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Electrospinning is the technique for producing nonwoven fibrous structures, to mimic the fabrication and function of the native extracellular matrix (ECM) in tissue. Prepared fibrous with this method can act as potential polymeric substrates for proliferation and differentiation of stem cells (with the cellular growth pattern similar to damaged tissue cells) and facilitation of artificial tissue remodeling. Moreover, such substrates can improve biological functions, and lead to a decrease in organ transplantation. In this chapter, we focus on the fundamental parameters and principles of the electrospinning technique to generate natural ECM-like substrates, in terms of structural and functional complexity. In the following, the application of these substrates in regenerating various tissues and the role of polymers (synthetic/natural) in the formation of such substrates is evaluated. Finally, challenges of this technique (such as cellular infiltration and inadequate mechanical strength) and solutions to overcome these limitations are studied.
Department of Nanobiotechnology, Pasteur Institute of Iran, Iran
Arezoo Ghadi
Department of Chemical Engineering, Ayatollah Amoli Branch, Islamic Azad University, Iran
Elmira Azmoun
Department of Chemical Engineering, Islamic Azad University, Gaemshahr branch, Iran
Niloufar Kalantari
Department of Chemical Engineering, Ayatollah Amoli Branch, Islamic Azad University, Iran
Iman Mohammadi
Department of Chemical Engineering, Ayatollah Amoli Branch, Islamic Azad University, Iran
Hossein Hemati Kordmahaleh
Department of Chemical Engineering, Ayatollah Amoli Branch, Islamic Azad University, Iran
*Address all correspondence to: azadeh.izadyari@gmail.com
1. Introduction
Nowadays, tissue engineering is known as a multi-disciplinary science that leads to the regeneration of damaged/lost tissues via combining the cell and scaffold [1, 2]. In this technique, the engineered scaffolds act as micro/nano/smart environments for improving the interactions of cell-scaffold and cellular functions (such as proliferation, adhesion, differentiation, and growth) [3]. The methods that can be led to the design of scaffolds similar to extracellular matrices (ECM), with the properties of mechanical/biochemical support from the cells and imitation of architecture/structure and function of the tissues, play an important role in this field [4, 5, 6, 7].
Electrospinning is one of the unique approaches in this field that lead to the production of polymeric fibers with interconnecting pores and the opportunity to control the network and morphology of scaffolds, especially in bio-polymers processing. Such that, the polymeric solutions with low viscosity lead to shorter and finer scaffolds/substrates, while, more viscous solutions provide a relatively continuous scaffold. However, the morphology and diameter of the produced fibers depend on the processing conditions and the type of the polymer [8].
These conditions can be provided via controlling parameters of the solution, process, and ambient, such as an electric-field application, distance between the needle and collector, needle diameter, and flow rate, solution conductivity, the concentration of the polymeric solution, materials molecular weight, and solution viscosity [9, 10, 11, 12, 13].
In recent years, many studies have been carried out on electrospun substrates and their functions for tissue engineering applications, such as the regeneration of the blood vessels, skin tissue, cartilage, and bone, as well as muscle [14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. However, a better understanding of cellular responses to sophisticated structures derived from this technique can be effective in reaching ECM-liked substrates.
Hence, in this chapter, we discuss the principles of the electrospinning technique to analyze these sophisticated structures and generate natural ECM-like substrates. In the following, the application of these substrates in regenerating various tissues and the role of polymers (synthetic/natural) in the formation of such substrates is evaluated. Finally, challenges of this technique and solutions to overcome these limitations are studied.
In this simple technique (spinning technique), a very high electrical field (high voltage), in the range of 10–50 kV, is applied for accelerating the charged polymer jet and producing ultrafine fibers (Figure 1A). Moreover, the electrospinning machine includes a syringe pump along with a syringe (with a metallic needle) that is loaded with the polymeric solutions, so that the tip needle is attached to one of the negative or positive terminals of the high-voltage electrical field, and pendant-shaped droplets of the polymer solution are held through surface tension. Notably, the needle tip is usually attached to the positive terminal of the electrical field [24]. In these conditions, the increase of the voltage is led to the formation of the Taylor cone in the needle tip [25]. Afterward, increased voltage leads to the creation of the critical value above which the electrostatic forces can overcome the surface tension forces so that it results in ejecting out the fine-jet of the solutions from the tip of the Taylor cone (Figure 1B). In the following, solvents are evaporated at a low boiling point due to contact with the atmosphere and subsequently the charged polymeric strands deposited on the collector. The collectors can play a crucial impact in reaching the various structures of the scaffold. Such that, unidirectionally oriented nanofibers, aligned nanofibers, and nonwoven nanofibers can be designed by square frame collector, rotating collector-drum, and flat plate stationary collector [26], respectively (Figure 1C).
Figure 1.
(A) Schematic of electrospinning process, (B) Taylor cone formation via increasing the voltage, (C) the fibers derived from electrospinning process with different collectors.
The parameters of the electrospinning process play an important role in understanding the nature of this process and conversing polymeric solutions into nanofibers. Indeed, control of these parameters can be led to electrospun fibers with a desired morphology and diameter. Hence, this section has been focused on these parameters and their influence on the properties of produced fibers. The mentioned parameters have been listed in Table 1.
Parameters
Details
Description
References
Solution
Concentration
There are four critical concentrations for this parameter:
Very low concentrations that led to polymeric micro/nanoparticles
Little higher concentrations that led to the mixture of bead and fiber.
Suitable concentrations that led to smooth nanofibers.
Very high concentrations that led to helix-shaped micro-ribbons.
Notably, adjusting the concentration can tune the polymeric solution viscosity.
This parameter can reflect the entanglement of polymer chains in the polymeric solution. However, when sufficient intermolecular interactions are supplied via oligomers, the control of Mw is not essential for electrospinning processing. Generally, in constant concentrations, the reduction of molecular weight is led to the formation of beads, rather than smooth fibers. Likewise, the increase in the polymer molecular weight provides smooth fibers. Notably, the too-high molecular weights can form micro-ribbon and some patterned fibers, even in low concentrations.
The selection of suitable viscosity plays a critical impact in the determination of the fiber morphologies, so that, the very low viscosity cannot provide the continuous/smooth fibers. Moreover, very high viscosity leads to the harder ejection of the jet from polymeric solutions. The concentration and molecular weight are the effective parameters on the viscosity, such that, adjustment of these two parameters can lead to adjustment solution viscosity.
This parameter is considered as the solvent composition function in the polymeric solutions and plays a crucial impact in the electrospinning process. Indeed, surface tension can act as a dominant factor for the low viscosity of the solutions and lead to the bead/beaded fiber formation. In these conditions, the controlled constant concentration can reduce the surface tension and beaded fibers convert into smooth fibers. Moreover, given that different solvents possess different surface tensions, the change of the mass ratio of the solvent mix can lead to an adjustment in solution viscosity and surface tension.
This parameter is usually determined and tuned via the type of solvent (such as formic acid), polymer (such as PCL), and salts (such as KH2PO4, NaCl). Accordingly, the use of ionic salts and organic acids leads to the production of nanofibers with small diameters and solutions with high conductivity, respectively. Generally, biopolymers are led to more poor fibers compared to synthetic polymers; due to their polyelectrolytic nature that led to an increase in the carried charge by ions, and higher tension by the electric field
In this parameter, the voltages higher than the threshold voltage can lead to the ejection of the charged jet from Taylor Cone. Moreover, the applied voltage plays an important role in adjusting the diameter of fibers, so that, based on the studies, high voltage can facilitate the formation of fibers with a large diameter. There are also several reports that show the increased voltages and consequently increase of electrostatic-repulsive forces of the charged jets can provide the fibers with a smaller diameter. Moreover, some studies also indicated that higher voltages can increase the formation of beads
Flow rate of polymeric solutions within the syringe
Based on the reports, a lower flow rate can be more effective in the electrospinning process due to the better polarization of polymeric solution. Indeed, in very high flow rates, bead fibers (thick diameters) form rather than the smooth fibers (thin diameters) that can be due to lower stretching force and the short time of drying polymeric solution (prior to contacting the collector)
The collectors (mainly Al foil) are usually used as conductive substrates for collecting the charged fiber. In this field, there are many collectors such as wire meshes, parallel or gridded bars, pins, rotating rods or wheels, liquid baths, grids, etc.
Distance between the collector and the syringe tip
This parameter also plays a crucial impact in controlling the diameter of fibers and their morphology [12]. Such that, in the too-short distances, the fibers do not possess enough time for solidifying prior to contacting the collector. Likewise, too-long distances lead to the formation of bead fibers. Indeed, this parameter is known as the physical factor of electrospun fibers and plays an important role in drying solvent
The temperature and humidity are known as ambient parameters that can be effective on the diameter of fibers and their morphology. Based on the reports, the increase in process temperature can lead to the formation of fibers with a thinner diameter, as well as low humidity can be resulted in increasing solvent evaporation velocity and drying the solvent. Likewise, higher humidity can form the fibers with thick diameters due to the neutralization of charge on the jet and smaller stretching force
Nowadays, natural and synthetic polymers are widely used in the design of electrospun scaffolds for tissue engineering applications [6, 51, 52, 53, 54, 55, 56]. In this field, synthetic polymers possess high flexibility in the electrospinning process and can provide fibers with better mechanical properties [56, 57]. Although, these polymers are also highly cost-effective than bio/natural polymers, however, a comparison of these two polymers indicates that synthetic polymers lack bioactivity and need more modification to improve biological properties [53, 56, 58]. In contrast, natural polymers possess the properties of inherent bioactive and can be led to an increase in the interactions of scaffold-cell and cell–cell (i.e., adhesion, proliferation, differentiation) [3]. These polymers have a relatively low immune response (in terms of chemical degradation) and can provide a structure similar to native ECM. In recent years, more than 200 natural/synthetic/copolymer/hybrid polymers have been designed and studied to obtain electrospun scaffolds with suitable physicomechanical and biological properties for use in tissue engineering [16, 17, 59, 60, 61, 62, 63, 64, 65]. Some of these polymers and their applications have been listed in Table 2.
The type of polymer
Name
The conditions for the electrospinning process
Applications in tissue engineering
References
Natural
Collagen
Collagen (type I), in the presence of EDC and NHS (as chemical crosslinking) solvent: ethanol-PBS 5 mL syringe (21 gauge), voltage: 20 kV, pump rate: 0.5 ml/h, relatively low humidity (20%), the speed of drum rotating: 5 m s−1, and with a distance of 12 cm from the needle and the electrospun fibers Results:
The mean diameter of obtained fibers: 0.42 ± 0.11 μm
– The increase of the viscosity by adding crosslinker EDC to the collagen solution
To produce water-insoluble nano-fibers and create a uniaxial tensile behavior similar to native tissue.
The syringe with an 18-gauge, rate of source solution by syringe pump: 0 to 25 ml/h, solvent: HFP, voltage: 15–30 kV, mandrel rotated: ∼500 rpm, the optimal air gap distance: ∼125 mm Results:
100 nm fibers with the 67 nm banding pattern
The control of fiber orientation led to tailoring subtle mechanical properties into the matrix
The promotion of cell growth and its penetration into the electrospun collagen matrix
To optimize the concentrations, input voltage, delivery rate, air gap distance, and mandrel motion in electrospinning of collagen (type-I)
Solvent: hexafluoro-2-propanol (HFP), syringe pump, and a 3 mL syringe with a 27½-G needle, voltage: 15 kV, distance between the needle tip and the collector: 15 cm Results:
The improvement of adhesion and proliferation of rabbit conjunctiva fibroblast on aligned collagen scaffolds
Solvent: HFP, a syringe with a needle diameter of 500 lm, injection: onto a metal collector, injection rate: 0.06 ml/h, Voltage: 12 kV/8 cm, temperature: 37°C. Results:
The co-solvents can be effective for electrospinning water-soluble natural polymers
Solvent: HFP, 5.0-mL syringe (18-gauge needle) into a syringe pump, infection rate: 1.8 mL/h, voltage: 22 kV, distance between the needle tip and grounded target: 10 cm, rotating rate: 500 rpm. Results:
The efficient penetration of rat cardiac fibroblasts an electrospun matrix
The excellent candidate for soft tissue applications
To design biomimicking fibrous scaffolds for tissue engineering applications
4 mm diameter syringe with a 23¾-gauge, the syringe pump flow rate: 1.9 ml/h, voltage: 22 kV, distance between the needle tip and collector: 12.5 cm or 20 cm. Results:
High extensibility, low modulus
To apply in tissue engineering and polymer composite and biomimetic.
The electrospinning process consists of a steel capillary tube (1.5 mm), volume flow rate: constant via the electric potential, the control of the distance between the capillary tip and collection (aluminum foil), and flow rate for creating a stable jet without dripping. Results:
The increase of vascular cell growth
The formation of a short cord-like structure derived from HAECs after 4 days.
The formation of interconnection network of capillary tubes with lumens, after 7 days.
Suitable mechanical properties along with slow degradability
Solvent: DMF and DCM, needle: 18-G and inner diameter of 1.2 mm, the distance between the needle tip and the collector: 10 cm, a rotating disk along with a flat aluminum plate, and rotating rate: 1000 rpm, voltage: 12 kV. Results:
Solvent: HFP, and voltage of 25 kV, the needle with18 gage, flow rate: 3.0 mL/h. Distance between the needle tip and circular mandrel: 15 cm, and rotation rate: 500 rpm. Results:
Suitable tissue composition and ideal mechanical properties.
Biocompatible with cell interactions and without systemic/local toxic effect.
Solvent: chloroform/DMF, a syringe pump with a needle (inner diameter: 0.21 mm). Distance between the needle tip and aluminum plate: 15 cm, rotating rate of aluminum: 1000 rpm, voltage: 15 kV. Results:
Improvement of endothelial cell spreading.
The promotion of proliferation and control and growth of cell orientation.
Volume flow rate: 1.5 ml/h with a needle (ID = 0.8 mm), in the range of voltage: 15–20 kV, the distance between the capillary tube and the grounded target: 12–15 cm, and rotating rate: 300 r/min. Results:
The improvement of mechanical properties
The improvement of biochemical functions of nanofibers
The increase in the motility of skin fibroblast
The decrease in the limitations of electrospun scaffolds
Solvent: formic acid: HFIP (30/70 v/v), 5 ml syringe with a needle tip diameter of 0.96 mm, solution flow rate: 2.54 ml h−1, voltage: 23 kV, the distance between needle tip and collector: 10 cm. Results:
Voltage: 17 kV, syringe pump with 10 ml syringe and needle of 21 gauges, the target: aluminum foil fixed on a wooden stand, spinning rate: 0.1 ml/h, the distance between the needle tip and aluminum target: 5 cm. Results:
The increase in thermal stability of sodium alginate/PVA fibers, due to the existence of ZnO
Solvent: water and DMF, syringe with a 23-gauge needle, syringe pump flow rate: 0.5 mL/h, voltage: 25 kV, distance between the needle tip and aluminum collector: 20 cm). Results:
Reduction of the production of pro-inflammatory cytokines
Wound healing and skin regeneration
To design a hybrid scaffold with antibacterial and anti-inflammatory activities
Solvent: 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), distance between the needle tip and target: 7 cm, voltage: 17 kV, the mass flow rate: 4 ml/h, room temperature. Results:
The gradual decrease in the diameter of fibers occurred by increased chitin concentration
The improvement of cell attachment, spreading of epidermal keratinocyte and dermal fibroblast
PLLA-gelatin scaffold with a layer of electrospun PDLA
Solvent: DCM and DMF For PDLA solution: plastic syringe with the 18-gauge needle, at the rate of 5 ml h−1, rotating (∼2000 rpm), and the distance: 15 cm, voltage: +12 kV and −5 kV. For gelatin/PLLA scaffold: the working distance: 5 cm (onto the PDLA layer), and voltages: +18 kV and −7 kV Results:
The increase of compressive mechanical properties.
Hydroxyapatite incorporation with PLLA/gelatin scaffold provided a significant effect on the mineral depositions on this scaffold.
The used polymers in the electrospinning process to produce nano/microfibers.
4.1 Natural polymers
4.1.1 Collagen
Collagen is one of the main components of the native ECM with diameters in the range of 10–500 nm that plays an important role in providing mechanical strength of tissue and stimulating cell attachment and its proliferation [67, 83, 84]. Generally, type I collagen is the most common type of this protein in the dermis (70–80%), compared to other types of collagens (i.e., type II and type III) [85]. Given that collagen possesses a low young modulus (0.8 GPa) [83], the processes, such as chemical modification [by covalent of amine/imine linkage], cross-linking [by Glutaraldehyde (GA), NHS, and EDC, genipin as the cross-linking agent], and physical treatment [by UV irradiation, gamma radiation and dehydrothermal treatment (DHT)], can be led to an increase in mechanical properties of electrospun nanofibers based on this biopolymer [84, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96].
4.1.2 Gelatin
Gelatin derived from collagen is also one of the other biopolymers whose surface charge depends on the gelatin processing methods, such as acidic/alkaline processing [97]. The mechanical strength of this biopolymer can also increase via the physical mixing with other polymers or cross-linking process and immersing of gelatin-based scaffolds into glutaraldehyde (25%), carbodiimides, and genipin [83, 98].
4.1.3 Chitosan
Chitosan is another biopolymer that is widely used in biomedical/tissue engineering applications due to its low toxicity, non-immunogenic, biodegradability, and antibacterial properties [51, 98]. This polysaccharide as a cationic biopolymer can interact with structural molecules of the ECM due to having positively charged and be led to the formation of two-component scaffolds with suitable physicomechanical/biological properties when mixed with other anionic biopolymers [99].
4.1.4 Fibrinogen
Fibrinogen is a soluble biopolymer derived from the blood plasma and plays an important role in tissue engineering applications and the development of electrospun substrates/scaffolds [100, 101]. Based on the reports, fibrinogen electrospun fibers are more extensible and elastic compared to other biopolymer-based electrospun fibers [98, 102]. Notably, the mechanical resistance of this biopolymer and its degradation rate can be controlled by crosslinking process or supplementing culture medium [103].
4.1.5 Elastin
Elastin is a biopolymer of highly insoluble with difficult processing, hence the approaches, such as cross-linking and blending with other polymers can be effective in reaching elastin-based scaffolds [104].
4.1.6 Silk fibroin
Silk is a protein-biopolymer derived from Bombyx more (most commonly)/other insects and included two proteins of fibroin (70–80%) and sericin (20–30%) or other insects [105, 106, 107, 108, 109]. This biomacromolecular possesses suitable biocompatibility, biodegradability, and mechanical properties and plays an important role in the biomedical applications and development of engineered scaffolds [110, 111, 112, 113, 114]. Based on the reports, the electrospun nanofibers of this biopolymer can modulate cellular interactions (such as adhesion, spread, the expression level of genes and proteins) [115, 116].
4.1.7 Hyaluronic acid
Hyaluronic acid (HA) is known as a linear polysaccharide and plays an important role in the ECM structure [117, 118]. This glycosaminoglycan (GAG) is a suitable candidate for hydrogel production and tissue regeneration due to its molecular weight (100–8000 kDa) and hygroscopic nature [118, 119, 120]. However, the high viscosity of produced hydrogels leads to limitations in the electrospinning process, hence, the electrospun fibers can form by blending/dissolving this hydrogel with other polymers/ in other solvents [65].
4.1.8 Alginate
Alginate is a copolymer derived from β-D-mannuronic acid and α-L-guluronic acid that is widely used in tissue engineering applications [121, 122]. This biopolymer is known as one of the other polysaccharides that are commercially produced from brown algae or some bacteria, such as Azotobacter chroococcum, Azotobacter vinelandii, and some species of Pseudomonas [121, 123]. The salt of this polymer (alginate sodium) is water-soluble and can also form a highly viscous solution at very low concentrations [124]. Moreover, the electrospinning of alginate sodium solutions carries out in presence of synthetic polymers (PVA, PEO, etc.), owing to the reduction of the repulsive forces among the poly-anionic chains of alginate. Methods, such as cross-linking, are also necessary for resulting scaffold stability in the aqueous environment [65].
4.2 Synthetic polymers
4.2.1 Polylactic acid (PLA)
PLA as thermoplastic polymer fabricates from the polymerization of lactic acid and possesses isomers of poly(L-lactic acid) and poly(D-lactic acid) [125, 126]. This aliphatic polyester possesses biodegradability properties and plays a critical role in the design of tissue-engineered scaffolds [127]. However, PLA is usually copolymerized with other polymers or made as a composite due to its low modulus, especially in bone tissue engineering [128, 129].
4.2.2 Polycaprolactone (PCL)
This polymer is a semicrystalline polyester that is widely used in the applications of tissue engineering due to its biodegradability, nontoxicity, and biocompatibility properties, as well as mechanical strength [130, 131, 132]. This synthetic polymer can improve cellular penetration into the engineered scaffolds due to the presence of cell recognition sites [51, 133, 134]. However, the degraded product of this polymer (the acids of polylactide and glycolide) affects on stability and functions of proteins and bioactive molecules. PCL is also known as the most famous synthetic polymer in the design of bone-engineered scaffolds, due to its low degradation rate and high modulus [83].
4.2.3 Polyglycolic acid (PGA)
PGA is the aliphatic thermoplastic polyester (simple linear) that is usually applied in the applications of bone tissue engineering. This polymer possesses a high young modulus (7 GPa) and can be completely degraded within 4–6 months [133, 135].
4.2.4 Polyethylene glycol (PEG)
PEG is known as one of the most popular synthetic polymers in tissue engineering applications and can lead to a promotion of cellular adhesion and improvement of cell–cell signaling, due to its hydrophilic properties and interactions with the chains of polysaccharides or peptides [51, 136]. Notably, copolymerization of this polymer with other hydrophobic polymers, such as polyglycolic acid, polycaprolactone, and polylactic acid, can lead to an increase in the degradation rate of these polymers and neutralization of their acidic products [137, 138].
4.3 Copolymer/hybrid polymers
Tissue engineering is a strategy for the design of tissue-liked scaffolds/ substrates (in terms of biological and physiological functions). In this field, the combination of natural or synthetic polymers as copolymers or hybrid scaffolds can be played an important role in overcoming the limitations of mono-component systems and improving the interactions of cell/cell and cell/scaffold. Sodium alginate/PVA electrospun mats are a sample from these copolymers that aimed to prepare the antibacterial substrates [79]. Such substrates can be used in wound dressings to reduce wound infection and prevent scars [79, 139]. PCL/HA nanofibrous scaffolds are also one of the other composite scaffolds that can provide substrates with better mechanical and biochemical properties. Based on the reports, such scaffolds lead to an increase in fibroblasts infiltration into the scaffold, cellular proliferation, and consequently tissue regeneration [77]. In this field, the combination of HA and collagen has been reported as an ideal matrix in electrospun dressings that play an important role in reducing scar via proteinase secretion and metalloproteinase inhibition [78]. Alginate-PEO nanofibers containing lavender essential oil are another scaffold that can be used for wound healing and reducing the production of pro-inflammatory cytokines [80]. The PLLA-gelatin scaffold with a layer of electrospun PDLA is one of the other samples in this field [82].
5. Application of electrospun polymers in tissue engineering
The cells play an important role in the formation of organ-dependent extracellular matrix (ECM), and to this end, they need microenvironments to improve their functions. However, the body is unable to repair damaged tissue when tissue damage is severe or extensive. In this field, although, the xenografts, autografts, and allografts approaches can be used, however, the problems of donor sites, antigenicity, and immunogenicity have been limited to the use of these therapeutic methods [51]. In recent years, tissue engineering as a new method has been overcome the mentioned problems via designing engineered substrates with suitable physicomechanical and biological properties [3, 51]. There are many studies that show electrospun substrates can be effective in this field. Such that, the electrospinning process of natural and synthetic polymers can help to address cell requirements, improve its functions, and finally regenerate damaged tissue.
Blood vessels are one of the important organs in the body that need to be repaired quickly in case of damage. Vascular-engineered scaffolds play a key role in this regard so that electrospun matrices based on the natural/synthetic/hybrid polymers can support the adhesion, differentiation, and proliferation of vascular cells and be led to tissue regeneration [140]. Accordingly, the study of Bondar et al. shows that there is ideal intercellular contact between endothelial cells on the nano/micro-scale electrospun silk fiber that led to vascular endothelial cadherin expression [141]. Soffer et al. also designed silk fibroin into a tubular structure (inner-diameter: ∼3 mm, the average wall thickness: 0.15 mm). They reported that the average strength of such scaffolds is much more than collagen scaffolds [142].
Skin is another organ that possesses an important role in the protection of the body against infection and environmental agents. Such that, loss of a large surface of the skin due to burn, wound, etc. can lead to patient death. However, dermis-engineered scaffolds can be an ideal therapeutic option for skin regeneration [6]. In this field, Min et al. stated that silk electrospun substrates with coating collagen I can increase adhesion and spreading of keratinocytes. Moreover, they found that laminin coating can stimulate cellular spreading, but not cellular adhesion [112]. Based on the studies of Pezeshki-Modaress et al., the gelatin/chitosan electrospun scaffolds as the structures containing protein and polysaccharide play a crucial role in the proliferation of dermal fibroblast cells and wound healing. Such scaffolds can maintain their morphology in culture medium and increase the proliferation and attachment of cells [143]. Law et al. also assessed electrospun collagen nanofibers for applications of skin tissue engineering. They stated that collagen nanofibers possess low mechanical properties, hence are usually cross-linked/blended with synthetic polymers [144]. In this field, Jin et al. showed that collagen/poly(l-lactic acid)–co-poly(3-caprolactone) electrospun scaffolds can differentiate mesenchymal stem cells to epidermal and lead to an increase in cell proliferation [145].
One of the other applications of electrospun scaffolds is related to the design of calcified extracellular matrices. These substrates consist of calcium phosphates, carbonated hydroxyapatite, growth factors, and bone marrow stromal cells (MSCs) or osteoblasts and osteoblast-like cells, such as osteoprogenitors and osteocytes [140]. In this regard, Ki et al. designed the 3D silk matrices to produce bone with MC3T3-E1 cells. They found that cell proliferation and spreading increase on the 3D matrices compared to 2D matrices. This can be due to the higher porosity of 3D matrices that provides better cellular adhesion [146]. In another study, Yin et al. showed that electrospun scaffolds can be effective on the regeneration of various tissues, via topography-dependent induction of lineage-specific differentiation [147]. They evaluated the differentiation pathway of MSCs in forming new tissues and observed that these scaffolds can lead to the formation of tendon-like tissue in the Achilles tendon injury models, as well as, chondrogenesis and bone tissue formation via ossification. Delgado-Rangel et al. also developed collagen/poly (vinyl alcohol)/chondroitin sulfate and collagen/poly (vinyl alcohol)/hyaluronic acid 3D electrospun scaffolds to apply tissue engineering [148]. Based on their reports, these scaffolds can increase the biocompatible cross-linker. Moreover, the scaffolds possess the behavior of pH-sensitive swelling and can be used in drug delivery systems.
Flaig et al. also studied the application of electrospun scaffolds in cardiac tissue engineering. They found that electrospun scaffolds based on poly (glycerol sebacate) elastomer and poly (lactic acid) can induce neovascularization without the inflammatory responses and support cardiomyocyte development [149]. Moreover, Vogt et al. stated that poly (ε-caprolactone)/poly (glycerol sebacate)-based electrospun scaffolds possess better mechanical properties compared to native myocardium; hence can be potentially suitable to apply cardiac tissue engineering [150].
Collectively, the studies indicate that electrospun scaffolds possess an inductive role in the regeneration of tissues and the use of hybrid polymers can provide effective insight into the design and development of smart scaffolds for applications of tissue engineering.
6. Challenges and resolutions of the electrospinning process
The techniques of tissue engineering hold promise for developing functional networks similar to native tissue. The designed substrates in this technique can support the formation of 3D tissues by mimicking ECM functions. Among the fabrication techniques of the engineered scaffold, the electrospinning process is known as an outstanding one that can produce a nonwoven structure.
Although this method is considered as the potential technique in the design of tissue-engineered scaffolds, however, it possesses limitations of mechanical strength and cellular infiltration in the application of load-bearing.
Based on the reports, the optimum size of pores for cell infiltration to tissue is in a range of 100–500 μm [151], while, the size of pores in electrospun scaffolds is much lower than the mentioned size. This can lead to inhibition of vascular growth and the creation of the hypoxic region. Moreover, the density of the fibers in electrospun substrates can be one of the reasons for poor cellular infiltration [152].
There are several solutions to overcome these limitations that pore architecture of scaffolds and their surface morphology control are some of the most important solutions. Generally, the diameter of fibers strongly relates to the pore diameter in the electrospun substrates, so that, fibers with smaller diameters lead to smaller pores. Hence, attention to surface topography plays a crucial role in the removal of waste and diffusion of nutrients [153, 154].
Indeed, the manipulation of characteristics of the electrospun scaffolds for enlarging the diameter of pores or reduction of the fibers density, help migration of cells into internal parts of the scaffold. There are other four approaches in this field, including [155]:
Adding biological factors
Electrospraying or layering of cells
Dynamic cellular culture
Combination of electrospinning with other fibers-fabrication techniques.
The electrospinning process is known as the powerful, simple, and inexpensive tool to fabricate tissue-engineering substrates that are capable of the formation of ECM-mimicking networks. Although, this technique, in clinical applications; has the limitations, such as low cellular infiltration, high-density of fibers, possible toxicity of solvent/cross-linker, and insufficient mechanical strength. However, some solutions, such as the increased diameter of pores, reduced density of fibers, and electrospinning polymers along with cells can overcome these problems. Combining robust materials or structures also provides the more robust electrospun substrate for the design and production of tissue substitutes with the desired target.
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Written By
Azadeh Izadyari Aghmiuni, Arezoo Ghadi, Elmira Azmoun, Niloufar Kalantari, Iman Mohammadi and Hossein Hemati Kordmahaleh
Submitted: 24 November 2021Reviewed: 11 January 2022Published: 08 July 2022
Open access peer-reviewed chapter
