Recent advances in nanotherapeutics for the treatment of burn wounds

Abstract

Moderate or severe burns are potentially devastating injuries that can even cause death, and many of them occur every year. Infection prevention, anti-inflammation, pain management and administration of growth factors play key roles in the treatment of burn wounds. Novel therapeutic strategies under development, such as nanotherapeutics, are promising prospects for burn wound treatment. Nanotherapeutics, including metallic and polymeric nanoformulations, have been extensively developed to manage various types of burns. Both human and animal studies have demonstrated that nanotherapeutics are biocompatible and effective in this application. Herein, we provide comprehensive knowledge of and an update on the progress of various nanoformulations for the treatment of burn wounds.

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Burns & Trauma, 2021, 9, tkab026
https://doi.org/10.1093/burnst/tkab026
Review
Review
Recent advances in nanotherapeutics for the
treatment of burn wounds
Rong Huang1, Jun Hu2,*, Wei Qian3, Liang Chen4and Dinglin Zhang1,5,*
1Department of Chemistry, College of Basic Medicine, Third Military Medical University (Army Medical University),
Chongqing 400038, China, 2Department of Neurology, Southwest Hospital, Third Military Medical University (Army
Medical University), Chongqing 400038, China, 3Institute of Burn Research, Southwest Hospital, Third Military Medical
University (Army Medical University), Chongqing 400038, China, 4Department of plastic surgery, Southwest Hospital,
Third Military Medical University (Army Medical University), Chongqing 400038, China and 5State Key Laboratory of
Trauma, Burn and Combined Injury, Chongqing, 400038, China
*Correspondence. Jun Hu, Email: hujuncq@163.com; Dinglin Zhang, Email: zh18108@163.com
Received 19 January 2021; Revised 24 March 2021; Editorial decision 28 May 2021
Abstract
Moderate or severe burns are potentially devastating injuries that can even cause death, and
many of them occur every year. Infection prevention, anti-inflammation, pain management and
administration of growth factors play key roles in the treatment of burn wounds. Novel therapeutic
strategies under development, such as nanotherapeutics, are promising prospects for burn wound
treatment. Nanotherapeutics, including metallic and polymeric nanoformulations, have been
extensively developed to manage various types of burns. Both human and animal studies have
demonstrated that nanotherapeutics are biocompatible and effective in this application. Herein, we
provide comprehensive knowledge of and an update on the progress of various nanoformulations
for the treatment of burn wounds.
Key words: Burn wounds, Metal and metal oxide nanotherapeutics, Polymeric nanotherapeutics, Therapeutic mechanism, Wound
healing
Highlights
•The recent progress of various nanotherapeutics for the management of burn wounds and their therapeutic mechanisms are
systematically reviewed.
•Assessment of burn wounds treated with nanotherapeutics is briefly summarized.
Background
Skin is the most active immune system organ and the largest
organ of the body, as well as the main barrier between the
environment and the internal organs [1]. Acute skin wounds
usually result from traumas, abrasions or burns. Burn wounds
are the fourth greatest cause of traumatic injuries, usually
rupturing the skin layers and/or subcutaneous tissue or even
damaging the viscera by physical, chemical or radioactive
contact [2]. Survivors of severe burn injuries can suffer from
scars, disabilities or deformities, and they can even die, which
is tragic for their families and society [3].
Today, we have a deep understanding of the pathogenesis
of burn wounds. The main factors determining burn wound
progression include bacterial infection, excessive inflamma-
tory reaction and low expression levels of various growth
factors (GFs). Of these, bacterial infection is the most serious

2Burns & Trauma, 2021, Vol. 9, tkab026
complicating factor [4]. In accordance with the pathogenesis
of burn injuries, therapeutic strategies such as anti-infection
[4], stem cell therapy [5,6] and administration of GFs to
facilitate wound healing [7] have been used to treat these
wounds. These interventions greatly reduce infection rate and
shorten healing time [8]. Of these strategies, anti-infection
plays a particularly key role in wound healing, since the
injured skin is susceptible to bacteria. Antibiotics [9], metallic
ions and metal oxides [10], reactive oxygen species (ROS) [11]
or ROS generators [12] and other antibacterial agents have
been intensely used to eradicate bacteria from the surface of
burn wounds. However, transdermal or systemic administra-
tion might not ensure that adequate therapeutics reach the
infection site. Furthermore, sustained antibiotic administra-
tion might increase antibiotic resistance. Another therapeutic
strategy is applying GFs to the burn wound surface to shorten
healing time. For example, keratinocyte formation growth
factor (KGF), transforming growth factor beta (TGF-β), epi-
dermal growth factor (EGF), nerve growth factor (NGF),
basic fibroblast growth factor (bFGF), vascular endothelial
growth factor (VEGF) and platelet-derived growth factor
(PDGF) can trigger a cascade reaction to induce endothelial
cell (EC) activation and promote neovascularization; there-
fore, all of these GFs have been used to treat burn wounds
[13]. Nevertheless, certain physicochemical properties of GFs
such as poor stabilization restrict their clinical application for
this purpose.
Marked breakthroughs in the field of nanotechnology
offer an opportunity to solve some critical medical prob-
lems. In recent decades, nanotherapeutics and nanodiagnos-
tics have been extensively used to diagnose and treat various
diseases, including cancer [14], cardiovascular disease [15],
inflammatory diseases [16], infections [17], neurological dis-
eases [18] and dermatological diseases [19]. Compared with
traditional medicine, nanotherapeutics have some treatment
advantages, such as altering the physicochemical properties
of conventional therapeutics, enhancing the accumulation
thereof at diseased sites and decreasing drug dosage and dose
frequency [20]. The great recent progress in nanomedicine
also provides a chance to develop nanotherapeutics that effi-
ciently prevent infection and facilitate healing of burn wounds
(Figure 1). Some nanomaterials (e.g. silver [Ag], zinc oxide
[ZnO] nanoemulsions and chitosan nanoparticles [NPs]) can
serve as anti-bacterial agents to prevent infection of burn
wounds, since these materials have intrinsic anti-bacterial effi-
cacy [10]. In addition, researches have encapsulated antibi-
otics in polymeric materials (e.g.cellulose, polysaccharide) to
treat burn wounds [21,22]. GFs have been encapsulated into
NPs to boost cell proliferation, which helps facilitate wound
healing [23,24]. Nanotherapeutics for the treatment of burn
wounds have some outstanding advantages, such as broad-
spectrum anti-bacterial efficacy, overcoming bacterial drug-
resistance, shortening wound healing time and satisfactory
biocompatibility. The efficacy and biocompatibility of nan-
otherapeutics for the treatment of burn wounds have both
been demonstrated in human and animal models. Although
nanotherapeutics have made great achievements in treating
these wounds, progress in this field continues, as summarized
by several reviews [23,25]. Herein, we provide a comprehen-
sive acknowledgment of and an update on the progress of
recent research into various nanoformulations for treatment
of burn wounds.
Review
Strategies for burn wound treatment
The mechanism of burn wound healing Wang, Jahromi et al.
have systematically reviewed the mechanism of burn wound
healing [7,23]. The process usually includes four phases:
homeostasis, inflammation, granulation tissue hyperplasia
and re-epithelialization/remodeling (Figure 2)[7]. Homeosta-
sis occurs in the early stages of burn wounds (within 10 min
after wound infliction) to minimize damage (Figure 2a). In
this phase, a blood clot containing hyaline, fibronectin (FN),
fibrin and thrombin-sensitive protein (TSP) forms a scaffold-
like matrix for the migration of fibroblasts, leukocytes, ker-
atinocytes and ECs as well as for the resulting aggregation of
GFs at the wound site [26]. An inflammatory reaction appears
1–3 days after burn wounds. In this phase, neutrophils are
accumulated at the burn sites which release inflammatory
factors such as tumor necrosis factor alpha (TNF-α)and
interleukins-1 and -6 (IL-1, IL-6); this activates the inflam-
matory response and stimulates VEGF and IL-8 secretion in
order to repair blood vessels (Figure 2b). In addition, mono-
cytes are transformed into activated macrophages that accu-
mulate at the wound site to produce various GFs such as TGF-
α,TGF-β, FGF, PDGF and VEGF to stimulate cell prolifera-
tion and migration [27]. The granulation tissue’s hyperplasia
phase, which includes re-epithelialization, neovascularization
and granulation tissue formation, usually occurs 3–10 days
after the burn wound is inflicted (Figure 2c). In this phase, re-
epithelialization induced by activated cytokines causes expan-
sion of keratinocytes, ECs, stem cells and fibroblasts at the
wound site. In addition, high expression of various GFs (e.g.
VEGF, PDGF, FGF-βand GM-CSF) at the site can facili-
tate growth of ECs. Alternatively, fibroblasts, granulocytes
and macrophages can form granulation tissue that becomes
fibrous tissue, eventually forming a scar [28]. In the 2–3 weeks
to 1 year after the burn occurs, the wound heals completely,
this is defined as the tissue plasticity period (Figure 2d)[29].
Strategies for accelerating burn wound healing Clinical
therapy for burn wounds usually includes four procedures:
preventing further injury to the wound, wound cleaning and
drainage, prevention of wound infection and promotion of
wound healing. Therapeutic strategies for the various treat-
ment principles are summarized in Table 1.
Debridement and drainage comprise the first step to
keeping the wound clean and decreasing the chance it will
become infected. After debridement and drainage, infection
prevention must be considered since bacterial infection
significantly affects the wound healing process. Serious
infection can damage the remaining epithelial tissue, which

Burns & Trauma, 2021, Vol. 9, tkab026 3
Figure 1. Nanotherapeutics for treatment of burn wounds. NPs nanoparticles
prolongs wound healing time. Importantly, if sepsis occurs
after wound infection, epithelial growth is terminated,
which makes healing difficult [30]. In addition, partial
infection occurring on the wound surface will lead to
persistent inflammatory response, resulting in an increase
of necrotic tissue, blockage of collagen formation, prevention
of tissue regeneration and prolongation of the recovery stage.
Consequently, preventing infection of the wound is vital
to facilitate its healing. Susceptible bacteria groups such
as Methicillin-resistant Staphylococcus aureus (S. aureus)
(MRSA), Pseudomonas aeruginosa (P. aeruginosa)and
Escherichia coli (E. coli) are the predominant pathogens that
delay wound healing. Currently, therapeutics used for infected
wounds include immune-based antibacterial agents (such as
antimicrobial peptides) [31], therapeutic micro-organisms
[32], various antibiotics and ROS [33]. Antibiotics are the
most effective therapy for wound infections. In addition,
many metallic ions or particles such as gold (Au), silver (Ag),
zinc (Zn) and copper (Cu) show broad-spectrum antibacterial
activity and have been widely used to treat various wound
infections.
In addition to controlling wound infection, appropriate
control of inflammatory reaction at the wound site is benefi-
cial for wound healing, as is the administration of GFs such as
GM-CSF, TGF, VEGF, bFGF and PDGF [34]. In conclusion,
thanks to in-depth research into the pathological mechanisms

4Burns & Trauma, 2021, Vol. 9, tkab026
Figure 2. The healing mechanisms of burn wounds. TGF-αtransforming growth factor alpha, FGF fibroblast growth factor, PDGF platelet-derived growth factor,
VEGF vascular endothelial growth factor, IL-8 interleukin 8, TNF-αtumor necrosis factor alpha
Ta b l e 1 . Current strategies for accelerating burn wounds healing
Principles Strategies Applied drugs or materials
Proper first aid Preventing further injury, immediate cold
treatment, promote microcirculation of wounds,
keeping wound in a wet environment, providing
an ideal wet microenvironment for wounds,
anti-inflammatory and antioxidant therapy
Alprostadil, Chinese herbs (shengmai, saff lor
yellow, etc.) and vitamin C
Early debridement and complete drainage Removal of the necrotic tissue and foreign
matter in the wound, and drainage of blister
fluid or other wound effusion, to provide a clean
environment for wounds
Ultrasound, proteases, maggot, etc.
Prevention and treatment of wound infection Topical and systemic application of
antimicrobial agents
Chinese herbs (Coptis chinensis, phellodendron,
eucalyptus leaves, etc.), chemical disinfectant
(iodophor, hydrogen peroxide, chlorhexidine
acetate, benzalkonium bromide, etc.),
antimicrobial agents (mupirocin, fusidic acid,
silver sulfadiazine, mafenide, etc.)
Promoting wound healing Addition of growth factors FGF, EGF, PDGF, GM-CSF, etc.
Application of functional dressings Hydrocolloids, hydrogels, alginates, foams,
hydrofibres, anti-microbial dressings, etc.
Negative pressure wound therapy Negative pressure pump, sealing film, negative
pressure patch or biocompatible porous
materials
Platelet-rich plasma therapy PDGF, TGF-β, IGF, EGF, VEGF
FGF fibroblast growth factor, EGF epidermal growth factor, PDGF platelet-derived growth factor,GM-CSF granulocyte macrophage colony stimulating factor,
TGF-βtransforming growth factor β,IGF insulin-like growth factor, VEGF vascular endothelial growth factor
of burn wounds, various therapeutic strategies have been
developed to treat these wounds [3], significantly reducing
risk of infection and obviously shortening healing time.
Nanotherapeutics for promoting burn wound healing The
rapid development of nanotechnology over the past 20 years
has provided opportunities for the treatment of various dis-
eases. Nanotherapeutics are the drugs, biomacromolecules
(e.g. DNA, peptides, proteins) and therapeutic materials (e.g.
some metals/metal oxides, chitosan), or pharmaceuticals that
have nanoscale structure in at least one dimension [35].

Burns & Trauma, 2021, Vol. 9, tkab026 5
Ta b l e 2 . Metal and metal oxide nanotherapeutics for treatment of burn wounds
Nanomaterials Size In vitro assays Animal models Reference
Ag NPs - P. aeruginosa Rats bearing burn wound infected with P. aeruginosa [52]
15 nm -Rats bearing burn wound [122]
7–26 nm S. aureus Mice bearing acute burn wound infected with S. aureus [71]
82–140 nm E. coli, P. aeruginosa, S.
aureus
Promoting healing of burn wound on rats [123]
- - Patients with 15–40% partial thickness thermal burns [55]
AgCl NPs 42 ±15 nm - Rats with second-degree burn wound [120]
AgSD NPs ∼282 nm S. aureus, P. aeruginosa, E.
coli
Rats with scald wound [124]
Ag/AgCl NPs ∼10 nm S. aureus, E. coli Mice bearing second degree burn wound [54]
Au NPs 520–525 nm - Repair of burn wound in rats [68]
28–37 nm S. aureus Mice bearing burn wound infected with S. aureus [69]
25 nm -Improving mitochondrial activity of rats bearing burn wound [70]
∼10 nm P. aeruginosa Against infection of rats bearing burn wound [125]
ZnO NPs 30–80 nm E. coli, P. vulgaris, S. aureus Acceleration healing of wound on rats [66]
∼100 nm E. coli, S. aureus Rats with burn wound [65]
S. aureus staphylococcus aureus, P. aeruginosa pseudomonas aeruginosa, E. Coli escherichia coli, NPs nanoparticles
Nanotherapeutics have multiple advantages in treating bac-
terial infection, as they can (1) enhance interactions between
drugs and bacteria or change the pathway of the drug to
improve its anti-bacterial effects; (2) increase drug concen-
tration at infection sites, which helps reduce drug dosage and
alleviate toxic side effects; (3) improve drug penetration into
tissue barriers and bacterial biofilms to overcome bacterial
resistance; and (4) improve the stability and prolong the half-
life of drugs [36]. Due to their abovementioned advantages,
polymeric, metal, metal oxide and other nanotherapeutics
have been widely employed to treat burn wounds. Metal-
lic nanomaterials (Ag, ZnO, Au, Cu) have broad-spectrum
anti-bacterial activity by breaking down biofilms, damag-
ing bacterial DNA or generating ROS to inhibit bacterial
growth [37,38]. However, the toxicity of these nanothera-
peutics should be considered, as it can restrict their fur-
ther in vivo application. Compared with metal nanomateri-
als, polymeric nanomaterials (e.g. polysaccharide, polyester,
polyamide) have excellent biocompatibility and biodegrad-
ability and have been extensively used in various biomedical
fields. Some cationic polymeric nanomaterials, such as chi-
tosan, have bactericidal and bacteriological properties due to
the positive charge of the polymer; they adhere to bacterial
surfaces, inducing damage of the membrane wall, which
prevents microbial growth [39]. Encapsulating antibiotics
in polymeric nanomaterials is another crucial strategy in
preventing wound infection [40], while encapsulating GFs
in such materials to shorten wound healing time has also
been extensively investigated [41]. In summary, nanother-
apeutics have been developed to treat burn wounds and
exhibit good antibacterial effect, shortened wound healing
time and reduced bacterial drug resistance. Therefore, they
are a promising prospect for clinical treatment of burns [23].
In the following section, we summarize the uses of various
nanomaterials and nanotherapeutics in burn wounds and
discuss their merits and disadvantages in such applications.
Metal and metal oxide nanotherapeutics for burn
wound healing
Metal and metal oxide nanotherapeutics (e.g. Au, Ag and
ZnO NPs) have been broadly employed to treat burn wounds
as well as various other cutaneous infections [42,43], since
they possess a broad spectrum of antimicrobial properties.
Furthermore, these nanotherapeutics can overcome bacterial
resistance in multiple ways, such as DNA damage, enzyme
activity disruption, cell wall destruction, plasmid damage,
inhibition of biofilm formation and oxidative stress [36,44].
The applications of metal and metal oxide nanotherapeutics
for the management of burn wounds are summarized in
Table 2.
Ag NPs Ag ions are exceptional anti-microbial agents
due to their superior antibacterial capability and broad-
spectrum antimicrobial effects against bacteria, viruses and
other eukaryotic micro-organisms [45,46]. Ag NPs in par-
ticular have better antimicrobial activity than ionic silver
due to their superior permeation and retention effects [47].
Therefore, they have been extensively used to treat burn
wounds [48–50]. For example, ‘Acticoat’, an Ag NPs-based
bandage for treating burn wounds, has been approved by
the US Food and Drug Administration (FDA) and is used in
clinical practice. Ag NPs-based topical creams, ointments and
gels have been widely used to prevent the spread of microbial
infections in injured patients [51].
For stabilization and convenient administration, Ag NPs
are usually loaded on polymer, inorganic materials or animal
tissues to prepare antibacterial materials for the treatment
of burn wounds. Susceptible pathogenic bacteria such as

6Burns & Trauma, 2021, Vol. 9, tkab026
P. aeruginosa, S. aureus and E. coli have been used to evaluate
the in vitro antibacterial activity of Ag NPs; meanwhile,
to assess these NPs’ in vivo efficacies, rats and mice with
bacterially infected burn wounds have been used as animal
models. For example, porcine-derived small intestinal sub-
mucosa (PSIS) is an acellular, xenogenic biological material
widely used to repair and regenerate wounded and dysfunc-
tional tissues. Zhang et al. used Ag NPs-loaded PSIS as a
biological-derivative dressing for treatment of P. aeruginosa-
infected partial-thickness burn wounds in a rat model [52].
The authors found that Ag NPs-loaded PSIS can significantly
promote wound healing and recover the normal growth of
rats due to suppression of inflammation and stimulation of
re-epithelialization during the wound healing process. His-
tological section results reveal that Ag NPs-loaded PSIS can
obviously decrease inflammatory cell infiltration and accel-
erate re-epithelialization and neovascularization of burned
tissues.
Release of Ag+from Ag NPs often causes side effects
due to the toxicity of Ag+in mammalian cells, resulting in
argyria and argyrosis in humans [53]. To circumvent this
issue, a highly efficient, stable and biocompatible Ag NPs-
based bactericide was developed via fabrication of ultrafine
Ag/AgCl NPs coated with graphene; these have been success-
fully used to treat burn wounds in animal models [54]. An
Ag/AgCl nanophotocatalyst with negligible release of Ag+
can generate a high number of oxidative radicals to kill
bacteria. Histopathological results show that the Ag NPs-
loaded graphene can obviously promote epidermal regener-
ation, which is beneficial in accelerating burn wound healing.
Importantly, the therapeutic efficacy of Ag NPs for treat-
ment of burn wounds has been evaluated in patients with
15–40% partial thickness thermal burns. For instance, Gaba
and co-workers compared the efficacy of silver nanoparticle
gel (SG), nanosilver foam (SF) and collagen (C) dressings in
partial-thickness burn wounds [55]. Interestingly, pain scores
were significantly decreased when patients were treated with
SF dressing at days 5 and 10 (Figure 3a), indicating that
this treatment could relieve patient pain during therapy. Scar
quality at 3 months as assessed by observers and patients was
found to be similar across various parameters (Figure 3b).
In particular, clinical-assessment results suggested that SF
dressings were more efficacious for re-epithelialization and
healing than either SG or C dressings in partial-thickness
burns (Figure 3c–e)[55]. These results indicate that Ag nan-
otherapeutics show promising potential in clinical practice for
the treatment of burn wounds.
ZnO NPs Zinc, which has a long lifetime in living cells,
is an essential micronutrient in tissue regeneration and can
increase keratinocyte count to accelerate wound healing [56–
60]. The underlying antibacterial mechanism is that ZnO
NPs are captured by the bacterial cell wall, resulting in
ineffectiveness and cleavage of the cell membrane of bacteria
[61,62]. Importantly, ZnO NPs can improve cell adhesion,
proliferation and cell migration via GF-mediated pathways
due to Zn’s semiconductor properties. Therefore, ZnO NPs
can also serve as sustained sources of ionic Zn for wound
treatment due to their anti-bacterial, anti-inflammatory and
low cytotoxicity properties [63,64], and indeed they have
been widely used to treat various types of burn wounds.
ZnO NPs are usually loaded on polymer or polysaccha-
ride for bandage preparation, which makes administration
convenient. ZnO NPs-loaded bandages have been extensively
developed for various types of burn wounds in animal models.
For example, a ZnO NPs-loaded keratin-chitosan bandage
displayed high porosity, which was encouraging for the aug-
mentation of fibroblasts [65]. This bandage demonstrated
good antibacterial activity, tensile strength and biodegrada-
tion. In vivo experiments demonstrated that this bandage
could facilitate wound curing via quicker skin cell construc-
tion and collagen development. Alternatively, plant extracts
such as Barleria gibsoni have also been used to stabilize ZnO
NPs; these NPs also showed good antibacterial properties and
were proven to be efficient antimicrobial formulations for
healing burn infections in rats [66].
Au NPs Au NPs possess robust physical and chemical
stability in biological media, as well as superb biocompat-
ibility. They have been proven capable of penetrating the
stratum corneum and thus the skin barrier [67]. For example,
phytochemical-capped Au NPs have been used for transder-
mal treatment of skin with surgical or burn wounds [68]. One
study investigated the biological activities and therapeutic
potential of phytochemical-capped Au NPs by using them to
treat the dorsal skin of rats via transdermal drug delivery in
order to regenerate surgically wounded and burnt skin. In
vivo experiments demonstrated that the treatment effected
by Au NPs in these rats accelerated the growth efficiency of
dorsal skin, increased dermal and epidermis thickness, sup-
pressed collagenase expression and contributed to the induc-
tion of antioxidants. Au NPs have also been encapsulated in
Pluronic 127 and hydroxypropyl methylcellulose to prepare
thermoresponsive gels for treating infected burn wounds in
mice [69]. Histopathological experiments have demonstrated
that these Au NPs formulations show antibacterial activity
with the highest wound healing values. In addition, Au NPs
can significantly reduce oxidative damage parameters and
obviously increase levels of antioxidant defense enzymes in
burn wound tissues; this indicates that they can improve
mitochondrial functioning and oxidative stress parameters,
which contribute to tissue repair [70].
In conclusion, metal and metal oxide nanotherapeutics
have been extensively employed to facilitate burn wound
healing due to their strong broad-spectrum antibacterial
properties. In vivo experiments have verified that these
nanotherapeutics can distinctly decrease bacteria counts in
burnt tissues [52,69,71]. Importantly, the therapeutic efficacy
of Ag NPs has been evaluated in patients with satisfactory
outcomes [55]. Metal and metal oxide nanotherapeutics
therefore show promising potential in clinical practice for
the treatment of various types of burn wounds.

Burns & Trauma, 2021, Vol. 9, tkab026 7
Figure 3. Ag-based nanotherapeutics for treatment of burn wound on patients with 15-40% partial thickness thermal burns. (a) Comparison of assessment of
pain; (b) assessment of scar quality at 3 months [silver nanoparticle gel (SG), nanosilver foam (SF), collagen (C)]; (c–e) clinical photographic assessment in
patient; (c) SG: left leg, SF: right leg, C: bilateral thighs; (d) SG: left buttock, SF: right buttock, C: back torso; (e), SG: left upper limb, C: right upper limb, SF: torso
[55]. (Copyright 2018 by Elsevier Ltd)
Polymeric nanotherapeutics for management of burn
wounds
As previously mentioned, polymeric nanomaterials, with
their excellent biocompatibility and biodegradation, have
been widely employed to fabricate various nanotherapeutics
(NPs, nanoemulsions, nanogels, liposomes, nanofibres
and nanosheets) for the treatment of burn wounds [25].
Either hydrophilic/hydrophobic drugs or GFs can be
encapsulated into polymeric nanomaterials to form various
nanotherapeutics [72]. Polysaccharides (e.g. chitosan,
dextran), polyesters (e.g. PLGA), phospholipids, hyaluronic
acid (HA) or polyvinyl alcohol can serve as carriers for
encapsulating therapeutics [73,74]. The application of
various polymeric nanotherapeutics for the treatment of
burns is summarized in Table 3.
Nanogels Nanogels, which hare particle size <200 nm, are
composed of hydrophilic or amphiphilic polymers through
physical or chemical crosslinking with nanoparticles [75].
Polymeric materials such as polyacrylic acid [76], polyacry-
lamide [77], Pluronic [78], polysaccharide [79], polyethylene
glycol and derivatives thereof are usually employed to pre-
pare nanogels. These materials can be crosslinked through
amine reactions, click chemistry, photo-induced crosslink-
ing, physical crosslinking or heterogeneous polymerization
of monomers to form nanogel systems. Hydrogel sheet or
plasters, impregnated hydrogels and amorphous hydrogels
have been commercialized for the treatment of burns and
other skin wounds [80,81].
Metal or metal oxide antimicrobial agents (e.g. Ag or
ZnO NPs) are loaded on nanogels to prevent infection
and facilitate healing of burn wounds [82–85]. In vitro
experiments indicate that these nanogels loaded with metallic
antimicrobial agents have excellent antibacterial activity
against Gram-negative and -positive bacteria such as P.
aeruginosa, E. coli, S. aureus and MRSA. Their therapeutic
efficacy has also been evaluated in animal models. In vivo

8Burns & Trauma, 2021, Vol. 9, tkab026
Ta b l e 3 . Polymeric nanotherapeutics for treatment of burn wounds
Nanoformulations Carriers Payloads Size In vitro assays Animal models Reference
Nanogels Aerva javanica Ag NPs 8–21 nm P. aeruginosa, MRSA Mice with burn wound infected with P.aeruginosa or MRSA [82]
Sodium-alginate Ag NPs - E. coli, S. aureus Mice bearing burn wound [83]
Aloe vera gel/carbopol 940 Ag NPs - - Rats bearing second degree burn wound [84]
Gelatin/HA/chitoson ZnO/CuO - Fibroblast cells Rats bearing second degree burn wound [85]
Gelatin/pluronic Curcumin 7–16 nm Fibroblast cells Mice bearing second degree burn wound [86]
Pluronic/chitosan EGF - Human keratinocytes Mice bearing second degree burn wound [87]
Polystyrene Peptide - - Rats bearing burn wound [88]
PEG - - NIH3T3 cells Animal with second degree burn wound infected with P. aeruginosa [126]
Silk fibroin-sodium
alginate/poly(N-isopropylacrylamide)
Vancomycin/EGF - Fibroblast cells S. aureus infected rats bearing burn wound [127]
Nanofibres Gelatin/poly-3-hydroxybutyric acid AgSD NPs 100–140 nm - Rats bearing pseudomonas infected burn wound [89]
Zn–Al layered double hydroxides/PVA Cefotaxime - - Rats bearing burn wound [90]
Alginate Lavender oil 91–93 nm S. aureus Promoting healing of burn wound on mice [91]
poly(octyl cyanoacrylate) Fumarate 800 nm -Recovery of mild skin burn on mice [92]
Gelatin Dopamine/antibiotics ∼1000 nm Candida albicans, S. aureus, E.
coli, P. aeruginosa, et al.
Treatment of burn injury on piglets [93]
Gelatin/starch Lawsonia inermis 87 nm S. aureus, E. coli Antibacterial and anti-inflammatory for burn wound on mice [94]
- Peptide amphiphile - hFBs, HUVECs Enhancing burn wound healing on rats [95]
- Peptide - - Rat bearing burn wound for investigation of hair growth [96]
Heparin mimetic peptide - - - Promoting regeneration of burn injury on mice [97]
PCL/chitosan/PVA - - - Rats bearing full thickness round burn wound [128]
PCL/chitosan/PVA ∼136 nm. - Dogs bearing full-thickness third-degree burn wounds [121]
Nanosheets Bacterial cellulose ZnO NPs - E. coli, P. aeruginosa, S. aureus,
Citrobacter freundii
Treatment of burn wound on mice [10]
PLA/PVA AgSD NPs 38 nm MRSA Mice bearing burn wound infected with MRSA [98]
Chitosan Ag NPs 7–33 nm S.aureus, P. aeruginosa Antibacterial/tissue regeneration of burn wound on rats [99]
- Ag NPs - -Rabbits with deep second-degree scald models [100]
Chitosan/sodium alginate Tetracycline 142–177 nm P. aeruginosa Mice bearing burn wound infected with P. aeruginosa [129]
Chitosan/dextran siRNA - NIH-3 T3, HeLa, MDA-MB-231
cells
Reduction of cutaneous scar contraction in third-degree burn on rats [101]
PEO Silk fibroin - - Acceleration of burn wound healing on rats [102]
PLGA/chitosan Minocycline - S. aureus, P. aeruginosa Acceleration of burn wound healing on rats [130]
Nanoemulsions Histidine Ag NPs 120 nm Klebsiella pneumoniae Mice bearing third-degree burn wound infected with K. pneumoniae [131]
Labrasol®,Plurol
®AgSD 25–71 nm E. coli, S. aureus Treatment of burn wound on mice [132]
Virgin coconut oil, olive oil, vitamin E Bromelain 27–126 nm - Treatment of thermal-induced burn wound on rabbits [112]
Tween 80, poloxamer 147,lutrol F68, span 40Fusidic acid 20–110 nm S. aureus Mice bearing burn wound infected with S. aureus [109]
Tween 80/PEG Chlorhexidine acetate ∼63 nm S. aureus MRSA-infected burn wound mice [108]
Poly-3-caprolactone-pluronic Chloramphenicol/essential oil 123 nm S. aureus, P. aeruginosa, C.
albicans, Candida glabrata
Treatment of MRSA–candida co-infected chronic burn wound on mice [133]
Veg et ab l e oi l - - P.aeruginosa Reduction of bacterial wound infection and inflammation after burn injury on
rats
[107]
BAC/CPC/poloxamer 407/tween 20 - 212–336 nm - Rats with scald burn infected with P. aeruginosa or S. aureus [110]
Liposomes DMPC/CTAB Chlorine e6 ∼110 nm C. albicans Rats bearing skin burn wound infected with C. albicans [134]
Lecithin/cholesterol bFGF ∼100 nm NIH/3 T3 fibroblast cells Mice bearing deep second-degree scald [135]
DOTAP/tween 80 EGF 16–87 nm HaCaT Rats bearing burn wound [114]
- Keratinocyte growth factor - - Improving wound healing of scald burn on mice [136]
Lipid NPs Poloxamer®F-127, gellucire®44/14 Fusidic acid ∼310 nm MRSA Prevention of infection from burn wound on mice [116]
Dendrimers Dendrimer Ag NPs - RAW264.7, J774.1 cells Anti-inf lammatory for mice bearing burn wound [118]
MSCs - Fe3O4/PDA NPs - MSC Rats bearing laser burn wound [117]
NPs PCL TiO2–Ag ∼16 μm E. coli and S. aureus Mice bearing burn wound [119]
S. aureus staphylococcus aureus, P. aeruginosa pseudomonas aeruginosa, E. Coli escherichia coli, C. albicans candida albicans, MRSA methicillin-resistant Staphylococcus aureus, NPs nanoparticles, EGF epidermal
growth factor, hFBs normal human fibroblast, PEG polyethylene glycol, HUVECs human umbilical vein endothelial cells, PCL poly(caprolactone), PVA poly(vinyl alcohol), PEO polyethylene oxide, BAC benzalkonium
chloride, CPC cetylpyridinium chloride, DMPC dimyristoyl-sn-glycero-phosphatidylcholine, CTAB cetyltrimethyl ammonium bromide, DPTAP 1,2-Dioleoyl-3-trimethylamonium propane chloride, bFGF basic fibroblast
growth factor, MSC mesenchymal stem cell

Burns & Trauma, 2021, Vol. 9, tkab026 9
experiments have demonstrated that nanogels loaded with
metallic antimicrobial agents can significantly facilitate
wound healing by reducing inflammation, eliminating
pathogenic bacteria and accelerating tissue regeneration.
Histological analysis of wounds has verified that nanogel
treatment can promote granulation tissue formation, collagen
deposition, neovascularization and re-epithelialization, all of
which are beneficial in facilitating wound healing.
In addition to metallic antimicrobial agents, phy-
tomedicines (e.g. curcumin), peptides and GFs (e.g. EGF)
have also been encapsulated into nanogels for treatment of
burn wounds [86–88]. For example, Dang et al. fabricated
injectable nanocurcumin-dispersed gelatin/Pluronic nanogels
for this purpose [86]. The nanocurcumin-dispersed gelatin/-
Pluronic solution can form nanogels on warming, up to 35◦C.
Curcumin-loaded nanogels have good biocompatibility and
can promote fibroblastic proliferation. In vivo experimental
results suggested that the application of curcumin-loaded
nanogels can accelerate the wound healing process.
In conclusion, nanogels as dressings possess multiple
advantages such as good biocompatibility and biodegrada-
tion and easy preparation. Importantly, such dressings can
provide a moist, anti-infectious healing environment and can
be easily removed without trauma. Consequently, various
nanogels containing antibacterial agents or GFs have been
successfully used to treat burn wounds.
Nanofibres Nanofibres are fibres 1–100 nm in diameter.
Polymers such as polyurethane, polydimethylsiloxane,
polyethylene terephthalate, polyethersulfone, poly (acrylic
acid) (PLA) and poly (methyl methacrylate) have been
employed to fabricate nanofibres. Antimicrobials (e.g. Ag
NPs, cefotaxime), plant extracts (e.g. Lawsonia inermis,
lavender oil) and peptides are loaded onto nanofibres to
treat bacteria-infected burn wounds and facilitate the healing
thereof [89–97]. For instance, heparin mimetic-peptide
nanofibres have been employed to promote regeneration
of full-thickness burn injuries in order to alleviate the
progressive loss of tissue function at the post-burn wound
site (Figure 4a, b)[97]. Interestingly, bioactive nanofibres can
form scaffolds that recapitulate the structure and function of
the native extracellular matrix (ECM) by signaling peptide
epitopes, which can trigger angiogenesis via their affinity
for GFs. In vivo animal experiments indicate that heparin-
mimetic peptide nanofibres can support the repair of full-
thickness burn injuries by mediating wound contraction
and re-epithelialization, preventing scar formation and
stimulating the development of skin appendages (Figure 4d).
Investigation into the underlying mechanism has shown
that peptide nanofibres can promote GF (e.g. VEGF, bFGF)
overexpression and facilitate neovascularization at burn
wound sites (Figure 4c, e).
Self-assembling short-peptide nanofibres have been
developed to boost aesthetic repair of burn wounds [96].
Hair follicle growth, hair growth length, and expression of
bFGF and EGF were evaluated in a rat model treated with
nanofibres. The in vivo animal experiments indicated that
levels of all of the above parameters in the experimental
group were better than those in the control group. These
results suggest that self-assembling short-peptide nanofibres
might potentially facilitate the aesthetic repair of burn
wounds.
In summary, because nanofibres can simulate the fibrous
component of natural ECM, they can therefore serve as ECM
analogues for skin regeneration. In addition, nanofibres can
form a protective barrier against penetration of pathogens
into wounds, retain moisture in damaged skin, allow for gas
exchange and absorb wound exudate. In addition, nanofibres
can also be loaded with various bioactive molecules, such as
growth and angiogenic factors, to facilitate healing of burn
wounds.
Nanosheets Nanosheets, which are tens of nanometers
thick, have unique physical properties such as high flexibility,
strong adhesiveness and high transparency [98]. Wounds
coated with nanosheets not only protect wounds from
the environment but also provide a visual field for the
observation of wound recovery. Consequently, bacterial-
cellulose and polymer (e.g. PLA, chitosan, polyethylene
oxide) nanosheets loaded with antimicrobial agents (e.g.
ZnO NPs, Ag NPs) [10,98–100], short interfering ribonucleic
acid (siRNA) [101], and silk fibroin [102] have been
extensively used to treat various types of burn wounds.
For example, Ito et al. prepared silver sulfadiazine (AgSD)-
loaded PLA nanosheets and tested their antimicrobial
properties (Figure 5a)[98]. These nanosheets had a high
degrees of f lexibility, adhesive strength and transparency that
made them suitable for treating burn wounds. An in vitro
Kirby–Bauer test indicated that these nanosheets exerted
antimicrobial efficacy against MRSA. In vivo evaluation
using a mouse model of infected partial-thickness burn
wounds verified that the nanosheets significantly reduced
MRSA bacteria count on the lesions and suppressed the
inflammatory reaction (Figure 5b, c). These drug-loaded
transferrable nanosheets have high potential for treating burn
wounds via controlled drug-release. Nanosheets have also
been employed to deliver siRNAs for local silencing of GFs
to reduce cutaneous scars. For instance, connective-tissue
growth factor (CTGF) has been demonstrated to function
as a key mediator of scar formation in vivo, and mediating
its expression is an effective way to reduce scar formation
[101]. Castleberry et al. exploited nanosheets for controlled
delivery of siRNAs to improve scar outcomes in a third-
degree burn-induced scar model in rats [101]. The authors
demonstrated that knockdown of CTGF can significantly
alter local expression of alpha-smooth muscle actin (α-SMA),
tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen
(Col1a1), which play roles in scar formation. The authors
also verified that improved tissue remodeling, reduced scar
contraction and regeneration of papillary structures within
the healing tissue occurred with knockdown of CTGF in the
burn wounds.
Nanoemulsions Nanoemulsions are thermodynamically
stable carrier systems of small size, with a low polydispersity

10 Burns & Trauma, 2021, Vol. 9, tkab026
Figure 4. Nanofibres for management of burn wounds. (a) Chemical structures of peptide and characterization of peptide nanofibres at pH 7.4 by SEM. (b)
Representative images of burn wounds after nanofibres treatment and quantification of wound areas treated with HM-PA peptide nanofibres. (c)Proteinand
mRNA levels of genes associated with angiogenesis and wound repair at the burn wound sites; qRT-PCR analyses were performed for vascular endothelial
growth factor (VEGF) and basic fibroblast growth factor (bFGF), while Western blot analyses were performed for VEGF and α-smooth muscle actin (alpha-
SMA). (d) Masson’s trichrome staining of wound tissues and quantitative analysis of granulation tissue, re-epithelization, crust area, wound distance and skin
appendages of burn wounds. (e) Staining of blood vessels and quantification of blood vessels. ∗p<0.05, ∗∗p<0.01, and ∗∗∗p<0.0 01. K-PA positively charged
peptide amphiphile, E-PA negatively-charged peptide amphiphile, SEM scanning electron microscope, HM-PA nanofibres, heparin-mimetic peptide nanofibres
[97]. (Copyright 2017 by Elsevier Ltd)
index and high kinetic stability that are formed spontaneously
by water, oil and surfactants. Nanoemulsions formed by
oils with antimicrobial properties (e.g. Cleome viscosa
essential oil; garlic, cinnamon and clove oils) demonstrate
antibacterial activities [103–105]. The oil in a nanoemulsion
can physically fuse with the lipids of microbial outer
membranes, leading to membrane destabilization and lysis
of pathogens [106]. Nanoemulsion formulations have been
shown to exhibit broad antimicrobial properties and are
widely used to treat burn wounds [107,108]. For example,
Thakur et al. employed fusidic acid-loaded cationic bilayered
nanoemulsions to prevent bacterial penetration and act as

Burns & Trauma, 2021, Vol. 9, tkab026 11
Figure 5. Silver sulfadiazine (AgSD) nanoparticles (NPs)-loaded nanosheets for treatment of burn wound in mice. (a) Scheme for the preparation of AgSD-loaded
nanosheets. (b) Wound healing potency of AgSD-loaded nanosheets 6 days after treatment ((•no infection, o sham, AgSD (−), AgSD (+)), (n=6, ∗p<0.05)
(inset) (a and b) macroscopic images of the wound before a and after b applying the AgSD-loaded nanosheets. (c) Histological images of the wound area 3 days
after injury, a no infection, b sham, c AgSD (−),anddAgSD(+). Ddermis, Ssubcutaneous layer, Aadipose tissue, Hhair root, PLA poly(lactic acid), PVA,
poly(vinyl alcohol) [98]. (Copyright 2015 by Elsevier Ltd)
a drug reservoir [109]. Cationic bilayered nanoemulsions
have multiple advantages in burn wounds, such as enhanced
drug permeation, reduced bacterial load, accelerated wound
contraction and facilitation of re-epithelialization. Both ex
vivo and in vivo studies have verified that treating burn
wounds with cationic bilayered nanoemulsions can rapidly
decrease bacterial counts. Furthermore, these nanoemulsions
can form a continuous film over the wound surface that can
improve healing. Nanoemulsions composited with cationic
or nonionic surfactants are utilized to treat P. aeruginosa
and S. aureus infected burn wounds [110]. Interestingly, in
rats bearing burn wounds, nanoemulsions can significantly

12 Burns & Trauma, 2021, Vol. 9, tkab026
Figure 6. EGF-loaded liposomes for treatment of burn wound in rats. (a) Graphic illustration. (b) Representative photos of full partial-thickness burn wound treated
with EGF-loaded liposomes at various time points. (c) Wound closure rate of full partial-thickness burn wound at various time points. ∗p<0.05, ∗∗p<0.01. TRA
all-trans retinoic acid, TRA DLs all-trans retinoic acid loaded deformable liposomes, EGF CD Ls epidermal growth factor cationic deformable liposomes, DOTAP
1,2-dioleoyl-3-trimethylamonium propane chloride, PC phosphatidyl choline [114 ]. (Copyright 2019 by Royal Society of Chemistry)
decrease colonies of both bacterial species, reduce inf lamma-
tion and facilitate wound healing progression. Bromelain is
known in clinical practice for debridement in burn treatment,
but it is easily inactivated by light, high temperatures and
high pH values [111]. To increase the efficacy and stability
of bromelain in such treatment, Rachmawati et al.prepared
a bromelain-encapsulated nanoemulsion [112]. They then
evaluated its efficacy on the burnt skin of rabbits by observing
wound contraction, eschar score, erythemic score, pus score
and oedema. Their results verified that the nanoemulsion

Burns & Trauma, 2021, Vol. 9, tkab026 13
Figure 7. Fe3O4@polydopamine (Fe3O4@PDA) nanoparticles (NPs)-labelled mesenchymal stem cells (MSCs) for treatment of burn wounds in rats. (a)Fe
3O4@PDA
NPs preparation and internalization by MSCs. (b) The viability and proliferation potential of Fe3O4@PDA NPs-labelled MSCs. (c)EffectsofFe
3O4@PDA NPs on
MSCs migration in vitro. (d) Effects of MSCs on burn injury and their therapeutic effects in a living rat model. FBS fetal bovine serum [117 ]. (Copyright 2019 by
Royal Society of Chemistry)
showed better activity than free drug. In conclusion,
compared with conventional administration, nanoemulsion
showed enhanced antibacterial activity that is beneficial to
accelerating the healing of burn wounds.
Liposomes and solid lipid NPs Liposomes are closed
vesicles with one or more waterborne chambers formed by
dispersing insoluble phospholipids and other amphiphilic
substances in water. A variety of natural and synthetic
phospholipids are available for the preparation of liposomes,
such as phosphatidyl choline, ceramide cholesterol and
phosphatidyl ethanolamine. Liposomes can directly fuse with
the bacterial cell membrane and release drugs either into
its interior or within the membrane. They can also be used
effectively to cover wounds to create a moist environment on
the wound surface, which is very conducive to wound healing
[113]. GFs (e.g.bFGF, EGF, KGF) and photosensitizers
(e.g. chlorine e6) are encapsulated into liposomes to treat
various types of burn wounds. For instance, Lu et al.
prepared trans-retinoic acid deformable liposomes and EGF
cationic deformable liposomes for the treatment of deep
partial-thickness burns (Figure 6a)[114]. The results of a
scratch wound recovery assay suggested that both types of
liposome not only synergistically enhanced cell proliferation
and migration but noticeably boosted wound healing
and improved healing quality when incorporated together
into an ointment matrix (Figure 6b, c). Histopathological
examination further confirmed that these liposomes could
promote skin appendage formation and increase collagen
production, thereby improving healing quality. The authors
also found that trans-retinoic acid significantly upregulated
the expression of EGFR and heparin-binding epidermal
growth factor (HB-EGF) to enhance the therapeutic effect of
EGF. The dual liposome ointment might serve as a promising
topical therapeutic for burn wound treatment.
Solid lipid NPs-encapsulated fusidic acid has also been
used to treat burn wounds, since fusidic acid can inhibit
bacterial translation by blocking bacterial protein synthe-
sis [115]. Thakur et al. fabricated fusidic acid-loaded lipid-
polymer hybrid NPs and used these solid lipid NPs against
bacteria in MRSA-infected burn wounds [116]. Lipid NPs
coated with cationic chitosan can enhance the permeation and
retention of fusidic acid across skin layers, which is beneficial
to delivering fusidic acid into the deep dermis/epidermis
milieu. Therapeutic efficacy was further assessed in a model
of murine burn wounds infected with MRSA with parameters
such as bacterial burden, wound contraction, and morpholog-
ical and histopathological examinations of wounds. Bacterial
counts decreased drastically on day 3, and wounds shrank
significantly on day 5. In summary, liposomes can provide a
moist environment on the surface of wounded skin because
of their effective closure of epidermal cells to promote wound
healing, and therefore they are widely used to treat various
types of burn wounds.
In summary, polymeric nanotherapeutics have been
extensively studied as treatments for various kinds of
burn wounds due to their excellent biocompatibility,
biodegradation and high therapeutic efficacies. In particular,
biomacromolecules and drugs can be continuously released
from polymeric nanotherapeutics to maintain consistent
drug concentrations in wounds, which might permit dosing

14 Burns & Trauma, 2021, Vol. 9, tkab026
Ta b l e 4 . Assessment of burn wounds with nanotherapeutics treatment
Assessment methods Assessment items Outcomes
Counting of bacterial colonies E. coli, P. aeruginosa, S. aureus, P. vulgaris, C. albicans, C.
freundii, K. pneumonia, C. glabrata
Nanotherapeutics significantly reduce bacterial
infection at burn wounds
Macroscopic observation Healing rate of wounds Nanotherapeutics obviously facilitate wound
healing
Histopathology Re-epithelialization, coagulation, vascular growth,
dermis, hypodermis, panniculus carnosus, subcutaneous
layer, adipose tissue, granulation tissue, regenerated
sebaceous glands, skin appendage, neutrophils, scab,
ulceration, thickness of epidermis, number of
keratinocytes, hair roots, hair follicles
Nanotherapeutics can promote
re-epithelialization, vascular growth, granulation
tissue formation to boost burn wounds healing
Cytokines Interleukins (IL-1a, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10,
IL-13)
Nanotherapeutics can reduce inflammatory
factors expression and increase growth factors
expression to relieve inflammation and
accelerate tissue formation
Growth factors (KGF, IGF-1, IGF-BP3, FGF, TGF-β,
PDGF, HB-EGF, CTGF, α-VEGF, bFGF)
Chemokines (CXCL1, CXCL2, CINC-1, CINC-3)
Tumor necrosis factor (TNF-α)
Transforming growth factor-βfamily (TGF-β)
Adhesion molecules (ICAM1)
GM-CSF
Enzymes Lipid peroxidation, superoxide dismutase, glutathione
peroxidase, myeloperoxidase, MMP-2, MMP-9,
mitochondrial respiratory chain complexes I, II, III and IV
Some nanotherapeutics exhibit anti-oxidation
activity
Others Tissue inhibitor of metalloproteinases 1 (TIMP1),
α-smooth muscle actin (α-SMA), collagen type 1 alpha1
(Col1a1), C-reactive protein (CRP),
Nanotherapeutics can decrease α-SMA
expression to reduce scar formation
KGF keratinocyte formation growth factor, IGF insulin-like growth factor, IGF-BP insulin like growth factor binding protein, FGF fibroblast growth factor,
TGF-βtransforming growth factor beta, PDGF plateletderived growth factor, HB-EGF heparin binding epidermal growth factor, CTGF connective-tissue
growth factor, VEGF vascular endothelial growth factor, bFGF basic fibroblast growth factor, GM-CSF granulocyte macrophage colony stimulating factor,
MMP matrix metalloproteinase
frequency to be decreased. In addition, the bioavailability of
biomacromolecules and drugs can be improved, as NPs can be
internalized by macrophages and other cells via endocytosis
or pinocytosis.
Other nanotherapeutics In addition to the aforementioned
nanoformulations, other innovative strategies have also been
developed to treat burn wounds. For example, mesenchymal
stem cell (MSC)-based therapy is a promising strategy for
tissue regeneration and repair. To enhance migration of MSCs
to wound tissues, Li et al. prepared Fe3O4@polydopamine
(Fe3O4@PDA) NPs-labelled MSCs and evaluated their effect
at the injury site (Figure 7a)[117]. In vitro cell assays
indicated that MSCs labelled with Fe3O4@PDA NPs did not
affect cell proliferation (Figure 7b). By contrast, Fe3O4@PDA
NPs could enhance the migratory ability of the MSCs by
upregulating the expression levels of chemokine receptors
(Figure 7c). The researchers intravenously administrated
Fe3O4@PDA NPslabelled MSCs to rats with burns and
performed live imaging to monitor MSCs migration. The in
vivo images showed that Fe3O4@PDA NPslabelled MSCs had
prolonged retention time at burn injury lesions (Figure 7d).
Importantly, the group of Fe3O4@PDA NPslabelled MSCs-
injected rats showed less inflammation than rats injected
with unlabelled MSCs. Ag NPs-loaded dendrimer or
TiO2/Ag-encapsulated poly(caprolactone) (PCL) NPs have
also been used to treat burn wounds in mouse models
[118,119].
Assessment of burn wounds treated with
nanotherapeutics
Both in vitro and in vivo models have been extensively
employed to evaluate the therapeutic efficacies of nan-
otherapeutics. Anti-bacterial, anti-inflammatory and cell
proliferation experiments have been mainly used to assess
in vitro therapeutic efficacies of nanotherapeutics. However,
many studies have focused on the animal models to evaluate
the in vivo therapeutic efficacies of nanotherapeutics. Animals
such as mice [54], rats [120], rabbits [100,112], dogs [121],
and piglets [93] bearing burn wounds with or without
bacterial infection have been used in a broad range of studies
to evaluate the therapeutic effects of nanotherapeutics on
such wounds. Abazari et al. have synthetically reviewed the
establishment of various types of burn wounds (e.g. second vs.
third-degree, partial- vs.full-thickness) in animals [25]. The
clinical application of nanotherapeutics was also studied in
humans with 15–40% partial-thickness thermal burns [55].
Antibacterials, anti-inflammatories and mediation of GF
expression are still the primary strategies in nanotherapeutic

Burns & Trauma, 2021, Vol. 9, tkab026 15
treatment of burn wounds. Macroscopic photography
provides visual images to evaluate healing of burn wounds by
nanotherapeutic treatment. Macroscopic images demonstrate
that nanotherapeutics can facilitate better burn wound
healing than their conventional counterparts. Bacterial
colonies in wounds are also counted to assess nanotherapeutic
antibacterial efficacy. Antibacterial tests indicate that
nanotherapeutics can significantly reduce bacteria count and
prevent infection to accelerate wound healing. Histopatho-
logical images of skin tissue are useful in investigating the
mechanism of wound healing (Table 4). For example, these
images can demonstrate how nanotherapeutics promote re-
epithelialization, neovascularization and granulation tissue
formation in wounded tissues to boost wound healing. The
therapeutic mechanisms of nanotherapeutics are further
revealed via detection of inflammatory cytokines and GF
expression at burn wound sites (Table 4). For instance,
inflammatory cytokines such as TNF-α, IL-1, and IL-6 are
typically used to appraise the anti-inflammatory efficacy of
nanotherapeutics. GFs including VEGF, TGF-α,TGF-β,FGF
and PDGF are also detected to estimate cell proliferation
after nanotherapeutics treatment. In summary, various
methods have been utilized to investigate the therapeutic
efficacy and mechanisms of nanotherapeutics in burn
wounds.
Conclusions
A wide range of NPs have been explored for management of
burn wounds. Using nanotherapeutics to treat these wounds
has some advantages, such as increasing antibacterial effect,
overcoming bacterial drug resistance, facilitating cell prolif-
eration and decreasing drug administration frequency. The
therapeutic efficacy of nanotherapeutics has been evaluated
in various animal models on different types and degrees
of burns. Some nanotherapeutics exhibit satisfactory thera-
peutic effects in patients with burn injuries, making them
promising candidates for further studies of their role in the
management of these wounds. Although gratifying therapeu-
tic effects have been achieved, the toxicity of nanotherapeutics
due to their particular physicochemical properties cannot be
ignored. How to prepare multifunctional nanotherapeutics
with good biocompatibility and efficacy for the treatment of
burns needs further investigation. In particular, the systemic
toxicity of nanotherapeutics should be investigated in various
animal models before proceeding to patient applications.
How to prepare nanotherapeutics for clinical practice on a
large scale must also be considered. Although some problems
must be overcome before this can happen, we believe that
more burn patients can profit from nanotherapeutics in the
future.
Abbreviations
AgSD: Silver sulfadiazine; α-SMA: Alpha-smooth muscle
actin; BAC: Benzalkonium chloride; bFGF: Basic fibroblast
growth factor; C: Collagen; CINC: Cytokine-induced
neutrophil chemoattractant; Col1a1: Collagen type 1 alpha
1; CPC: Cetylpyridinium chloride; CXCL-1: Chemokine
(C-X-C motif) ligand 1 protein; CRP: C-reactive pro-
tein; CTAB: Cetyltrimethyl ammonium bromide; CTGF:
Connective-tissue growth factor; DMPC: Dimyristoyl-
sn-glycero-phosphatidylcholine; DNA: Deoxyribonucleic
acid; DOTAP: 1,2-Dioleoyl-3-trimethylamonium propane
chloride; EC: Endothelial cell; ECM: Extracellular matrix;
EGF: Epidermal growth factor; EGF CDLs: EGF cationic
deformable liposomes; FBS: Fetal bovine serun; FDA:
Food and Drug Administration; FGF: Fibroblast growth
factor; FN: Fibronectin; GFs: Growth factors; GM-CSF:
Granulocyte macrophage colony stimulating factor; HA:
Hyaluronic acid; HaCaT: Human immortal keratinocyte cell
line; HB-EGF: Heparin binding epidermal growth factor;
hFBs: Normal human fibroblast; HM-PA: Heparin-mimetic
peptide; HUVECs: Human umbilical vein endothelial cells;
ICAM-1: Intercellular adhesion molecule-1; IGF: Insulin-like
growth factor; IGF-BP: Insulin like growth factor binding
protein; IL: Interleukin; KGF: Keratinocyte formation growth
factor; MMP: Matrix metalloproteinase; MRSA, Methicillin-
resistant Staphylococcus aureus; MSC: Mesenchymal stem
cell; NGF: Nerve growth factor; NPs: Nanoparticles; PBS:
Phosphate buffer saline; PC: Phosphatidyl choline; PCL:
Poly(caprolactone); PDA: Polydopamine; PEG: Polyethy-
lene glycol; PEO: Polyethylene oxide; PDGF: Platelet-
derived growth factor; PSIS: Porcine-derived small intestinal
submucosa; PLA: Poly(lactic acid); PLGA: Poly(lactic-co-
glycolic acid); PVA: Poly(vinyl alcohol); ROS: Reactive
oxygen species; SG: Silver nanoparticle gel; SF: Nanosilver
foam; siRNA: Short interfering ribonucleic acid; TGF-β:
Transforming growth factor beta; TIMP-1: Tissue inhibitor
of metalloproteinase-1; TNF-α: Tumor necrosis factor alpha;
TRA: All-trans retinoic acid; TRA DLs: All-trans retinoic
acid loaded deformable liposomes; TSP: Thrombin-sensitive
protein; VEGF, Vascular endothelial growth factor.
Funding
This work supported by the Open Project Program of the
State Key Laboratory of Trauma, Burn and Combined Injury,
Third Military Medical University (No. SKLKF201905,
SKLKF201918).
Authors’ contributions
R.H. drafted the manuscript. J. H. and D. Z. designed this
project and revised the manuscript. W. Q. prepared the
revised manuscript. L. C. prepared some figures and tables.
All authors read and approved the final manuscript.
Conflict of interest
The authors declared that they have no conflicts of interest
to this work.

16 Burns & Trauma, 2021, Vol. 9, tkab026
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