Latest Progress in Electrospun Nanofibers for Wound Healing

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Latest Progress in Electrospun Nanofibers for Wound Healing Applications Tuerdimaimaiti Abudula, Halimatu Mohammed, Kasturi Joshi Navare, Thibault Colombani, Sidi Bencherif, and Adnan Memic ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00637 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on January 31, 2019

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ACS Applied Bio Materials

Latest Progress in Electrospun Nanofibers for Wound Healing Applications Tuerdimaimaiti Abudula 1, 2, Halimatu S. Mohammed3, Kasturi Joshi Navare3, Thibault Colombani3, Sidi A. Bencherif3,4,5,6,*, Adnan Memic *1 1Center

of Nanotechnology, King Abdul Aziz University, Jeddah, Saudi Arabia

2Department

of Chemical and Materials Engineering, Faculty of Engineering, King Abdul Aziz

University, Jeddah, Saudi Arabia 3Department

of Chemical Engineering, Northeastern University, Boston, MA, USA

4Department

of Bioengineering, Northeastern University, Boston, MA, USA

5Harvard

John A. Paulson School of Engineering and Applied Sciences, Harvard University,

Cambridge, MA 02138, USA 6Sorbonne

University, UTC CNTS UMR 7338, Biomechanics and Bioengineering, University of

Technology of Compiegne, Compiegne, France KEYWORDS: Electrospinning; wound healing; bioactivity; mechanical properties; antibacterial performance

ACS Paragon Plus Environment

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ABSTRACT: Electrospinning is a versatile technique used to create native tissue-like fibrous scaffolds. Recently, it has gained a large amount of attention for generation of bioactive dressing materials suitable for treatment of both chronic and acute wounds. In this review, we focus on the latest advances made in application of electrospun scaffolds for bioactive wound healing. We first provide a brief overview of the wound healing process and electrospinning approaches. We then discuss fabrication of scaffolds made from natural and synthetic polymers via electrospinning for effective wound treatment and management. Natural polymers used for wound healing included in our review cover protein based polymers such as collagen, gelatin and silk, and polysaccharide based polymers such as chitosan, hyaluronic acid and alginate. In addition, we discuss aliphatic polyesters, super hydrophilic polymers and polyurethanes as some of the most commonly used synthetic polymers for wound healing and wound dressing applications. Next, we review multifunctional and ‘smart’ scaffolds developed by electrospinning based approaches. We place an emphasis on how flexibility of the electrospinning process enables production of advanced scaffolds such as core-shell fibrous scaffolds, multilayer scaffolds and surface modified scaffolds. Taken together, it is clear that electrospinning is an emerging technology that provides a unique opportunity for engineering more effective wound dressing, management and care products.

1. INTRODUCTION Skin is the largest organ of the human body, which protects the internal tissues from thermal, chemical and/or bacterial damage. It prevents pathogens from invading the body while simultaneously maintaining homeostasis 1. Thus, disruption of skin’s anatomic structure due to topical wounds represents a major problem and requires prompt healing 2. Skin wounds can be classified into two categories; (i) acute wounds, which can be caused by surgical procedures,


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traumas, irradiations, abrasions and superficial burns; (ii) chronic wounds, which are produced because of specific diseases and include diabetic ulcers, pressure ulcers, and venous leg ulcers 3. During the past few decades, wound care appeared as a major public health concern along with the economic burden it presents. In the United States alone in 2000, 40 million inpatient and 31 million outpatient surgeries were performed that required post-surgical wound care 4. Moreover, currently around 6.5 million patients have been affected by chronic wounds every year, incurring a $25 billion healthcare cost. This amount continues to increase due to the combination of healthcare inflation, the aging population, and the increase in diabetes and obesity incidence 5. In addition, wound treatments represent a huge commercial enterprise, with a $15 billion annual market for wound care products and $12 billion for wound scarring treatments. The standard of wound care consists of (i) debridement or removal of non-viable tissue to promote cell proliferation, (ii) swabbing and cleaning the wound area to treat infections, and (iii) dressing to both protect the wound from infections and to enhance the healing process

6, 7.

Dry

gauze is presently the most commonly used wound dressing as it is both inexpensive and readily available. However, it possesses several disadvantages, such as a high absorbent capacity, leading to wound dehydration and bacterial growth promotion, as well as possible re-injury of the renewed epithelium upon gauze removal 8. Therefore, more complex dressings have been developed with low adherent and semipermeable properties. For example, hydrocolloids and hydrogels take advantage of their hydrophilic properties, allowing absorption of exudate and gas exchange while maintaining a moist environment and preventing microbial penetration 9. Additionally, they may have biological properties and serve as antimicrobials, stimulate local cell migration and proliferation, and enhance appropriate matrix deposition 10. However, these materials are not able to closely recapitulate the architecture of the skin extracellular matrix

11

(ECM) as well as the


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biomechanical cues of the skin, altering the fate of recruited cells and, ultimately, the wound healing efficiency 12. There have also been a number of other challenges which continue to hinder progress in wound dressing products. Among them, infection is a prominent technical challenge to overcome for effective wound recovery, with over 10% of all surgical wounds reported to develop infections 13. Other global challenges in wound management is the issue of good antibiotic stewardship and delayed wound healing, which is often not well understood14,

15.

Thorough

understanding of the different types of wounds at both the molecular and cellular levels has over the years hindered the development of more effective wound therapies. Recently, electrospinning has gained tremendous interest for the development of scaffolds in wound healing applications (Figure 1). This technology can produce biomimetic scaffolds composed of micro- and nanofibers from a wide variety of synthetic and natural polymers, which can mimic the native dermal ECM while creating a high surface area-volume ratio and interconnected porosity 16, 17. Electrospun nanofibers can be designed to closely emulate both the tensile strength and elastic modulus of human skin 18, 19, while serving as an excellent drug delivery device for wound healing therapeutics

19

(e.g. antimicrobial agents, growth factors, anti-

inflammatory drugs and anesthetics). Moreover, for extensive skin defects, these three dimensional (3D) scaffolds can be used as a replacement for epidermal grafts. Indeed, recent studies have demonstrated their potential for epidermal regeneration when combined with fibroblasts mesenchymal stem cells

22, 23.

20, 21

or

However, despite this potential, electrospinning is limited by its

bulky and expensive setup. Nonetheless, recent advances in miniaturization of electrospinning devices has led to the development of battery-operated, light weight, and small volume, portable devices, holding promise for the practical utilization of electrospun nanofibers in our day to day lives 24.


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In this review, we will first discuss the basic concepts of wound healing, with a special focus on wound dressings. Next, we will illustrate the current advances in the development of different electrospinning methods. We will then pivot to discussing electrospun materials for wound healing and discuss advantages and challenges of using natural or synthetic polymers for wound dressings. Finally, we will give an overview of recently developed multifunctional scaffolds and their impact on the healing process. The goal of this review is to link a fundamental understanding of wound healing, particularly of the crucial role of the wound dressing, to the rational and practical design of electrospun biomaterials for the development of more suitable tools for wound care. 2. WOUND HEALING Injured tissue goes through a complex natural process involving a cascade of interacting cellular events, resulting in eventual reconstruction and regeneration. Collectively, this complex biological phenomenon is known as wound healing 25, 26. 2.1 Wound healing process The entire wound recovery process is combined into four stages (Figure 2), namely, haemostasis/bleeding, inflammation, proliferation and remodeling

27.

Haemostasis, which is

initiated by vascular constriction, leads to coagulation of the blood to slow the flow of blood in the locale of injured tissue. This is followed by the inflammatory phase, in which blood that is rich in nutrients is supplied to the site of injury, causing the injured tissue to swell. Other characteristics of this phase include angiogenesis

28-30

and subsequent release of signaling cells, such as

proteins/cytokines, which are required to prevent infection and initiate the healing process. The next step of the healing process is the proliferation phase, which is characterized by the formation of new cells, causing granulation of the injured tissue as well as production of collagen by


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fibroblast cells that help with healing. As new cells continue to form around the edge of the wound, a scar is formed while collagen remodeling leads to closure of the wound. This is known as the remodeling phase. 2.2. Types of wound dressings In the past, wound dressing was considered a digression in proper wound care due to concerns of increased infection. However, years of work in wound healing research have shown significant advantages of wound dressings in the wound healing process 31, 32. These results have shown that wound dressings enhances cellular proliferation, migration, and other factors that overall enhances the healing of wounds. In fact, there is evidence that suggests that the development of scabs over exposed, dry wound surfaces hinders epidermal regeneration, causes more pain, and promotes scaring 33, 34. A major breakthrough in wound healing research was the correlation between wound moisture and healing enhancement 35, 36. This correlation suggests that dressing is essential in the healing process of wounds as it helps maintain moisture in the wound bed 37. A dressing has to promote quick yet effective healing by preventing/minimizing infection and facilitating the proper restoration of injured tissue. Additionally, effective wound care requires that the appropriate dressing be chosen for each specific type of injury. For example, factors to consider in choosing a wound dressing include the severity, size and location of the injury. There are over 3000 types of wound dressings on the market ranging from relatively simple and cheap to more complex and expensive dressings. These can be classified into four main categories, namely passive, interactive, advanced, and bioactive. Passive wound dressings are often dry and have minimum to no control of the amount of moisture in the wound bed. They are known to protect the wound bed from bacterial infiltration and mechanical trauma. However, removal of such dressings may induce mechanical trauma to


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the wound 38. Therefore low adherent materials are preferred for dressing, which allows wound exudate to pass through and maintain moisture while minimizing adherence to the wound bed. This dressing is particularly good for minor wounds 39. A bandage is a classic example of a passive dressing that can be fabricated from both synthetic and natural materials, and is commonly used together with other wound dressings 38. Interactive dressings are known for their flexibility, which makes them suitable for wounds in joints and other hard to reach areas of the body. One type of interactive dressings are film or foam dressings made of polyurethanes and transparent silicones. These are used for primary wound care, are permeable to oxygen and water vapor but not to fluids and bacteria. They also provide thermal insulation to dressed wound beds, and are highly absorbent. These dressings consist of a hydrophilic and hydrophobic component. The hydrophilic component is often in direct contact with the wound surface, enabling uniform dispersion of wound exudate while the hydrophobic backing component prevents exterior leakage. This dressing is advantageous over the other categories discussed as it can contain the exudate while preventing further damage to the wound 38.

Hydrogel dressings, another type of interactive dressing, promote moist wound bed formation,

allow absorption of wound exudate, and promote debridement and autolysis. Therefore, these types of dressings are good for the management of necrotic wounds but can be used for diverse types of wounds with little to no fluid leakage. Other advantages of this type of dressings are that it can be used for second-degree burns and infected wounds while minimizing pain and enhancing the patient’s comfort 34, 40, 41. Advanced dressings include dressings fabricated by hydrofibers, alginates, and hydrocolloids that may facilitate wound healing by maintaining wound environment moisture 41. Hydrocolloids are made up of pectin, elastomers, gelatin, and sodium carboxymethylcellulose materials that are


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linked to semipermeable film carriers to form a flat dressing. Hydrocolloid gels are often used at the surface of wounds to promote healing and can be used for dry wound rehydration. They contain water vapor and air and are simultaneously bacteria impermeable. Other attractive properties of this dressings are their biodegradability, lifetime and ease of use. This class of dressings has also been shown to reduce pain without causing epidermal deprivation and maceration

42.

Together,

these properties make the hydrocolloids very effective in preventing infection and promoting wound healing. Another type of the advanced dressings are those made of alginates 43, which are naturally composed of sodium salts of alginic acids and calcium and are biodegradable after usage. They are particularly used for highly exuding wounds, burns and some ulcers. Alginates absorb the oozing fluids, creating a gel to facilitate the quick healing of the wound. The main drawback in the canonical wound dressings discussed above is the limited suitability for fast healing of chronic wounds. Current research strategies to improve the functionality (i.e. wound healing capability) of these dressings involves blending different dressing materials of specific properties together or incorporating antimicrobial agents6 to achieve a more ideal or effective product. The resulting dressings involve the development of wound dressings made up of highly complex biopolymers or their blends containing antibiotic/antimicrobial agents including gentamicin

44,

tetracycline

45,

vitamin

46

etc. This new class of wound dressings is commonly

known as the bioactive dressing, which is designed to allow interaction with the physiological condition of the wound. This interaction therefore helps to enhance rapid healing of the wounds effectively by facilitating inflammation and proliferation, reducing scarring, and prolonging usage of the dressing46-50. 3. ELECTROSPINNING


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Electrospinning is a technique used to fabricate micro and nanofibrous substrates from various polymers51. To do so, a high voltage positive charge is applied to a viscoelastic liquid droplet extruded from the endpoint of a metallic needle. The electric charge polarizes the droplet, and leads to formation of a conical shape with ~49.3o semi-vertical angle, known as tailor cone, and that eventually leads to the ejection of a charged jet to form fibers. Fibers collect on the anode, forming a continuous fiber mat as shown in Figure 3

52.

Fiber morphology and mechanical

characteristics of electrospun fibers are governed by process parameters such as applied voltage, feed rate and needle tip-collector distance, system properties such as solution viscosity, solvent volatility, polymer molecular weight and solution conductivity, and environmental conditions 53, 54.

3.1 Advantages of electrospinning The fibrous bandages provide more promising wound care compared to traditional bandages, due to their ability to partially recapitulate the native ECM structure. This favors attachment, growth and migration of fibroblast, and consequently promotes regeneration of skin tissue in the wound area52, 55-57. Compared to other nanofibers manufacturing techniques, electrospinning is a simple, robust and directly applicable technique to produce fibrous scaffolds composed of a wide variety of materials with tunable properties, compositions, shapes and dimensions

58.

These

advantages allow researchers to use electrospinning in order to create wound dressing materials that can mimic the native tissue microenvironment and better treat the wound area. Meanwhile the highly interconnected porous structure of the electrospun meshes enable them to permeate oxygen, absorb wound exudate, exchange fluids and protect the wound area from dehydration59, 60. Additionally, recent technological advances have enabled electrospinning setups at a wide range of scales. For example, numerous large industrial scale electrospinning setups have been


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commercialized61, despite several obstacles such as low productivity, difficulty in the process monitoring and quality control

62.

To address these challenges, recently, a battery operated,

portable electrospinning machine was developed by Long et al., with a total device size of only 10.5*5*3 cm3

63.

This development could make electrospinning more readily available in the

hospital and medical care center settings permitting more tailored individualized wound care 64. Advanced bioactive wound dressings often require controlled, on-demand release of therapeutic agents, in order to promote recovery within the wound area without causing undesired effects such as infection65,

66.

In this regard, electrospinning shows great promise, since it offers various

approaches for loading drugs and other biomolecules. Furthermore, scaffolds made by electrospinning can have tailored physiochemical properties such as tunable degradation and drug release rates. For example, bioactive agents could be either attached after electrospinning or incorporated into the scaffolds during electrospinning (Figure 3D-G). In the following section, we describe some of the most common techniques to create drug loaded electrospun scaffolds. 3.2 Types of electrospinning and post-spinning treatments to load drugs 3.2.1 Physical or chemical conjugation High porosity and high surface area of electrospun scaffolds can allow immobilization of bioactive agents via chemical or physical approaches. For example, scaffolds can be made using polymers that have or can be treated to have functional groups such as amines, carboxyl or hydroxyl groups, in order to chemically conjugate a desired drug 67. More specific scaffold surface functionalization chemistries can be developed to preserve the bioactivity or functionality of drugs affected by high electrical field or solvent(s) used during electrospinning 68. Similarly, to improve physical adsorption of drugs, manipulating electrostatic or van der Waals interactions between the drug and the scaffolds might be necessary 69.


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3.2.2 Initial blending If the drug(s) can be dissolved or uniformly mixed (such as nanoparticle dispersions), they can be added into the polymer solution prior to electrospinning 70. This type of initial blending offers high loading of homogeneously dispersed drugs

70, 71.

However this method often causes

accelerated or burst release of drugs that might only be suitable in a narrow array of applications 70.

One example where burst release might be beneficial is in the delivery of non-steroidal anti-

inflammatory drugs (NSAIDs), when a faster release could help reduce pain and inflammation as part of the wound treatment process 72. Additionally this technique can be used as a very effective approach for loading and time-dependent release of hydrophobic drugs 73. 3.2.3 Coaxial electrospinning When initial burst release of the drugs needs to be avoided or their functionality is affected by the polymer solvents, coaxial electrospinning is preferable71. In this technique, two or more solutions are separately delivered from different channels to the concentric needle, and form coreshell layered fibers. Usually the drug containing solution is placed in the core. The drug release profile can be fully or partially controlled by the thickness and biodegradation rate of the shell polymer layer

74.

This method can also be used to tune the bioadhesive and biocompatibility

profiles of the scaffolds and their nanofibrous surface

74.

Several studies using coaxial

electrospinning have generated scaffolds with improved cell and skin-friendly surface properties such as improved hydrophobicity and cell affinity75-77. 3.2.4 Emulsion electrospinning Emulsion electrospinning is another technique to encapsulate water soluble drugs and proteins, in order to prevent their undesirable burst release. In this technique, immiscible droplets containing


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the drugs are dispersed into the polymer solution, and core-sheath layered fibers are produced from a single nozzle configuration. Compared to coaxial electrospinning, this technique provides higher reproducibility and lower complexity78. However, the advantage of coaxial over emulsion electrospinning is that coaxial approaches can provide more precisely controlled drug delivery 79. 4. Natural and synthetic polymer dressings 4.1 Natural polymer dressings Various types of natural biopolymers have been utilized to produce non-woven electrospun meshes for engineered local skin regeneration (Table 1). These polymers are generally categorized into two classes: (i) protein based natural polymers and (ii) carbohydrate based natural polymers. Among the protein based polymers, gelatin, collagen, elastin and silk fibrinogen have been most extensively studied for wound healing. While chitosan, hyaluronic acid, dextran, and cellulose are the most widely explored carbohydrate based polymers52, 54, 56. These polymers exhibit excellent biocompatibility, low antigenicity, and favorable bioactivity promoting cell attachment and proliferation. Moreover the chemical structure of electrospun dressing materials produced from these natural polymers are evidently more similar to the native ECM80, 81. Nevertheless, natural polymers have very complex chemical structures and large variations in physicochemical characteristics as they are derived from different sources and in different forms. For example, some natural polymers exhibit high viscosity associated with their high molecular weight while others undergo degradation in solution or are difficult to dissolve in adequate solvents 52. Therefore it is often challenging to produce smooth and uniform fiber structures by electrospinning of natural polymers. Furthermore, the poor mechanical properties obtained from natural polymer fibers limits their application as sustainable wound dressing materials.


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4.1.1 Electrospun wound healing dressings using carbohydrates Hyaluronic acid, sodium alginate and chitosan are the most widely used carbohydrates for nanofiber electrospinning and therefore discussed in more detail. Hyaluronic acid is a glycosaminoglycan that is present in most living organisms and is a main component of ECM in the skin, joints, eyes, and a number of other organs. A primary biological function of hyaluronic acid is structural maintenance. In addition, hyaluronic acid has other important roles in numerous biological processes that could have positive implications in the wound healing process

82.

Conversely, one drawback is the high viscosity of hyaluronic acid solutions, even at low concentrations, which makes the electrospinning challenging. Despite this limitation, PabjańczykWlazło et al.

53, 82

optimized the electrospinning process parameters to fabricate hyaluronic acid

nanofibrous mats enriched with nano-additives or antibiotics, which promote their use for various biomedical purposes. Additionally, a hyaluronic acid/gelatin electrospun scaffold was made by Ebrahimi-Hosseinzadeh et al. 83 in which they applied the scaffold to second degree burn wounds in Wistar rats and observed faster wound closure. The next carbohydrate within the scope of the review is chitosan. It is a linear polysaccharide combined of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated unit) and Nacetyl-D-glucosamine (acetylated unit). Chitosan is a fully or partially (more than 50%) deacetylated derivative of the natural polysaccharide chitin

84.

Chitosan is a natural cationic

polymer with functional versatility, and can be electrospun by using water as a solvent59, 85-87. Chitosan electrospun mats are suitable wound dressings due to their increased absorption capacity and antibacterial activity. For example, Chen et al.

86

found that electrospun chitosan mats had

superior absorption capacity and antibacterial activity when synthesized with pectinate. The efficacy of similar chitosan mats was demonstrated by Antunes et al.59, who found that chitosan


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mat wound dressings were able to improve tissue regeneration and wound closure rates in Wistar rats. Furthermore, Dragostin et al. 85 assessed the wound dressing potential of chitosan nanofibrous mats derivatized with different sulphonimides. Sodium alginate is another algal polysaccharide which has numerous biological properties favorable for wound healing applications88, 89. Sodium alginate aqueous solutions are often mixed with either poly vinyl alcohol (PVA) or poly ethylene oxide to get uniform and smooth fibers by introducing sufficient entanglement. Chen et al.

86

fabricated electrospun alginate fibers, which

showed superior antibacterial performance and exudate absorption capacity. Wongkanya et al. fabricated vancomycin encapsulated sodium alginate/soy protein blended fibers by electrospinning. Their studies showed that presence of soy protein improves the bioactivity of sodium alginate by improving cell adhesion to the scaffold 90. Poor mechanical properties and low thermal resistance can limit potential of alginate scaffolds in wound dressing applications. To address these challenges, Silva et al.88 incorporated metal oxides into the sodium alginate fibrous mats. They suggested that tensile strength and thermal stability of sodium alginate can be greatly enhanced by incorporating small amounts of magnesium oxide nanoparticles. 4.1.2 Electrospun wound healing dressings using proteins Gelatin, silk fibroin, and collagen are the most commonly used proteins for electrospun wound healing applications and have hence been primarily considered in this review. Gelatin is derived from partial hydrolysis of collagen, the major component of skin and connective tissue. It possesses an array of beneficial biological features such as biodegradability, non-antigenicity, macrophage activation ability and a high hemostatic effect55, 87, 91. Butcher et al.

92

studied the

effects of solution properties on the morphology and mechanical properties of electrospun fibers of gelatin. Gelatin from cold-water fish showed different rheological properties and low


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temperature of gelation owing to relatively low percentage of proline and hydroxyproline 93. Gu et al.

78

optimized solution parameters for uniform bead free scaffolds. Controlled evaporative

water loss from Gelatin/PLLA fibers was found to improve fluid drainage and biocompatibility of the scaffolds. Similarly, Jalaja et al.

94

reported that electrospinning of gelatin in water based

solution and cross linking by sucrose oxidation reduces its toxicity, and improves the cell viability. Silk fibroin is derived from a variety of insects and spiders and is another protein widely used for scaffold electrospinning. With its favorable mechanical and biological properties

91,

silk

fibroin stands as an effective biomaterial for skin, vascular, cartilage, bone, neural, tendon, tracheal, ligament, and bladder tissue regeneration

95-97.

Chouhan et al.

98

tested silk fibroin

electrospun dressings for wound healing in an alloxan-induced diabetic rabbit model. They found that non-mulberry silk fibroin wound dressings derived from Bombyx mori exhibit faster healing than PVA or commercial bandages for tissue remodeling, and angiogenesis owing to the existence of cell binding motifs. In another study by the same research group56, functionalized non-mulberry silk fibroin mats synthesized with epidermal growth factor and ciprofloxacin-HCl showed desirable (i.e. matching native tissue) mechanical properties and accelerated wound healing in an in vivo rabbit model. Incorporation of sulfate groups in silk fibroin also enhanced the anticoagulant activity of the scaffolds and facilitated growth and expansion of vascular cells96. The most abundant protein in the human body, collagen, is a main component of the ECM and widely used for electrospinning of nanofibers due to its bioactive and mechanical properties (Table 1)55, 99, 100. Hall Barrientas et al.

100

reported the fabrication of electrospun scaffolds of type I

collagen with poly (lactic acid) (PLA) as a supporting synthetic polymer. They further characterized its physicochemical properties, bacterial response, drug loading and biofunctionalization. The scaffolds showed sustained drug release and a good antibacterial


15


performance. Zhou et al.

101

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successfully combined bioactive glass and fish collagen to make

electrospun nanofibrous mats having enhanced tensile strength and antibacterial activity. The produced collagen/bioglass fibers also facilitated propagation, migration, and secretion of human umbilical vein endothelial cells and showed an excellent wound healing ability (Figure 4). Yao et al. 102 developed collagen/poly(L-lactic acid-co-ε-caprolactone) (PLCL) scaffolds for engineering a conjunctival equivalent containing proliferative cells and goblet cells with good cell viability without invoking an inflammatory reaction. 4.2 Synthetic polymer dressings Due to their superior mechanical strength and processing flexibility, numerous synthetic biopolymers have been extensively studied for wound healing application using electrospinning103105.

Unlike natural polymers, synthetic polymers usually have simple and controlled chemical

structures and thus can be easily electrospun to create a fibrous micro pattern similar to that of native ECM105-107. This provides an optimal environment for cell propagation, migration, and differentiation to produce sustainable skin grafts 106. Additionally, immunogenicity and pathogen transmission during the wound healing process can be avoided through the use of synthetic polymers

105.

However, most synthetic polymers have poor bioactivity and inferior antibacterial

performance 107, 108. Subsequently, bioactive components, such as growth factors and therapeutic agents, can be incorporated into the synthetic polymers to produce effective and fully integrated wound dressing scaffolds109-111. Among synthetic polymers, aliphatic polyesters, such as poly(glycolic acid) (PGA), PLA, their copolymer (PLGA), and polycaprolactone (PCL) have been most extensively investigated for biomedical application, including wound healing

103, 107, 112.

These polymers are biodegradable,

have high biocompatibility, and usually release non-toxic degradation products 105, 113. The desired


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biodegradation rate can be achieved by modifying their composition, molecular weight and structure. Most importantly, they gained approval by the FDA (Food and Drug Administration) for some clinical applications several decades ago

105, 114.

On the other hand, super hydrophilic

polymers such as polyethylene glycol (PEG), PVA and polyvinyl pyrrolidone (PVP) have shown many interesting characteristics favorable for wound dressing applications

115, 116.

For example,

their ability to retain humid environments, their structural resemblance to skin tissue, their high efficiency in adsorbing drugs, proteins, and growth factors, and their controlled release of these compounds makes them excellent candidates for wound healing applications116-119. In several reports, aliphatic polyesters have been combined with super hydrophilic polymers as polymer blends, copolymers or core-shell fibers by electrospinning to surpass the shortcomings of individual materials (Table 2) 109, 120-123. Belenkaya et al.

120

contrived a fully biodegradable and hydrophilic fibrous platform by the

electrospinning of PLGA/PVP blends in different ratios for wound healing applications. This patented platform has an outstanding adsorption capability of biological liquids, including blood (at least 20 w/w), without swelling, a predictable biodegradation rate, and good antimicrobial activity. Appreciable hemostatic properties and antiseptics abilities were also interestingly observed for this platform. With other advantages such as a good mechanical strength, skin compatibility, and a self-adhesive property, the potential of this platform for many types of wound dressings is tremendous. These include, but are not limited to, first aid wound dressing, drugdelivery based dressing, chronic wound dressing, and diabetic ulcer dressing. Lee et al.124 examined the performance of metformin-eluting PLGA scaffold on diabetic wound healing. Interestingly fiber morphology, wettability and water uptake capacity of the PLGA was greatly improved by simply adding metformin. The scaffold showed a sustainable drug release


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profile, and metformin was found to be active for more than three weeks. Consequently, the metformin-eluting PLGA scaffold exhibited much faster would healing performance, compared to commercial gauze sponge. Meanwhile, the nanofibrous scaffold reduced formation of granulated tissue and infiltration of inflammatory cells, and encouraged well formation of stratum corneum (Figure 5). Choi et al. 121, 122 studied performance of an electrospun nanofibrous mesh composed of PCLPEG copolymer and PCL on diabetic ulcers after immobilizing human epidermal growth factor (EGP) by physical and chemical conjugation. In vitro testing showed that the composite nanofiber significantly improved cell propagation and differentiation when compared to PCL fibers with or without EGP. Animal based in vivo testing demonstrated an accelerated wound closure rate of the composite nanofiber with chemically conjugated EGP, in which 50% of burnt mouse dorsal ulcers recovered in one week. These results suggested that an alleviated initial burst release and a slower deactivation rate of chemically conjugated EGP is the main attribution for the outstanding wound repair performance. Yang et al.

109

investigated the effects of basic fibroblast growth factor (bFGF) loaded PELA

(PEG-PLA copolymer) fibrous mats on skin regeneration. By modified emulsion electrospinning the researchers were able to imbed bFGF inside PELA fibers having a core-shell structure. The group observed that encapsulated bFGF exhibited a sustainable release profile with consistently high biological performance. Specifically, PELA mats remarkably enhanced fibroblast attachment, propagation, and cell viability and collagen expression. To further validate these models, a skin regeneration test using diabetic ulcers of mice was performed, while the mice were allowed to behave normally. They found that bFGF encapsulated fiber mats re-epithelialized the entire wound area in three weeks without causing inflammation, infection or granulation. The structure and the


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surface of the regenerated area were also found to be similar to native skin tissue while allowing normal hair growth and the ability to wrinkle. Polyurethane (PUs)-based scaffolds have also been utilized for wound healing, owing to their resistance to tear and abrasion, capability to adsorb exudates, and gas/vapor permeability 126.

106, 125,

Unnithan et al. 126 explored the potency of estradiol loaded electrospun polyurethane-dextran

nanofibers for post-menopausal wound treatment. The composite fibrous mat showed a superb blood clotting capability and sustainable drug release controllability. Further in vitro cell studies suggested that the presence of estradiol promotes cell affinity and growth and accelerates cell proliferation. The estradiol loaded composite nanofibers also proved prominent in wound closure efficiency, in which 95% re-epithelialization of the wound was achieved in two weeks. A relatively new synthetic polymer, polyglycerol sebacate (PGS)

127,

was also adopted for

wound healing application due to its excellent biocompatibility, softness, elastomeric property and surface erodibility128, 129. Memic et al. 128, 130 developed a wound dressing scaffold by coating silver on PGS/PCL nanofibrous scaffolds. These scaffolds showed excellent cell compatibility and remarkable antibacterial performance. Their electrical properties, elasticity, ductility, and biodegradation rate were found to be tunable by controlling PGS-PCL ratio and/or the thickness of silver coating. Overall the developed scaffold could be a promising candidate for controlled release-based antibacterial applications in wound dressings. 5. MULTIFUNCTIONAL SCAFFOLDS More recently researchers have been moving to design fully integrated, multifunctional scaffolds which can compromise all the essential properties required for effective wound treatment. For example, ECM simulated morphological properties, mechanical integrity, physiochemical characteristics, biological performance and antibacterial activity are all simultaneously important


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for the design of the next generation of wound healing scaffolds. Among them, some multifunctional scaffolds have been generated by mixing different natural or synthetic polymers, nanoparticles, nano fibrils and bioactive agents for electrospinning. Other multifunctional scaffolds have been fabricated through a combination of electrospinning with other advanced techniques such as smart materials synthesis. 5.1 Blended and composite scaffolds Motealleh et al. 131 embedded chamomile into a blend of electrospun PCL and polystyrene (PS) for wound healing applications. In their studies, chamomile was used to aid wound closure upon usage as an ointment or extract for wound dressings132-134. Additionally, the use of polystyrene in the fabrication was due to its stiffness, transparency, and mechanically hard and brittle nature. On the other hand, PCL is a semi-crystalline and biodegradable polymer, and it is a good carrier for electrospinning. A low water vapor permeability and mechanical flexibility are other attractive characteristics of PCL for wound management. The authors therefore harnessed the combined features of the components, PCL, chamomile, and PS, to create a suitable wound dressing with enhanced wound healing capabilities. The results of their work suggested that these electrospun PCL/PS containing chamomile fibers show good antibacterial, antifungal activities and enhanced wound healing. Sadri et al.

135

electrospun green tea extract in a polymeric nanofiber of chitosan/PEO and

investigated its use as a wound dressing. Additionally, they investigated its antibacterial activity due to the release of green tea extract. Chitosan was chosen in this nanofiber for its biodegradability, biocompatibility, mucoadhesive properties as well as its functionality in promoting cell proliferation, facilitating wound healing, and providing antibacterial activity 136, 137. Although chitosan has low solubility, low stability, and inferior mechanical properties138-143, these


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difficulties can be overcome by mixing it with other biopolymers, like PEO

38, 138, 144.

The

antibacterial activity of the chitosan/PEO green tea scaffold was investigated against gram-positive bacteria Staphylococcus aureus and gram-negative bacteria Escherichia coli. Their work confirmed the bactericidal activity of the chitosan/PEO/green tea with inhibition zones observed both in the presence of gram-negative and gram-positive bacteria. Yuan et al. 145investigated the effects of electrospun poly(hydroxybutylate-co-hydroxyvalerate) (PHBV) mixed with modified keratin on wound recovery. Keratin, a protein mainly produced by keratinocytes, has been widely explored for its importance in wound management. In particular, this is due to its roles in maintaining structural durability of tissues, cell differentiation, and wound healing 146, 147. PHBV, a biodegradable polymer, has been extensively investigated for its potential in skin wound healing applications. Electrospun meshes of PHBV were previously reported to facilitate the healing progression of wounds and helped reduce skin scarring by maintaining wound moisture

148.

Therefore, the researchers proposed electrospun m-keratin-PHBV blends as an

advanced wound dressing. The results of their work accelerated wound recovery, thereby making the m-keratin-PHBV scaffold a viable wound dressing. Lai et al. 149 reported the development of sponges made of hyaluronic acid (HA) and collagen (Col) containing vascular endothelial growth factor (VEGF), which were then loaded with nanofibriles targeted to heal diabetic wounds. The attracting properties of HA, Col, and their blends have been well discussed elsewhere in this review and in many other reports 150-154. Growth factors, a class of proteins including endothelial growth factor (EGF), platelet-derived growth factor (PDGF) and VEGF, are known to facilitate cell behavior as well as aid in wound healing when used in polymers or when directly applied to wounds 149, 155-159. For example, the controlled release of VEGF in developed sponges was found to facilitate the proliferation of human vein


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cells, the formation of tubular tissue structures by inducing angiogenesis, and the acceleration of re-epithelialization. Therefore, it can be considered as a potential bandage for chronic wounds. Tonda-Turo et al. 160, recently introduced a “green”, one-step facile approach for formation of a crosslinked electrospun nanofibrous gelatin containing the bioactive, silver nanoparticles (AgNPs) or gentamicin (GS). One of the main advantage of this technique is the ability to perform the entire experiment in water and hence, could promote usage in cell experiments while minimizing cytotoxicity

161.

Although relatively inexpensive, but structurally weak adhesive protein, gelatin

compared to collagen continues to be widely explored for wound healing and other biomedically related applications162-165. Choice of gentamicin and AgNPs was due to their abilities to enhance the wound healing process by limiting bacterial wound colonization 166, 167. In particular, silver is a known strong antibacterial agent 165, 168, that can inhibit bacterial strains that have resistance to antibiotic 169. Herein, the authors combined the powerful wound healing properties of gelatin with the antibacterial property of gentamicin and AgNPs to produce the reported electrospun scaffold. The fabricated scaffold of electrospun nanofibrous gelatin containing uniformly distributed gentamicin or AgNPs structures were confirmed by EDS and SEM analysis. The resulting gelatin based scaffold was investigated for its ability to effectively promote tissue healing while maintaining potent antibacterial activity against Gram-positive and Gram-negative bacteria. Overall, the fabricated scaffolds demonstrated good cell proliferation with low cytotoxicity and effective antibacterial activity. Similarly, Chen et al. 170 incorporated both silver and gentamicin in PCL nanofiber-based sutures and investigated the antibacterial activity of the co-delivered antibacterial agents against Pseudomonas aeruginosa. After 1-hour co-incubation of fabricated scaffold doped with GS, silver and combination of GS and silver, significant inhibition of bacterial growth was observed in each


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sample. However, further incubation (up to 2 hours) resulted in complete inhibition of bacterial growth in samples treated with sutures containing PCL nanofibers that have been doped with a combination of GS and AgNPs compared to those treated with either silver alone or GS alone 170. Therefore, combination of silver and GS in suture scaffold led to a more effective antibacterial activity and wound healing compared to using individual antibacterial agents. 5.2 Smart scaffolds “Smart” materials are able to undergo change in their physiochemical properties governed by external stimuli such as heat, light and electric field

171

(Table 3). These types of materials are

highly attractive for wound healing applications, since they can provide several advantages compared to naïve materials such as regulated, on-demand delivery of therapeutic agents172. Unlike other biomaterials such as hydrogels, electrospun scaffolds have only recently been developed using approaches that incorporate smart materials. Nevertheless, electrospun scaffolds could provide improved properties and features such as shorter stimuli response time and more precisely controlled drug release173 versus their hydrogel counterparts. Li et al.

174

engineered a thermoresponsive hybrid scaffold by electrospinning blends of poly

(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) and poly(l-lactic acid-co-εcaprolactone) (P(LLA-CL) for advanced wound healing. Due to presence of PDEGMA, the wetting behavior of the scaffold was distinctively affected by temperature change. For example, contact angle of the hybrid scaffold with 1/3 of PDEGMA declined from 120o to 15o, when the temperature decreased from 45 to 20 oC. The scaffold showed sustainable drug release, but more importantly the authors showed interesting cell attachment and detachment behavior at different temperatures. The researcher observed that the scaffolds promoted the attachment and growth of L929 fibroblasts at 37 °C, while the cells could be detached from the scaffold when the temperature


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was reduced to 25 °C. This could provide easy removability of the scaffold from wound area without causing secondary injuries or pain. In vivo results showed better recovery of the wound area when compared to commercial dressings. Han

et

al.

172

synthesized

self-immolative

polymer

(SIP)

using

phenyl

(4-

(hydroxymethyl)phenyl) carbamate and dibutyltin dilaurate as a reagent, and combined the SIP and polyacrylonitrile (PAN) to encapsulate different functional materials by coaxial electrospinning. They showed that SIP depolymerizes under the right chemical stimuli, and the response of SIP based core-shell fibers to such stimuli is 25 times higher than that of a cast film. They observed negligible drug release without the chemical trigger. The authors 175 also made pH responsive core-shell fibrous membrane using Eudragit L (EL100) as a core and Eudragit S (ES100) as a shell by coaxial electrospinning. Similarly the membrane showed immediate response and controlled drug release to different pH environments that could have important wound healing applications. Li et al.

176

designed a light responsive composite fibrous membrane composed of poly

(N‐isopropylacrylamide)

(PNIPAM),

polyhedral

oligomeric

silsesquinoxanes

(POS),

2‐ethyl‐4‐methylimidazole (EMI) and silica‐coated gold nanorods. In this scaffold, thermoresponsive PNIPAM was cross-linked by POS using EMI as a catalyst in order to stabilize the polymer under its lower critical solution temperature (LCST). Then high photo thermal efficient gold nanorods were added into the polymer solution, in order to control the scaffold temperature using near inferred (NIR) light. The membrane was found to be capable of rapidly shrinking by 83% with NIR stimulation, and could recover to its original shape when the NIR light was switched off. Combining its ECM simulated structure, the scaffold revealed not only ondemand release of drugs, but also controlled release of therapeutic cells upon the NIR exposure.


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When the authors loaded doxorubicin as a model drug, they showed that doxorubicin therapeutic activity was not affected by electrospinning and/or NIR treatment. They selected NIH3T3 fibroblasts, which play a critical role in wound recovery, as a model cell line for the controlled cell release. Similarly, after the release, the cell line retained its normal phenotype and cell differentiation function. Tamayol et al. 66 investigated electrical heat integrated, PEGylated-chitosan drug carrier loaded PGS-PCL fibrous platform for on-demand drug delivery using flexible biodegradable wound bandages. The authors incorporated PEGylated-chitosan drug carriers into PGS-PCL by electrospinning. Next, the fiber mats were coated with bioresorbable electrically conductive patterns. PEGylated-chitosan was used for controlled thermal transition and antibacterial activity as compared to other thermoresponsive polymers

177.

The resulting platform was effective in

accurately controlling antibiotic release by simply adjusting the applied voltage (and therefore the scaffold temperature), with excellent inhibition against bacterial growth. The bioactivity of the fully degradable platform (i.e. bioresorbable heater and biodegradable polymers) was significantly better than the platform without the conductive pattern (Figure 6). Hao et al.178 developed a super magnetic scaffold by combining γ-Fe2O3 nanoparticles, hydroxyapatite nanoparticles (nHA) and PLA during electrospinning, and studied the ability to regulate fibroblast phenotypes. Magnetization of the scaffold generated mechanical stimuli, which could affect fibroblasts behavior and time-dependent secretion profiles. As a result, the scaffold significantly increased the production of type I collagen, VEGF, and transforming growth factorβ1. Simultaneously, the scaffold suppressed secretion of pro-inflammatory cytokines, including interleukin-1β (leukocytic pyrogen) and monocyte chemoattractant protein-1. Overall modulation of fibroblasts using magnetic stimuli promoted fibroblast migration, suppressed myofibroblasts


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differentiation, enhanced VEGF expression and activated integrin signaling that could be of great importance in scaffold-guided tissue regeneration (Figure 7). 6. CONCLUSION Electrospinning has become one of the most attractive techniques to develop advanced bioactive wound dressings due to its simplicity, flexibility, and capability to imitate the native ECM structure, recapitulate the wound healing process and provide biomaterial tunability. Modification of the electrospinning process, such as using co-axial and/or emulsion electrospinning, can provide controllable and effective approaches for incorporation of drugs, antibacterial agents, and/or growth factors. Natural polymers have high biocompatibility, and they easily stimulate cell growth and regulation. On the other hand, synthetic polymers provide mechanically durable and humid environments to support wound healing and skin regeneration. Additionally, controlled release of antibiotics is most often required to prevent infections during wound recovery. Therefore, more recently researchers have turned to developing multifunctional and smart scaffolds that could provide better control over scaffold properties and wound healing outcomes. Overall, these recently developed electrospun scaffolds can fulfill most of the very essential requirements for accelerated wound healing including minimized infections. However, challenges remain including large scale-industrial utilization of these materials, owing mainly to their low production rates. Even though portable electrospun setups exist, the ability to control cell behavior on a personalized, patient level remains elusive, including the potential need to generate fully engineered skin grafts. Ultimately, fine-tuned control of biodegradation rates, drug release and other scaffold properties needed to match the native wound healing processes still have to be overcome. However, despite some of these perceived drawbacks, electrospinning based approaches have a very bright future in wound healing and wound care product development.


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Corresponding Author *Corresponding authors: [email protected] and [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH) – King Abdulaziz City for Science and Technology - the Kingdom of Saudi Arabia – award number (12-MED3096-3). The authors also, acknowledge with thanks Science and Technology Unit, King Abdulaziz University. This work was also supported by the Scientific WAQF Fund at King Abdulaziz University (KAU), Jeddah under grant number 17/1436, also Northeastern University (Boston, MA, USA) Seed Grant/Proof of Concept Tier 1 Research Grant and startup funds provided by the Department of Chemical Engineering. Burroughs Wellcome Fund (BWF) and Thomas Jefferson/Face foundations awards. Authors would like to acknowledge help from Ian Hardingand for his grammatical proofreading the manuscript. REFERENCES 1. Proksch, E.; Brandner, J. M.; Jensen, J. M., The Skin: An Indispensable Barrier. Exp. Dermatol. 2008, 17 (12), 1063-1072. 2. Enoch, S.; Leaper, D. J., Basic Science of Wound Healing. Surgery (Oxford) 2005, 23 (2), 37-42. 3. Moore, K.; McCallion, R.; Searle, R. J.; Stacey, M. C.; Harding, K. G., Prediction and Monitoring the Therapeutic Response of Chronic Dermal Wounds. Int. Wound. J. 2006, 3 (2), 8998.


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TABLES AND FIGURES Table 1. Natural polymers and their properties as candidate materials for electrospinning. Natural Polymers

Advantageous Properties

Disadvantageous Properties

Carbohydrates

Hyaluronic Acid

Biocompatibility, Good mechanical strength, High viscosity at relatively low stimulation of cell migration, differentiation and concentrations associated with proliferation, regulation of the metabolism and high molecular weight53, 82. organization of the ECM, Maintenance of skin hydration, elasticity, moisture53, 82.

Chitosan

Biocompatible, biodegradable, low Poor solubility, slower and immunogenicity, antimicrobial, and antioxidant uncontrollable biodegradation activity, enhances infiltration of inflammatory rate87. cells into the wound region, promotes fibroblasts migration and proliferation, natural blood clotting, blocks nerve endings and collagen deposition. Additionally, promotes erythrocytes aggregation, activates the coagulation cascade59, 84-86.

Sodium Alginate

Low cost, biocompatibility, biodegradability, Insufficient chain entanglement, low toxicity, non-immunogenicity and it lack of cell recognition sites90. possesses good film forming characteristics. Additionally, it can activate macrophages and increase cytokine levels in wounds88, 89. Proteins

Gelatin

Silk Fibroin

Collagen

Biodegradable and non-antigenic, macrophage Limited solubility in water, activation and a high hemostatic effect 55, 91. inferior mechanical strength and elasticity, shape instability, thermal instability87. Mechanical properties (strength, toughness, elasticity, lightweight), controllable biodegradation rate, good permeability of water vapor and oxygen, inflammatory resistence, ability to promote adhesion and proliferation of keratinocytes and fibroblasts 91.

Degumming procedure is necessary for removal of sericin (a glue-like protein that holds together fibroin) might affect mechanical strength179.

Low antigenicity, good biocompatibility, Tendency to break down quickly promotes cell proliferation, adhesion, cell during degradation55. chemoattractant for granulation tissue formation, exhibit high in vivo stability and maintain a high biomechanical strength over time 99, 100.


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Table 2. Common synthetic polymer for wound dressing application Polymer Name

Advantageous Properties

Disadvantageous Properties

Aliphatic polyesters Poly(lactic (PLA)

acid) Modern biodegradation rate, a good mechanical Mechanical brittleness, low strength, mechanical sustainability in-vitro or crystallization rate, in- vivo, thermal stability, renewability, hydrophobicity versatility and easy processability105, 112.

Poly (lactic-co- Tunable wetting property, biodegradation rate, Low ductility, relatively low glycolic acid) mechanical and thermal behavior with varying drug loading efficiency, high (PLGA) synthesis cost, poor cell affinity lactic/glycolic acid ratios, solubility in a broad 182, 183 range of common solvents 180, 181 Poly caprolactone Flexibility, high crystallization rate, long term A slow biodegradation rate, low (PCL) mechanical strength and durability105, 130 hydrophobicity105, 184 Super hydrophilic polymers Poly(ethylene glycol) (PEG) Poly(vinyl alcohol) (PVA) Poly vinylpyrrolidone (PVP)

High biocompatibility, sensitivity to different physical and chemical stimuli, Neutrality, solubility in wide range of organic solvents and water116, 185

Non biodegradability, lack immunogenicity and antigenicity, possibility to cause contact allergy186, 187

Flexibility, ability to retain moist environment, Non biodegradability, low gas permeability116, 120 strength, low thermal stability120, 188

Simple and clean synthesis procedure with Non biodegradability, lower cost, softness, ability to store large mechanical weakness, and lower amounts of water without loosing mechanical thermal stability 120, 189 integrity 116, 189


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Table 3. Smart scaffolds for wound dressing application Types of stimuli

Scaffold

Synthesizing technique

Mechanism

PVP/SIP-PAN (core/shell) 172

Coaxial electrospinning

Depolymerization of SIP in trifluoroacetic acid

EL100/ES100 (coreshell) 175

Coaxial electrospinning

Different dissolution rate of the EL polymer in different pH

Thermal

PDEGMA)/P(LLACL) 174

Electrospinning

Wetting behaivior of the PDEGMA can be controlled by temperature change

Light

PNIPAM–POSS– Au@SiO 176

cross-linking +electrospinning

Gold nanorods converts the adsorbed light to heat, and control the scaffold temperature

Electrospinning+RF sputtering

The temperature of the scaffold can be controlled by electrical heating over conductive pattern, which influence on drug release behavior of thermoresponce PEGylatedchitozan

Electrospinning

Magnetization generates mechanical stimuli, and remotely control cell regulation

Chemical

Electrical

Magnetic

PEGylatedchitosan/PGS-PCL /Zinc pattern

γ-Fe2O3/nHA/ PLA 178


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120 80 40 0

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" Electrospinning" AND " Wound"

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

160

3000 2500 2000 1500 1000

" Electrospinning" AND " Wound"

500 0

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Number of citations

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Number of publications


e

Figure 1. Annual number of publications and citations about electrospinning on wound healing: data obtained from ISI Web of Science, July 1, 2018.


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Figure 2. Schematic representation of the basic steps of cutaneous wound healing. After the initial injury, wound healing takes place in four interrelated dynamic stages or phases that could be partially overlapped with time: Hemostasis (Phase I), Inflammation (Phase II), Fibroblast Proliferation (Phase III), Tissue remodeling (Phase IV).


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Figure 3. Schematic illustration of the electrospinning process for nanofiber fabrication : (a) Electrospinning process equipment, (b) Basic principles of tailor cone formation (drawn according to

190)

, (c) Representative morphology of the electrospun nanofibers observed with a scanning

electron microscope (adapted from

191

with permission. CC BY 4.0 MDPI) and different


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techniques to incorporate bioactive agents into the scaffolds by electrospinning: (d) Physical or chemical conjunction, (e) Initial blending, (f) Coaxial electrospinning, and (g) Emulsion electrospinning.


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Figure 4. Electrospun fish collagen/bio glass composite fibers for skin regeneration: (a) SEM micrograph of collagen/bio glass (Col/BG) fibers, (b-c) Strain-stress curves of the fibers in dry and wet condition, (d) S. aureus colonies were collected after culturing on cover slips (control), collagen and Col/BG for 1 day, (e) Wound areas at different time points without treatment (control), after treatment with kaltostat and Col/BG, and (f) Immunostaining (CD31) of wound sections treated with the Col/BG fibers demonstrates secretion of blood vessel (BV) cells. Reused with some rearrangement with permission of 101. CC BY-NC 3.0 Dove Medical Press


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Figure 5. Metformin-Eluting PLGA scaffold for diabetic wound treatment: (a) metformin _ PLGA scaffold with 443 ± 121nm of fiber diameter and 47.47° of water contact angle; (b) pure PLGA scaffold with 772 ± 326 nm of fiber diameter and 104.83° of water contact angle; (c) water uptake capacity of the PLGA with or without metformin; (d) Appearance of healing wound treated by


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commercial sponge; (e) Appearance of healing wound treated by metformin PLGA scaffold; (f) Daily release of metformin from PLGA scaffold; (g-h) histological images of treated wounds in metformin PLGA scaffold (g) and commercial sponge (h) after 3 days of wound treatment. Reused from the American Chemical society with some rearrangement 124.


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Figure 6. Biodegradable heater decorated PGS-PCL fibrous platform containing PEGylatedchitosan drug carrier, in which antibiotics delivery can be controlled by electronics: (a) Principle of the operation system for the electrically controlled drug release; (b) SEM micrograph of a zinc heater decorated electrospun membrane; (c) Temperature change in the zinc decorated membrane under different voltage; (d) Bioresorption of zinc in phosphorus buffer solutions (2.5 mM NaOH in the buffer); (e) Controlling accumulative release profile of cefazolin by cyclic thermal stimulation using electrical actuator; (f) Antibiotic effect of cefazolin released from the membrane at 38 oC, (g) Effects of nanoparticles and the flexible heater on metabolic activity of human keratinocytes; and (h) Actin-DAPI staining image of the cultured cell on the heater decorated fibrous platform. Reused with some rearrangement with permission of

66.

CC BY 4.0 Nature

Publishing Group


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a

b

c

d

e

f

g

h

i

Figure 7: Modulating effects of nanofibrous super magnetic scaffolds on the phenotypes of fibroblasts: (a) SEM and TEM image of the scaffold; (b) Magnetization curve of the scaffold; (c) fibroblast proliferation rate on the scaffold under a magnetic field with different intensity; (d-f) Effect of magnetic stimuli on fibroblast migration rate (d), differentiation of preosteoblasts (e) and angiogenesis (f); (g) general mechanism for fibroblasts modulation to wound-healing phenotype by magnetically stimulation; (h) enhancement of bFGF expression on the fibroblast with/without magnetic stimuli; (i) reduction of interleukin (IL)-1β expression on the fibroblast with/without magnetic stimuli. Reused from the American Chemical society with some rearrangement 178.


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Electrospun Nanofibers for Wound Healing Applications 254x190mm (96 x 96 DPI)


Latest Progress in Electrospun Nanofibers for Wound Healing

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