Advances in skin regeneration: application of electrospun scaffolds.

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Advances in Skin Regeneration: Application of Electrospun Scaffolds Mohammad Norouzi, Samaneh Moghadasi Boroujeni, Noushin Omidvarkordshouli, and Masoud Soleimani* were burned severely who required medical attention. Furthermore, more than 6 million patients suffer from chronic skin ulcers only in the USA.[7] Damage to skin can be categorized regarding their extent. In traumas with the least damage, epidermis, the outermost layer of skin is involved. Epidermis consists of keratinocyte’s layers in different stages of differentiation serving as a barrier against infection and moisture loss.[3,8,9] More serious traumas may cause damage to both dermis and hypodermis layer. Dermis, just under the epidermis layer, is a connective tissue composed of an extracellular matrix (ECM). The ECM is made of interconnected structure of proteins (collagen, elastin, fibronectin and laminin), proteoglycans (heparan sulfate, chondroitin sulfate, and keratan sulfate) and glycosaminoglycans.[10] This layer provides skin with elasticity and mechanical strength and supports vascular and lymphatic systems as well as nerve bundles. The main cell types within this layer are fibroblasts responsible for synthesis of ECM proteins. Endothelial cells, smooth muscle cells and mast cells also exist in this layer.[3,9,11] Hypodermis is composed of adipose and collagen linking the dermis to bone and muscle and has a key role in the thermoregulatory and mechanical properties of the skin.[1,9] In case of slight damage, wound healing occurs via re-epithelialization without any skin transplantation. Nevertheless, in deep skin defects due to lack of remained cell sources for regeneration, it takes a long period of time for re-epithelialization to be completed and scars may be formed on the base.[5,12] Wound healing is an interactive and constant process which can be defined by four classic phases; hemostasis, inflammation, proliferation and remodeling/maturation.[13] This complex process relies on the interaction between cells, growth factors, cytokines, macrophages and so forth.[14,15] Conventional skin substitutes such as autografts, allografts and xenografts have been employed for skin regeneration. Autografts are known as gold standard therapies inasmuch as they do not face any rejection yet, because of the limited availability, the risk of donor site morbidity and scar formation, they need to be replaced with safer substitutes.[2,4,16–19] Allografts and xenogafts as alternatives are more available but they always have the risk of disease transmission and immunological rejection.[2,3,17,18,20,21]

The paucity of cellular and molecular signals essential for normal wound healing makes severe dermatological ulcers stubborn to heal. The novel strategies of skin regenerative treatments are focused on the development of biologically responsive scaffolds accompanied by cells and multiple biomolecules resembling structural and biochemical cues of the natural extracellular matrix (ECM). Electrospun nanofibrous scaffolds provide similar architecture to the ECM leading to enhancement of cell adhesion, proliferation, migration and neo tissue formation. This Review surveys the application of biocompatible natural, synthetic and composite polymers to fabricate electrospun scaffolds as skin substitutes and wound dressings. Furthermore, the application of biomolecules and therapeutic agents in the nanofibrous scaffolds viz growth factors, genes, antibiotics, silver nanoparticles, and natural medicines with the aim of ameliorating cellular behavior, wound healing, and skin regeneration are discussed.

1. Introduction Skin, the largest organ of the human body, behaves as a barrier with protective, immunologic, thermoregulatory and sensory functions. It is composed of three layers, epidermis, dermis and hypodermis.[1–5] Generally, a defect in the skin’s structure or function is referred to as a wound.[6] According to WHO, 265 000 deaths are annually ascribed to burn injuries. In 2004, nearly 11 million people worldwide M. Norouzi Department of Nanotechnology and Tissue Engineering Stem Cell Technology Research Center Tehran, Iran S. M. Boroujeni Department of Chemical and Petroleum Engineering Sharif University of Technology Tehran, Iran N. Omidvarkordshouli Department of Chemical Engineering Tarbiat Modares University Tehran, Iran Dr. M. Soleimani Department of Hematology Faculty of Medical Sciences Tarbiat Modares University Tehran, Iran E-mail: [email protected]

DOI: 10.1002/adhm.201500001

Adv. Healthcare Mater. 2015, DOI: 10.1002/adhm.201500001

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Recent attempts have been focused on the development of bioengineered substitutes as a promising therapeutic alternative for the treatment of acute and chronic wounds as well as burns capable of facilitating skin regeneration and wound healing. Tissue engineering which is the concept of using biodegradable scaffolds as a three-dimensional supportive structure in combination with cells and biomolecules, tries to resemble the natural ECM.[22,23] The efficacy of these replacements is widely dependent on the choice of their materials, structures and physicochemical properties. Incorporation of special biomolecules within the scaffolds in addition to the structural and biochemical similarity of the scaffolds to the natural ECM, can also improve cell behavior as well as tissue regeneration.[24,25] In skin tissue engineering, an ideal scaffold should mimic the native skin environment, stimulate wound healing, be permeable to moisture and oxygen, be biocompatible and biodegradable, protect the wound from infection and mechanical irritation, enable the exudate removal, establish cosmetic satisfaction and provide appropriate cell infiltration, adhesion and proliferation.[20,26–31] Different forms of scaffolds such as films, sponges, microand nanofibers made of natural and synthetic polymers have been developed to date.[28,32] Amidst those, nanofibers have received much attention because of their architectural resemblance to the fibrillar structure of the natural ECM.[33] A number of fabrication techniques such as electrospinning, selfassembly, phase separation, drawing and template synthesis have been employed to produce nanofibers.[23,34] Electrospinning is considered as a straightforward and multifunctional technique to produce ultra-fine fibers with diameters in the range of nanometers to micrometers. The electrospinning equipment briefly consists of a high voltage power supply, a syringe, a digital syringe pump and a conductive collector (Figure 1). Applying high voltages in order to overcome the liquid surface tension of the polymer solution or melt and enable the formation of polymer jet is the fundamental of electrospinning. Then the polymer jet is elongated and whipped by electrostatic repulsion and moved towards the collector while solvent evaporates and finally the nanofibers are deposited on the target.[24,35–37] The formation of fibers and their architectural attributes can be manipulated by the precursor solution features (polymer concentration, viscosity, conductivity, surface tension and solvent), variables of electrospinning process (applied voltage, flow rate, tip-to-target distance, collector geometry, needle gauge), and ambient conditions (temperature and humidity).[38] Generally, high-specific surface area, high aspect ratio and high microporosity make electrospun nanofibers efficient in resembling ECM architecture and therefore ameliorating cell behavior.[39,40] In addition, the high-specific surface area is an advantage for nanofibers as it enhances the fluid absorption, dermal drug delivery and exhibits better absorption of functional proteins such as albumin, fibronectin and laminin on the surface.[41] Moreover, the high porosity of the nanofibrous scaffolds facilitates oxygen, water and nutrient exchange as well as removal of metabolic waste. Additionally, the small-sized pores restrain the penetration of microorganisms.[34] Several approaches can be used to incorporate bioactive or therapeutic agents in the electrospun nanofibers for the

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Mohammad Norouzi obtained his M. Eng. in 2012 and joined the department of nanotechnology and tissue engineering of Stem Cell Technology Research Center as a postgraduate researcher. His research activities have been mainly focused on tissue engineering, skin regeneration, drug delivery systems, and novel cancer treatments.

Masoud Soleimani is associate professor of hematology department of Tarbiat Modares University and head of Stem Cell Technology Research Center. He received his PhD in hematology from Tarbiat Modares University in 2004. Then, he was a visitor scientist at the University of California, Davis. He has published over 200 papers in peer-reviewed journals. His research focuses on tissue engineering, stem cell, and molecular biology.

purposes of bio-functionalization as well as drug delivery. These include electrospinning of polymer/drug blends or polymer/nanoparticle blends, co-axial electrospinning, emulsion electrospinning, and post-spinning modifications including physical surface absorption and chemical conjugation. These methods have been discussed in detail by Yoo et al.[42] and Rieger et al.[35] Briefly, in blend electrospinning, biomolecules/drugs are mixed with the polymer solution before the spinning process. However, since most of the biomolecules are charged, they migrate towards the surface of the polymer jet as a result of charge repulsion during electrospinning.[24] In coaxial electrospinning, two concentrically arranged nozzles are utilized for different solutions in order to preserve the biomolecules and enable a sustain release of them. This technique fabricates a core—shell structure in which the shell made of polymer, and the core made of encapsulated bioactive agents (Figure 2).[35] In emulsion electrospinning, an emulsion of biomolecule and polymer is employed to embed the bioactive agents in the polymeric fibers.[24,32,43] The aim of this paper is to review the recent developments in preparation of bioengineered nanofibrous scaffolds for the purpose of skin tissue engineering. The applications of natural, synthetic, composite polymers and various bioactive agents in designing bio-functionalized scaffolds are discussed in detail.




2. Polymers 2.1. Natural Polymers Natural polymers due to their biocompatibility, biodegradability, biological characteristics and similarity to macromolecules recognized by cells have been widely used in biomedical applications.[9,44–50] Nanofibrous scaffolds of natural polymers not only can mimic the native ECM by component, but also have the architectural resemblances. There are numerous reports on the application of nanofibrous scaffolds made of natural polymers for skin substitutes and wound dressings. Table 1 summarizes the reports on electrospun scaffolds made of natural, synthetic and composite polymers for skin tissue engineering applications. Collagen is the most abundant protein in the human body and the main component of the ECM which imparts structural integrity and tensile strength to tissues. To date, up to 28 different types of collagen have been identified.[100–102] Collagen type I is the most abundant which is predominant in skin,

Figure 2. Transmission electron microscope (TEM) image of a core-shell electrospun nanofiber. The bright phase indicates polymer (PLGA) and the dark phase shows encapsulated protein.


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Figure 1. A) Scheme of electrospinning system. B) Scanning electron microscope (SEM) image of an electrospun scaffold.

tendon and bone. Collagen type II in cartilage, type III in blood vessels and in minor amounts in skin, type IV and VII in the basement membrane layers are found. This protein is composed of triple-helical polypeptide chains with the repeating sequence of (Glycine–X–Y) where X and Y are most often found to be proline and hydroxyproline, respectively.[101,103,104] The presence of adhesion domains in collagen provides an attractive surface for cell attachment. In native ECM, collagen exists in a fibrillar structure with a diameter in the range of 50–500 nm which can enhance cell adhesion and proliferation.[105–107] In addition, collagen with respect to the hemostatic effect, acceleration of wound healing, creating a suitable environment for fibroblast and keratinocyte proliferation, has been widely used as skin substitutes and wound dressings.[105,108] Biobrane, Integra are acellular and Apligraf, Transcyte are cellular examples of commercial skin substitutes based on collagen.[109] Electrospinning of collagen type I and type III was reported for the first time by Matthew et al.[110] In one study, Powell et al.[51] compared collagen nanofibrous scaffolds produced by freezedrying and electrospinning methods as skin substitutes. Although both collagen scaffolds exhibited similar compatibility to the cells in vitro and in vivo, the benefit of reduced wound contraction for the lesion treated with the electrospun scaffold compared to the freeze-dried one was reported. Histological observation also revealed that the bovine collagen retained in the wound covered with freeze-dried scaffold at week 8, while there was no trace of bovine collagen in the electrospun group. Aligned collagen nanofibers also exhibited an increase in cell proliferation in vitro when compared to the random nanofibers.[54] Controlling the alignment of nanofibers using three different forces, i.e., mechanical, electrostatic and magnetic forces has been reviewed by Liu et al.[111] While fluoroalcohols have been commonly employed as the solvent for electrospinning of collagen, Zeugolis et al.[112] showed that many characteristics of collagen are lost and it can be denatured when it is electrospun into nanofibers out of fluoroalcohols such as hexafluoroisopropanol (HFIP) or trifluoroethanol (TFE). Therefore, they suggested coating of electrospun scaffolds with collagen as an alternative method. Additionally, Chakrapani et al.[8] focused on replacing HFIP with a mild solvent and they used acetic acid for electrospinning a blend of collagen/polycaprolactone (PCL). In order to enhance mechanical stability of collagenous biomaterials and reduce their degradation rate in wet condition, several cross-linking methods including chemical methods such as using glutaraldehyde (GTA), genipin 1,6-diisocyanatohexane, transglutaminase (TG), N-[3-(dimethylamino) propyl]-N′-ethylcarbodiimide hydrochloride (EDC), and physical methods such as dehydrothermal (DHT) treatment and UV light exposure have been reported.[51,113] Giner et al.[114] compared different cross-linking methods, TG, EDC/N-hydroxysuccinimide (NHS), genipin and UV light exposure. TG or EDC/ NHS showed the best results to obtain fully functional crosslinked biomaterials without reduction of cell viability. NHS can prevent the formation of side products and also increase the rate of reaction. GTA is also an efficient and fast cross-linker in stabilizing collagenous materials though it has the risk of toxicity in high concentration.[115] Genipin and glyceraldehyde are also used as crosslinkers due to their less cytotoxicity.[116,117]



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www.MaterialsViews.com Table 1. Electrospun nanofibrous scaffolds for skin regeneration and wound healing applications. Polymer

Solvent

Cell

Highlight

Ref.

Collagen

HFIP

HDF, HEK

Superior wound contradiction and cell proliferation on electrospun scaffold rather that freeze-dried scaffold.

[51]

Acetic acid

NIH 3T3 fibroblast

The nanofibrous scaffold was better than gauze and commercial collagen sponge in wound healing rate.

[52]

Collagen/silk fibroin

HFIP

HEK, HEF

Better cell behavior on hybrid nanofibrous matrix compared to the blend nanofibrous matrix.

[53]

Gelatin

TFE

HEK, HDF

Scaffolds with interfiber distances between 5 and 10 µm allowed favorable cell infiltration.

[45]

Gelatin

HFIP

RCFs

Spindle-like appearance elongation of the cells on aligned fibers was similar to native tissues.

[54]

Gelatin

HFIP

L929 fibroblast

Comparison between cross-linking with UV radiation and genipin showed better cell proliferation on genipin-crosslinked mat.

[55]

TFE, water

HDF

The electrospinning parameters were optimized.

[56]

Collagen/chitosan/PEO

Gelatin/GAG Hyaluronic acid

D. water

–

Full recovery of pigs’ wound.

[57]

HFIP, formic acid

HFF

Hyaluronic acid could facilitate scarless wound healing.

[58]

Chitosan

TFA, DCM

HDF

Sonication of chitosan mats enhanced porosity and hydrophilicity.

[59]

Chitosan/Chitin nanocrystals

Acetic acid

ADSCs, L929 fibroblast

Incorporation of chitin nanocrystals within chitosan nanofibers enhanced tensile strength and modulus of chitosan nanofibers.

[29]

Chitosan/collagen

Acetic acid

3T3 fibroblast/HaCaT keratinocyte

Sequential electrospinning (chitosan) and freeze-drying (collagen).

[60]

HFIP, TFA/HFIP

L929 fibroblast

The antibacterial effect of composite nanofibers was dependent on type of bacteria.

[61]

Chitosan/PEG

acetic acid/D. water

HMEC, HDF, HEK

Nanofibrous structure compared to the 2-D film and the 3-D sponge improved re-epithelialization and vascularization.

[9]

Chitosan/PVA

D. water (chitosan was dissolved with HOBt, TPP or EDTA)

Chitosan-EDTA/PVA nanofibres performed better than gauze in decreasing acute wound size and antibacterial activity.

[62]

Hyaluronic acid/collagen

Chitosan/silk fibroin

CM-chitosan/PVA

D. water

L929 fibroblast

Using water soluble CM-chitosan eliminated the presence of toxic organic solvents.

[4]

Silk fibroin

Formic acid

HOK, HEK, HGF

–

[47]

Silk fibroin

HFIP

HEK

Oxygen plasma treatment increased cell attachment and spreading on the scaffold.

[49]

Silk fibroin

Formic acid

HOK

The scaffold enhanced cell adhesion and spreading of type I collagen better than SF film.

[48]

Fibrinogen

HFIP, MEM (Earle’s salts)

–

A small amount of MEM was used as a co-solvent to dissolve fibrinogen.

[63]

Fibrinogen

HFIP, MEM (Earle’s salts)

–

Aprotinin addition to culture media reduced enzymatic degradation of the scaffold.

[64]

Fibrinogen

HFIP, MEM

HFF

EDC and genipin were found to be effective crosslinkers.

[65]

HFIP

L929 fibroblast

The cells had polygonal shape on the hybrid scaffold compared to a round shape on PLLA-CL scaffold.

[66]

Alginate/PEO

D. water

HFF

A dual crosslinking process using calcium and glutaraldehyde. PEO nanofibers were removed by wet treatment on the composite scaffold.

[44]

Alginate/PEO

D. water

HDF

Lecithin was used as a natural surfactant to fabricate uniform nanofibers.

[67]

PCL

Acetone

–

Surface hydrolysis of the polymer in vivo formed some functional groups promoting cell attachment.

[68]

PCL

Chloroform

NIH 3T3

A human-skin-patterned nanofibrous mat was fabricated using a specific collector.

[69]

Fibrinogen/PLLA-CL

Continued

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Table 1. Continued Polymer

Solvent

PCL/chitosan

Cell

Formic acid, chloroform, NIH 3T3, MG 63, L929 fibroblast acetone

Highlight

Ref.

Chitosan improved bioactivity and protein adsorption on the scaffold.

[70]

PCL/chitosan

DMF, chloroform

L929 fibroblast

With increasing chitosan content, zeta potentials of the scaffold increased leading to a better cell adhesion.

[71]

PCL/chitosan

Chloroform

Keratinocyte

Chitosan was deposited through LbL technique on the surface of the functionalized electrospun PCL nanofibers.

[72]

PCL/collagen

HFIP

HDF

Integrinβ1 level was increased on aligned nanofibrous scaffold.

[73]

PCL/collagen

DMF, chloroform

NIH 3T3 fibroblast

Collagen was immobilized through glutaraldehyde crosslinking on aminolysed PCL nanofibers enhancing fibroblast proliferation.

[74]

PCL/collagen

Methanol, chloroform/HFIP

HDF

–

[75]

PCL/collagen

TFE

HDF

Coaxial electrospinning of collagen-PCL showed superior cell proliferation than roughly collagen-coated PCL.

[76]

PCL/collagen

HFIP

HDF, HEK

The minimum amount of PCL to fabricate scaffolds with optimum mechanical strength and biological properties was ca. 10%.

[77]

PCL/collagen

HFIP

HEK

A collagen gel coated PCL/collagen nanofibers.

[78]

PCL/gelatin

HFIP

HDF, HEK

Increasing the core diameter of coaxial fibers (core: PCL and shell: gelatin) improved ultimate tensile strength and stiffness of the scaffold.

[79]

PCL/gelatin

TFE, acetic acid

Mouse fibroblast, HEK

Acetic acid-doped TFE solvent system was used to prevent phase separation during electrospinning.

[33]

Chloroform, methanol (for PCL)/acetic acid (for gelatin & collagen)

L929 fibroblast

PCL/gelatin scaffold grafted with collagen showed high cell proliferation.

[2]

TFE

HDF

PCL/gelatin nanofibers were electrospun on PU dressing acting as a synthetic epidermis to protect the wound.

[5]

PCL/PLGA (nanofibers) Chitosan/gelatin(hydrogel)

THF/DMF/DCM (nanofiber) Acetic acid/d. water (hydrogel)

L929 fibroblast, HEK

PCL/PLGA nanofibers, the upper layer of the membrane, provided mechanical support and reduced degradation rate of the hydrogel layer. The porous chitosan/gelatin hydrogel in the bottom could retain moisture.

[80]

PCL/Silk fibroin/Hyaluronic acid

HFIP (for PCL, SF)/HFIP, Formic acid (for HA)

HDF

Hyaluronic acid incorporation enhanced cell infiltration and reduced fibrosis tissue thickness.

[50]

PLLACL/collagen

HFIP

MSCs

Epidermal differentiation and growth of MSC on PLLACL/ collagen nanofibers was higher than that on pure PLLACL nanofibers.

[81]

PLLACL/gelatin

HFIP

HFF

Plasma treated PLLACL/gelatin scaffolds showed high cell adhesion and proliferation.

[82]

PLA/gelatin

HFIP

Human embryonic fibroblast

PLA-based scaffolds containing 30% gelatin enhanced fibroblast adhesion and proliferation.

[83]

PLA/chitosan

DCM/DMSO

L929 fibroblast

Core-shell structure (core: PLA and shell: chitosan) promoted cell growth and attachment.

[84]

PLA/chitosan

Formic acid, chloroform, acetone

HDF

Fabrication of aligned nanofibers using a collector made of parallel blades.

[85]

Chloroform/acetic acid

HDF

Dual-layer of nano/microfibrous structure: random PDLLA microfibrous matrix covered with aligned CS nanofibers resulted in a directional penetration of cells into 3-D domain.

[86]

Acetone, DCM

HDF

Incorporation of PEG in PDLLA nanofibers converted surface degradation pattern to bulk degradation.

[87]

HFIP

BAECs

Heparin coating on the scaffolds prevented cell clot formation enabling more cells to penetrate into the scaffolds.

[88]

Chloroform, acetone (for PCL)/formic acid (for silk fibroin, gelatin)

NIH 3T3 fibroblast

–

[89]

PCL/gelatin/collagen

PCL/gelatin/PU

PDLLA/chitosan

PDLLA/PEG PLLA PLA/silk fibroin/gelatin

Continued




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www.MaterialsViews.com Table 1. Continued Polymer

Solvent

Cell

Highlight

Ref.

Chloroform

HDF

–

[90]

DCM

Platelet and erythrocyte

Chitosan coating caused aggregation of the erythrocytes and platelets and blood coagulation on the scaffold.

[46]

DCM, DMF

NIH 3T3 fibroblast

–

[91]

PLGA

DCM

HEK, HEF

Increasing the percentage of glycolide to lactide in the copolymer increased the rate of degradation in vitro and in vivo.

[92]

PLGA

HFIP

HEK

Combination of solution and melt electrospinning resulted in a better cell proliferation in the 3-D organization of micro/ nanofiber structure.

[93]

PLGA

THF

HDF

High porosity (92.4%) resulted in high HDF viability, collagen deposition, cell migration and infiltration inside the scaffold.

[94]

PLGA

THF,DCM

HDF

Cells on the scaffolds with fiber diameter in the range of 350–1000 nm showed superior proliferation and collagen type III expression compared to the thinner and thicker ones.

[20]

Chloroform, DMF/ TFA,DCM

hESF

Hybrid and core/shell PLGA/chitosan nanofibrous scaffolds were prepared by co-electrospinning and coaxial electrospinning, respectively.

[95]

THF,DMF/acetic acid

RDF

PLGA and chitosan/PVA were simultaneously electrospun from different syringes and mixed on a rotating drum.

[96]

PLGA/collagen

HFIP

HDF

Incorporation of collagen into PLGA enhanced cell attachment and proliferation and ECM secretion.

[97]

PLGA/collagen

HFIP

HFF

The scaffold was better than gauze and commercial dressing in promoting wound healing.

[98]

Chloroform, DMF/formic acid

L929 fibroblast

The hybrid scaffold reduced wound area in diabetic rats.

[99]

PDLLA-LL PLLA/PEG/chitosan PPDO-co-PLLA-b-PEG PLLA-bPEG/PPDO (20:70:10)

PLGA/chitosan

PLGA-chitosan/PVA

PLGA/SF

HFIP: Hexafluoroisopropanol, HDF: Human dermal fibroblast, HEK: Human epidermal keratinocyte, PEO: Poly(ethylene oxide), HEF: Human epidermal fibroblasts, TFE: Trifluoroethanol, RCF: Rabbit conjunctiva fibroblasts, D. water: Distilled water, HFF: Human foreskin fibroblast, TFA: Trifluoroacetic acid, DCM: Dichloromethane, PEG: Poly (ethylene glycol), ADSCs: Adipose derived stem cells, HMEC: Human microvascular endothelial cells, PVA: Poly(vinyl alcohol), HOBt: Hydroxybenzotriazole, TPP: Thiamine pyrophosphate, EDTA: Ethylenediaminetetraacetic acid, CM-chitosan: Carboxymethyl chitosan, HOK: Normal human oral keratinocytes, HGF: Normal human gingival fibroblasts, MEM: Minimal essential medium, EDC: N-[3(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, PLLA-CL: poly(L-lactic acid)-co-poly (epsilon-caprolactone), HFF: Human foreskin fibroblasts, PCL: Poly(e-caprolactone), PU: Polyurethane, THF: Tetrahydrofuran, PLGA: Poly (lacto-co-glycolic acid), MSCs: Mesenchymal stem cells, PLA: Polylactic acid, DMSO: Dimethyl sulfoxide, BAECs: Bovine aortic endothelial cells, PPDO : Poly (p-dioxanone-co-L-lactide), PDLLA-LLpoly(D/L-lactide-co-L-lactide), hESF: Human embryo skin fibroblasts, RDF: Rabbit dermal fibroblasts

Furthermore, it has been reported that bioactivation of collagen scaffolds with connexion 43 antisense oligonucleotides (Cx43 asODN) can reduce inflammatory response as well as Cx43 and Cx26 elevation in wound edge keratinocytes and therefore improve scaffold biocompatibility and wound healing process.[15,118] Gelatin is obtained through partial hydrolysis of collagen in which the triple-helical structure of collagen is turned into single-strand molecules.[5,27] Presence of arginine-glycineaspartic acid (RGD) sequences within the gelatin enhances cell adhesion and migration. Additionally, gelatin has lower immunogenicity than collagen.[119–121] The effect of density of electrospun gelatin nanofibers on dermal cell behavior was studied by Powell et al.[45] Scaffolds with interfiber distances between 5 and 10 µm, made organized dermal and epidermal layers similar to the normal skin while interfiber distances larger than 10 µm caused deep infiltration of fibroblasts which led to lack of a dense and continuous cell layer for attachment of keratinocytes. Gelatin nanofibers were also prepared via needleless technology, in which a rotating spinning electrode was partially submerged in the polymer solution and a thin layer of the

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polymer was raised by the electrode rotation and subsequently nanofibers were produced between the electrode and the collector in the high electrostatic field (10–100 kV). Wound healing properties of these nanofibers were also approved by Dubský et al.[122] Hyaluronic acid (HA), a natural linear polysaccharide composed of repeating glucuronic acid and N-acetylglucosamine which belongs to glycosaminoglycans (GAGs), is one of the main components of the connective tissue ECM and it has many important biological functions.[58] HA helps in faster and scar-free wound healing, angiogenesis by enhancing the mitosis of epithelial cells and adjusts phagocytosis by regulating the movement of the macrophages.[57] Hyaff, Laserskin, and Hyalograft are current HA-based commercial wound care products.[123] Due to the high viscosity, surface tension and water capacity of HA, its electrospinning faces difficulties. Um et al.[124] electrospun HA solution by air blowing technique. Hot air aided in rapid evaporation of solvent and producing consistent nanofibers. Uppal and colleagues[57] made a comparison between an adhesive bandage, a solid HA, a gauze bandage coated with vaseline, an antibiotic-dressing and a HA nanofibrous wound dressing. Preclinical evaluations on five pigs





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revealed that wounds treated with HA nanofibers were fully covered by the epithelial tissue. Furthermore, the healing rate of the wounds with HA nanofibers were fastest among all the groups. Chitosan is a partially deacetylated derivative of chitin, mainly found in arthropod exoskeletons and shells of crustaceans. It is a linear polysaccharide consisting of β(1–4) linked d-glucosamine residues with a variable number of randomly located N-acetyl-D-glucosamine groups.[125] Owing to the wound healing, hemostatic, antibacterial and antifungal properties of chitosan, it has found wide applications in wound and burn treatments. As a hemostatic agent, it activates platelets and accelerates natural blood clotting.[125,126,59] Chitosan can stimulate fibroblast proliferation, macrophage activation, cytokine production, angiogenesis and promotes collagen deposition by the gradually depolymerization and release of N-acetyl-D-glucosamine. It can also induce a high level of natural hyaluronic acid synthesis at the wound site which in turn can improve wound healing and decrease scar formation.[127] As a result of the ionic characteristics, electrospinning of pure chitosan faces serious obstacles. Using trifluoroacetic acid (TFA) as a solvent results in the formation of salt between TFA and amino groups of chitosan chain, which decreases the rigid interaction between chitosan molecules, making the electrospinning of the chitosan feasible.[113] Moreover, addition of dichloromethane (DCM) to the chitosan-TFA solution improved the homogeneity of the electrospun chitosan nanofibers.[128] Shiffman et al. reported crosslinking of chitosan nanofibers via GA vapor (a post-treatment process)[129] and GA solution (a one-step electrospinning-crosslinking process).[130] As mentioned earlier, interaction of cells with biomaterials in addition to the inherent biological characteristics are strongly dependent on the architecture of the biomaterials. Therefore, in a comparison between electrospun nanofibrous scaffolds, 2-D films and 3-D sponges of chitosan, better adhesion, growth and differentiation of the three main skin cell types, i.e., keratinocytes, fibroblasts and endothelial cells, were observed on the chitosan nanofibrous scaffolds. Furthermore, chitosan nanofibers as a wound dressing improved re-epithelialization, enhanced vascularization (Figure 3) and remodeling of the granulation tissue which in turn improved recovery of full thickness wounds in mice, while for 3-D chitosan sponge, formation of a foreign body granuloma was observed.[9] The hemostatic attribute and thrombogenic activity of chitosan nanofibers were also reported to be superior to the Surgicel, a commercial gauze bandage, and a chitosan sponge.[59] Silk is a typical fibrous protein which is mainly produced by silkworms. Silk proteins are of two kinds, hydrophobic fibroin and hydrophilic sericin.[131] Fibroin has been utilized as tissue engineering scaffolds due to its biocompatibility, biodegradability, oxygen and water vapor permeability and minimal inflammatory reactions.[47,132] Some attention has been paid to the application of the electrospun silk fibroin scaffolds as wound dressings. Min et al.[48] evaluated three types of silk fibroin (SF) matrices, including a woven matrix from SF microfibers, a matrix of SF film and a non-woven matrix of SF nanofibers. Promoted cell adhesion and better spreading of the coated collagen were observed on SF nanofibrous matrix. For crystallization and stabilization, SF nanofibers are usually

Figure 3. Blood vessel formation in the leisure site. a,c) control group, b,d) chitosan-treated leisure. Blood vessels were detected using an antitype IV collagen antiserum. Reprinted with permission.[9] Copyright 2011, American Chemical Society.

treated with methanol or other organic solvents which converts the random coil conformation to β-sheet.[48] Fibrinogen, a glycoprotein which is synthesized by the liver and found in blood plasma, has a key role in coagulation cascade and wound healing.[65] For the first time, Wnek et al.[63] electrospun fibrinogen nanofibers from solutions composed of human or bovine fibrinogen fraction I, dissolved in HFIP and a minor amount of minimum essential medium (MEM, Earle’s salts), as fibrinogen is not soluble in HFIP alone. Since fibrinogen nanofibers lose their integrity several days after in vitro cell culture. Sell et al.[65] employed three different chemical crosslinkers: GA vapor, EDC and genipin to improve the mechanical properties. Glutaraldehyde cross-linking could not improve the mechanical features of fibrinogen while EDC and genipin not only improved the mechanical properties of the electrospun scaffolds, but also decreased the degradation rate. Lysine residues of fibrinogen are hidden within the folded tertiary protein structure and they are just exposed when fibrinogen converts to fibrin. The fact of unavailability of lysine can be a reason for why GA vapor was not a suitable crosslinker for fibrinogen.[64] Alginate is a water soluble negative charged polysaccharide derived from marine brown algae. It comprises repeating units of α-L-guluronate and β-D-mannuronate.[133] The high water absorption ability of alginate leads to absorb wound exudate and retain moist wound environment.[67,134] Electrospinning of alginate alone due to the high conductivity faces serious impediments. However, blending it with water-soluble polymers such as polyethylene oxide (PEO)[67] or polyvinyl alcohol (PVA)[134] forms hydrogen bonding between the ether oxygen of PEO (or the hydroxyl groups of PVA) and the hydroxyl groups of alginate[135] and reduces the repulsive force among polyanionic sodium alginate molecules which makes electrospinning of the polymer blend possible. However, scaffolds composed of pure alginate can be obtained by removing PEO or PVA constitutes in a post-treatment.[44] Guluronate units in alginate enable the polymer to be crosslinked through divalent cations such as Ca2+. Additionally,



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Leung et al.[44] proposed a dual crosslinking process using calcium and glutaraldehyde to enhance degradation resistance of alginate nanofibers in sodium-rich environments. Poly-L-ysine was also incorporated in to improve fibroblast attachment.

2.2. Synthetic Polymers Aliphatic polyesters, the most common kind of biodegradable synthetic polymers, due to their adjustable properties, mechanical strength, processability and their non-toxic degradation products have been extensively used in biomedical applications.[136] The main advantage of synthetic biopolymers is their ability to be tailored to specific functions and properties by altering chemical composition, crystallinity, molecular weight, copolymerization, etc.[137–139] FDA approved-aliphatic polyesters such as polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL) and their copolymers have

extensive applications in skin tissue engineering, wound dressing and drug delivery systems. Degradation of aliphatic polyesters normally occurs through hydrolysis of the ester bonds.[24,111,140–146] Electrospun nanofibers of poly(lactic acid-co-glycolic acid) (PLGA) as dermal substitutes which varied in the ratio of PLA-co-PGA to PGA was prepared and investigated in terms of biodegradability by Blackwood et al.[92] PLGA mats with different ratios of PLA:PGA, 50:50, 75:25, 85:15 lost half of their mass within 2 weeks, 3 months and 4 months, respectively. The 85:15 nanofibrous mat disappeared almost completely by 5–6 months, while the PLLA scaffold remained largely intact after one year in vivo with merely some slight reduction in fiber diameter over this period (Figure 4). In fact, increasing the percentage of glycolide to lactide in the copolymer increases the rate of degradation in vitro and in vivo. Similarly, Cui et al.[87] reported that blending poly(ethylene glycol) (PEG) with poly(DLlactide) (PDLLA) led to the more hydrophilic surface of the

Figure 4. Light microscope H&E images of A–C) PLLA, D–F) PLGA 85:15, G–L) PLGA 75:25 implanted into the flank of adult male Wistar rats at different times (2 weeks to 1 year). Implanted scaffold has been labelled as (ES), with underlying muscle (M) and skin (S). Scale bar = 1 mm. Reprinted with permission.[92] Copyright 2008, Elsevier.

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electrospun nanofibers and a bulk degradation pattern, while a degradation pattern between surface erosion and bulk degradation was observed in the lower amount of PEG. In terms of morphology, the correlation between PLGA nanofiber diameters and fibroblast proliferation was appraised by Kumbart et al.[20] Fibroblast cultured on the scaffolds with fiber diameter in the range of 350–1000 nm demonstrated superior proliferation and collagen type III expression compared to the thinner and thicker fibers. In order to overcome poor infiltration of cells into electrospun scaffolds which arises from small-sized pores, some techniques include leaching of selective water-soluble fibers, using micrometer-sized fibers, cell-nanofiber layer-by-layer fabrication and cell electrospinning have been utilized.[147–151] Yang et al.[148] fabricated a novel 3-D multilayerd cell-nanofiber constructs utilizing electrospinning of nanofibers and seeding human dermal fibroblast (HDF) layer by layer. In this study, the first layer of electrospun nanofibers was immersed in cell growth medium, followed by HDF seeding and this procedure was repeated until the desired number of cell-nanofiber layers were deposited. The results indicated uniform cell distribution between the layers (Figure 5), cell proliferation and new ECM deposition. Townsend-Nicholson et al.[152] and Jayasinghe et al.[150] reported cell electrospinning, a unique biotechnique to fabricate scaffolds comprised of multiple cell types. To this end, they used coaxial

electrsospinning systems in which a living biosuspension flowed through the inner needle and a low conducting high viscosity biopolymer flowed through the outer needle. In this system, the rotating conducting collector was submerged in cell culture media containing essential nutrients in order to prevent cell dehydration. In vitro and in vivo studies showed that the electrospinning cells did not cause any damage and the cells maintained their functions.[153] In another study, a 3-D fibrous scaffold of PLGA micro/ nanofibers (average micro and nanofiber diameters = 28 µm and 530 nm, respectively) was produced by combination of solution and melt electrospinning. Keratinocyte and fibroblast cultured on the micro/nanofibrous scaffold showed significantly better cell attachment and proliferation compared to PLGA microfiber scaffold.[93] Nevertheless, Lowery et al.[154] reported a greater impact of pore size on cell proliferation compared to fiber diameter. HDF seeded on PCL nanofibrous scaffolds was able to bridge pores with 6.5 µm diameter, while merely extended along single fibers in scaffolds with pores > 20 µm. A human-skin-patterned nanofibrous mat was fabricated using a human-skin-patterned mold as a collector. This pattern was able to provide morphological guidance for cell growth.[69] Also, in another study, Ma et al.[155] presented a unique sandwich-type electrospun PCL scaffolds consisting of radially aligned nanofibers at the bottom, nanofiber scaffolds with square arrayed microwells and nanostructured cues at the top, seeded with microskin tissues in microwells in between. This class of scaffolds showed the benefits of an even distribution of microskin grafts, improved the take rate of microskin tissues and simultaneously guided cell migration by nanotopographic cues which led to better re-epithelialization of wounds. The effect of nanofiber alignment was studied by Kurpinski et al.[88] Aligned PLLA nanofibers improved cell infiltration into the scaffolds in vitro and in vivo in comparison to the random one. Furthermore, they demonstrated that heparin, a sulfated glucosaminoglycan, immobilization improved cell infiltration into PLLA scaffolds which was attributed to the anti-clotting effects and biomoleculebinding capabilities of heparin. The prevention of clot formation allows more cells to penetrate the scaffold.

2.3. Composite Polymers

Figure 5. Microscopic images of the multilayered cell–fiber construct. A) Light microscope H&E of the cross sections of fiber–cell construct. B) Fluorescent image of DAPI-stained cross sections of fiber–cell construct cultured for 2 days. C,D) Confocal microscopic images of cross sections of the cell–fiber constructs with controlled thickness of the fiber layer (C: thickness = 5 µm, electrospinning time: 30 s, D: thickness of nanofibers layer = 10 µm, time of electrospinning = 1 min). Fibers were labeled with FITC (green), and cells were stained blue with DAPI (n = 3). Reprinted with permission.[148] Copyright 2008, Mary Ann Liebert.


Composite nanofibrous scaffolds made of natural and/or synthetic polymers offer advantages of each polymer with different physicochemical properties to overcome the limitations of the individual material and with the aim of satisfying the criteria of skin substitutions and wound dressings.[156] Hsu et al.[58] fabricated hyaluronate–collagen composite nanofibers with an average



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diameter of 200 nm. They found that the ratio of expression of TIMP1 to MMP1 was lower for foreskin fibroblast cultured on HA–collagen nanofibrous matrix than of those cultured on collagen matrix. The characteristics of scarless wound and remodeling of collagen are known to be related to a decreased ratio of TIMP to MMP expression. It has also been proved that the incorporation of HA into nanofibrous scaffolds can enhance fibroblast (FEK4) infiltration into the nanofibrous scaffolds in vitro, reduce fibrosis tissue thickness and macrophage adhesion in vivo and simulate the migration of FEK4 through the interactions between HA and CD44, a cell surface glycoprotein.[50] Yeo et al.[53] fabricated collagen/silk fibroin composite nanofibrous matrix and compared them with collagen/silk fibroin hybrid one. Superior attachment and spreading of keratinocytes and fibroblasts on the hybrid scaffolds were observed which may be related to the fiber diameter and crystallinity. Since the main disadvantage of synthetic polymers is the lack of cell-recognition signals, amalgamating the favorable biological properties of the natural polymers and physical attributes of the synthetic polymers represents an emerging class of alternative nanostructured biomaterial scaffolds.[50,157] Wu et al.[95] fabricated fibrous membranes of hybrid PLGA/chitosan (H-PLGA/chitosan) and core/shell PLGA/chitosan (C-PLGA/chitosan) by co-electrospinning and coaxial electrospinning, respectively. H-PLGA/chitosan and C-PLGA/chitosan nanofibers revealed higher hydrophilicity than PLGA and the C-PLGA/chitosan membrane exhibited similar hydrophilicity with chitosan membrane. The H-PLGA/chitosan and C-PLGA/chitosan membranes also showed higher tensile properties than chitosan nanofibers. These scaffolds facilitated cell adhesion, promoted cell-scaffold and cell–cell interactions and increased cell migration. In another study, it was reported that chitosan coating on PLLA scaffolds led to significant adhesion of erythrocytes on the scaffold surface and the scaffold was able to show an antibacterial activity against S. aureus.[46] Furthermore, the benefit of chitosan in PCL- grafted-chitosan nanofibrous scaffolds was proved through an increase in zeta potential of the scaffold surface suitable for the attachment of the anionic cell surface and cell adhesion.[71] Poly(lactic-co-glycolic acid) (PLGA)/collagen composite nanofibrous scaffold fabricated by Liu et al.[98] In vivo studies showed that rat wound covered with PLGA/collagen mats had complete re-epithelialization and healed faster compared with a gauze bandage and a commercial dressing. Huang et al.[73] also reported a high level of active integrinβ1 through triggering the signaling pathway in HDF cultured on aligned PCL/collagen nanofibers compared to the random ones. Activation of integrinβ1 besides increasing the phosphorylation focal adhesion kinase (FAK), enhanced the fibroblast migration along the fibers and closed the wound gap completely by 48 h. Stimulation of Integrinβ1-FAK signaling also improved the myofibroblastic differentiation which facilitated wound closure by drawing the wound margins together. It was also reported that human adipose stromal cells grown on aligned scaffolds showed elongated morphology, higher proliferation and migration rate, as well as higher synthesis of ECM proteins.[158–160]

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3. Bioactive Agents 3.1. Growth Factors Growth factors (GFs) are crucial modulators in the wound healing process. Indeed, they are responsible for transmitting signals required for cell proliferation, differentiation and ECM secretion.[1,161] Considering this fact, clinicians have been focusing on the application of the GFs to promote and accelerate wound healing as well as skin regeneration with the least scar formation. However, there are some hindrances in the topical application of GFs owing to the fast diffusion and elimination by exudate before meeting the wound bed as well as their degradation in vivo.[162–164] Therefore, a variety of systems for topical delivery of the GFs have been fabricated. Utilizing a controlled release from the scaffolds enables the protection of GFs against in vivo degradation and provides the essential signals at the efficient concentration for a prolonged duration in the local tissue microenvironment.[163,164] The literature review indicated that growth factor-loaded electrospun fibers showed considerably better wound recovery in vivo than those fibers without GFs.[165,166] There have been some efforts to incorporate various GFs such as epidermal growth factor (EGF),[165,167–173] basic fibroblast growth factor (bFGF),[166,173–175] vascular endothelial growth factor (VEGF)[173,176] and platelet derived growth factor (PDGF)[173,176] into electrospun nanofibrous scaffolds (Table 2). It has been admitted that EGF is involved in keratinocyte migration, fibroblast proliferation and differentiation, as well as granulation tissue formation which consequently improves wound recovery.[1,179] bFGF stimulates angiogenesis and formation of granulation tissue and regulates proliferation and differentiation of dermal fibroblasts, keratinocytes, endothelial cells and melanocytes.[1,166,174] VEGF is responsible for angiogenesis and granulation tissue formation in the early stage of wound healing process.[1,162] KGF also induces epithelial as well as keratinocyte proliferation and migration. The expression of this factor is up-regulated 100-fold during the first 24 h of normal wound healing and lasts for several days.[1] PDGF is released by means of degranulating platelets and activated macrophages in wound fluid and stimulates fibroblasts to produce ECM, promotes proliferation and migration of endothelial as well as smooth muscle cells.[1,162] Choi et al.[174] fabricated PCL-PEG electrospun nanofibrous matrix supplemented by bFGF and EGF through encapsulation and chemical conjugation techniques, respectively. bFGF solution was encapsulated as the core layer in a shell layer of PCLPEG via coaxial electrospinning. Subsequently, EGF was immobilized covalently on the surface of the nanofibers through conjugating surface-exposed amine groups of the nanofibers to the carboxylate groups of EGF. Therefore, EGF was directly exposed to the cells on the surface and whose release rate was less than 2% in 7 days which was attributed to the PCL-PEG degradation while, bFGF had a burst release of about 30% in the first 12 h due to the rapid diffusion from the thin shell layer. The bFGF/ EGF-supplemented nanofibrous mat increased human primary keratinocyte and fibroblast proliferation. Moreover in vivo tests showed that by administrating this mat, the wound closure rate of diabetic ulcers increased, keratin 14, 5, 1 expressions were




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Table 2. Electrospun scaffolds containing growth factors (GFs) for wound healing applications. Polymer

Solvent

Cell

Method

Ref.

EGF

Growth Factor

PCL or PCL–PEG/PCL

Methanol, chloroform

Keratinocyte

Immobilization

[165]

EGF

PLGA/gelatin

Chloroform, acetone/acetic acid

HDF

Emulsion

[177]

EGF

Silk fibroin

–

HDF

Blend

[168]

EGF

PCL and PCL/collagen

PCL: DMF, DCM PCL/ collagen :HFIP

Human dermal keratinocyte

Immobilization

[170]

EGF (1,25-dihydroxyvitamin D3

PLLACL/collagen

HFIP

Bone marrow mesenchymal stem cells

_

[167]

EGF (insulin, hydrocortisone, and retinoic acid)

Gelatin/PLLACL

HFIP

ADSCs

Blend/co-axial

[169]

EGF (and silver sulfadiazine)

Silk/PEO

–

_

Blend/coating

[171]

Gelatin, PLLACL/P3GF

P3HT: chloroform/ methanol Gelatin, PLLACL: HFIP

Fibroblasts and ADSCs

Co-axial

[172] [166]

EGF bFGF bFGF, EGF bFGF VEGF, PDGF, bFGF, EGF Blood-derived growth factors

PELA

Chloroform

Mouse embryo fibroblast

Emulsion

PCL- PEG

Methanol, chloroform

Keratinocyte and fibroblast

Coaxial/immobilization

[174]

PDLLA

DCM

Mouse embryonic fibroblast

Immobilization

[175]

Collagen- hyaluronic acid/ gelatin nanoparticle

Hyaluronic acid: NaOH/ DMF Collagen: acetic acid

Human umbilical vein endothelial cell

Blend: bEGF/EGF: In nanoparticle: VEGF/PDGF

[173]

Chitosan/PEO

Acetic acid

Keratinocyte, fibroblast

Blend

[178]

bFGF: basic fibroblast growth factor, PELA: Poly (ethylene glycol)- poly (DL-lactide), EGF: Epidermal growth, factor, VEGF: Vascular endothelial growth factor, PDGF-BB: Platelet-derived growth factor-BB, PLLACL: poly (L-lactic acid)-co-poly-(e-caprolactone), P3HT: Poly (3-hexylthiophene), ADSCs: Adipose-derived stem cells

up regulated and collagen as well as a cemented matrix of keratin accumulation increased. Some researchers have employed heparin to immobilize bioactive agents on the surface of the polymers to achieve a sustained release and maintain their bioactivity.[175,180] For this purpose, Zou et al.[175] loaded bFGF on the heparinzed surface of PCAAP (a novel PLA-based polymer containing reactive pendent hydroxyl groups) electrospun fibers through electrostatic interaction which reduced the initial burst release of bFGF from 85% to 40% in the first 24 h. As well, it was revealed that by increasing heparin molecular weight or the amount of grafted heparin, the release of bFGF increased. Mesenchymal stem cells derived from bone marrow (BMMSCs) have been using as the main donor cells in tissue engineering researches.[181–185] More recently, adiposederived stem cells (ADSCs) have been utilized since they are easily obtainable in sufficient amount with minimally invasive techniques and they can improve wound healing.[123] In order to study the epidermal differentiation potential of ADSCs, Jin et al.[169] loaded EGF, insulin, hydrocortisone and retinoic acid in gelatin/poly(l-lactic acid)-co-poly-(εcaprolactone) (PLLCL) nanofibers by two different electrospinning methods: blend and core–shell electrospinning. The results revealed superior proliferation of ADSCs on the core-shell nanofibers. Additionally 62% of ADSCs differentiated to epidermal cells on the core-shell nanofibers while the amount of this differentiation was 43% for those cultured on the blend nanofibers. This could be attributed to the sustained release of the EGF from the core–shell nanofibers. In addition, the advantage of sustained release of bFGF from scaffolds over the bFGF solution on the continuous cell mitosis has been reported.[166]


In another study, Xie et al.[176] designed a chitosan/PEO nanofibrous scaffold for dual release of VEGF and PDGF-BB. For this purpose, VEGF was blended with the electrospinning solution while PDGF-BB was encapsulated into PLGA nanoparticles and afterward dispersed into the solution. The results indicated rather fast release of VEGF and sustained release of PDGF-BB. These release patterns were considered appropriate inasmuch as the VEGF fast release could promote angiogenesis in early stage and sustained release of PDGF-BB would accelerate wound healing in entire procedures. This system not only possessed the benefit of VEGF and PDGF-BB release but also displayed antibacterial effects against E.coli and S.aureus due to chitosan constitution. In vivo results revealed that this mat represented faster wound contraction and re-epithelialization, more vascularization, faster collagen deposition and earlier remodeling relative to the open wound control and commercial Hydrofera Blue wound dressing.

3.2. Genes Gene therapy is a method to induce the expression of molecules involved in the regenerative response of a target tissue.[186–189] In contrast to proteins with short half-life, gene delivery offers an alternative to facilitate protein expression for an extended period of time and temporal regulation of transgene expression.[163,190–192] In fact, whilst growth factors act extracellularly and start a biological response through binding to cell surface receptors, target genes have intracellular effects by integrating into the host genome of endogenous cells and transmuting the transfected cells into local bio-activated performers to promote tissue formation.[193]



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The delivery of genes can be administered under either in vivo or ex vivo conditions. Direct injection of DNA into the target tissue faces some limitations such as low transfection efficacy and degradation. Therefore, most gene therapy systems employ vectors to ameliorate DNA entry into target cells and expression of genes.[15,192] The gene delivery vectors are divided into two categories including viral and nonviral. Viral vectors include adenovirus, baculovirus, adeno-associated virus, retrovirus/ lentivirus, etc, while the most common nonviral vectors are plasmids, lipoplexes, and polyplexes.[191,194,195] Nonviral vectors possess some advantages over viral vectors such as low immunogenicity, low tumorigenic potential and reproducibility, though they have lower transduction efficiency.[191,196–198] Hence, nonviral vectors have attracted a great deal of attention in order to deliver therapeutic nucleic acids to the wound site.[191,198] Additionally, the usage of different polymeric materials such as liposomes, poly(ethylenimine) (PEI), chitosan nanoparticles and dendrimers as the non-viral gene delivery vehicles have been reported.[194,199,200] These delivery vehicles are Figure 6. Representative images of skin leisure treated with Fb2, Fa2 scaffolds with and without usually positively charged in order to enable pbFGF polyplex infiltration and untreated wound (control) for 1, 2, 3, and 4 weeks. Bars reprecomplexation with negatively charged nucleic sent 10 mm. Fb2: PELA fibrous mats encapsulating pbFGF; Fa2: PELA fibrous mats soaked in acids.[195] Moreover, since the gene-loaded a solution of pbFGF polyplexes. Fa2: PELA fibrous mats without pbFGF polyplexes. Number 2 vehicles are required to penetrate into the cell, represents the molecular weight of PEG (2kD).The wounds treated with Fb2 fibers were almost the size of delivery vehicles should be small closed after 3 week treatment, while the unhealed areas were approximately 13%, 22% and 33% of the initial size after treatment with polyplex-infiltrated Fa2 fibers, Fa2 fibers and control enough.[194] In fact, naked DNA encoding a group, respectively. Reprinted with permission.[203] Copyright 2012, American Chemical Society. therapeutic protein is usually complexed with the vectors before blending with the polymer release of pbFGF polyplexes, PEG was introduced into the fiber solution in order to protect the DNA and increase the transfecshell. In vivo tests indicated implanting pbFGF-loaded fibrous tion efficiency in the wound site.[163] Various techniques such as mats to the wound area of diabetic rats led to remarkably immobilization,[201] layer-by-layer (LbL) deposition[202] and emulhigher wound recovery rate (Figure 6), better vascularization, sion electrospinning[203] have been employed to incorporate increased collagen deposition and maturation as well as complasmid encoding growth factors into electrospun nanofibers. plete re-epithelialization and skin formation. In one study, linear polyethyleneimine (LPEI) was chemically Kobsa et al.[202] also employed the technique of layer-by-layer immobilized on the surface exposed amine groups of PCL-PEG nanofibers through matrix metalloproteinase (MMP)-cleavable deposition of a cationic polymer (PEI) and negatively charged linkers, followed by electrostatic incorporation of plasmid plasmid DNA on nanofibers in order to immobilize plasmids DNA encoding human EGF (phEGF) onto the nanofibers. The encoding keratinocyte growth factor (KGF) on the surface of release of phEGF/LPEI complex was attributed to the digesPCL-PLA electrospun scaffold. It was shown that there is a direct tion of the MMP-cleavable linker by endogenous MMP-2. Sigcorrelation between the number of DNA:PEI bilayers and the nificantly higher hEGF expression of HDF and wound recovery amount of DNA on the electrospun mats. Although DNA incorwere observed for phEGF-incorporated nanofibers in comparporation efficiency increased with increasing PEI concentration ison to the phEGF solution and phEGF/LPEI complex. Morein layer-by-layer method, localized cationic polymers may interact over, neocollagen accumulation and cytokeratin production with cellular components such as plasma membrane which were enhanced.[201] leads to inflammation or cytotoxicity in the wound site.[163,204–206] Yang et al.[203] took the advantage of emulsion electrospinning and DNA condensation techniques in order to incorporate polyplexes of basic fibroblast growth factor-encoding plasmid 3.3. Antibiotics (pbFGF) with poly(ethyleneimine) into electrospun fibers. pbFGF and PEI were encapsulated into emulsion electrospun Bacterial contamination menaces wound healing process and PELA fibers with a core−shell structure. In order to adjust the about 75% of the mortality following burn injuries stems from

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levofloxacin,[229,233] vancomycin,[218] mupirocin,[212] and ampicillin.[234] A list of different antibiotics incorporated in electrospun scaffolds for wound healing applications is presented in Table 3. Fluoroquinolone antibiotics, which are efficient against a broad range of Gram-positive and Gram-negative bacteria, namely ciprofloxacin hydrochloride (Cipro), levofloxacin hemihydrate (Levo) and moxifloxacin hydrochloride (Moxi) were incorporated into electrospun nanofibers by Toncheva et al.[229] It was revealed that release profile of antibiotics was affected by the polymer composition of fibers and PLA/PEG/antibiotic nanofibrous scaffolds showed a faster release within 2 first hours than that of PLA/antibiotic mats yet, their release profile did not differ significantly after that. The mats supplemented by Cipro or Levo presented bacteriostatic activity while those with Moxi completely killed bacteria which was attributed to the bacteria resistant to Cipro and Levo. In another study, fast burst release of cefoxitin sodium from PLGA fibers was attributed to the limited physical interactions

REVIEW

infection.[207] Whilst, infections may be controlled by the systemic administration of antibiotics, this is often associated with the development of antibiotic resistant bacterial strains and possibility of systemic poisoning owing to high concentration of the antibiotics which are required for efficient decontamination.[208] Therefore, a great deal of effort has been made to develop appropriate topical delivery systems for antibiotics. Topical method not only leads to higher antibiotic concentration at the wound site for the duration of infection, but also prevents systemic toxicity of them.[209–211] To kill all bacteria through a few days, drug quantities higher than the minimum inhibitory concentration (MIC) values are needed to be released from electrospun mats. Regarding this fact, a release profile with a moderated burst release followed by a sustained release is considered ideal.[212–215] There are many reports on incorporation into electrospun fibers and controlled release of various kinds of antibiotics such as gentamicin,[216–218] amoxicillin,[219,220] rifampin,[221,222] cefoxitin,[223] tetracycline hydrochloride,[224–228] ciprofloxacin hydrochloride,[210,229–232] moxifloxacin hydrochloride,[229] cefazolin,[209]

Table 3. Electrospun scaffolds containing antibiotics for wound healing applications. Antibiotic

Antibiotic concentration [wt%]

Polymer

Polymer solvent

Bacteria

Method of electrospinning

Amoxicillin

–

Cellulose/PVP

Acetone, water/ethanol, water

–

Coaxial

[219]

Amoxicillin

4

PLGA

Acetone

–

Blend

[220]

Ampicillin

1, 1.5, 2.0

PU

THF,DMAC

S. aureus, K. pneumonia

Blend

[234]

Cefazolin

10, 30

PLGA

THF,DMF

–

Blend

[209]

Cefoxitin

1, 5

PLGA and PLGA/ PEG-b-PLA

DMF

S. aureus

Blend

[223]

Ciprofloxacin

5, 10

PVA/PVAc

Acetic acid

–

Blend

[210]

Ciprofloxacin, Levofloxacin, Moxifloxacin

10, 30

PLA/PEG

DCM,DMSO

S.aureus

Blend

[229]

Ciprofloxacin

10

PU/dextran

DMF,THF

E. coli, S. typhimurium, V. vulnificus, S. aureus, B. subtilis

Blend

[230]

Ciprofloxacin

–

PU

THF,DMF

S. aureus, E. coli

Blend

[231]

Ciprofloxacin

–

PVA PVA/Alginate

D. water

–

Blend

[232]

Gentamicin

5

PLA–collagen

HFIP, chloroform/HFIP-water

S. epidermidis, P. aeruginosa, E. coli

Blend and coaxial

[216]

Gentamicin

10, 20, 30

PCL

Chloroform, ethanol

–

Coaxial

[217]

Ca. 15

PLGA/collagen

HFIP

S. aureus

Coaxial

[218]

2

Chitosan/PCL

Acetic acid/TFE

–

Coaxial

[233]

Vancomycin, gentamicin Levofloxacin.

Ref.

Mupirocin

7.5

PLLA

HFIP

S. aureus

Blend

[212]

Rifampin

3

PLLA/PEG

Chloroform

–

Blend

[221]

Rifampin

4, 8, 12, 16

PLGA

THF,DMF

–

Blend

[222]

Tetracycline

1, 3

PEG–PLA

Chloroform

S. aureus

Emulsion

[224]

Tetracycline

Ca. 0.15 to 0.4

PLA/PCL

Chloroform, DMF

S. aureus

Blend

[225]

Tetracycline

1, 2

PLGA

THF,DMF

S. aureus

Blend

[226]

Tetracycline

5

Zein/PCL

TFE,DCM

Methicillin-resistant S. aureus

Blend

[227]

Tetracycline

3, 5

PCL/PEVA

Chloroform, methanol

B. subtilis, E. coli, E.faecalis, P. aeruginosa, S. typhimurium, S. aureus.

Blend

[228]

DMAC: Dimethyl acetamide, PVAC: Poly (vinyl acetate), PEG: Poly (ethylene glycol), PEVA: poly(ethylene-co-vinyl acetate)




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between the polymer and the drug with high ionic characteristic resulting in localizing most of the drug on the surface of nanofibers. Adding the amphiphilic PEG-b-PLA led to the encapsulation of some molecules in hydrophilic part of PEGb-PLA and as a result the release of the drug was prolonged up to one week.[223] A dual drug release scaffold was fabricated by electrospinning of PLLA-lidocaine hydrochloride (LH) and PLLA-mupirocin solutions simultaneously using a dual-spinneret electrospinning system. Although LH presented an initial burst release of about 80%, mupirocin exhibited only 5% burst release followed by a sustained release profile. The divergence between their release patterns was justified through the crystallization attitude of the drugs. In fact, LH, a hydrophilic drug, was crystallized out of electrospun fibers leading to a fast burst release, while mupirocin, a lipophilic drug, was not crystallized out of the lipophilic polymer and uniformly distributed in PLLA fibers with almost no burst release. The release kinetics of lidocaine and mupirocin were considered favorable since not only was the burst release of lidocaine supposed to relieve the pain but also sustained release of mupirocin led to antibiotic activity during several days.[212] Furthermore, a long-term release of the drugs was achieved by using an electrospun sandwich-structured membrane composed of PLGA/collagen for the shell layer and PLGA/vancomycin, gentamicin and lidocaine for the core layer. Vancomycin-loaded and gentamicine-loaded scaffolds revealed antibacterial effect against E. coli and S. aureus, respectively, within 24 days and as the concentration of the antibiotics decreased, their antibacterial effects declined.[218] It is generally acknowledged that the release rate of drugs is dependent on some factors such as polymer composition, polymer-drug interaction, fiber diameter, porosity as well as position of drugs in nanofiber structure.[212,229] Furthermore, it is noteworthy to mention that in physiological conditions, the release profile of bioactive agents may be affected by additional factors such as enzymes through degradation of the matrix. Huang et al,[224] found the ability of proteinase K in catalyzing the hydrolysis of PLA molecules. Since polymer degradation contributes to the drug release, it can be deduced that release profile in vitro and in vivo might differ.

3.4. Nano Silver Silver nanoparticles (Ag NPs) have found applications in wound management products due to their extensive antimicrobial activities and minimization of infection risk from antibiotic-resistant strains.[251] Silver-based wound dressings such as Acticoat and Actisorb are commercially available.[252] Major mechanisms which have been suggested for the antimicrobial properties of Ag NPs include: 1) adhesion of the nanoparticles to the cell surface and interact with membrane proteins affecting their correct functions and altering the membrane properties. They can also degrade lipopolysaccharide molecules; 2) accumulation in the cell membrane by forming pits which cause large increases in membrane permeability; 3) silver ions released from nanoparticles can inactive vital enzymes in bacterial cell and damage DNA. Indeed, Ag NPs release silver ions

14


due to dissolution or by cellular uptake and a cascade of intracellular oxidative reactions.[253–257] In practice, Ag NPs can simply be oxidized, so its effectiveness could be reduced or even divested.[251,258] Therefore, incorporation of Ag NPs into polymer matrix in electrospun nanofibers can prevent oxidation of silver, create a sustainable release of silver ions and prolong the antibacterial performance.[259] There have been a lot of efforts to incorporate Ag NPs to electrospun nanofibers summarized in Table 4. Amina et al.[246] fabricated virgin olive oil/poly(urethane) (PU) electrospun nanofibers decorated with Ag NPs. Olive oil contains vitamin E, antioxidants and phenol which can affect production of cytokine by skin cells and promote skin recovery when applied topically. In addition, the olive oil/ PU-Ag electrospun nanofibers exhibited antibacterial effects against E. coli due to the antibacterial ability of Ag NPs and olive oil while they were shown to be non-cytotoxic towards fibroblast. Nanofibrous scaffolds of chitosan/PEO or N-carboxyethylchitosan/PEO and Ag NPs were fabricated through in situ reduction of AgNO3 in the electrospinning solution using formic acid as the solvent and reducing agent.[236,237] Albeit organic solvents such as formic acid and DMF are extensively employed to reduce silver nitrate to silver nanoparticles,[236,260] alternative aqueous methods using green reducing agents such as glucose, PEI, PVA, vitamin C have been reported to synthesize Ag NPs.[241,243,247,248] Nguyen et al.[248] utilized PVA as a reducing agent for Ag NPs synthesize under microwave-irradiation. Then the electrospun PVA/Ag NPs nanofibers were subjected to a heat treatment process in order to draw the nanoparticles to the fiber surface where they can be most effective. Furthermore, the water resistance of PVA nanofibers can be improved by heat treatment through physical crosslinking.[261] In recent studies, Mohiti-Asli et al.[244,262] suggested the usage of silver microparticles or silver ions as alternatives to Ag NPs with desirable antibacterial performance and lower toxicity. Apart from Ag nanoparticles, there are some reports on the antibacterial activity of TiO2[263,264] and ZnO nanoparticles[134] yet, concern about the safety of nanoparticles in wound management products should be clarified. It is believed that nanoparticles can penetrate biological membranes and access cell because of their small size.[265] Moreover, toxicity of common Ag NPs against a variety of cells and organs has been studied. It has been acknowledged that Ag NPs may accumulate inside the cells and in some cases damage tissues such as liver, lungs and olfactory bulbs or penetrate the blood–brain barrier.[266] AshaRani et al.[267] indicated that disruption of the mitochondrial respiratory chain, interruption of ATP synthesis and production of ROS which in turn cause DNA damage and chromosomal aberrations are possible mechanisms of silver nanoparticle toxicity which can hinder the wound healing process.[35] Similarly, some studies reported cytotoxicity of some Agbased wound dressings such as Acticoat™ on both human keratinocytes and fibroblasts in vitro as well as inhibition of wound repithelialization in vivo.[268–270] Additionally, the most prevalent health effect associated with prolonged exposure to silver ions is the development of irreversible pigmentation of the skin (argyria) and the eyes (argyrosis).[271]




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Table 4. Electrospun scaffolds containing Ag NPs for wound healing applications. Polymer

Solvent

Bacteria

Cell

Ag Np size [nm]

Ref.

Acetone, water

–

–

20-300

[235]

Chitosan or CE-chitosan/PEO

Formic acid

–

–

–

[236]

CE-Chitosan/PEO

Formic acid

S.aureus

–

4-6

[237]

PVA/CM-chitosan

D. water

E. coli

–

4–14

[238]

Chitosan/PVA

Acetic acid

E. coli

–

1.2–3.1

[239]

Chitosan

TFA/DCM

P. aeruginosa Methicillin-resistant S. aureus

–

10 ± 2

[240]

Chitosan/PVA

Acetic acid

E. coli

–

20 ± 5

[241]

Gelatin

Acetic acid

P. aeroginosa, S. aureus, E. coli, methicillin-resistant S. aureus

–

11–20

[242]

PCL

DCM,DMF

S. aureus

–

30

[243]

PLA

Chloroform, DMF

S. aureus

HEK

20

[244]

DMF,MEK, 2-butanone/D. water

E. coli

–

6–90

[245]

DMF, THF

E. coli

NIH 3T3

–

[246]

Cellulose acetate

PU/PEO PU PU

THF

K. pneumonia

L929/MSC

5–20

[247]

PVA

D. water

E. coli, S. aureus

–

5–100

[248]

PVA

D. water

–

–

25 –50

[249]

D. water/formic acid

E. coli, S. aureus

–

2.1–3.5

[250]

PVA/silk fibroin

CE-chitosan: N-carboxyethylchitosan, MEK: Methyl ethyl ketone

3.5. Herbal Medicine Since ancient times, herbal extracts have been extensively used in burn and wound treatment. Some herbal extracts, which are biocompatible and nontoxic, show preference to the available chemical or synthetic drugs by virtue of having less side effects.[272] There have been some efforts to incorporate herbs such as crude bark extract of Tecomella undulate,[273] Aloe vera,[274,275] shikonin,[276,277] alkannin,[276] Garcinia cowa,[278] asiaticoside,[279] curcumin,[279–283] Garcinia mangostana,[274,284] Indigofera aspalathoides,[285] Azadirachta indica,[285] Memecylon edule,[285] Myristica andamanica,[285] chamomile,[272] Lawsonia inermis (henna),[286] thymol,[287] gum tragacanth,[288] ginsenoside-Rg3,[289] and tea tree oil[290] into electrospun nanofibrous scaffolds. For example, curcumin has acquired much attention due to its anti-bacterial, antitumor and anti-inflammatory effects.[291–293] Fu et al,[282] fabricated PCL-PEG-PCL copolymer (PCEC) composite electrospun nanofibers containing curcumin which exhibited considerable anti-oxidant ability and could efficiently absorb free radicals. Additionally, they revealed low cytotoxicity on mouse fibroblast cells in vitro, while the curcumin content reached 20 wt%. Moreover, PCEC/curcumin showed a higher wound healing rate in full-thickness dermal defects of Wistar rats compared to the blank control and the pure PCEC groups and at 21 days post-operation, the wound closure rate reached ca. 93% for PCEC/curcumin, while it was ca. 77% for untreated control and ca. 80% for pure PCEC. Ranjbar-Mohammadi et al.,[288] electrospun PVA/gum tragacanth (GT) and nanofibers at 60/40 PVA/GT ratio were uniform without bead. Antibacterial properties of the scaffolds against S.aureus and P. aeruginosa were observed and human


fibroblast showed well attachment and proliferation on the PVA/GT nanofibers. Moreover, Avci et al.,[294] incorporated Lawsonia inermis into PEO and PVA electrospun nanofibers. They reported that 2.79 wt% henna in PVA and PEO based solutions showed bactericidal efficacy against S. aureus and bacteriostatic action to E. coli. This antibacterial feature was dependent on the concentration of henna extract. Apart from the above four categories of macromolecules and medicines, some additional agents such as vitamins, vitamin A acid and vitamin E,[295] enzymes such as Lysozyme[296] and Lysostaphin,[297] honey,[298] and also some synthesized drugs such as metformin,[299] naproxen,[300] diclofenac sodium,[301] lidocaine hydrochloride,[301] benzalkonium chloride,[301] salicylic acid,[302] fusidic acid,[303] and ibuprofen[304] have been incorporated into electrospun nanofibers for wound healing applications.

4. Summary Electrospun nanofibrous scaffolds owing to their high specific surface area, high aspect ratio and high microporosity provide similar architecture to the natural ECM leading to improved cell adhesion, migration and proliferation. Natural polymers due to their biocompatibility, biodegradability and biological characteristics have found extensive applications in skin substitutes and wound dressings. Additionally, in order to take the advantages of controllable mechanical and physical characteristics of synthetic polymers, composites of biocompatible natural and synthetic polymers have been fabricated. Controlled release of multiple bioactive agents from the scaffolds can improve cell behavior, accelerate wound healing and tissue regeneration and



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inhibit infection. To this end, a variety of bioactive agents such as growth factors, genes, antibiotics, silver nanoparticles and herbal medicines have been incorporated to the electrsospun nanofibers. In conclusion, application of electrospun nanofibrous scaffolds supplemented by bioactive agents and/or cells can be considered as a promising approach in skin tissue engineering with the aim of facilitating burn and wound healing. Received: January 1, 2015 Published online:

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