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Therapeutic agents loaded chitosan-based nanofibrous mats as potential wound dressings: A review
Materials Today Chemistry 12 (2019) 386e395
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Materials Today Chemistry journal homepage: www.journals.elsevier.com/materials-today-chemistry/
Therapeutic agents loaded chitosan-based nanofibrous mats as potential wound dressings: A review R. Ranjith, S. Balraj, J. Ganesh, M.C. John Milton* P.G. and Research Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 December 2018 Received in revised form 15 February 2019 Accepted 30 March 2019 Available online 3 May 2019
Wound dressings have evolved significantly since the ancient times. Chitosan-based nanofibrous mats obtained by electrospinning technique show excellent potential as wound dressings owing to its numerous advantages, including large surface area-to-volume ratio, smaller pore size, drug delivery ability, biodegradability, biocompatibility, and hemostatic and antimicrobial activities. Recently, chitosan-based nanofibrous wound dressings loaded with therapeutic agents (antimicrobial, antioxidant and anti-inflammatory agents) emerged as an effective choice to reduce the wound infections and accelerate the wound healing process. This review describes the main clinical challenges associated with the wound healing process, and we provide an overview of the latest research on chitosan-based nanofibrous wound dressings. Furthermore, we intended to outline the recent studies in the delivery of therapeutic agents using chitosan-based nanofibrous mats. Finally, we discussed the recent advances have used nanofibrous mats with dual therapeutic/multi-therapeutic agents delivery for wound healing applications. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Electrospinning Drug delivery Wound healing Nanofibrous dressing
1. Introduction Clinically, wound healing remains challenging for humans and requires an efficient wound management [1,2]. Wound is defined as damage/disruption of the anatomical structure and function of the normal skin [3,4]. Based on healing time frame, wounds are categorized as acute wounds (caused by various factors, including freezing, heat, chemicals, electricity, and radiation) and chronic wounds (diabetic foot ulcers, vascular ulcers, and pressure ulcers) [3,5e7]. Wound healing is a complex process and involves sequential and intercorrelated stages (hemostasis, inflammation, proliferation, and remodeling) that help to restore anatomical continuity and function [4,8e10]. Typically, healing of acute wounds occurs through overlapping of the natural healing stages [11]. However, the inflammatory stage is prolonged in chronic wound healing, which suppresses proliferation, and remodeling stages result in excessive levels of proteases and reactive oxygen species [12,13]. Hence, the excessive protease level breaks down the growth factors and destructs the extracellular matrix, which end up attracting more inflammatory cells [14]. In addition, the excessive level of reactive oxygen species causes further cell damage [15].
* Corresponding author. E-mail address: [email protected] (M.C. John Milton). https://doi.org/10.1016/j.mtchem.2019.03.008 2468-5194/© 2019 Elsevier Ltd. All rights reserved.
These circumstances are not only amplifying the inflammation cycle but also causing persistent bacterial infections that lead antibiotic-resistant biofilm formation [13,16]. In aggregate, these pathophysiologic events are results of the failure of chronic wound healing [13]. Wounded skin needs to be covered with a wound dressing material to create a favorable environment to enhance reepithelialization [6,17e19]. An ideal wound dressing should possess numerous attributes such as maintaining a moist wound healing environment, being non-allergenic and non-toxic, facilitating gaseous exchange, absorption of wound exudate, and an impermeable protection from further trauma/infection and an infrequent dressing change, which increase the epithelial migration rate across the wound bed [20e23]. Electrospinning is a promising approach to fabricate the polymeric nanofibrous wound dressings for effective and rapid healing of both acute and chronic wounds due to its various advantages, including large surface area-tovolume ratio and smaller pore size [24e26]. Nanofibrous wound dressings provide numerous advantages compared with conventional wound dressings and also promote hemostasis, gas permeation, cell respiration, and fluid absorption [22,27e30]. Chitosan, a polycationic natural polysaccharide, is widely used in making of wound dressings for wound healing applications owing to its various beneficial properties including biodegradability,
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biocompatibility, hemostatic and antimicrobial potential, and mucoadhesive properties [31e33]. 2. Chitosan: a biomaterial for wound healing applications Chitosan, a linear amino polysaccharide and a deacetylated product of chitin, is composed of D-glucosamine and N-acetylglucosamine [32,34]. The degree of deacetylation is an important aspect, which determines the physiochemical and biological characteristics of chitosan [35]. The cationic nature of chitosan facilitates an electrostatic interaction with negatively charged mucin macromolecules, resulting in excellent mucoadhesive properties [36e38]. As a polycationic polysaccharide, chitosan has numerous biological properties such as biodegradability, non-toxicity, biocompatibility, hemostatic, antioxidant activities, and antimicrobial and antifungal activities, which are necessary to accelerate the wound healing process [36,39]. The antimicrobial properties of chitosan are mainly dependent on its degree of deacetylation, the type of derivative, the molecular weight, environmental conditions, and the species of target microorganisms [40e42]. Chitosan is extensively used in developing wound dressings because it stimulates hemostasis and also accelerates the wound healing rate [43e47]. 3. Chitosan-based electrospun nanofibrous mats as wound dressings An electrospinning apparatus consists of several components such as a syringe pump, the spinneret, a high voltage supply, and the collector (Fig. 1) [48]. During electrospinning, a high voltage is initiated to fabricate an electrically charged liquid jet of the polymer solution, which is directed to the collector by an electrostatic force that leads to nanofibrous mat formation [49]. Typically, the features of nanofibrous mats are determined by certain electrospinning working parameters such as solution parameters (concentration, molecular weight, viscosity, surface tension, solvent volatility, and conductivity), processing parameters (applied voltage, flow rate, and tip-to-collector distance), and ambient parameters (temperature and humidity) [50,51]. The control of these working parameters has a direct impact on the size and arrangement of the fabricating nanofibrous mats [49].
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Chitosan, owing to its cationic polyelectrolytes in acidic solution, forms enormous repulsive forces between positively charged groups and complicates its electrospinnability [52e54]. Fiberforming facilitating additives (natural/synthetic polymers) can be used to overcome the electrospinnability challenges of chitosan [55e60]. In a study, Chen et al. [61] fabricated the nanofibers using collagen, chitosan, and polyethylene oxide by electrospinning, which enhanced wound healing rate in vivo. Nanofibers composed of chitosan and silk fibroin with different ratios inhibited the growth of Escherichia coli; in addition, the fabricated nanofibers exhibited increased antibacterial activity with an increase in concentrations of chitosan [57]. The coaxial electrospinning process was adopted to fabricate the core/shell nanofibers of polylactic acid, and chitosan exhibited the antibacterial activity against E. coli [62]. In a study carried out by Charernsriwilaiwat et al. [58], the composite nanofibrous mats were fabricated by blending polyvinyl alcohol with a different chitosan aqueous salt (chitosan dissolved with hydroxybenzotriazole, thiamine pyrophosphate, and ethylenediaminetetraacetic acid individually); the results showed that chitosaneethylenediaminetetraacetic acid/polyvinyl alcohol nanofibrous mats exhibited good antibacterial (against Staphylococcus aureus and E. coli) and wound healing activity in vivo when compared with other groups. Core/shell nanofibers of polylactic acid/chitosan obtained by coaxial electrospinning showed the spreading tendency of L929 mouse fibroblast cells on fabricated nanofibers [63]. Furthermore, chitosan/polyethylene oxide blended electrospun nanofibers exhibited the moderate antimicrobial activity against E. coli and Candida albicans [55]. Composite nanofibers made of chitosan/sericin obtained by electrospinning showed an excellent antibacterial activity against for both gram-negative bacteria (E. coli) and gram-positive bacteria (Bacillus subtilis) [64]. Chitin nanocrystalereinforced chitosan/ polyethylene oxide electrospun fiber mats exhibited non-cytotoxic activity and were compatible with adipose-derived stem cells in vitro [65]. A study by Prasad et al. [66] used chitosan and polycaprolactone to prepare the blended electrospun fibrous mat, which favored better adhesion and proliferation of human keratinocytes (HaCaT) in vitro. In another approach, Ahmadi Majd et al. [67] developed the wound dressing made of chitosan and polyvinyl alcohol electrospun nanofibers that exhibited the significant
Fig. 1. Schematic showing an electrospinning setup.
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reduction in the length of the epidermis and dermis region in streptozotocineinduced diabetic rats. Electrospun nanofibers made of chitosan and polyethylene oxide interacted with the negatively charged bacterial cell wall, thereby inducing membrane rupture and perforation and resulting in leakage of intracellular components (proteins and nucleotides) [68]. Composite nanofiber scaffolds fabricated using chitosan and polycaprolactone improved in vivo wound closure rate and also increased re-epithelialization, maturation of neo-epidermal tissue, and collagen deposition [59]. Recently, chitosan-based electrospun nanofibrous mats attract attention as drug delivery systems to deliver the therapeutic agents (antimicrobial, antioxidant and antiinflammatory agents) (Fig. 2), which further accelerate the wound healing process [69e73]. 4. Antimicrobial agenteincorporated chitosan-based electrospun nanofibrous mats Wound dressings with the controlled delivery ability of the antimicrobial agent have gathered further attention to target diverse aspects of wound healing process, including preventing infections and expediting the healing rate with better quality scar tissue [74,75]. Levofloxacin, an antibiotic loaded into core/shell nanofibrous scaffolds of chitosan/polycaprolactone by coaxial electrospinning, displayed its sustained release for over seven days [76]. Fluoroquinolone antibiotics (ciprofloxacin hydrochloride and moxifloxacin hydrochloride) incorporated individually into electrospun chitosan/polyethylene oxide nanofibrous mats exhibited similar release profile for both ciprofloxacin hydrochloride and moxifloxacin hydrochloride; the fabricated nanofibrous mats that showed an excellent in vitro cytocompatibility with porcine endothelial cells also showed good antibacterial activity against S. aureus and E. coli [77]. Abbaspour et al. [78] studied the antimicrobial activity of mafenide acetateeloaded chitosan/polyvinyl alcohol nanofibers, and the results revealed that fabricated nanofibers showed greater antibacterial activity against S. aureus and Pseudomonas aeruginosa. Imipenem-incorporated chitosan/poly(L-lactide) composite nanofibers demonstrated excellent proliferation and growth of mouse fibroblast cells and inhibited the growth of E. coli [79]. Zupancic et al. [56] developed metronidazole-loaded chitosan/ polyethylene oxide nanofibers by electrospinning and studied metronidazole release using three different in vitro methods (a dissolution apparatus, vials, and a Franz diffusion cell); the results displayed that the Franz diffusion cell method supports slower metronidazole release with a limited amount of medium than the other two methods that contained larger volumes of medium, and this study demonstrated that the fabricated nanofibers can be used to release the metronidazole when a limited volume of body fluid is available at a diseased site (such as chronic wounds and inflamed and infected periodontal pockets). Chitosan/polylactic acid nanofibrous membranes loaded with different concentrations of tetracycline hydrochloride exhibited an initial burst release within the first 4 h, and increase in tetracycline hydrochloride concentrations increased the percentage of cumulative release, resulting in increased antibacterial activity against S. aureus [80]. Sustained release of cefazolin (a glycopeptide antibiotic) from chitosan/ polyethylene oxide nanofibers increased the antibacterial activity against both gram-negative (E. coli) and gram-positive (S. aureus) bacteria and accelerated wound healing in vivo [81]. Polyvinyl alcohol/chitosan electrospun nanofiber mats loaded with tetracycline hydrochloride showed an initial burst release during the first 2 h; the fabricated nanofibers inhibited the growth of E. coli, Staphylococcus epidermidis, and S. aureus and also exhibited good in vitro cytocompatibility with rabbit aortic smooth muscle cells
[82]. The preliminary clinical trials demonstrated that tinidazole release from fabricated chitosan/polycaprolactone nanofiber membrane significantly reduced the clinical markers (probing pocket depth, score of gingival index, clinical attachment level, and score of bleeding on probing) of periodontitis; the in vitro results showed sustained tinidazole release from fabricated nanofibers up to eighteen days and inhibited the growth of S. aureus [83]. The emergence of bacterial resistance to multiple antibiotics has increased significantly [84]. Plant-derived essential oils possess antibacterial properties and are indicated as potential sources of new antimicrobial compounds to combat microbial resistance [84e86]. Release of cinnamaldehyde (a volatile essential oil) from fabricated chitosan/polyethylene oxide electrospun nanofibers exhibited high antibacterial activity against E. coli and P. aeruginosa [87]. Electrospun polyethylene oxide/chitosan/polycaprolactone nanofibers loaded with olive oil showed good antibacterial activity against E. coli and S. aureus [88]. The nanoparticles such as silver, magnetic iron oxide, and zinc oxide are other effective antimicrobial agents, and their incorporation into electrospun nanofibrous mats has received growing attention [89e92]. Silver nanoparticles, an effective antimicrobial agent incorporated into chitosan/polyethylene oxide electrospun membranes, showed good bacteriostatic effect on gram-negative bacteria (E. coli) [93]. The addition of silver nanoparticles into nanofiber mats made of chitosan and polyvinyl alcohol indicated good bactericidal activity against E. coli [94]. A study by Wang et al. developed chitosan/polyethylene oxide nanofiber mats with added silver nanoparticles, which showed an excellent antibacterial activity against S. aureus and E. coli [95]. Green synthesized silver nanoparticles from the leaf extract of Falcaria vulgaris, when released from chitosan/polyethylene oxide electrospun mats, exhibited an excellent antibacterial activity against S. aureus and E. coli [96]. Cai et al. [97] prepared antibacterial nanofibers of chitosan/gelatin loaded with magnetic iron oxide nanoparticles, which exhibited good antibacterial activity against E. coli and S. aureus. Nanofibrous dressings of chitosan and polyvinyl alcohol incorporated with zinc oxide nanoparticles possessed excellent antioxidant and antibacterial potential in vitro, thereby accelerating wound healing in vivo [31]. 5. Antioxidant and anti-inflammatory agenteloaded chitosan-based electrospun nanofibrous mats Curcumin, a phenolic compound, is extensively studied in wound healing treatment because of their antioxidant and antiinflammatory properties [98e101]. Topical administration of curcumin improved in vivo wound healing with increased collagen content at the wound site and antioxidant potential with decreased lipid peroxide levels and increased the levels of catalase, superoxide dismutase, and glutathione peroxidase [102]. In an attempt to improve the bioavailability, water solubility, and stability of curcumin, it has been loaded into biodegradable electrospun nanofibers [103e105]. Curcumin release from electrospun nanofibers composed of chitosan and polylactic acid revealed no cytotoxic activity to L-929 fibroblast cells and increased antioxidant activity in vitro; furthermore, the fabricated nanofibers exhibited significant wound reduction in the excision and incision rat wound model [106]. Curcumin-incorporated polycaprolactone/chitosan nanofibers obtained by electrospinning indicated 80% of curcumin release during the first hundred hours [107]. Asiaticoside, a triterpene glycoside, isolated from Centella asiatica, is extensively used in wound healing applications owing to its antioxidant and anti-inflammatory activities [108e110]. Treating the deep partial-thickness burn injury with asiaticoside-loaded
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Fig. 2. Schematic diagram of the fabrication of therapeutic agent (antimicrobial, antioxidant and anti-inflammatory agents) loaded chitosan-based nanofibrous mats.
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Table 1 Summary of recent studies on chitosan-based nanofibrous mats containing therapeutic agents.
Antimicrobial agents
Antioxidant and anti-inflammatory agents
Dual therapeutic/ multi-therapeutic agents
Therapeutic agents incorporated
Carrier for therapeutic agents
Electrospinning method
Applications
References
Levofloxacin Ciprofloxacin hydrochloride Moxifloxacin hydrochloride Mafenide acetate Imipenem Metronidazole Tetracycline hydrochloride Cefazolin Tetracycline hydrochloride
Chitosan/polycaprolactone Chitosan/polyethylene oxide Chitosan/polyethylene oxide Chitosan/polyvinyl alcohol Chitosan/poly(L-lactide) Chitosan/polyethylene oxide Chitosan/polylactic acid Chitosan/polyethylene oxide Polyvinyl alcohol/chitosan
Coaxial Single Single Single Single Single Single Single Single
[76] [77] [77] [78] [79] [56] [80] [81] [82]
Tinidazole Cinnamaldehyde Olive oil
Chitosan/polycaprolactone Chitosan/polyethylene oxide Polyethylene oxide/chitosan/polycaprolactone Chitosan/polyethylene oxide Chitosan/polyvinyl alcohol Chitosan/polyethylene oxide Chitosan/polyethylene oxide Chitosan/gelatin Chitosan/polyvinyl alcohol Chitosan/polylactic acid Polycaprolactone/chitosan Alginate/polyvinyl alcohol/chitosan Chitosan/pullulan Chitosan/asolectin Polycaprolactone/chitosan Chitosan/polyethylene oxide/cysteine
Single Single Two-nozzle
Local drug delivery Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Local drug delivery Antibacterial activity Burn wound healing Antibacterial activity; in vitro wound healing activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Diabetic wound dressings Wound healing activity Local drug delivery Deep partial-thickness burn injury Antibacterial activity Local drug delivery Wound healing activity Local drug delivery
[93] [94] [95] [96] [97] [31] [106] [107] [111]
Silver nanoparticles Silver nanoparticles Silver nanoparticles Biosynthesized silver nanoparticles Magnetic iron oxide nanoparticles Zinc oxide nanoparticles Curcumin Curcumin Asiaticoside Tannic acid Vitamin B12 þ curcumin þ diclofenac Ferulic acid þ resveratrol Tetracycline þ triamcinolone acetonide
alginate/polyvinyl alcohol/chitosan coaxial electrospun nanofibers enhanced wound healing in vivo by upregulation of vascular endothelial growth factor, cluster of differentiation 31, and proliferating cell nuclear antigen and downregulation of interleukin 6 and tumor necrosis factor alpha [111]. Ferulic acid, a phenolic compound which possesses antioxidant, anti-inflammatory, and angiogenic activities, could exert beneficial effects in wound healing applications [112e116]. Poornima and Korrapati [117] used coaxial electrospinning technique to develop the nanofibrous wound dressings composed of chitosan and polycaprolactone loaded with ferulic acid and resveratrol, which possessed antioxidant activity and exhibited high compatibility with keratinocytes (HaCaT) in vitro as well as accelerated wound healing in vivo. Tannic acid, a polyphenolic compound, is used in wound healing applications owing its antioxidant and anti-inflammatory properties [118,119]. Forcespinning technique was adopted to develop the biocompatible composite nanofibers made of tannic acid/chitosan/ pullulan, which exhibited an excellent antibacterial activity against E. coli also effectively promoted the attachment and growth of NIH 3T3 mouse embryonic fibroblast cells [120]. Herein, some of the recent studies on chitosan-based nanofibrous mats containing therapeutic agents are summarized in Table 1. 6. Conclusions and future perspectives Chitosan-based electrospun nanofibrous mats hold great promise for the development of suitable drug carriers for a range of bioactive molecules and therapeutic agents. The research on therapeutic agents incorporated chitosan-based nanofibrous mats provides the perception for various biomedical and pharmaceutical
Single Single Single Single Single Single Single Single Coaxial Forcespinning Single Coaxial Single
[83] [87] [88]
[120] [121] [117] [122]
applications. Therapeutic agents loaded nanofibrous mats obtained by electrospinning technique have numerous advantages such as controlled and targeted drug delivery for a prolonged period, which could be beneficial in wound healing applications. An ideal wound dressing should be antibacterial, non-antigenic, non-toxic, permeable for gaseous exchange, and able to reduce pain and healing time. Antimicrobial agenteloaded nanofibrous mats have been developed to confer bactericidal activity to wound dressings. Although further improvements of wound dressings with antibacterial, antioxidant and anti-inflammatory properties are demanded to enhance/accelerate the wound healing rate [123]. Recently, controlled dual therapeutic/multi-therapeutic agents delivery strategies using electrospun nanofibrous mats have been explored to enhance/accelerate the wound healing potential. A study carried out by Mendes et al. [121] prepared electrospun chitosan/phospholipid hybrid nanofibers loaded with vitamin B12 (as an essential factor in deoxyribonucleic acid synthesis), curcumin (as an antioxidant and anti-inflammatory agent), and diclofenac (non-steroidal anti-inflammatory drug, as a potent antiinflammatory, antipyretic, and analgesic agent) for transdermal drug delivery applications. The dual delivery of ferulic acid (antiinflammatory) and resveratrol (proangiogenic) from electrospun chitosan/polycaprolactone nanofibers obtained by coaxial electrospinning conferred antioxidant activity and accelerated wound healing of full-thickness excision skin wounds in vivo [117]. In another study, Behbood et al. [122] fabricated tetracycline (antibiotic) and triamcinolone acetonide (anti-inflammatory) loaded chitosan/polyethylene oxide/cysteine mucoadhesive electrospun nanofibers. In the near future, incorporation of nanocarriers containing therapeutic agents into chitosan-based nanofibrous mats (Fig. 3) would lead to an increased therapeutic outcome also, which
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Fig. 3. Future perspectives in the development of chitosan-based nanofibrous mats containing therapeutic agent (antimicrobial, antioxidant and anti-inflammatory agents) encapsulated nanocarriers to enhance the wound healing process.
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Fig. 4. Scheme illustrating the strategy for dual therapeutic/multi-therapeutic agents delivery from chitosan-based nanofibrous mats containing therapeutic agents (antimicrobial, antioxidant and anti-inflammatory agents) encapsulated nanocarriers to accelerate the wound healing rate.
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can open up new avenues for the development of wound dressings with highly advantageous properties including dual therapeutic/ multi-therapeutic agents delivery (Fig. 4) to accelerate the wound healing process.
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Therapeutic agents loaded chitosan-based nanofibrous mats as potential wound dressings: A review R. Ranjith, S. Balraj, J. Ganesh, M.C. John Milton* P.G. and Research Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 December 2018 Received in revised form 15 February 2019 Accepted 30 March 2019 Available online 3 May 2019
Wound dressings have evolved significantly since the ancient times. Chitosan-based nanofibrous mats obtained by electrospinning technique show excellent potential as wound dressings owing to its numerous advantages, including large surface area-to-volume ratio, smaller pore size, drug delivery ability, biodegradability, biocompatibility, and hemostatic and antimicrobial activities. Recently, chitosan-based nanofibrous wound dressings loaded with therapeutic agents (antimicrobial, antioxidant and anti-inflammatory agents) emerged as an effective choice to reduce the wound infections and accelerate the wound healing process. This review describes the main clinical challenges associated with the wound healing process, and we provide an overview of the latest research on chitosan-based nanofibrous wound dressings. Furthermore, we intended to outline the recent studies in the delivery of therapeutic agents using chitosan-based nanofibrous mats. Finally, we discussed the recent advances have used nanofibrous mats with dual therapeutic/multi-therapeutic agents delivery for wound healing applications. © 2019 Elsevier Ltd. All rights reserved.
Keywords: Electrospinning Drug delivery Wound healing Nanofibrous dressing
1. Introduction Clinically, wound healing remains challenging for humans and requires an efficient wound management [1,2]. Wound is defined as damage/disruption of the anatomical structure and function of the normal skin [3,4]. Based on healing time frame, wounds are categorized as acute wounds (caused by various factors, including freezing, heat, chemicals, electricity, and radiation) and chronic wounds (diabetic foot ulcers, vascular ulcers, and pressure ulcers) [3,5e7]. Wound healing is a complex process and involves sequential and intercorrelated stages (hemostasis, inflammation, proliferation, and remodeling) that help to restore anatomical continuity and function [4,8e10]. Typically, healing of acute wounds occurs through overlapping of the natural healing stages [11]. However, the inflammatory stage is prolonged in chronic wound healing, which suppresses proliferation, and remodeling stages result in excessive levels of proteases and reactive oxygen species [12,13]. Hence, the excessive protease level breaks down the growth factors and destructs the extracellular matrix, which end up attracting more inflammatory cells [14]. In addition, the excessive level of reactive oxygen species causes further cell damage [15].
* Corresponding author. E-mail address: [email protected] (M.C. John Milton). https://doi.org/10.1016/j.mtchem.2019.03.008 2468-5194/© 2019 Elsevier Ltd. All rights reserved.
These circumstances are not only amplifying the inflammation cycle but also causing persistent bacterial infections that lead antibiotic-resistant biofilm formation [13,16]. In aggregate, these pathophysiologic events are results of the failure of chronic wound healing [13]. Wounded skin needs to be covered with a wound dressing material to create a favorable environment to enhance reepithelialization [6,17e19]. An ideal wound dressing should possess numerous attributes such as maintaining a moist wound healing environment, being non-allergenic and non-toxic, facilitating gaseous exchange, absorption of wound exudate, and an impermeable protection from further trauma/infection and an infrequent dressing change, which increase the epithelial migration rate across the wound bed [20e23]. Electrospinning is a promising approach to fabricate the polymeric nanofibrous wound dressings for effective and rapid healing of both acute and chronic wounds due to its various advantages, including large surface area-tovolume ratio and smaller pore size [24e26]. Nanofibrous wound dressings provide numerous advantages compared with conventional wound dressings and also promote hemostasis, gas permeation, cell respiration, and fluid absorption [22,27e30]. Chitosan, a polycationic natural polysaccharide, is widely used in making of wound dressings for wound healing applications owing to its various beneficial properties including biodegradability,
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biocompatibility, hemostatic and antimicrobial potential, and mucoadhesive properties [31e33]. 2. Chitosan: a biomaterial for wound healing applications Chitosan, a linear amino polysaccharide and a deacetylated product of chitin, is composed of D-glucosamine and N-acetylglucosamine [32,34]. The degree of deacetylation is an important aspect, which determines the physiochemical and biological characteristics of chitosan [35]. The cationic nature of chitosan facilitates an electrostatic interaction with negatively charged mucin macromolecules, resulting in excellent mucoadhesive properties [36e38]. As a polycationic polysaccharide, chitosan has numerous biological properties such as biodegradability, non-toxicity, biocompatibility, hemostatic, antioxidant activities, and antimicrobial and antifungal activities, which are necessary to accelerate the wound healing process [36,39]. The antimicrobial properties of chitosan are mainly dependent on its degree of deacetylation, the type of derivative, the molecular weight, environmental conditions, and the species of target microorganisms [40e42]. Chitosan is extensively used in developing wound dressings because it stimulates hemostasis and also accelerates the wound healing rate [43e47]. 3. Chitosan-based electrospun nanofibrous mats as wound dressings An electrospinning apparatus consists of several components such as a syringe pump, the spinneret, a high voltage supply, and the collector (Fig. 1) [48]. During electrospinning, a high voltage is initiated to fabricate an electrically charged liquid jet of the polymer solution, which is directed to the collector by an electrostatic force that leads to nanofibrous mat formation [49]. Typically, the features of nanofibrous mats are determined by certain electrospinning working parameters such as solution parameters (concentration, molecular weight, viscosity, surface tension, solvent volatility, and conductivity), processing parameters (applied voltage, flow rate, and tip-to-collector distance), and ambient parameters (temperature and humidity) [50,51]. The control of these working parameters has a direct impact on the size and arrangement of the fabricating nanofibrous mats [49].
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Chitosan, owing to its cationic polyelectrolytes in acidic solution, forms enormous repulsive forces between positively charged groups and complicates its electrospinnability [52e54]. Fiberforming facilitating additives (natural/synthetic polymers) can be used to overcome the electrospinnability challenges of chitosan [55e60]. In a study, Chen et al. [61] fabricated the nanofibers using collagen, chitosan, and polyethylene oxide by electrospinning, which enhanced wound healing rate in vivo. Nanofibers composed of chitosan and silk fibroin with different ratios inhibited the growth of Escherichia coli; in addition, the fabricated nanofibers exhibited increased antibacterial activity with an increase in concentrations of chitosan [57]. The coaxial electrospinning process was adopted to fabricate the core/shell nanofibers of polylactic acid, and chitosan exhibited the antibacterial activity against E. coli [62]. In a study carried out by Charernsriwilaiwat et al. [58], the composite nanofibrous mats were fabricated by blending polyvinyl alcohol with a different chitosan aqueous salt (chitosan dissolved with hydroxybenzotriazole, thiamine pyrophosphate, and ethylenediaminetetraacetic acid individually); the results showed that chitosaneethylenediaminetetraacetic acid/polyvinyl alcohol nanofibrous mats exhibited good antibacterial (against Staphylococcus aureus and E. coli) and wound healing activity in vivo when compared with other groups. Core/shell nanofibers of polylactic acid/chitosan obtained by coaxial electrospinning showed the spreading tendency of L929 mouse fibroblast cells on fabricated nanofibers [63]. Furthermore, chitosan/polyethylene oxide blended electrospun nanofibers exhibited the moderate antimicrobial activity against E. coli and Candida albicans [55]. Composite nanofibers made of chitosan/sericin obtained by electrospinning showed an excellent antibacterial activity against for both gram-negative bacteria (E. coli) and gram-positive bacteria (Bacillus subtilis) [64]. Chitin nanocrystalereinforced chitosan/ polyethylene oxide electrospun fiber mats exhibited non-cytotoxic activity and were compatible with adipose-derived stem cells in vitro [65]. A study by Prasad et al. [66] used chitosan and polycaprolactone to prepare the blended electrospun fibrous mat, which favored better adhesion and proliferation of human keratinocytes (HaCaT) in vitro. In another approach, Ahmadi Majd et al. [67] developed the wound dressing made of chitosan and polyvinyl alcohol electrospun nanofibers that exhibited the significant
Fig. 1. Schematic showing an electrospinning setup.
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reduction in the length of the epidermis and dermis region in streptozotocineinduced diabetic rats. Electrospun nanofibers made of chitosan and polyethylene oxide interacted with the negatively charged bacterial cell wall, thereby inducing membrane rupture and perforation and resulting in leakage of intracellular components (proteins and nucleotides) [68]. Composite nanofiber scaffolds fabricated using chitosan and polycaprolactone improved in vivo wound closure rate and also increased re-epithelialization, maturation of neo-epidermal tissue, and collagen deposition [59]. Recently, chitosan-based electrospun nanofibrous mats attract attention as drug delivery systems to deliver the therapeutic agents (antimicrobial, antioxidant and antiinflammatory agents) (Fig. 2), which further accelerate the wound healing process [69e73]. 4. Antimicrobial agenteincorporated chitosan-based electrospun nanofibrous mats Wound dressings with the controlled delivery ability of the antimicrobial agent have gathered further attention to target diverse aspects of wound healing process, including preventing infections and expediting the healing rate with better quality scar tissue [74,75]. Levofloxacin, an antibiotic loaded into core/shell nanofibrous scaffolds of chitosan/polycaprolactone by coaxial electrospinning, displayed its sustained release for over seven days [76]. Fluoroquinolone antibiotics (ciprofloxacin hydrochloride and moxifloxacin hydrochloride) incorporated individually into electrospun chitosan/polyethylene oxide nanofibrous mats exhibited similar release profile for both ciprofloxacin hydrochloride and moxifloxacin hydrochloride; the fabricated nanofibrous mats that showed an excellent in vitro cytocompatibility with porcine endothelial cells also showed good antibacterial activity against S. aureus and E. coli [77]. Abbaspour et al. [78] studied the antimicrobial activity of mafenide acetateeloaded chitosan/polyvinyl alcohol nanofibers, and the results revealed that fabricated nanofibers showed greater antibacterial activity against S. aureus and Pseudomonas aeruginosa. Imipenem-incorporated chitosan/poly(L-lactide) composite nanofibers demonstrated excellent proliferation and growth of mouse fibroblast cells and inhibited the growth of E. coli [79]. Zupancic et al. [56] developed metronidazole-loaded chitosan/ polyethylene oxide nanofibers by electrospinning and studied metronidazole release using three different in vitro methods (a dissolution apparatus, vials, and a Franz diffusion cell); the results displayed that the Franz diffusion cell method supports slower metronidazole release with a limited amount of medium than the other two methods that contained larger volumes of medium, and this study demonstrated that the fabricated nanofibers can be used to release the metronidazole when a limited volume of body fluid is available at a diseased site (such as chronic wounds and inflamed and infected periodontal pockets). Chitosan/polylactic acid nanofibrous membranes loaded with different concentrations of tetracycline hydrochloride exhibited an initial burst release within the first 4 h, and increase in tetracycline hydrochloride concentrations increased the percentage of cumulative release, resulting in increased antibacterial activity against S. aureus [80]. Sustained release of cefazolin (a glycopeptide antibiotic) from chitosan/ polyethylene oxide nanofibers increased the antibacterial activity against both gram-negative (E. coli) and gram-positive (S. aureus) bacteria and accelerated wound healing in vivo [81]. Polyvinyl alcohol/chitosan electrospun nanofiber mats loaded with tetracycline hydrochloride showed an initial burst release during the first 2 h; the fabricated nanofibers inhibited the growth of E. coli, Staphylococcus epidermidis, and S. aureus and also exhibited good in vitro cytocompatibility with rabbit aortic smooth muscle cells
[82]. The preliminary clinical trials demonstrated that tinidazole release from fabricated chitosan/polycaprolactone nanofiber membrane significantly reduced the clinical markers (probing pocket depth, score of gingival index, clinical attachment level, and score of bleeding on probing) of periodontitis; the in vitro results showed sustained tinidazole release from fabricated nanofibers up to eighteen days and inhibited the growth of S. aureus [83]. The emergence of bacterial resistance to multiple antibiotics has increased significantly [84]. Plant-derived essential oils possess antibacterial properties and are indicated as potential sources of new antimicrobial compounds to combat microbial resistance [84e86]. Release of cinnamaldehyde (a volatile essential oil) from fabricated chitosan/polyethylene oxide electrospun nanofibers exhibited high antibacterial activity against E. coli and P. aeruginosa [87]. Electrospun polyethylene oxide/chitosan/polycaprolactone nanofibers loaded with olive oil showed good antibacterial activity against E. coli and S. aureus [88]. The nanoparticles such as silver, magnetic iron oxide, and zinc oxide are other effective antimicrobial agents, and their incorporation into electrospun nanofibrous mats has received growing attention [89e92]. Silver nanoparticles, an effective antimicrobial agent incorporated into chitosan/polyethylene oxide electrospun membranes, showed good bacteriostatic effect on gram-negative bacteria (E. coli) [93]. The addition of silver nanoparticles into nanofiber mats made of chitosan and polyvinyl alcohol indicated good bactericidal activity against E. coli [94]. A study by Wang et al. developed chitosan/polyethylene oxide nanofiber mats with added silver nanoparticles, which showed an excellent antibacterial activity against S. aureus and E. coli [95]. Green synthesized silver nanoparticles from the leaf extract of Falcaria vulgaris, when released from chitosan/polyethylene oxide electrospun mats, exhibited an excellent antibacterial activity against S. aureus and E. coli [96]. Cai et al. [97] prepared antibacterial nanofibers of chitosan/gelatin loaded with magnetic iron oxide nanoparticles, which exhibited good antibacterial activity against E. coli and S. aureus. Nanofibrous dressings of chitosan and polyvinyl alcohol incorporated with zinc oxide nanoparticles possessed excellent antioxidant and antibacterial potential in vitro, thereby accelerating wound healing in vivo [31]. 5. Antioxidant and anti-inflammatory agenteloaded chitosan-based electrospun nanofibrous mats Curcumin, a phenolic compound, is extensively studied in wound healing treatment because of their antioxidant and antiinflammatory properties [98e101]. Topical administration of curcumin improved in vivo wound healing with increased collagen content at the wound site and antioxidant potential with decreased lipid peroxide levels and increased the levels of catalase, superoxide dismutase, and glutathione peroxidase [102]. In an attempt to improve the bioavailability, water solubility, and stability of curcumin, it has been loaded into biodegradable electrospun nanofibers [103e105]. Curcumin release from electrospun nanofibers composed of chitosan and polylactic acid revealed no cytotoxic activity to L-929 fibroblast cells and increased antioxidant activity in vitro; furthermore, the fabricated nanofibers exhibited significant wound reduction in the excision and incision rat wound model [106]. Curcumin-incorporated polycaprolactone/chitosan nanofibers obtained by electrospinning indicated 80% of curcumin release during the first hundred hours [107]. Asiaticoside, a triterpene glycoside, isolated from Centella asiatica, is extensively used in wound healing applications owing to its antioxidant and anti-inflammatory activities [108e110]. Treating the deep partial-thickness burn injury with asiaticoside-loaded
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Fig. 2. Schematic diagram of the fabrication of therapeutic agent (antimicrobial, antioxidant and anti-inflammatory agents) loaded chitosan-based nanofibrous mats.
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Table 1 Summary of recent studies on chitosan-based nanofibrous mats containing therapeutic agents.
Antimicrobial agents
Antioxidant and anti-inflammatory agents
Dual therapeutic/ multi-therapeutic agents
Therapeutic agents incorporated
Carrier for therapeutic agents
Electrospinning method
Applications
References
Levofloxacin Ciprofloxacin hydrochloride Moxifloxacin hydrochloride Mafenide acetate Imipenem Metronidazole Tetracycline hydrochloride Cefazolin Tetracycline hydrochloride
Chitosan/polycaprolactone Chitosan/polyethylene oxide Chitosan/polyethylene oxide Chitosan/polyvinyl alcohol Chitosan/poly(L-lactide) Chitosan/polyethylene oxide Chitosan/polylactic acid Chitosan/polyethylene oxide Polyvinyl alcohol/chitosan
Coaxial Single Single Single Single Single Single Single Single
[76] [77] [77] [78] [79] [56] [80] [81] [82]
Tinidazole Cinnamaldehyde Olive oil
Chitosan/polycaprolactone Chitosan/polyethylene oxide Polyethylene oxide/chitosan/polycaprolactone Chitosan/polyethylene oxide Chitosan/polyvinyl alcohol Chitosan/polyethylene oxide Chitosan/polyethylene oxide Chitosan/gelatin Chitosan/polyvinyl alcohol Chitosan/polylactic acid Polycaprolactone/chitosan Alginate/polyvinyl alcohol/chitosan Chitosan/pullulan Chitosan/asolectin Polycaprolactone/chitosan Chitosan/polyethylene oxide/cysteine
Single Single Two-nozzle
Local drug delivery Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Local drug delivery Antibacterial activity Burn wound healing Antibacterial activity; in vitro wound healing activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Antibacterial activity Diabetic wound dressings Wound healing activity Local drug delivery Deep partial-thickness burn injury Antibacterial activity Local drug delivery Wound healing activity Local drug delivery
[93] [94] [95] [96] [97] [31] [106] [107] [111]
Silver nanoparticles Silver nanoparticles Silver nanoparticles Biosynthesized silver nanoparticles Magnetic iron oxide nanoparticles Zinc oxide nanoparticles Curcumin Curcumin Asiaticoside Tannic acid Vitamin B12 þ curcumin þ diclofenac Ferulic acid þ resveratrol Tetracycline þ triamcinolone acetonide
alginate/polyvinyl alcohol/chitosan coaxial electrospun nanofibers enhanced wound healing in vivo by upregulation of vascular endothelial growth factor, cluster of differentiation 31, and proliferating cell nuclear antigen and downregulation of interleukin 6 and tumor necrosis factor alpha [111]. Ferulic acid, a phenolic compound which possesses antioxidant, anti-inflammatory, and angiogenic activities, could exert beneficial effects in wound healing applications [112e116]. Poornima and Korrapati [117] used coaxial electrospinning technique to develop the nanofibrous wound dressings composed of chitosan and polycaprolactone loaded with ferulic acid and resveratrol, which possessed antioxidant activity and exhibited high compatibility with keratinocytes (HaCaT) in vitro as well as accelerated wound healing in vivo. Tannic acid, a polyphenolic compound, is used in wound healing applications owing its antioxidant and anti-inflammatory properties [118,119]. Forcespinning technique was adopted to develop the biocompatible composite nanofibers made of tannic acid/chitosan/ pullulan, which exhibited an excellent antibacterial activity against E. coli also effectively promoted the attachment and growth of NIH 3T3 mouse embryonic fibroblast cells [120]. Herein, some of the recent studies on chitosan-based nanofibrous mats containing therapeutic agents are summarized in Table 1. 6. Conclusions and future perspectives Chitosan-based electrospun nanofibrous mats hold great promise for the development of suitable drug carriers for a range of bioactive molecules and therapeutic agents. The research on therapeutic agents incorporated chitosan-based nanofibrous mats provides the perception for various biomedical and pharmaceutical
Single Single Single Single Single Single Single Single Coaxial Forcespinning Single Coaxial Single
[83] [87] [88]
[120] [121] [117] [122]
applications. Therapeutic agents loaded nanofibrous mats obtained by electrospinning technique have numerous advantages such as controlled and targeted drug delivery for a prolonged period, which could be beneficial in wound healing applications. An ideal wound dressing should be antibacterial, non-antigenic, non-toxic, permeable for gaseous exchange, and able to reduce pain and healing time. Antimicrobial agenteloaded nanofibrous mats have been developed to confer bactericidal activity to wound dressings. Although further improvements of wound dressings with antibacterial, antioxidant and anti-inflammatory properties are demanded to enhance/accelerate the wound healing rate [123]. Recently, controlled dual therapeutic/multi-therapeutic agents delivery strategies using electrospun nanofibrous mats have been explored to enhance/accelerate the wound healing potential. A study carried out by Mendes et al. [121] prepared electrospun chitosan/phospholipid hybrid nanofibers loaded with vitamin B12 (as an essential factor in deoxyribonucleic acid synthesis), curcumin (as an antioxidant and anti-inflammatory agent), and diclofenac (non-steroidal anti-inflammatory drug, as a potent antiinflammatory, antipyretic, and analgesic agent) for transdermal drug delivery applications. The dual delivery of ferulic acid (antiinflammatory) and resveratrol (proangiogenic) from electrospun chitosan/polycaprolactone nanofibers obtained by coaxial electrospinning conferred antioxidant activity and accelerated wound healing of full-thickness excision skin wounds in vivo [117]. In another study, Behbood et al. [122] fabricated tetracycline (antibiotic) and triamcinolone acetonide (anti-inflammatory) loaded chitosan/polyethylene oxide/cysteine mucoadhesive electrospun nanofibers. In the near future, incorporation of nanocarriers containing therapeutic agents into chitosan-based nanofibrous mats (Fig. 3) would lead to an increased therapeutic outcome also, which
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Fig. 3. Future perspectives in the development of chitosan-based nanofibrous mats containing therapeutic agent (antimicrobial, antioxidant and anti-inflammatory agents) encapsulated nanocarriers to enhance the wound healing process.
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Fig. 4. Scheme illustrating the strategy for dual therapeutic/multi-therapeutic agents delivery from chitosan-based nanofibrous mats containing therapeutic agents (antimicrobial, antioxidant and anti-inflammatory agents) encapsulated nanocarriers to accelerate the wound healing rate.
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can open up new avenues for the development of wound dressings with highly advantageous properties including dual therapeutic/ multi-therapeutic agents delivery (Fig. 4) to accelerate the wound healing process.
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