1. Introduction
The skin covers the surface of the human body and is itslargest organ.
The surface area of an adult is approximately 2 m2.
The skinfunctions as a protective barrier between the human body and the
external environment, playing an important role in moisturizing,
temperature control, sensory perception, humoral balance maintenance and
external pathogensresistance(Dabrowska et al., 2018). Due to long-term
exposure, the skin bears the brunt of various external stimuli. The
wounds caused by destruction of the skin’s integrity facilitates the
occurrence of diseases. The most common wounds are burns, surgical
incisions and cuts, bruises, and lacerations caused by trauma. There are
signs of healing in most of these wounds within 3 months due to the
self-healing properties of the organism. However, in some cases, such as
an uncontrolled infection, these acute wounds can develop into chronic
wounds, which last for months or even years(Hoversten et al., 2020).
Recently, with the prevalence of chronic diseases such as obesity,
diabetes and vascular dysfunction that have risen significantly over
time, an increasing number of patients suffer from chronic wounds.
Diabetic patients have a 15-25% risk of developing diabetic chronic
ulcers(Spampinato et al., 2020). In addition, some infectious skin
diseases, such as hidradenitis suppurativa, swimming pool granuloma,
sporotrichosis, certainautoimmune skin diseases
includingBehcet’ssyndrome, dermatomyositis,some physical skin diseases,
such as radioactive dermatitis, bedsores, and some malignant skin
tumors, can also make patients vulnerable to chronic wounds. The
subcutaneous tissue of chronic and nonhealing wounds is exposed to the
external environment for a long period of time, which predisposes
patients to bleeding and osteomyelitis. This leads tothe risk of
amputation or death for patientsin serious condition. The existence of
chronic wounds not only reduces the quality of life of patients and
increases their economic burden but also results in adverse mental,
motor and psychosocial problems. Expanded medical resources have
contributed to a growing burden on the healthcare system. Chronic wounds
are so common that they are called silent epidemics(Lindholm et al.,
2016).
Wound healing has always been a difficult problem for clinicians, and
new materials and methods are urgently needed. With the rapid
development of nanotechnology in this century, the nanomaterials
produced by the combination of multiple disciplines have beenapplied in
the fields of medicine, pharmacy, chemical industry and national
defense. Nanomaterials (usually less than 100 nm in diameter) exhibit
special physicochemical properties due to their unique structure, which
leads to small size effects, surface effects, and macroscopic quantum
tunneling effects. In recent years, nanomaterials have also been widely
used in wound healing due to their excellent adsorption capacity and
antimicrobial properties(Berthet et al., 2017). Wound dressings, which
work as temporary skin substitutes, play an important role in
hemostasis, infection control and the promotion of wound closure.
Various dressing materials have been developed since immemorial time.
Traditional wound dressings, such as gauze and bandages, just fill the
skin defect(Mihai et al., 2019). The ideal dressing should not only
simulate the extracellular matrix
(ECM) to provide a moist environment but also have antimicrobial
properties and promote cell proliferation and angiogenesis, thus
requiring special materials with excellent properties (Table 1).The very
large market demand for these materials has accelerated the development
of nanomaterial dressings(Han et al., 2017). Currently, new nanomaterial
dressings such as hydrogels, nanofibers and films are being widely used.
The global market for these products is expected to exceed $20.4
billion by 2021(Homaeigohar et al., 2020).
Although an increasing number of new nanomaterials have been reported
for use in wound healing in recent years, their mechanisms have not been
comprehensively summarized. Here, we review the potential mechanisms and
recent application progress of nanomaterials that promote wound healing
fromdifferent aspects, as well as their possible toxicity. Importantly,
we propose the limitations of the current clinical applications and
mechanistic research of the nanomaterials in wound healing and provide
solutions and new research ideas, which may be research directions in
the future.
2. Hemostasis
A rapidhemostasis process is vital in
the first phase of wound healing. Nanomaterials have been widely used in
wounds due to their excellent hemostatic properties. Compared with
traditional gauze, nanoscale sponges have porous structures and a strong
capability to absorb water. Nanomaterials cancover the wound surface and
promote the formation of blood clots from wetted blood. Both endogenous
and exogenous coagulation systems are activated to stop bleeding, and
the possible mechanisms of this process have been explored.Nanomaterials
recruit blood cells, including erythrocytes, platelets and leukocytes,
through electrostatic adsorption or the interaction between sulfhydryl
groups and blood cells. The aggregation of erythrocytes occludes the
blood vessels and increases the blood viscosity to facilitate the
margination of platelets. Expression of the adhesion molecule PECAM-1
increases, which enhances the interaction betweenendothelial cells and
platelets(de la Harpe et al., 2019). At the same time, the nanomaterials
initiate the activation of platelets by inducing interactions with
glycoprotein IIb/IIIa receptors and the influx of extracellular
Ca2+(Simak et al., 2017). As the platelets
aggregate,
blood clots are formed, and subsequently, the nanomaterials accelerate
the coagulation cascade by regulating the expression of
prothrombin(Onwukwe et al., 2018). On the other hand, the
nanomaterialspromote the adhesion and migration of fibroblasts and the
crosslinking of fibrin stabilizesthe clot. In addition to the hemostatic
ability of the nanomaterials themselves, they are can also be used for
wound hemostasis by loading hemostatic drugs. Thrombin-loaded scaffolds
potentiate the release of thrombin and activation ofplatelets to reduce
bleeding time. The nanomaterials mediate rapid and effective hemostasis
to promote wound healing (Figure 1A). Compared with traditional gauze
and hemostatic methods, nanomaterials can facilitate clotting through
their physical and chemical properties.They show unique advantages for
the hemostasis of acute wounds with poor hemostasis effects by suture
bleeding and patients with blood coagulation disorders. Thus, the use of
nanomaterials is a convenient and effective hemostatic method for
chronic open wounds with microvascular bleeding.
3.Anti-wound infections
Wound infection is the most common complication in wound healing.
Because of the damaged skin barrier, external microorganisms easily
invadeinto wounds. The infection impedes wound healing and involves
muscles and bones when the infection spreads. Therefore, controlling
wound infection is a prerequisite for the promotion ofwound healing.
3.1 Antimicrobial properties
Studies have examined the antimicrobial actions of nanomaterials against
bacteria and fungi.Common pathogenic microorganisms of wound infections,
such asStaphylococcus aureus , Escherichia coli andCandida glabrata, wereinhibited by nanomaterials in
vitro(Pena-Gonzalez et al., 2017). The mechanism of action of
nanomaterials showa wide range of antimicrobial
abilities.Nanomaterials can increase
bacterial cell membrane permeability by piercing with their sharp edges
or interacting with membrane proteins. This loss incell membrane
integrity leads to the leakage of cytoplasmic components and eventually
bacterial lysis(Liao et al., 2019).On the other hand, the
nanomaterialscan infiltrate bacterial cells to destroy proteins, DNA and
lipids by binding via sulfurbonds or inducing oxidative stress(Mihai et
al., 2019; Singh et al., 2020)(Figure 1B). The widespread abuse of
antibiotics has led to bacterial resistance, which is related to
microbial target modification, antimicrobial agent modification and the
pumping out of the drug from the cell(Mofazzal Jahromi et al., 2018).
However, an in vitro study found that there was no significant
difference in the bacteriostatic efficacy of nanomaterialsbetween
methicillin-resistant S.
aureus (MRSA) and nonantibiotic-resistant S. aureus (Mohamed et
al., 2020).Thisresult demonstrated that nanomaterials have the advantage
of avoiding antimicrobial resistance mechanisms and are effective
against resistant microorganisms.
In addition, microorganisms exist in the form of biofilms in most
chronic wounds. In a biofilm, one or multiple bacterial communities are
closely linked together in a dynamic and orderly manner, forming an
enclosed film outside the cells. The biofilm develops a reactive
oxygen-dependent state that is insensitive to oxidative stress and
protects the bacteria from attack by the host immune response. Studies
have explored the antibiofilm mechanisms of nanomaterials. A nanosystem
made from theF-127 surfactant,
tannic acid and polymetforminnanoparticles(FTPNPs), has hydrophilic
poly(ethylene glycol) (PEG) chains
on the surface of the NPs. The PEG chains assistthe NPs in infiltrating
into the biofilms todestroy themby increasing membrane permeability(Li
et al., 2020).Moreover, nanomaterials can inhibit the formation of
biofilms by reducing interbacterial adhesion through surface charge,
hydrophobicity and surface morphology, as well as
disturbingquorum sensing (QS)(Ong
et al., 2019; Qais et al., 2020).
Notably,most
of the current research has focused on common microorganismsthat are
usually curable by traditional treatments. However, the challenge of
wound healing lies in complex infectionsfrommultidrug-resistant
microbes, including bacteria and fungi. Although studies have indicated
that nanomaterials have inhibitory effects againstboth bacteria and
fungi, there is a lack of in vivo studies fungal wound infections due to
difficulty in establishing animal models. Most studies use only a single
pathogenic biofilm model. However,synergistic effects among
different microorganisms can increase
virulence, so it is necessary to evaluate the antimicrobial efficacy of
mixed infections. The chronic fungal skin diseasessuch as
chromoblastomycosis, sporotrichosis and penicilliosismarneffeiare
usually accompanied by skin wounds. There are few drugs with long
treatment cycles and high costs for the treatment of wounds with chronic
fungal infections. It will be of great benefit to patients if
nanomaterials can have clearantifungal effects and greatly shorten
treatment time.
In addition, most in vivo wound biofilm models are constructed by
inoculation of microorganisms onto
excision wound sites. These microorganisms may just be planktonic on the
wound surface without an orderly arrangement to form a biofilm(Li et
al., 2020). Becauseof various factors, including the host immune
response, there are individual differences between differentin vivo
biofilm studies. A stable in vivo model and an ideal in vitro model are
still needed to explore the antibiofilm mechanism of nanomaterials.
Moreover, we should be concerned about the potential risk
ofnanomaterials that may lead to microbial variation. Nanomaterials have
the ability to cause DNA damage and epigenetic changes. Studies have
shown that nanomaterials can lead to drug resistance mutations, and
further potential side effects should be considered in addition
tofocusing on their antimicrobial properties(Bainomugisa et al., 2018).
3.2 Antimicrobial drug delivery
For a long time, antibiotics have been the first choice for the
treatment of wound infections. Considering the impaired blood
circulation in chronic wounds, an efficient local delivery system may be
an appropriate way to improve the sterilization efficiency of drugs.The
high surface area of nanomaterials allows them to deliver antimicrobials
to the wound for infection control. Ceftriaxone, gentamicin and
itraconazole have been loaded intonanomaterials to develop nanocomplexes
with high loading capacities and a slow sustained release of
theantimicrobial(Alhowyan et al., 2019; Chen et al., 2020).Moreover,
nanomaterials have synergistic antibacterial effects by enhancing the
internalization of the antibiotics. Nanomaterialscan increase membrane
permeability by affecting the membrane potential and ultrastructure of
bacterial cells, which makes infiltration by antibiotics
easier(Vazquez-Munoz et al., 2019).
However, with the evolution of antibiotic-resistant bacteria,
nanomaterials as drug carriers cannot solve the problem of antibiotic
resistance. Antibiotic delivery nanosystems are being replaced by
nonantibiotic active ingredient-loaded nanomaterials. It has been proven
that tetrahedral framework nucleic
acids (tFNAs)can increase the bacterial absorption of antimicrobial
peptides by promoting instability of the bacterial membrane. tFNAsalso
protect antimicrobial peptides from degradation in the protease-rich
extracellular environment(Liu et al., 2020).A number of antimicrobial
agents are being developed for wound infections, such as defensins,
therapeutic microorganisms (bacteriophages and probiotics) and
photodynamic therapy
(PDT)(Mofazzal Jahromi et al., 2018). There are currently few studies on
nanomaterials as carriers or protectants for these antimicrobial agents.