1. Introduction
Skin, as the largest organ of the human body, can regulate body temperature and resist the invasion of various pathogens and microorganisms
[1], a natural barrier for the internal environment of the human body to directly contact the outside world. Therefore, skin integrity is very important for human health
[2]. Wounds can be caused by the injury and destruction of skin tissue, and many accidents in daily life can easily lead to wounds. After trauma, the skin recovery process is dynamic and complex, including four stages: hemostasis, inflammation, cell proliferation and remodeling
[3]. Moreover, special diseases such as diabetes also affect the wound microenvironment and extend its healing time. According to the difference in wound recovery time, wounds can be divided into acute and chronic. For chronic wounds, the recovery time is long, and the risk of exogenous negative interference is high. To protect wounds from external pollution, avoid wound deterioration and promote wound healing, the use of wound dressings is very critical for wound treatment. Due to the complex and dynamic process of wound healing, wound dressings need good biocompatibility, stability, certain mechanical properties, permeability, and the ability to absorb the excess tissue osmotic fluid produced by the wound. Further, the ideal wound dressing should also have antibacterial and anti-inflammatory functions to promote cell growth and accelerate wound healing
[4].
Wound dressings have a long history, dating back to 1550 BC, when wound dressings were a mixture of oil, honey, and cotton wool. With the continuous expansion of research, multifunctional dressings that can provide an ideal wound recovery environment are applied to wound healing. At present, the main forms of wound dressings are gauze, bandages, sponges
[5], films
[6], scaffolds
[7], hydrogels
[8] and nanofibers, among which gauze and bandages are traditional dressings with low-cost performance, but their effects on wound healing are limited to protecting the wound from external stimulation, and there is a risk of secondary injury caused by adhesion to the wound. Sponge, hydrogel, and nanofiber dressings are new dressings developed by researchers according to the characteristics of wound healing to accelerate wound healing. Compared with these wound dressings, nanofibers have significant advantages, such as high permeability and specific surface area.
Meanwhile, nanofibers can also form a structure similar to the natural extracellular matrix (composed of interwoven protein fibers), providing a favorable environment for the adhesion and proliferation of cells and promoting the transport of nutrients. Moreover, some studies have shown that cells adhere to fibers smaller in diameter than themselves
[9]. The rapid development of nanotechnology positively impacts the preparation of nanofibers. The preparation methods of nanofibers mainly include melt blowing, rotary jet spinning, manual spinning, pressurized rotary spinning and electrospinning
[10][11][12][13][10,11,12,13], which have been developed for manufacturing drug-loaded nanofiber scaffolds.
Electrospinning is a low-cost, simple, and flexible process for producing nanofibers. Nanofibers prepared by electrospinning technology have strong programmability, and the nanofibers with controllable structure and uniform continuity can be fabricated by adjusting the preparation process parameters
[14], which makes them widely used in catalysis
[15], filtration
[16], electrochemistry
[17] and food engineering
[18]. Furthermore, the structure and composition of electrospun NFM can be similar to those of the natural extracellular matrix, and their high porosity can promote the attachment, migration and proliferation of cells
[19], which makes them have great potential in the fields of biosensors
[20], drug transportation
[21] and wound dressing
[22]. Especially as wound dressings, electrospun NFMs with high surface area and high porosity can provide a good environment for the exchange of water and gas between the wound surface and the outside world, which is conducive to the absorption of tissue osmotic fluid at the wound and the carrying of therapeutic factors
[23]. Moreover, the inherent high flexibility and toughness of NFMs provide convenience for using different parts of wounds. Meanwhile, the design and combination of materials and structures for electrospun nanofibers can also make them more likely to simulate the structure and function of natural skin and promote wound healing
[24].
2. The Application of Electrospun Nanofibers in Wound Dressings
2.1. Matrix Materials
Polymers are the main matrix materials for electrospun nanofibers, which can be divided into natural polymers and synthetic polymers. Natural polymers have the advantages of good biocompatibility, friendly structure, and nontoxicity, which make them popular materials in the biomedical field. Meanwhile, it has been proven that materials with good biocompatibility and degradability can be recognized by cell surface receptors in wound recovery, thus causing cell adhesion and proliferation
[25][58]. Common natural polymers include polysaccharides (such as chitosan, cellulose, hyaluronic acid, and alginate) and proteins (such as collagen, silk fibroin, gelatin and fibrin).
Chitosan has become a vital member of the wound dressing material family due to its excellent biological and antibacterial properties
[26][59]. In the inflammatory stage of wound recovery, chitosan can promote the migration of cells to the wound area, which is conducive to the elimination of microorganisms by macrophages, decomposition of dead cells, and stimulation of cells related to tissue and angiogenesis. However, chitosan has poor solubility and is difficult to directly electrospun
[27][60]. A common strategy is to prepare chitosan-based electrospun nanofibers by controlling chitosan’s molecular weight and deacetylation degree or blending with other materials
[28][29][61,62]. Cellulose has excellent thermal stability, chemical resistance, and good biological properties, which can reduce pain and promote the formation of granulation and epithelization at the wound. Due to the limited solubility of cellulose, cellulose acetate based on modified cellulose is mostly used to prepare nanofibers
[30][31][63,64]. In addition, bacterial cellulose has good biological function and excellent mechanical, which has a positive impact on vascular regeneration, damaged tissue remodelling and wound healing
[32][65]. Collagen is a three-dimensional network structure composed of nanoscale fibrils and extracellular matrix proteins
[33][66]. Therefore, electrospun nanofibers prepared with collagen are very similar to the natural extracellular matrix of cells and have tissue formation promotion and cell function regulation
[34][67]. Zhou et al.
[35][68] extracted marine type I collagen from tilapia and prepared electrospun nanofibers with smooth surfaces. In vitro studies have shown that the collagen fibers were conducive to the adsorption of human keratinocytes and significantly promote cell proliferation, with good cell compatibility. However, collagen nanofibers have drawbacks of easy solubility in water, poor thermal stability, and insufficient mechanical properties. Chemical crosslinking treatment is an effective method for improving collagen fibers, but it may be toxic
[36][69]. In addition, other natural polymers such as alginate, gelatin, fibroin, and nucleotides can also serve as good substrates for electrospun fibers and are widely used in wound dressing research
[37][38][70,71]. However, electrospun nanofibers composed of natural polymers have problems with unstable structures and poor mechanical properties
[39][72].
Synthetic polymers, such as polycaprolactone (PCL), polyvinyl alcohol (PVA), polylactic acid (PLA), polyethylene oxide (PEO) and polyacrylonitrile (PAN), are widely used in electrospun nanofibers because of their excellent mechanical properties, good thermal stability, and processing flexibility
[40][73]. PCL has excellent mechanical properties and controllable biodegradability, which has been approved by the Food and Drug Administration (FDA) for use in many biomedical applications
[41][74]. Due to the lack of functional groups on the surface of PCL
[42][75], surface coating hydrolysis or other modification methods have been proposed, and surface alkali hydrolysis with sodium hydroxide is a simple and effective method
[43][76]. Further, the ammonolysis of PCL has been proven to be beneficial to cell adhesion. Chaiarwut et al.
[44][77] used sodium hydroxide to alkali hydrolyze the electrospun PCL NFM to improve its hydrophilicity and then used carbodiimide to fix the antibacterial peptide Pexiganan on PCL. After treatment, the hydrophilicity of NFM was significantly improved, and the antibacterial rate against gram-negative bacteria could be close to 100%. PVA is a nontoxic and hydrophilic synthetic polymer authorized by the FDA for biomedical and pharmaceutical purposes
[45][78]. However, it has been found that when PVA is used to prepare electrospun nanofibers, the PVA NFM soaked in water will lose its physical integrity and become unstable
[46][79]. Polylactic acid (PLA) has excellent biocompatibility, biodegradability, and eco-friendliness, which is a good medium for drug delivery, tissue engineering and regenerative medicine applications
[47][80]. Compared with conventional medical gauze, electrospun PLA NFMs have good hemocompatibility and wound-healing properties
[48][49][81,82]. It has been proved that electrospun PLA NFMs are beneficial to the adhesion and migration of skin cells and promote the deposition of collagen
[50][83]. However, PLA has low impact toughness and is sensitive to hydrolysis, which is not conducive to long-term work in the physiological environment
[51][84]. One solution is to obtain PLA stereocomplex by controlling the molecular weight of the homopolymer, which plays a positive role in improving the mechanical properties and hydrolysis resistance of PLA
[52][85]. PAN has good stability and mechanical properties, which have been applied in filtration membranes, aerospace technology and wound dressings
[53][54][86,87]. Due to the excellent fiber formability of PAN, it is easy to prepare electrospun fibers with good morphology and uniform diameter. It has been found that PAN may have potential antifungal properties
[55][88]. However, PAN nanofibers have the general hydrophobic properties of synthetic fibers. By adding amine groups on the surface of PAN nanofibers through triethylenetetramine or by changing the active nitrile groups on PAN into hydrophilic groups through a chemical reaction, the surface modification of PAN can be attained
[56][57][89,90].
Considering the characteristics of natural polymers and synthetic polymers, their combination can achieve a balance between the mechanical properties and biological functions of electrospun nanofibers. Notably, when natural and synthetic polymers are combined, their physical and chemical properties and their interactions need to be carefully considered. Introducing synthetic polymers mainly enhances the mechanical strength and spinnability of natural polymers. For example, some researchers blended chitosan with PCL for electrospinning to improve the spinnability of chitosan solution and the insufficient mechanical properties of nanofibers
[58][91]. Zulkifli et al.
[59][92] mixed collagen with PVA and hydroxyethyl cellulose for electrospinning, which improved the problems of easy water solubility and insufficient mechanical properties of collagen. Moreover, the composite NFM showed better cell adsorption, growth rate and mobility, which had great potential in skin tissue engineering applications.
2.2. Added Functional Factors for Wound Healing
The wound-healing process is dynamic and complex and can be divided into four stages: hemostasis, inflammation, proliferation, and remodeling
[60][93]. The formation of wounds means the beginning of the hemostasis phase, and then platelets, plasma fibers and fibrin form clots to seal the blood flow. During the inflammatory phase, neutrophils, macrophages, and lymphocytes accumulate and are activated, with antimicrobial and apoptotic cell removal effects. The proliferative phase is characterized by the neovascularization and promotion of epithelialization of blood vessels and cells. The remodeling phase is characterized by wound contraction and collagen deposition. The four phases of wound recovery represent the different functional requirements of wound dressings. Some natural polymers have inherent antibacterial or anti-inflammatory functions, but this is insufficient. To strengthen the function of electrospun nanofibers and better promote wound healing, more wound-healing-promoting factors are selectively added into the nanofibers to prepare drug-loaded nanofibers
[38][61][71,94]. Compared with conventional drug delivery systems, electrospinning technology can give nanofibers faster reaction rates and controllable release rates in the field of drug delivery. Various functions of factors, such as hemostatic
[62][95], anti-inflammatory
[63][96], promote cell proliferation or vascular remodeling and other therapeutic factors
[64][65][97,98], have been proven to better promote wound healing. Here, wound dressings for hemostasis, antibacterial and wound healing are discussed.
2.2.1. Hemostatic Factors
Rapid hemostasis is the first step in the treatment of wounds. The mechanism of thrombosis is represented in
[66][99]. The traditional method of hemostasis is to use gauze to press the wound to block the blood flow, which has the problems of more blood loss as well as adhesion between the gauze and the wound. To overcome these shortcomings, wound dressings prepared from materials with clotting properties (such as chitosan) or a porous expandable structure or containing hemostatic agents (such as aluminum chloride, tranexamic acid (TXA), and thrombin) have been extensively studied
[67][100]. Wu et al.
[68][101] electrospun composite NFMs by mixing polybutylene succinate and chitosan. The addition of polybutylene succinate effectively improved the spinnability of chitosan. The results showed that when the ratio of chitosan to polybutylene succinate was 9:1, the hemostatic performance of NFM was the best. Lamei et al.
[69][102] introduced tannic acid and zinc-based metal-organic frameworks (MOFs) into electrospun chitosan/PVA blend NFMs. The results showed that tannic acid could form a synergistic effect with chitosan to stop bleeding in wounds quickly. The zinc-based MOFs endowed fibers with a porous structure conducive to the rapid absorption of blood. Moreover, the presence of zinc ions generated electrostatic interactions with red blood cells, forming a new coagulation pathway. In addition, wound dressings with porous structures can effectively deal with pathogenic bleeding. Gu et al.
[70][103] conducted ultrasonic treatment on electrospun chitosan NFMs to obtain a porous structure. After ultrasonic treatment, the porosity of chitosan NFM could be increased by about 20%, and the water absorption time could be reduced by nearly 100 s. Compared with commercial hemostatic gauze, the porous chitosan NFM was 1.35 times more effective in clotting blood.
Aluminium chloride is a widely used material to stop bleeding
[71][104]. Nasser et al.
[72][105] electrospun poly-l-lactic acid (PLLA) NFM containing aluminum chloride by blending method. The results showed that aluminum chloride with 33%
w/
w had the best hemostatic performance. The NFM had a shorter blood clotting time and a stronger blood absorption capacity than traditional bandages. In another study, kaolin was added to the electrospun chitosan/PEO blend fibers. The layered structure and micro-pores on the surface of kaolin absorbed water in the blood and accelerated the aggregation of platelets and thrombin to achieve rapid hemostasis
[73][106]. Sasmal et al.
[74][107] introduced TXA into the electrospun chitosan/PVA NFM and evaluated its release and hemostatic effect. The results showed that TXA was released 90% within 10 h, and the presence of TXA reduced the blood clotting time by stabilizing coagulation. Mendes et al.
[75][108] implemented thrombin loading on PEO nanofibers through electrospinning. Studies on wound healing in vitro and in vivo showed that thrombin was released by water at the wound site as the NFM degraded, accelerating the clotting process. Moreover, the NFM was suitable for wounds with different morphologies and could be removed without external force after application.
2.2.2. Antibacterial Factors
Wound infection is a common problem in clinical practice that can not only affect the normal process of wound recovery but also aggravate the pain of patients and even endanger their lives. To effectively reduce the probability of wound infection, antimicrobial agents are added to wound dressings, which commonly include antibiotics, antimicrobial peptides, metals, and metal oxides
[76][109].
Antibiotics specifically affect inflammation caused by wound infection, but inappropriate dosage can lead to allergies and bacterial resistance
[77][110]. Xu et al.
[78][111] added amoxicillin (AMX) and MXene into a PVA spinning solution and prepared an antibacterial composite NFM. The release rate of AMX could be controlled by PVA, and MXene, as a photothermal agent, could convert near-infrared light into heat for local hyperthermia of the wound surface, thus promoting the release of AMX and assisting in sterilization by destroying the bacterial membrane. In a mouse skin defect model, the NFM showed outstanding bacteriostatic effects and wound healing ability after treating
Staphylococcus aureus infection. Yue et al.
[79][112] used fluorinated polyurethane and ethanol-soluble polyurethane to prepare a waterproof and breathable NFM through in-situ electrospinning technology, which could protect the wound from external stimulation.
Further, thymol was added to the NFM, which made the drug-loaded NFM have good antibacterial effects against
Escherichia coli and
Staphylococcus aureus. Sun et al.
[80][113] prepared puerarin-loaded electrospun composite NFMs with silk protein and polyvinylpyrrolidone (PVP) as matrix materials. It has been proven that puerarin improved the porosity, hydrophilicity, and antioxidant capacity of NFMs. In in vivo studies, the composite NFMs reduced the inflammatory response, promoted cell adhesion and proliferation, and accelerated wound healing.
Antimicrobial peptides are a new antibacterial agent with little drug resistance, strong bactericidal ability, good thermal stability, and no immunogenicity. Yu et al.
[81][114] used chitosan and PEO as matrices, added different contents of antibacterial peptides, and prepared antibacterial nanofibers using electrospinning technology. This NFM had a good inhibitory effect on
Escherichia coli and
Staphylococcus aureus. In the animal wound healing experiment, the wound healing rate of NFM containing antimicrobial peptides was better than that of NFM without drug loading and common gauze. Metals and metal oxides are widely used as antibacterial materials in wound dressings, among which ZnO quantum dots are a low-toxicity and inexpensive nanomaterial. Li et al.
[82][115] prepared PCL/collagen porous scaffolds containing ZnO quantum dots, which showed that adding ZnO quantum dots endowed the porous scaffold with high antibacterial performance against
Staphylococcus aureus and
Escherichia coli. Meanwhile, the composite scaffold exhibited excellent cell compatibility in promoting cell proliferation. In addition, the composite scaffold with vascular endothelial growth factor was proven to accelerate wound healing by promoting the expression of transforming growth factor-β (TGF-β) and vascular factor in tissues during the early stages of wound healing.
2.2.3. Growth Factors
The four stages of wound healing involve different cells, growth factors and proteins. For example, activated platelets at the hemostatic stage can secrete a large number of growth factors, such as transforming growth factors (TGF-α, TGF-β) and platelet-derived growth factors, which promote the migration of inflammatory cells
[83][116]. Therefore, the introduction of growth factors is very attractive for wound healing.
Skin reconstruction is accompanied by the release of growth factors
[84][117], which promote cell proliferation and granulation tissue formation and play an important role in different stages of wound healing
[85][86][118,119]. For example, epidermal growth factor (EGF) can promote the proliferation and epithelialization of keratinocytes and has synergistic effects with fibroblast growth factor. Platelet-derived growth factor (PDGF) can facilitate fibroblast proliferation and granulation tissue growth, playing a role in the initial stage of wound healing. Vascular endothelial growth factor (VEGF) accelerates angiogenesis and granulation tissue formation. Fibroblast growth factor (FGF) promotes mitosis and angiogenesis and plays a role in the later stage of wound recovery, among which basic FGF (bFGF) facilitates cell proliferation, migration, and differentiation. However, the stability of growth factors is poor, and their half-lives are short. The introduction of growth factors requires consideration of their concentration and biological activity. Electrospun nanofibers with a similar skin structure are undoubtedly a good growth factor carrier, which can provide a controlled release of therapeutic factors and protect their biological activity.
Dwivedi et al.
[87][120] prepared electrospun blended NFMs with poly(d, l-lactide co glycolide) (PLGA)/gelatin as the matrix. They introduced recombinant human epidermal growth factor (rhEGF) and gentamicin sulfate on their surface to accelerate the treatment of diabetes wounds. The composite NFM retained the stability and bactericidal properties of gentamicin sulfate, releasing only 36.64 ± 0.51% within 12 h, and the maximum inhibition rate of bacterial growth could reach 98.73 ± 0.68%. In the wound healing model of a mouse, the NFMs containing rhEGF played a positive role in the initial stage of wound healing, significantly increasing the wound closure rate. Chen et al.
[88][121] prepared collagen/GO nanofiber membranes containing bFGF through electrospinning. The maximum cumulative release rate of bFGF in the NFM containing bFGF was 30.94 ± 7.77%, with a release time of up to 27 days. In the wound healing model, the NFM showed a 96.39 ± 0.66% wound healing rate, and the promoting effect of growth factors on wound healing was demonstrated. Taborska et al.
[89][122] used poly(L-lactide-co-ε-caprolactone)/PCL nanofibers as a matrix containing human platelet lysates (hPL), and the fibrin network of VEGF and FGF as a coating to prepare a composite wound dressing. The results showed that the fibrin network was a good receptacle for bioactive molecules, and the sustained release of growth factors and hPL from the coating significantly increased the survival rate of human saphenous vein endothelial cells in collagen wound models.
2.2.4. Other Therapeutic Factors
Cell therapy is a treatment that uses living cells to renew and regenerate damaged tissue. Pluripotent cells such as macrophages, endothelial progenitors, and stem cells have been used in cell therapy
[90][123]. Among them, stem cells can self-renew and differentiate into various cells, which is of great significance for the repair and reconstruction of damaged tissues and shows great potential in wound healing. Bone marrow mesenchymal stem cells (BMSCs) are useful in the treatment of different types of wounds
[91][124]. Xu et al.
[92][125] prepared a PVA/BMSCs NFM through a handheld electrospinning device. The good biocompatibility of NFM was verified by cytotoxicity and cell proliferation experiments. The introduction of BMSCs had a positive effect on the formation of granulation tissue and epithelialization in full-layer skin wounds of rats. Compared with blank control, BMSCs could significantly accelerate wound healing. In another study, a PLGA electrospun NFM with LPS/IFN-gamma activated macrophage cell membrane was constructed and loaded with BMSCs. In vitro oxidative stress tests, the modified NFM had been shown to promote BMSCs proliferation and keratinocyte migration. In a diabetic wound healing model, the composite NFM exhibited faster-epithelialized regeneration, collagen remodeling and angiogenesis, accelerating wound healing, compared with the fibrous membrane without modification of the cell membrane
[93][126].
The combination of stem cells and growth factors is an effective strategy to enhance wound healing. Fu et al.
[94][127] constructed a composite sponge material loaded with nano-adipose tissue by using electrospun short fibers modified by polydopamine, in which nano-adipose tissue contained a variety of cells such as adipose-derived stem cells and could secrete various growth factors such as VEGF. The composite dressing could promote angiogenesis by releasing cells and growth factors, accelerate the growth of granulation tissue, and close the wound through granulation tissue, providing an enabling environment for tissue regeneration and repair. In addition, it is worth noting that the addition of therapeutic factors needs to consider their compatibility with the hydrophilic properties of polymers.
By designing the components of electrospun nanofibers, different parts of the wound healing process can be well promoted. The applications of electrospun nanofibers in hemostasis, antibacterial, and wound healing promotion have been summarized in Table 1.
Table 1.
The influence of electrospun nanofiber composition design on wound healing.
Base Materials |
Active Ingredients |
Types |
Functions |
Ref. |
polybutylene succinate/chitosan |
/ |
blend |
hemostatic |
[68][101] |
chitosan/PVA |
tannic acid, zinc-based MOFs |
blend |
hemostatic |
[69][102] |
chitosan/PEO |
kaolin |
blend |
hemostatic |
[73][106] |
PVA |
AMX, MXene |
blend |
bacteriostatic |
[78][111] |
polyurethane |
thymol |
blend |
antibacterial |
[79][112] |
chitosan/PEO |
antibacterial peptides |
blend |
antibacterial |
[81][114] |
PCL/collagen |
ZnO quantum dots |
blend |
antibacterial |
[82][115] |
PLGA/gelatin |
rhEGF, gentamicin sulfate |
blend |
bacteriostatic, promoting the wound closure |
[87][120] |
collagen/GO |
bFGF |
blend |
promote the wound closure |
[88][121] |
PVA |
BMSCs |
blend |
promote the formation of granulation tissue and epithelialization |
[92][125] |
PLGA |
LPS/IFN-gamma, BMSCs |
blend |
promote epithelialized regeneration, collagen remodeling and angiogenesis |
[93][126] |