 years. Therefore, we will summarize
synthesis of hydroxyproline, which is a good component in the application of self-healing hydrogels in the repair of damaged
collagen fibers that produced during wound repair. It is tissues in this section.
estimated that a wound requires at least 20 mmHg of tissue Self-healing hydrogels can be divided into physical self-
oxygen tension to heal, while the oxygen tension of a nonhealing healing hydrogels and chemical self-healing hydrogels based on
wound is measured as low as 5 mmHg. Therefore, hyperbaric the healing mechanism. Physical self-healing hydrogels
oxygen therapy is an effective method to treat chronic hypoxia reconstruct networks by forming dynamically noncovalent
wounds. Researchers have prepared a kind of oxygenated interactions (including hydrophobic interactions, host−guest
hydrogel dressing based on perfluorocarbon chain-modified interactions, hydrogen bonds, crystallization, polymer−nano-
methacrylamide CS, which can carry oxygen to the wound and composite interactions, and multiple intermolecular interac-
maintain the enhanced local oxygen levels to improve local tions) between molecules, oligomers, or polymer chains. Liu et
hypoxia environment, eliminating the use of complex oxygen- al. prepared a composite double-network hydrogel with gelatin
ating set-ups.217,218 Besides, a light-responsive MoS2 QDs methacrylate and tannic acid, and the dynamic hydrogen
integrated hemoglobin-GelMA inverse opal microcarriers was bonding of tannic acid provided hydrogel good self-healing
prepared. Due to the photothermal effect of MoS2 QDs, larger function.230 Bacterial cellulose modified by positive and negative
and faster oxygen release could be achieved from hemoglobin- fragments was prepared, respectively, and a self-healing hydrogel
modified microcarriers after temperature increases.219 was prepared by forming an ionic interlocking system in the
In addition to the delivery systems described above, other buffer solution with pH of 7.4.231 Host−guest noncovalent
delivery systems are used to facilitate wound healing. For interactions between the tripeptide Phe-Gly-Gly ester derivative
example, upregulation of miR-223-microRNAs (miRNAs) (FGG-EA) and cucurbit[8]uril were also exploited to yield a
revealed macrophage polarization to an anti-inflammatory supramolecular hydrogel. Benefiting from the dynamic nature of
(M2) phenotype, so adhesive hydrogels of HA NPs containing supramolecular hydrogels, it can dissolve after exposure to the
miR-223 5p mimics were developed to control tissue-macro- FDA-approved drug memantine, making it easy to remove from
phage polarization during wound healing (Figure 7D).31 wounds (Figure 8A).232 Our group has also prepared some self-
In addition, some other functional substances like peptides or healing hydrogels based on host−guest interactions between
protein are also used in hydrogel dressings to play a specific role cyclodextrins and NIPAM,233 amantadine,234 or silk fibroin.235
in promoting wound healing. For example, a feather keratin However, chemical self-healing hydrogels are now more
hydrogel showed good histocompatibility.220 A neurotensin widely reported, and they form reconstruction networks through
loaded hydrogel plays the role of an inflammation regulator, dynamic covalent bonding, including phenylboronate ester,
reduces the expression of inflammatory cytokines TNF-α, and disulfide, imines, acylhydrazone, reversible radical reaction, and
promotes wound healing.221 By enhancing angiogenesis, re- reversible Diels−Alder cycloaddition. Among the many
epithelialization, and collagen deposition, a laminin mimetic chemical self-healing hydrogels, Schiff base (imines) structures
peptide SIKVAV-conjugated hydrogel has also been shown to account for a large proportion of the dynamic chemical bonds
promote wound healing.41 used in the reparation of self-healing hydrogel wound
In addition, organic-modified montmorillonite is used to dressings.34,36,50,51,119,124,137,139,143 In this section, common
enhance the physical strength of hydrogels.222 Boron is involved amino suppliers include modified/unmodified CS, various
in a variety of metabolic pathways, and it has also been shown to hydrazide-modified natural polymers, and common aldehyde
promote wound healing by increasing matrix metalloproteinase group providers include benzaldehyde group-modified synthetic
expression and keratinocyte migration.223 A hydrophobic small polymer chains and oxidized polysaccharide. For example,
molecule proline hydroxylase inhibitor is encapsulated in a Huang et al. prepared a self-healing hydrogel based on the Schiff
supramolecular polymer hydrogels. This leads to a brief base bond between the amino of a water-soluble carboxymethyl
upregulation of hypoxia inducible factor-1α, which causes the chitosan (CMC) and the aldehyde of an oxidized cellulose
deep tissue to regenerate in a manner similar to surface nanocrystal (DACNC), which can quickly form after the
regeneration.224 injection to irregular and deep burn wound and completely fill
Self-Healing Hydrogel Wound Dressing. In addition to the wound area. Finally, the dressing can be painlessly removed
in situ formation, adhesion, and other properties to achieve the by on-demand dissolving using amino acid solution.236
rapid hemostasis, the physical barrier formed by the presence of Hydrazide-modified HA (HAAD) and benzaldehyde termi-
hydrogels is also an important means to prevent the wound from nated F127 triblock copolymers (BAF127) were developed and
external bacterial infection. However, general hydrogels are prepared a double-cross-linked hydrogel with dynamic covalent
prone to breakage or fracture when exposed to external tension chemistry and physical micelle, which showed rapid gelation and
or tissue activity. In addition to causing deterioration of their shear thinning properties (Figure 8B).237 Our group also
own properties or even loss, breakage in hydrogels will further prepared a self-healing hydrogel based on quaternized CS
cause invasion of external bacteria and result in wound infection. (QCS) and benzaldehyde-terminated PF127, which can still
So, it is also important to ensure the structural integrity of maintain good mechanical properties after bending, compres-
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Figure 9. Stimulus-responsive hydrogel wound dressing. (A) A sprayable in situ forming skin temperature responsive hydrogel based on
poly(NIPAM166-co-n-butyl acrylate9)-PEG-poly(NIPAM166-co-n-butyl acrylate9) copolymer (PEP) and Ag NPs-modified reduced GO (Ag@
rGO, denoted as AG). The display pictures for the adjustable temperature sensitivity indoor (high temperature) and outdoor (low
temperature). Reprinted and modified with permission from ref 79. Copyright 2019 American Chemical Society. (B) A GFs loaded
thermosensitive heparin-PF127 hydrogel. The sol−gel transition allows aFGF and bFGF to be fully mixed with heparin-PF127 solution at 4 °C.
Then, when the GFs-heparin-PF127 solution was applied to a live wound at 37 °C, gelation was allowed and GFs was successfully loaded into
the heparin-PF127 hydrogel. Reprinted and modified with permission from ref 202. Copyright 2016 American Chemical Society. (C) A
schematic diagram of antimicrobial peptide-based nanofiber network self-assembly at neutral pH and response to acidic conditions to release
peptides for biofilm clearance and promote chronic wound healing. Reprinted and modified with permission from ref 106. Copyright 2019
American Chemical Society. (D) A dual photoresponsive hydrogel dressing containing both photothermal nanomaterial GO and photobase
reagent MGCB. In addition to adjusting temperature in response to NIR light, ·OH can also be released by MGCB molecule in response to UV
light, resulting in gradient of pH value. Reprinted and modified with permission from ref 255. Copyright 2017 American Chemical Society.
sion, stretching, twisting, and knotting. A rhodamine B stained rheological recovery test (Figure 8C).50 Meanwhile, dynamic
hydrogel was cut into two pieces and was healed within 3 s. Self- acylhydrazone bonds also exist in the hydrogel, and Chen et al.
healing behavior of hydrogel was also further demonstrated by also reported self-healing hydrogels through the combination of
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dynamic Schiff base and acylhydrazone.42 On the other hand, confirmed that when NIPAM is copolymerized with other
Zhao et al. also prepared a self-healing hydrogels based on monomers, the addition of hydrophilic monomers increases the
phenylboronic-modified CS, PVA, and benzaldehyde-capped LCST, while hydrophobic monomers lower the critical point.73
PFG, which combined the Schiff base and dynamic phenyl- Conversely, it has been reported that the stability of hydrogels
boronate ester bonds.191 can be enhanced at low temperatures by decreasing the
In addition, the strategy of achieving dynamic cross-linking temperature sensitivity. Yan et al. prepared a sprayable in situ
through metal coordination has also been reported. For hydrogel dressing based on poly(NIPAM166-co-n-butyl acryl-
example, Shi et al. synthesized a phosphate-modified HA- ate9)-PEG-poly(NIPAM166-co-n-butyl acrylate9) copolymer
based supramolecular hydrogel with self-healing properties by (denoted as PEP) and Ag NPs-decorated reduced GO
dynamic metal−ligand coordination between phosphate and Ag nanosheets (Ag@rGO, denoted as AG) and confirmed that
ions.238 Chen et al. also prepared a hydrogel based on the the addition of AG changed the reversible sol−gel change of
dynamic properties of Ag−S coordination bond by cross-linking original PEP hydrogel at low temperature, providing good
multiarm thiolated PEG (SH-PEG) with AgNO3.77 It has also outdoor low-temperature resistance for PEP-AG hydrogels
been reported that self-healing hydrogels prepared using the (Figure 9A).79 In addition, the hydrophobicity of PNIPAM
synergistic effect between Fe3+ and COOH in HA with EDTA, hydrogel increased with the increase of temperature, resulting in
as the ligand can repeatedly self-heal within a few minutes.90 the decrease of swelling ratio.69 Thus, a thermally-sensitive drug
Besides, there have been some reports of dopamine-based release hydrogel dressing was prepared. In short, the hydrogel
self-healing hydrogels in recent years. Due to the covalent/ undergoes hydrophobic contraction at the physiological
noncovalent bond coexisting characteristics of dopamine during temperature that is higher than NIPAM’s LCST, then squeezes
self-cross-linking, dopamine-based cross-linking hydrogels have out excess water and accelerates drug release, but no drug is
both structural strength and self-healing properties. Our released at room temperature.204
research group prepared dynamic dopamine cross-linked PEG is an interesting amphiphilic molecule. In addition to
hydrogels between dopamine-grafted HA and PDA-coated providing effective stealthing properties, it also exhibits a
GO and proved the self-healing properties derived from negative temperature response in water environments. Many
coexistence of covalent/noncovalent bonds in dopamine PEG-based copolymer thermosensitive hydrogel wound dress-
cross-linked hydrogels.35 Zhao et al. also demonstrated the ings have been prepared, such as PEG-PCL-PEG,243,244
self-healing properties of hydrogels assembled from PDA- poly(lactic-co-glycolic acid) (PLGA)-PEG-PLGA,245 and
modified Ag NPs (PDA@Ag-NPs). It is believed that the PEG-PLGA-PEG,246 which all showed good gelation properties
interfacial hydrogen bond and π−π stacking mediated by at physiological temperature. Among all the PEG-based block
catechol can be dynamically associated and dissociated, thus copolymers, a popular system is commonly referred to as PF127,
providing excellent self-healing performance of the hydrogels.74 which contains both hydrophilic and hydrophobic segments,
In general, although the number of self-healing hydrogels for showing excellent thermal response. Many PF127-based
wound healing dressings have increased significantly in recent thermosensitive hydrogel dressings have also been devel-
years, most of the self-healing properties are still derived from oped.80,177,210 For example, Wu et al. prepared a GFs loaded
the dynamic Schiff base, and the macromolecular structure used thermosensitive heparin-PF127 hydrogel. The sol−gel tran-
to form Schiff base based self-healing hydrogels is still very sition allows aFGF and bFGF to be fully mixed with heparin-
limited. Therefore, self-healing hydrogel dressings based on PF127 solution at 4 °C. Then, when the GFs-heparin-PF127
more strategies need to be developed in the future. In addition, solution is applied to a live wound bed at 37 °C, heparin-PF127
the current self-healing hydrogels generally have insufficient gelation occurs, allowing GFs to be successfully loaded into the
strength, which needs to be further improved. heparin-PF127 hydrogel (Figure 9B).202 In 2018, our research
Stimulus-Responsive Hydrogel Wound Dressing. group also developed a PF127-based thermosensitive hydrogel
Stimulation-responsive hydrogels are responsive to changes in for curcumin sustained release (Figure 8C).50 In addition,
the external environment (such as temperature, pH, light) and thermosensitive hydrogel wound dressings based on other
can make size or shape changes of different ranges under external molecules such as polyisocyanopeptide,247 methylcellulose,95
environmental stimuli.156,239 They have a good application and hydroxybutyl CS67 have also been reported.
prospect in the field of wound dressing hydrogels. The pH-responsive hydrogel is a subset of the stimulus-
Based on the relatively common normal physiological responsive system that can respond to pH changes in the wound.
temperature of the human body of 37 °C, the thermal sensitive The pH of normal skin is maintained in the range of 4−6, which
materials used for hydrogel wound dressings generally exhibit provides skin with a good resistance to external effects.248 Once
lower critical solution temperature (LCST) around physio- the skin is injured, after a short period of acute repair
logical temperature, which guarantees the gelation behavior at (hemostasis and inflammation phase) with a slight decrease in
the normal human body temperature. The injectable low- pH, normal wounds show a certain increase in pH in the
temperature flowing hydrogel precursor solution can be rapidly proliferation phase, but eventually with the repair of the wound,
transformed into a nonflowing hydrogel state after it was the pH will return to normal levels (5.5−6.5).249 However, for
injected into a wound at a physiological temperature, which chronic wounds with abnormal continuous inflammation, such
greatly simplifies the use of hydrogels, making the therapeutic as infection, burns, bedsores, and diabetes, the pH value will
process simple and easy to implement. Therefore, the research always remain alkaline.249,250 Among many pH-responsive
on thermoresponsive materials has aroused great interest. hydrogel dressings, pH-responsive substance release accounts
NIPAM monomer is commonly used in the preparation of for a large proportion. In view of the lower pH in the acute phase
thermoresponsive hydrogels because its LCST is approximately of repair, some hydrogel dressings with enhanced release in
32 °C,239 close to the physiological temperature. PNIPAM- acidic pH have been widely developed. For example, tannic acid-
based thermoresponsive hydrogels have also been widely released antibacterial anti-inflammatory hydrogels were pre-
reported.32,61,89,189,190,212,233,240−242 Research by Mi et al. pared by the reduction of coordination between tannic acid and
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Figure 10. Conductive hydrogel wound dressing. (A) The preparation procedures of the conductive hydrogels based on dynamic Schiff base
between quaternized chitosan-g-polyaniline and benzaldehyde group functionalized poly(ethylene glycol)-co-poly(glycerol sebacate). It also
confirmed that the hydrogel with the conductive component PANI had a better effect on promoting the repair of damaged tissues than the
hydrogel without PANI. Reprinted and modified with permission from ref 36. Copyright 2017 Elsevier. (B) A conductive hydrogel wound
dressing based on HA-graf t-dopamine and dopamine coated rGO was preparaed by dopamine cross-linking induced by H2O2/HPR system. The
conductivity and photothermal antibacterial properties provided by rGO promoted the good effect of the hydrogel on skin tissue healing.
Reprinted and modified with permission from ref 35. Copyright 2019 Wiley-VCH. (C) Schematic illustration of the preparation of the
conductive poly(2-hydroxyethyl methacrylate) (polyHEMA)/polypyrrole (PPy) hydrogels. In situ doped PPy was realized by covalent
incorporation of 3-sulfopropyl methacrylate into hydrogel network, and good conductivity of this hydrogel was ensured in weak alkaline
physiological environment. Reprinted and modified with permission from ref 270. Copyright 2019 Elsevier. (D) A conductive hydrogels based
on gelatin-graf t-dopamine (GT-DA), CS, and dopamine coated CNTs (CNT@PDA). Reprinted and modified with permission from ref 57.
Copyright 2019 Elsevier.
metal ions under acidic conditions.251,252 Using the dissociation amphiphilic peptides with opposite charges at neutral pH was
of Schiff base structure under acidic conditions, better insulin disassembled under acidic conditions, which leads to better
release promotes diabetic wound healing,191 and better release of cationic antimicrobial peptides and promotes better
simultaneous release of Ag+ and deferoxamine (DFO) was antibacterial and repair of diabetic wounds (Figure 9C).106
also confirmed to promote both antibacterial and angio- However, the pH of chronic wounds is alkaline in the
genesis.253 In addition, a supramolecular hydrogel formed by subsequent chronic repair phase (including the late stage of
the intermolecular forces, hydrogen bonds, and π−π stacking of inflammation, and proliferation and remodeling phase), so some
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release-enhanced hydrogel dressings under alkaline conditions Conductive Hydrogel Wound Dressing. In the case of
have also been developed. For example, the high ionization of defects or wounds, the combination of positive charges in the
coordination between the carboxyl group of alginate and metal wound and negative charges around the entire skin forms what is
ions under neutral or alkaline conditions resulted in charge known as the skin battery, and the endogenous electric field at
exclusion, hydration, and swelling of hydrogel. So, hydrogel the wound site is also considered to be a directional signal
dressings with better release of bovine serum albumin254 and leading cells to migrate into the wound during wound healing.257
hyaluronan oligosaccharides133 under alkaline conditions have Studies have shown that applying external current to the
been used to promote the healing of chronic wounds. In general, electrode placed on the wound bed to simulate the endogenous
many hydrogels with pH-responsive release properties have current at the wound is conducive to the migration of
been used to promote wound repair. However, most of these macrophages, neutrophils, and keratinocytes and further
hydrogels contributed to more release of substances under acidic accelerate the closure of wound.258,259 Some important electrical
conditions, and there are still few specific release systems for signal molecules have also been found in this process, such as
alkaline chronic wounds. EGF receptor, integrin, V-ATPase H+ pump, and PI3 kinase/
On the other hand, some pH-responsive swelling behavior Pten (phosphoinositide 3-kinases/phosphatase and tensin
changes in hydrogel dressings have been reported. For example, homologue).257 However, the application of exogenous
alginate hydrogels showed a higher swelling ratio at higher pH electrical stimulation may require the use of large-scale external
because the carboxyl groups in calcium alginate are more easily electronic equipment, which brings inconvenience to patients.
ionized to result in increased electrostatic repulsion.133 So, electroactive dressings containing conductivity similar to
Similarly, acrylic acid and CMC hydrogels also exhibit the skin are developed and proved to be conducive to wound
same pH-responsive swelling properties, which is closely related regeneration and repair.260−268 Based on our previous research
to the carboxyl groups in its structure.71,85 In addition, some pH- on conductive polymers, Zhao et al. used polyaniline-based
sensitive hydrogel dressings are used to monitor the status of conductive hydrogel in skin wound repair in 2017. It is further
wound in real time, which will be described in detail in the confirmed that the hydrogel with the conductive component
corresponding sections. polyaniline had a better effect on promoting the repair of
The biggest advantage of photoresponsive hydrogel dressings damaged tissues than the hydrogel without conductive
is that it is easy to control. The most common example for the component (Figure 10A).36 On the basis of this work, Qu and
photoresponsive hydrogels is the photothermal behavior, which Zhao et al. prepared a conductive hydrogel based on oxidized
has already been covered in the photothermal antibacterial HA-graf t-aniline tetramer (OHA-AT) and CEC.30 Next,
section. In addition, Xu et al. reported a dual photoresponsive inspired by the dopamine chemistry, two multifunctional self-
healing antibacterial antioxidant conductive hydrogel dressings
hydrogel dressing containing both photothermal nanomaterial
with the conductivity of CNT or GO based on gelatin and HA
GO and photobase reagent malachite green carbinol base
were prepared, respectively, by Liang and Zhao et al. (Figure
(MGCB). In addition to adjusting temperature in response to
10B,D).35,57 Among them, the dopamine-polymerized hydro-
NIR light, OH− can also be released by the MGCB molecule in
gels between dopamine-grafted gelatin and dopamine-coated
response to ultraviolet (UV) light, resulting in a gradient of pH
CNT induced by H2O2/HRP were further used to repair S.
value (Figure 9D).255 Gao et al. reported a NIR light- aureus infected skin defects.57 On this basis, Liang et al.
controllable on-demand antibiotics release hydrogel dressing. generated an in situ forming hydrogels based on glycidyl
The release of antibiotics from the hydrogels is small under methacylate-functionalized QCS and methacrylate-function-
physiological conditions but promoted in the case of NIR light. alized gelatin. In addition, GO was compounded by electrostatic
At the same time, the NIR photothermal effect of PDA can also interaction to prepare a series of multi-antibacterial hydrogel
lead to the destruction of bacterial integrity, leading to the dressing systems with multiple antibacterial activities including
coinactivation of bacteria.60 At the same time, light-controlled intrinsic antibacterial, photothermal antibacterial, and drug
multiple and timed release of small extracellular vesicles has sustained release antibacterial abilities. The skin wound repair
been shown to be more effective than a single dose or multiple experiment of drug-resistant bacteria methicillin-resistant
dose release in diabetic wounds.256 Staphylococcus aureus (MRSA) infection verified the prominent
In addition to those hydrogel dressings that respond to a advantages of multiantibacterial in dealing with drug-resistant
single condition, there have also been some hydrogel dressings bacteria (Figure 13B).108 In summary, we have initially
that can respond to two or more conditions simultaneously. For confirmed that the conductive properties of the hydrogel have
example, hydrogels that have both light and pH responses. Due played a positive role in promoting wound healing based on the
to the protonation of the amino group of CS at acidic pH, the research of these conductive hydrogel dressing in our previous
subsequent electrostatic repulsion and enhanced hydrophilicity studies and further demonstrated the better promoting effects of
within the molecule caused the PF127-based thermoresponsive conductive hydrogel dressing compared to nonconductive
hydrogel to swell sharply and accelerate degradation, resulting in dressing in the common wound, infected wounds as well as
increased drug release.50 Another example is to provide the drug-resistant bacteria infection wound model through the
photoresponse by loading PDA, and pH response release of wound closure ratio, collagen deposition, granulation tissue
antibiotics by protonation of amino groups or hydrolysis of thickness, regeneration of some skin appendages such as hair
cellulose under acidic conditions, achieving a dual response to follicles and blood vessels, and immunofluorescence detection of
pH and light.55 In addition, a pH and glucose dual-responsive inflammation and angiogenesis.
hydrogels system has also been reported, in which the pH Some other research groups have also reported related
response is provided by changes in the stability of Schiff base conductive hydrogel dressings. For example, Xu et al. fabricated
under different pH, while the glucose response is provided by conductive injectable hydrogels (QCS-g-PTA/PEG-PSS-BA)
the competitive combination between glucose and phenyl- with poly(ethylene glycol)-co-poly(sorbitol sebacate) (PEG-
boronic acid.191 PSS-BA) copolymer conjugated with QCS-g-polytetraaniline
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Figure 11. Wound monitoring hydrogel wound dressings. (A) An advanced multifunctional dressing (GelDerm) for monitoring and
management of wounds; (a) schematic diagram of GelDerm hydrogel for the treatment of epidermal wounds; (b) schematic diagram of a 3D
bioprint with a coaxial flow microfluidic nozzle; (c) representative photographs of the dressing; (d) synthetic brilliant yellow and naturally
derived cabbage juice were used as model pH indicators for the fabrication of the sensors; and (e) GelDerm can maintain a conformal contact
with irregular surfaces. Reprinted and modified with permission from ref 272. Copyright 2017 Wiley-VCH. (B) Schematics of the structures and
working principles of the double-layer hydrogel sensor; (a) schematic diagram of sensor packaging and dressings construction; and (b)
conceptual diagram of the process of temperature detection of infected wounds and on-demand release of antibiotics. Reprinted and modified
with permission under a Creative Commons Attribution 4.0 International License from ref 273. Copyright 2020 Wiley-VCH.
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Table 2. Functional Requirements of Hydrogel Dressings in Different Types of Wounds

functional
wound requirements implementation strategy of dressing function
adhesion catechol145 and quadruple hydrogen bonding,29 skin secretion of Andrias davidianus,141 tyramine,142 carboxyl150
incisional
wound removability photothermal-induced hydrogen bond elimination29
acute
wound hemostasis chitosan142
excisional antibacterial property, adhesion and hemostasis, anti-inflammatory and anti-oxidation, substance delivery, self-healing, stimulus-
wound response, conductivity, wound monitoring
infected antibacteria photothermal (CNTs)57 and photodynamic antibacterial, cationic polymer (quaternary ammonium),108
wound antibiotics, inorganic metals and metal oxides
antibacteria physical barrier,299−301 honey,118,165,303 Ag75,95,98,101
moisture retention most hydrogels
removability thiol−thioester exchange,138 competitive dissociation of Schiff bases236
burn wound angiogenesis dextran,304 VEGF,162 LLKKK1846
anti-inflammatory resveratrol,162 LLKKK1846
cells delivery keratinocytes,192 fibroblasts,194 and ADSCs167
chronic
wound cytokines delivery EGF, VEGF,208 macrophage colony-stimulating factor (rhGM-CSF)213
cells and cytokines SDF-1,212 platelet-rich plasma,305 exosomes256
delivery
reducing blood GOx,130,275 insulin-releasing,191
glucose
diabetic
wound antibacteria IKFQFHFD (self-assembly antibacterial octapeptide),106 Ag96
anti-inflammatory curcumin,177 An NPs76
angiogenesis DFO,77 silicon,306 hyaluronic acid oligosaccharides and VEGF133
others oxygen delivery218
(QCS-g-PTA), which provide conductivity by using AT.269 Lin parameters near the wound are also changing constantly,
et al. prepared a hydrogel based on supramolecular assembly of which means that more strategies are needed to implement
PDA-modified Ag NPs (PDA@Ag-NPs), polyaniline, and PVA wound management and monitoring. In 2017, Akbari et al.
(PDA@Ag-NPs/CPHs), which provide conductivity by using doped pH responsive color-changing mesoporous resin beads
Ag NPs and polyaniline, which showed good therapeutic effect (Figure 11A) with alginate fibers and then constructed a
in diabetic wounds.74 Using the conductivity of GO, Tang et al. hydrogel containing porous pH sensor array through 3D
also developed a PDA-reduced GO-incorporated CS and SF printing. This hydrogel can provide real-time data on wounds,
(pGO-CS/SF) conductive hydrogel scaffold.178 such as bacterial infection and antibiotic release by measuring
As a common conductive polymer, polypyrrole (PPy) is also color changes. In addition, when connected to the image
used to prepare conductive hydrogel dressings. Lu et al. prepared acquisition equipment, the multifunctional dressing can also
a conductive hydrogel dressing based on the covalent cross- achieve digital remote diagnosis and treatment.272 Pang et al.
linking between poly(2-hydroxyethyl methacrylate) (PHEMA) developed a double-layer hydrogel sensor, with an upper layer of
and 3-sulfopropyl methacrylate and doped the conductive polydimethylsiloxane integrated with a temperature sensor and
component PPy into the hydrogel network under weak alkaline UV light-emitting diode, and a lower layer of UV-sensitive
physiological environment. They also confirmed that this antimicrobial hydrogel (Figure 11B). This dressing provides
conductive hydrogel dressing has improved the wound healing early infection diagnosis through integrated sensors that enable
effect than the traditional electrode-based electrical stimulation real-time wound temperature monitoring and on-demand
(Figure 10C).270 treatment of infections by releasing antibiotics from hydrogels
Polythiophene (PTh) is another widely studied conductive via in situ UV radiation.273 Furthermore, Mostafalu et al.
polymer, and PEDOT is a derivative of PTh. The properties of developed a commercial wound dressing that includes both pH
PEDOT are similar to PPy, but its electrical stability is better and temperature sensors. pH is one of the key parameters for
than PPy. Owing to its biocompatibility and high conductivity, monitoring chronic wounds, and temperature sensors are used
PEDOT has been widely used to develop electroactive to provide further information about wound inflammation.
substrates for cell culture and biosensor. Self-healing and When temperature changes are detected, the dressings can also
conductive hydrogels based on PEDOT:PSS/guar gum also be used to deliver on-demand drug release for inflammatory
showed great improvement in wound closure and tissue changes by loading a thermally responsive drug carrier hydrogel
reorganization.271 and electronically controlled flexible heaters, and the drug
In general, most of the current research on conductive release protocol can also be programmed for personalized
hydrogels is focused on wearable and implantable biomedical treatment.274 In 2019, Zhu et al. further developed a
devices, with little research on wound healing. In the future, we multifunctional zwitterionic hydrogel that can detect both pH
expect more multifunctional conductive hydrogel dressings for and glucose levels to monitor wound conditions in diabetic
wound healing and even wound monitoring. patients. The wound dressing can successfully monitor pH
Wound Monitoring Hydrogel Wound Dressing. From values of 4−8 and glucose concentrations of 0.1−10 × 10−3 M,
the beginning of the single function of wound dressings to the while providing a moist healing environment that promotes
development of multifunctional wound accessories in recent healing of diabetic wounds. This multifunctional wound
years, our focus has been on a simple one-time solution strategy, dressing can be used for the treatment of chronic wounds and
but wound healing is a complicated process and some guide the clinical application of diabetes.275
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Figure 12. Conventional acute wound healing. (A) Incision wound healing. (a) Representative pictures of rat incision wounds at different day
after surgery, scale bar: 5 mm; (b) relative tensile strength of healed skins after treated for 14 days; (c) Masson trichrome staining of harvested
healing skins at days 7 and 14 postsurgery, scale bar: 100 μm. Reprinted and modified with permission from ref 29. Copyright 2020 Wiley-VCH.
(B) Some evaluation indicators in excisional wound healing: (a) wound area; (b) HE staining for inflammation, re-epithelialization, and
regeneration of blood vessels and hair follicles; (c) granulation tissue; (d) collagen; (e) immunofluorescence for inflammation and regeneration
of blood vessels; and (f) Quantitative statistics of epidermal, vascular, and hair follicle regeneration through HE staining, and quantitative
statistics of inflammation and angiogenesis through immunofluorescence. Reprinted and modified with permission from ref 35. Copyright 2019
Wiley-VCH.
TYPE OF WOUND APPLIED WITH HYDROGEL which can be a huge burden on patients and the health care
DRESSING system.298 So in this part, we will first discuss the problems that
There are many types of skin wounds, and different types of need to be paid attention to in the process of repairing different
wounds often require different dressings.297 On the other hand, types of wounds, and then, we will start with some examples of
skin wound healing is an extremely complex process that relies chronic wounds caused by infection, burns, and diabetes and
on a complex interaction of highly regulated factors working discuss the special needs in chronic wound healing (Table 2).
together to restore the barrier function of damaged skin. Conventional Acute Wound Healing. Acute trauma
However, it can go wrong in many steps along the way, especially models are often similar to real surgery or trauma. The term
in an underlying disease state such as diabetes. When wound “acute” refers to the rapid introduction of damage and the
healing does not work properly, it can lead to chronic wounds, relatively rapid repair process. There are many types of acute
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Figure 13. (A) A photothermal antimicrobial strategy. (a) Heat maps of GT-DA/CS/CNT hydrogels after 10 min NIR irradiation; (b) ΔT-NIR
irradiation time curves; (c) NIR irradiation-induced in vitro antibacterial activity of hydrogels with 0, 1, 3, 5, and 10 min; (d) pictures of in vivo
antimicrobial ability; bacterial survival ratios of (e) S. aureus and (f) E. coli; and (g) in vivo antibacterial activity test of S. aureus. Reprinted and
modified with permission from ref 57. Copyright 2019 Elsevier. (B) A preparation strategy of multiple antibacterial hydrogel wound dressings
combining cationic antibacterial, photothermal antibacterial, and antibiotic release bactericidal. (a) Schematic diagram of the synthesis of
glycidyl methacrylate functionalized quaternized chitosan (QCSG) and (b) gelatin methacrylate; and (c) scheme of QCSG/GM/GO hydrogel’s
network and applications in sterilization and wound healing. (d) Representative images of antibacterial tests. Reprinted and modified with
permission from ref 108. Copyright 2020 American Chemical Society.
injuries, and we will use only two kinds of what are common in by the need to remove the suture, and the insufficient flexibility
the literature to illustrate the issues that need to be addressed in of the adhesive layer in the presence of commonly used
the healing process. cyanoacrylate tissue adhesives and potential toxicity after
Incisional wounds usually refer to tissue splitting wounds with degradation. This also poses challenges to the healing of
minimal collateral damage caused by sharp blade-like utensils. incisional wounds. Therefore, some hydrogel dressings based on
Strictly speaking, if the wound surfaces can be accurately butted incisional wounds have been proposed. For example, our
in time, supplemented by good sutures or bandaging operations, research group recently developed a physical double-network
it usually only produces a very small scar tissue, and its healing is hydrogel with shape adaptability, self-healing, tissue adhesion,
also easier to achieve perfect repair. Besides, incisional wounds antioxidant activity, and NIR/pH stimuli responsiveness based
are also suitable for the test of tissue mechanical properties after on poly(glycerol sebacate)-co-poly(ethylene glycol)-g-catechol
healing. However, there are also some problems, such as the prepolymer and UPy-hexamethylene diisocyanate synthon-
aesthetic appearance of the tissue near the wound caused by the modified gelatin (GTU). The Fe3+-mediated cross-linking of
traditional tissue suture and the complicated operation caused catechol groups and the quadruple hydrogen bonding between
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Figure 14. Hydrogel dressing for burn wound healing. (A) An on-demand dissolution burn wound hydrogel dressing based on Schiff base cross-
linking between CMC and DACNC guided by competitive binding strategy. (a) Images of hydrogel formation and dissolution after adding
competitive glycine; (b) schematic diagram of hydrogel structure, and dissolution caused by competitive binding of glycine; (c) representative
pictures of wound area at different time in different experimental groups during burn wound repair, scale bar: 1 cm; (d) quantitative statistics of
unhealed wound rate; and (e) H&E tissue staining and Masson staining images of wounds in different groups, scale bar: 200 μm. Reprinted and
modified with permission from ref 236. Copyright 2018 American Chemical Society. (B) A functional antibacterial hydrogel formed by mixing
AgNO3 with cytidine and B(OH)3 for the burn wounds. Reprinted and modified with permission from ref 75. Copyright 2019 American
Chemical Society.
ureido-pyrimidinone system gives the hydrogel a double dressings. Among the excisional wounds, full-thickness wounds
network. In addition to the strong response to multiple resistant in which the epidermal layer, dermal layer, and subcutaneous fat
bacteria and healing function for full-thickness wound are all lost are the most widely used. In this review, most of the
benefitting from good antimicrobial antioxidant properties, research used this kind of wound. The larger material-tissue
good tissue adhesion and ease of removal properties also allow it contact area makes it possible to obtain cells, tissues, RNA,
to demonstrate its potential as a tissue adhesive to facilitate exudate, and tissue specimens from larger cross-sectional area
wound healing in incisional wounds. A corresponding animal and volume, which is more conducive to the detection of some
test also proved its ability to promote better skin incision healing further biochemical and histological parameters. Specifically,
than sutures and tissue glue. In addition, the skin after healing various parameters such as wound closure rate, inflammation
with hydrogel adhesive also showed a significantly higher cell (not caused by bacteria), granulation tissue formation, re-
relative tensile strength than sutures and medical glue and close epithelialization, collagen deposition, angiogenesis, hair follicle
to normal skin (Figure 12A).29 Coincidentally, due to its formation, and a series of healing-related cells40,48,195,199 and
excellent tissue adhesion effect, a hydrogel adhesive prepared by cytokines were used to evaluate the healing process of excisional
Deng et al. based on the skin secretion of Andrias davidianus was wounds. Figure 12B shows an example of the preparation of
also used to heal incisional wound, in addition to repairing tissue nanocomposite adhesive conductive self-healing antibacterial
defects (Figure 4C).141 Hydrogels prepared by Lih et al. based anti-oxidation multifunctional hydrogel based on the enzyme-
on tyramine were also used to promote the healing of incisional catalyzed polymerization of dopamine between hyaluronic acid
wound.142 The hydrogel dressing for incisional wound healing grafted dopamine and GO coated dopamine. The work has
must have good tissue adhesion properties in order to join the systematically evaluated wound closure rates, granulation tissue,
wound interface quickly and firmly. Therefore, some of the collagen, and assessed the inflammation, re-epithelialization, and
researches we have previously mentioned in the adhesive regeneration of blood vessels and hair follicles by HE staining. In
hydrogel dressing are also used to promote healing of incisional addition, immunofluorescence was also used to evaluate
wounds.145,150 inflammation, and regeneration of blood vessels.35
Unlike incisional wounds, excisional wounds usually have Chronic Infected Wound Healing. Bacterial infections are
many tissue defects, which pose great challenges in repairing inevitable during wound repair and can even lead to serious
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complications, including sepsis. So, the control of infection has effectively prevent bacterial infection through physical bar-
been considered one of the most critical challenges in rier.299−301 Moreover, the good universality of hydrogel makes it
bioengineering applications, especially in tissue regeneration, able to load a variety of functional factors, which have become a
which poses a serious threat to public health. When a wound is promising dressing source in burn wounds. Easy removal ability
infected, the bacteria cause persistent inflammation at the of hydrogels also avoids secondary injury and pain during
infected site, delaying the healing process in the inflammatory dressing replacement (Figure 14A).138,236 According to the
phase, and severe inflammation often leads to unsuccessful main challenges of burn wound healing, the research progress of
wound healing. At present, the most widely used clinically hydrogel dressings for burn wounds is mainly introduced below.
antibacterial strategy in wound healing is still antibiotics. Infection is one of the most common complications
However, the use of antibiotics promotes the development of associated with burn wounds and, in severe cases, can lead to
drug resistance. In order to solve this problem, various septicaemia which can damage the immune and inflammatory
antibacterial hydrogels have been prepared by different responses throughout the body. Studies have shown that in
methods, including the physical loading of antibacterial burns covering more than 40% of the body surface area, sepsis or
substances and/or the inclusion of antibacterial components other complications caused by wound infection and the failure of
in the hydrogel network through chemical reactions. Among the some vital organs account for more than 75% of the deaths.
many nanoparticles reported as antimicrobial agents for the Thus, in the treatment of burn wounds, control of infection is a
hydrogel dressing, inorganic nanoparticles, including silver, particularly important link. Many researches focused on
copper, gold and zinc have been widely explored for potential reducing infection in burn wound healing.302 Honey, which
antimicrobial applications. However, the use of these inorganic reduces abscesses, ulcers, and has antibacterial properties, is
nanoparticles as antimicrobial agents is greatly limited by their often used as a wound dressing for burns.118,165,303 Silver
nonspecific biological toxicity or possible in vivo long-term hydrogels are also widely used as wound dressings for burns
retention. Recently, metal-free antimicrobial agents such as (Figure 14B),75,95,98,101 and there are already some clinically
antimicrobial peptides and polymers, GO, and quaternary available products such as silver sulfadiazine, Acticoat, and
ammonium salts have been reported for use in antimicrobial PolyMem silver.
therapy. However, there are still some problems in different Angiogenesis is important in the healing of deep burn wounds,
degrees, which limit their further application. On the other hand, which lose more dermal blood flow than the superficial burns.
the strategy of using local heat generated by some nano- The number of new blood vessels directly determines whether
photothermal agents such as gold, tungsten, and graphene under the nutrition and oxygen supply is adequate for the subsequent
NIR light to sterilize has attracted attention. For example, gelatin healing process, and whether the healing can be done quickly
grafted dopamine (GT-DA) and PDA-coated CNTs (CNT- and primarily, instead of delaying the healing and even leading to
PDA) were used to construct a antibacterial, adhesive, necrosis and traumatic scarring. Sun et al. prepared a dextran-
antioxidant, and conductive GT-DA/chitosan/CNT hydrogel allyl isocyanate-ethylamine (Dex-AE)/polyethylene glycol
by oxidative coupling of the catechol groups through a H2O2/ diacrylate hydrogel and confirmed that the material−organ-
HRP catalytic system. In addition, CNT-PDAs possess these ization interaction can stimulate rapid angiogenesis and
hydrogels excellent photothermal effect and shows good promote skin regeneration of burn wounds.304 In addition,
antibacterial activity against Gram-positive and Gram-negative excessive inflammation is also a major obstacle in burn wound
bacteria in vitro and in vivo (Figure 13A).57 However, they healing and skin regeneration. Some natural and synthetic
generally increase the potential for thermal damage to substances with anti-inflammatory properties are also used to
surrounding healthy tissue because a relatively high temperature compound influent gel dressings.167,180 But, reduced inflamma-
is required to kill bacteria. Therefore, we further developed a tion often does not provide the optimal healing environment for
multi-antibacterial strategy combining intrinsic antibacterial, the normal wound healing process, because inadequate local
antibiotic releasing antibacterial, and photothermal antibacterial angiogenesis may worsen the inflammatory response and lead to
and hope it can play a role in the future when facing the possible cell dysfunction, which makes wound healing more difficult.
complex infections (Figure 13B).108 But, in general, there is still Therefore, some hydrogel systems that have both anti-
no perfect strategy for dealing with infections in wound healing. inflammatory and vascular regeneration properties have been
Chronic Burn Wound Healing. Burns are the most developed. For example, a system loaded with VEGF to promote
common and destructive form of wound, often accompanied angiogenesis while encapsulated with resveratrol to achieve anti-
by life-threatening severe infections, excessive inflammation, inflammatory effects162 was designed. LLKKK18, an antimicro-
reduced angiogenesis, insufficient extracellular matrix produc- bial peptide that not only reduces oxidative stress and
tion, and insufficient stimulation of GFs, resulting in delayed inflammation but also increases VEGF and microvascular
healing. Rapid and dangerous fluid loss occurs when the skin is development in the body, has also been used in burn wound
affected by high temperature, and the coagulation and loss of dressings.46
proteins, including immunoglobulin, can lead to irreversible The complex wound healing process also requires the synergy
tissue damage and susceptibility to infection. In addition, of various tissue and cell lineages as well as extracellular and
membrane dysfunction can lead to severe changes in the intracellular signals. So, many cells such as keratinocytes,192
distribution of water and sodium, loss of extracellular fluid and fibroblasts,194 and ADSCs167 and cytokines such as EGF,
consumption of sodium will further reduce blood volume, VEGF,208 and macrophage colony-stimulating factor (rhGM -
change electrolyte balance, and lead to the death of burn CSF)213 and so on are all studied to promote the healing of burn
patients. Although superficial burns generally have less scarring wounds.
after healing, the current treatment is still not satisfactory Chronic Diabetic Wound Healing. Diabetes, the most
because second- and third-degree burns can damage many common metabolic disease, is a major health and economic
important functions of the epidermis and dermis. Hydrogel problem. Diabetes patients’ wounds take longer to heal than
dressing, while ensuring good moisturizing effect, can also normal wounds, and chronic wounds can even lead to
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Figure 15. Hydrogel dressing for wound healing in diabetes mellitus. (A) Scheme of zwitterionic PCB hydrogel dressing encapsulated with a pH
indicator dye (phenolic red) and two glucose-sensitive enzymes (GOx and HRP) for the detection of pH value and glucose concentration in
wound exudate. (a) Schematic diagram of hydrogel; (b) functionalized wound dressing for simultaneous detection of pH values (under visible
light) and glucose concentrations (under UV light). pH values: 5.0, 5.5, 6.0, 6.5, 7.0, and 7.5. Glucose concentrations: 0, 0.1, 0.5, 2, 5, and 10 ×
10−3 m. PCB-PR-E hydrogel discs in ① PBS and ② AWE solutions. Reprinted and modified with permission from ref 275. Copyright 2020 Wiley-
VCH. (B) A hydrogel wound dressing with pH and glucose dual-responsive insulin release function constructed by dynamic Schiff base and
phenylboronic acid ester. After loading fibroblasts, a wound healing promotion strategy combining drug therapy, cell therapy, and extracellular
matrix scaffolds was realized. Reprinted and modified with permission from ref 191. Copyright 2017 American Chemical Society. (C) A
antipollution silver nanoparticle hydrogel dressing for the condition of low systemic cellular immunity. The upregulated expression levels of
CD68+ and CD3+ indicated that hydrogel could trigger the immune response in the treatment of diabetic wound healing. Reprinted and
modified with permission from ref 76. Copyright 2019 American Chemical Society. (D) Schematic illustration of the self-healing Ag(I)-thiol
(Ag−S) coordinative hydrogel prepared by mixing 4-arm-PEG-SH, DFO, and AgNO3 for diabetic wound healing; DFO can promote the
secretion of hypoxia-inducible factor-1, so as to upregulate the expression of angiogenic GF. Reprinted with permission under a Creative
Commons Attribution 4.0 International License from ref 77. Copyright 2019 Springer Nature.
amputations, making therapies to promote healing of diabetic hypoxia, poor vascularization, cellular infiltration, and gran-
wounds particularly important. Specifically, diabetic wounds are ulation tissue formation. Successful wound healing requires the
characterized by hyperglycemia, prolonged inflammation, interaction of a highly organized sequential cascade of resident
ACS Nano 2021, 15, 12687−12722
and recruited cell types, GFs, and cytokines. In the following, we the same time, Shi et al. also developed a antipollution silver
will focus on the problems encountered in wound healing of nanoparticle hydrogel dressing for the condition of low systemic
diabetes mellitus and illustrate the current research progress one cellular immunity. The upregulated expression levels of CD68+
by one. and CD3+ indicated that hydrogel could trigger the immune
Cells delivered to diabetic skin trauma often do not have the response in the treatment of diabetic wound healing (Figure
high cell migration ratio that is found in many other tissues. Lee 15C).76
et al. prepared a thermosensitive hydrogel dressing from a Hypoxia is also thought to be a key factor in nonhealing
biodegradable and biocompatible triblock copolymer PEG- diabetic wounds. So, Patil et al. prepared a oxygen-containing
PLGA-PEG. In diabetic mouse models, the engraftment of biomaterial hydrogel wound dressing to treat diabetic wounds
muscle-derived stem cells was increased by 20−30 times, thus and showed increased collagen synthesis and angiogenesis as
significantly improving the healing of diabetic wounds.246 In well as increased skin tissue maturity.218
addition, exogenous cell and GFs can compensate for the Another main reasons for the difficulty of wound healing in
absence or deficiency of endogenous cell and GFs to overcome diabetes is wound vascularization. High glucose levels in the
the impaired wound healing in diabetic patients. So, many blood can block normal blood flow to the wounds, leading to a
hydrogel dressings loaded with various cells and cytokines have lack of nutrients, which can inhibit angiogenesis and delay the
been reported to promote healing of diabetic wounds. For healing of diabetic wounds. DFO can promote the secretion of
example, SDF-1 is loaded in a hydrogel dressing due to its ability hypoxia-inducible factor-1, so as to upregulate the expression of
to promote endothelial progenitor cell homing and angio- angiogenic GF (Figure 15D).77 Silicon ions can upregulate the
genesis.212 The use of platelet-rich plasma in diabetic wound expression of VEGF, so they are used in combination to promote
healing has also been reported because it can provide a large vascular regeneration in diabetic wounds.306 Besides, small
number of autologous platelet-derived GFs such as TGF-β, fragments or hyaluronic acid oligosaccharides have been shown
insulin-like GF-I, VEGF, and bFGF.305 Small extracellular in various experimental systems to stimulate endothelial cell
vesicles, commonly referred to as exosomes, are cell-based proliferation, migration and tubule formation, and induce
vesicles with diameters of 50−200 nm that contain not only angiogenesis, so it is used to promote blood vessels regeneration
miRNAs but also other biomolecules such as proteins, lipids, and along with VEGF.133
mRNA. It is also loaded into hydrogel to promote healing of
diabetic wounds.256 CONCLUDING REMARKS AND FUTURE PERSPECTIVES
Diabetic wound healing rates are significantly reduced by high Hydrogels have become the most competitive candidates in the
blood sugar levels because they prevent nutrients and oxygen last decades and show a trend of increasing year by year in the
from providing energy to cells. In view of this, there are also application of wound dressing. With the continuous deepening
studies to reduce the blood glucose around the wound by and refinement of clinical needs, the function of hydrogels has
loading glucose oxidase (GOx).130 For example, a pH indicator also changed from the original single physical coverage or
dye (phenolic red) and two glucose-sensitive enzymes, GOx and function to the current composite of multiple functions and
HRP, are encapsulated in zwitterionic poly carboxybetaine shows a trend of further intelligentization. Therefore, this review
(PCB) hydrogel dressings to detect both pH and glucose levels summarizes the enhanced functions of hydrogel dressings
and allow data to be transmitted to smartphones (Figure mentioned in the existing reports including antibacterial,
15A).275 Furthermore, Zhao et al. prepared a glucose-responsive adhesion and hemostasis, anti-inflammatory and antioxidant,
insulin-releasing hydrogel. The hydrogel dressing system is also substance delivery, self-healing, stimulus response, conductivity,
loaded with fibroblasts, combining drug therapy, cell therapy, and recently exposed wound monitoring and the strategies used
and extracellular matrix scaffolds into one (Figure 15B).191 to achieve these functions. Bacterial infection is the most
Excessive sugar in wound blood also causes bacteria to grow common and unavoidable challenges in wound healing.
faster than normal wounds, and high blood sugar levels also Therefore, antibacterial has become an eternal focus in the
prevent immune cells from fighting off invading bacteria. So, the field of wound dressing, and it also faces the problem of bacterial
infections in diabetic wounds can make healing particularly resistance caused by the abuse of antibiotics. Various
tricky and severely lead to complications such as gangrene or antibacterial strategies include improved antibiotics and their
sepsis. Therefore, many hydrogel dressings with antibacterial delivery systems, metal and metal oxide nanoparticle antimicro-
properties are also used in the treatment of diabetic wounds. For bial agents, cationic antimicrobial peptides and polymers,
more difficult repaired biofilm-forming bacteria-infected antimicrobial ingredients in natural products, photothermal
wounds, related hydrogel dressings have also been developed.106 antimicrobial agents, and combinations of multiple antimicro-
A hydrogel based on innate immune molecule lactoferrin and bial strategies have been proposed. However, there is still no
the rare sugar-alcohol xylitol was used to treat bacterial perfect strategy to deal with wound infections and ensure that it
biofilms.96 remains effective against unknown future drug-resistant bacteria.
Furthermore, although chronic and acute wounds go through Photothermal/photodynamic strategy and nanozyme antibacte-
similar stages of healing, high blood sugar prevents the immune rial may be a breakthrough in the future, but it is still far from
system from functioning effectively, increasing cellular inflam- clinical application. In addition, hydrogels in use are often
mation. Chronic wounds seem to stall during the inflammatory subjected to external forces in daily life, which often leads to
phase of wound healing, which means that unnecessary excessive hydrogel cracking and bacterial invasion. Therefore, many self-
inflammation must be reduced. So, the application of anti- healing hydrogels based on dynamic chemical bond cross-
inflammatory hydrogel dressings in diabetic wounds is also a linking have shown important application potential in wound
promising option. For example, in response to matrix metal- repair. On the other hand, the adhesion hydrogels can not only
loproteinases, which are often overexpressed in nonhealing prevent the shedding of dressings and the invasion of bacteria
wounds of diabetes, Liu et al. prepared gelatin microspheres but also quickly block the early bleeding of wound. However,
containing hydrogels loaded with curcumin nanoparticles.177 At how to remove the adhesive hydrogel dressing on demand after
ACS Nano 2021, 15, 12687−12722
use remains one of the biggest problems to be solved. Excessive AUTHOR INFORMATION
inflammation often leads to the formation of chronic wounds, so Corresponding Author
anti-inflammatory and antioxidant functions have also been Baolin Guo − Frontier Institute of Science and Technology and
proposed. In addition, based on the skin battery theory of charge State Key Laboratory for Mechanical Behavior of Materials,
changes near the wound and the transmission of electrical Xi’an Jiaotong University, Xi’an 710049, China; Key
signals between human cells, the promoting role of conductive Laboratory of Shaanxi Province for Craniofacial Precision
hydrogel in skin repair has also been confirmed by many studies. Medicine Research, College of Stomatology, Xi’an Jiaotong
Hydrogels as a delivery system have been widely studied. So in University, Xi’an 710049, China; orcid.org/0000-0001-
skin repair, some drugs, cells, cytokines, and other substances are 6756-1441; Phone: +86-29-83395340; Email: baoling@
also loaded into the hydrogel. In addition, in view of the mail.xjtu.edu.cn; Fax: +86-29-83395131
complexity of the wound repair process and the need for
Authors
coordination of various parts, hydrogels that can respond to
Yongping Liang − Frontier Institute of Science and Technology
environmental stimuli such as pH, light, and heat are also used
and State Key Laboratory for Mechanical Behavior of
for wound repair. The emergence of future-oriented smart Materials, Xi’an Jiaotong University, Xi’an 710049, China;
hydrogels that can monitor wound parameters is also an orcid.org/0000-0001-6335-0428
important direction for future development. Of course, many Jiahui He − Frontier Institute of Science and Technology and
composite multifunctional hydrogels have appeared in recent State Key Laboratory for Mechanical Behavior of Materials,
years. Our research group has also made some explorations in Xi’an Jiaotong University, Xi’an 710049, China
this regard. A series of hydrogels with injectable, antibacterial,
conductive, adhesive, hemostatic, sustained-release, and anti- Complete contact information is available at:
oxidant dressings have been prepared.29,30,35,36,50,57,107,108,155 https://pubs.acs.org/10.1021/acsnano.1c04206
However, due to the complexity of the wound repair process,
Author Contributions
many processes and the parameters involved are dynamically #
Y.L. and J.H. contributed equally to this work.
changing, which makes it difficult to have a dressing that can
Notes
meet the needs of the entire process at the same time. For
The authors declare no competing financial interest.
example, it is important to control inflammation during the
inflammation phage of wound healing, but it is not necessary in ACKNOWLEDGMENTS
other periods of wound repair. In addition, cells, cytokines, and
functional components loaded in wound dressings are usually This work was jointly supported by the National Natural Science
required only at a specific time, while at other times, they may Foundation of China (grant nos. 51973172 and 51673155),
Natural Science Foundation of Shaanxi Province (nos. 2020JC-
even play the opposite effect. Therefore, first, providing
03 and 2019TD-020), State Key Laboratory for Mechanical
functions on demand is a direction for further research.
Behavior of Materials, and Opening Project of Key Laboratory
Although we have seen some research on wound monitoring, of Shaanxi Province for Craniofacial Precision Medicine
how to achieve responsive delivery of required dressing Research, College of Stomatology, Xi’an Jiaotong University
functions after obtaining dynamic data on wounds remains a (no. 2019LHM-KFKT008) and the World-Class Universities
challenge. Second, another important point is that the pH value (Disciplines) and the Characteristic Development Guidance
of chronic wounds is alkaline, but most pH responsive systems Funds for the Central Universities.
seem to be more friendly to acidic pH at present. Therefore,
further development of hydrogel dressings that can provide VOCABULARY
functions on demand under alkaline conditions is also an Hydrogel, a gel with three-dimensional network structure and
important direction. Third, mice or rats are generally selected as water as the dispersion medium; granulation tissue, the bright
the model organism at present, but the skin of mice or rats will red granular, soft, and moist tissue formed during wound repair,
contract during the healing process, which is different from which resembles fresh granulation, is composed of new thin-
human skin, so it will also lead to deviations in experimental walled capillaries and proliferative fibroblasts and accompanied
results. Although some researches have adopted various by inflammatory cell infiltration; photothermal antibacterial, a
methods (like splint model) to reduce this error, they all have way for substances with photothermal ability to kill bacteria by
caused a greater workload and small improvements that do not converting absorbed light into heat; hemostatic cryogel, a
match the workload. So, more suitable animal models are also sponge-like hemostatic material with uniform macroporous
need to be explored. Besides, the length of the repair process will structure prepared by freezing gel technology; rGO@PDA, the
be affected by various factors. So some parameters such as reduction of graphene oxide caused by the self-polymerization of
angiogenesis, collagen deposition, and granulation tissue dopamine under alkaline conditions, forming a polydopamine
thickness may vary at a certain point in time, resulting in poor coating layer on the surface of reduced graphene oxide.
contrast between different research results. Further exploration
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Review

Functional Hydrogels as Wound Dressing to

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ABSTRACT: Hydrogels, due to their excellent biochemical and

the functional hydrogel as a wound dressing is still lacking. This

T he skin is a very important organ that covers the surface

© 2021 American Chemical Society https://doi.org/10.1021/acsnano.1c04206

Figure 2. Advanced functions appeared in hydrogel wound dressing.

ACS Nano 2021, 15, 12687−12722

Table 2. Functional Requirements of Hydrogel Dressings in Diﬀerent Types of Wounds

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