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.