Electrospinning For Tissue Engineering Applications

Progress in Materials Science xxx (xxxx) xxxx
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Progress in Materials Science

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Electrospinning for tissue engineering applications

Maryam Rahmatia, David K. Millsb, Aleksandra M. Urbanskac,
Mohammad Reza Saebd, , Jayarama Reddy Venugopale,f, Seeram Ramakrishnae,
⁎
Masoud Mozafarig,
⁎
a
Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, 0317 Oslo, Norway
b
School of Biological Sciences and the Center for Biomedical Engineering and Rehabilitation Science, Louisiana Tech University, Ruston, USA
c
Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, USA
d
Université de Lorraine, CentraleSupélec, LMOPS, F-57000 Metz, France
e
Center for Nanofibers & Nanotechnology, Nanoscience & Nanotechnology Initiative, Department of Mechanical Engineering, Faculty of Engineering,
National University of Singapore, Singapore
f
Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, 26300 Gambang, Kuantan, Pahang, Malaysia
g
Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences
(IUMS), Tehran, Iran
Abbreviations: ADSCs, adipose-derived stem cells; ALP, alkaline phosphatase; AP-g-GA, pentamer-graft-gelatin; AV, aloe vera; BDDGE, 1,4-buta
nediol diglycidyl ether; bFGF, basic fibroblast growth factor; BMP-2, bone morphogenetic protein-2; BMSCs, bone marrow stromal cells; β-TCP, beta
tricalcium phosphate; CaP, calcium phosphate; CDM, cartilage-derived matrix; CDPS, cistanche polysaccharide; ChABC, chondroitinase ABC; CMs,
cardiomyocytes; CNM, cardiac nanofibrous meshes; CORMs, carbon monoxide-releasing molecules; CPC, calcium phosphate cement; CTS, chitosan;
CVD, chemical vapor deposition; DMF, dimethylformamide; ECCs, engineered cardiac constructs; ECM, extracellular matrix; FBR, foreign body
response; GAGs, glycosaminoglycans; GBR, guided bone regeneration; GDNF, glial cell-derived neurotrophic factor; GO, graphene oxide; GT, ge
latin; GP, genipin; HA, hydroxyapatite; HAECs, human aortic endothelial cells; HAM, human amniotic membrane; hASCs, human adipose-derived
stem cells; HCASMCs, human coronary artery smooth muscle cells; HCNFs, hollow carbon nanofibers; HDFs, human dermal fibroblasts; hFobs,
human fetal osteoblasts; hMSCs, human mesenchymal stem cells; HOBs, human osteoblasts; HUVECs, human umbilical vein endothelial cells; LLA-
TMC, L-lactide-co-trimethylene carbonate; MC, methylene chloride; MSM, methylsulfonylmethane; MWNTs, multi-walled carbon nanotubes; NFS,
nanofibrous fibroin scaffold; NHOst, normal human osteoblasts; nHA, HA nanoparticles; NT-3, neurotrophin-3; PA, polyamide; PAA, poly(acrylic
acid); PAN, polyacrylonitrile; PANI, polyaniline; PBLG, poly-benzyl-L-glutamate; PBS, phosphate-buffered saline; PBMSC, peripheral blood mono
nuclear-stem cell; PCL, polycaprolactone; PCLEEP, caprolactone and ethyl ethylene phosphate; PCU, polycarbonate-urethane; PEO, poly(ethylene
oxide); PEOT/PBT, poly(ethylene oxide terephthalate)/poly(butylene terephthalate); PEDOT, poly(3,4-ethylenedioxythiophene); PELCL, poly
(ethylene glycol)-b-poly(L-lactide-co-ε-caprolactone); P-ESF, pore electrospun silk fibroin; PEU, poly(ester urea); PEUU, poly(ester-urethane) urea;
PG, poly(ε-caprolactone)/gelatin; PHB, polyhydroxybutyrate; PHBV, poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PGS, poly(glycerol sebacate);
PLA, polylactic acid; PLCL, poly(lactic acid-co-caprolactone); PLLA, poly(L-lactic acid); PLGA, poly(lactic-co-glycolic acid); PGA, polyglycolic acid;
POC, poly(1,8-octanediol-co-citrate); PMMA, poly(methyl methacrylate); PSAN, poly(styrene-co-acrylonitrile); PRP, platelet-rich plasma; PTFE,
polytetrafluoroethylene; PU, polyurethane; PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; Pμ, PCL microfibers; PμPn, PCL microfibers with PCL
nanofibers; RBMCs, rat bone marrow cells; rhBMP-2, recombinant bone morphogenetic protein-2; SDF-1α, stromal cell derived factor-1α; SEM,
scanning electron microscope; SF, silk fibroin; SIS, small intestine submucosa; SMC, smooth muscle cell; SrBG, strontium-substituted bioactive glass;
SrCO3, strontium carbonate; TCD, tip-to-collector distance; TGF-β, transforming growth factor beta; TPU, thermoplastic polyurethane; UV, ultra
violet; 2D, two-dimensional; 3D, three-dimensional; 3DF, 3D fiber deposition; nMP, nano-magnesium phosphate; HPG, hyperbranched polyglycerol;
iPSCs, induced pluripotent stem cells; CNT, carbon nanotube; GAS, glucosamine sulfate; ACs, rat articular chondrocytes; CP5, an articular cartilage
progenitor cell line; KGN, kartogenin
⁎
Corresponding authors at: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada (M.
Mozafari).
E-mail addresses: mrsaeb2008@gmail.com (M.R. Saeb), mozafari.masoud@gmail.com, m.mozafari@utoronto.ca (M. Mozafari).
https://doi.org/10.1016/j.pmatsci.2020.100721
Received 22 October 2016; Received in revised form 28 July 2020; Accepted 9 August 2020
0079-6425/ © 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Maryam Rahmati, et al., Progress in Materials Science, https://doi.org/10.1016/j.pmatsci.2020.100721
M. Rahmati, et al. Progress in Materials Science xxx (xxxx) xxxx
ARTICLE INFO ABSTRACT
Keywords: Tissue engineering makes use of the principles of medicine, biology and engineering and in
Electrospinning tegrates them into the design of biological substitutes to restore, maintain and improve the
Nanofibers functions of tissue. To fabricate a functional tissue, the engineered structures have to be able to
Scaffolds mimic the extracellular matrix (ECM), provide the tissue with oxygen and nutrient circulation as
Biomaterials
well as remove metabolic wastes in the period of tissue regeneration. Continued efforts have been
Nanofibrous constructs
Porous structures
made in order to fabricate advanced functional three-dimensional scaffolds for tissue en
Tissue engineering gineering. Electrospinning has been recognized and served as one of the most useful techniques
Regenerative medicine based on the resemblance between electrospun fibers and the native tissues. Over the past few
decades, a bewildering variety of nanofibrous scaffolds have been developed for various bio
medical applications, such as tissue regeneration and therapeutic agent delivery. The present
review aims to provide with researchers an in-depth understanding of the promising role and the
practical region of applicability of electrospinning in tissue engineering and regenerative medi
cine by highlighting the outcomes of the most recent studies performed in this field. We address
the current strategies used for improving the physicochemical interactions between the cells and
the nanofibrous surface. We also discuss the progress and challenges associated with the use of
electrospinning for tissue engineering and regenerative medicine applications.
1. Introduction
In the past few years, biomedical engineers have placed substantial focus on fabricating multidisciplinary platforms to mimic the
structural and physicochemical features of natural tissues [1–3]. Researchers from diverse fields such as medicine, nanotechnology,
biology and engineering are working closely to integrate their findings into a modern technology for appropriate mimicking the
natural tissues [4–6]. Tissue engineering is known as a reliable methodology to combat the tissue injuries by mimicking the phy
siological microenvironment [7–9]. In addition, recent nanotechnological advances provide an opportunity for further improving the
properties of tissue-engineered scaffolds [10–13]. Using nanoscience approaches, novel substitutes are developing fast, which make
possible to mimic the extracellular matrix (ECM) conditions of the natural tissues, more precisely than those of the macro- or micro-
scale biomaterials [14–16]. The success in making new strategies adjust to the regenerative medicine, e.g. cell-based therapies,
artificial organs and engineered living tissues, roots in proper design of multi-functional biomaterials with optimal physichochemical
properties [17]. Manipulating the physicochemical properties of biomaterial surface in view of the target application is the most
challenging aspect of engineering the injured organs, tissues and/or cells, for they play key roles in supporting the cell survival and
stimulating autologous tissue growth in situ [2,18,19]. A biomaterial should additionally have proper mechanical properties, as
complements to the target cell stiffness, making possible stimulating the neo-tissue formation [2]. There are several fabrication
methods available to obtain biomaterials with optimal physicochemical properties matching with those of the target tissue, such as
self-assembly [20], template synthesis [21], phase-separation [22], melt-blowing [23], and electrospinning [24]. Table 1 provides a
summary of the advantages and disadvantages of the main fabrication methods applied in producing scaffolds.
Among the available techniques, electrospinning is one of the most promising methods frequently used in tissue engineering
Table 1
Comparison of various methods applied in scaffold fabrication in terms of benefits and difficulties associated with their usage [25–27].
Scaffold Fabrication Advantage Disadvantage
Method
Electrospinning Uniform, aligned fiber, strong interconnectivity of porosity, 80–95% Needs high voltage apparatus, solvents used may be
porosity, 100–1100 nm fiber diameter, < 80% cell viability, ECM like toxic, and difficulties in packaging, shipping, and
structure, superior mechanical properties, large surface area, and handling
facile and simple fabrication
Self-assembly 80–90% porosity, 70–90% cell viability, 5–300 nm Using peptides, complex process, not scalable, poor
control over fiber dimension
Phase Separation Simple fabrication, 60–95% porosity Use of potentially toxic solvents, poor control over
architecture, and restricted range of pore sizes
Gas Foaming Solvent-free, no loss of bioactive molecules in the scaffold matrix Needs high pressure, poor interconnectivity of porosity,
the existence of skimming film layers on the scaffold
surface
Solvent Casting Simple fabrication, high mechanical stability Lacks reproducibility, uncontrolled structure
Freeze Drying 30–80% porosity, 50–450 nm, cell viability < 90%, it needs neither Need freeze-dryer, limited to small pore size, irregular
high temperature nor a separate leaching step porosity, long processing time
3D Printing Fabrication desired structure (flexibility in production) Needs 3D printer, uses toxic organic solvents, lacks the
mechanical strength
2
applications. This technique has several advantages over the other techniques mentioned above, mainly the possibility of producing
fibers from micro- to nanometer scale with a large surface area [28–30]. Hence, the global interest in this field of research has gained
an ascending trend, such that many studies designed, fabricated and used electrospun nanofibrous scaffolds for different tissues
[31–34]. Inspired by a number of reliable reviews [35–38], the present review aims to revisit the current state of research and to
comprehensively summarizes the key studies on electrospinning in designing tissue-engineered scaffolds. The common techniques
used for evaluating the characteristics of the nanofibers were reviewed; besides, challenges associated with the usage of electrospun
fibers in the field were discussed.
2. General requirements for designing biomaterials
The American National Institute of Health (NIH) defines a biomaterial as “any substance or combination of substances, other than
drugs, synthetic or natural in origin, which can be used for any period of time, which augments or replaces partially or totally any
tissue, organ or function of the body, in order to maintain or improve the quality of life of the individual” [39]. When designing
biomaterial scaffolds as templates to stimulate the neo-tissue formation, a set of requirements should be considered including the
possibility of assessing how the host respond to the biomaterials (known as biocompatibility), physicochemical surface properties,
and the economic aspects related to biomaterials used in the clinical practice. Biocompatibility is defined as “the ability of a material
to perform with an appropriate host response in a specific situation” [40]. The response of the host to the biomaterials should be
evaluated both in vitro and in vivo. The implanted biomaterial should allow the stimulation of the host reactions known as foreign
body response (FBR), which commonly causes restricted in vivo functionality and durability of the biomaterials [41,42]. On the other
hand, this phenomenon essentially requires eliminating the cellular debris and controlling over infection [43]. In addition, resistance
arising from the FBR against biomaterials, e.g. featured by infiltration of macrophages, which may severely destruct the tissue [44].
Hence, recognizing the mechanisms activating or deteriorating the immune system are essential in designing biomaterials. An FBR is
traditionally described as a combination of protein adsorption as well as acute and chronic phases of the inflammation. The me
chanism is initiated with protein adsorption and desorption (Vroman binding) at the surface of biomaterial after implantation. Based
on the physicochemical properties of biomaterial surface (such as porosity, size, surface charge, and roughness), proteins send signals
to the cells [45,46]. Monocytes subsequently differentiate into type 1 macrophages, which are responsible for the acute inflamma
tion. After several days, type 1 macrophages differentiate into type 2 macrophages, which are in charge of chronic inflammation [47].
The chronic phase of inflammation is recognized by the presence of mononuclear cells, such as monocytes, plasma cells, and lym
phocytes [47,48]. Chronic inflammatory responses are commonly characterized by the presence of macrophages, tissue granulation,
fibroblast infiltration, and neovascularization [49]. Granulation of the tissue may be considered as the precursor of fibrous capsule
formation, and is detached from the biomaterial surface by the cellular constituents of FBR [50]. However, this definition remains
invalid for systems in which the host responses belong to the recently developed degradable nanofibers used in tissue regeneration
applications [51–54]. Elaborated nanofibers are formulated to be responsible for a strong affinity to targeted cells making it possible
to stimulate biochemical signaling pathways toward the neo-tissue formation. This ability is entirely dependent on the specific
chemical characteristics of both the nanofibers and the biological environment of targeted tissue [46].
The biochemical perspective, different mechanotransduction, physiological, macromolecular adsorptions and biochemical sig
naling pathways are designed and practised, which behave differently from tissues to cells [51,52]. Moreover, the biochemical cues of
innate and adaptive immune systems should be dealt with differently, for they respond to the nanofibrous scaffold implantation
individually [55].
The materials engineering point of view, the physicochemical properties of nanofibrous scaffold surface (such as topographical
features, stiffness, functional groups, and interfacial free energy) can strongly affect the biochemical mechanisms. For example, the
scaffold architecture should provide an appropriate cellular environment so as to make it possible to promote the neo-tissue for
mation, remodeling, vascularization, and integration. The scaffold structure must be either porous or stable allowing for the diffusion
of nutrients and metabolites into the scaffold without the risk of collapse [56]. Designing nanofibrous scaffolds with optimal pore size
based on the target tissue and cells allows for cell migration into the scaffold and minimum ligand density on the scaffold surface [4].
Biodegradability is another key factor in designing smart scaffolds. A scaffold can only be considered as a support structure if the
body can gradually replace it with the ECM components. Waste products originating from scaffold degradation must be non-toxic and
removed without disturbing the surrounding organs [4].
The surface stiffness of nanofibers is also a key player in directing biochemical signaling pathways and cellular behavior such as
cell adhesion, spreading, migration, differentiation [57,58]. A balance between the various mechanical properties and the porosity
allows the scaffold to support sufficient infiltration and vascularization, in addition to providing the correct stability upon im
plantation [56].
When fabricating a scaffold, considering factors involved in the manufacturing process is also of crucial importance to ensure that
producing the scaffold in large scales is feasible. Such factors include production complexity, cost effectiveness, suitable manu
facturing processes, production rate, delivery methods, and scaffold storage. In terms of fabrication, the scaffold must be cost ef
fective, with an easily attainable transition of the production from a small-scale aseptic laboratory procedure to a high-quality batch
production [17,19,59]. As previously mentioned, electrospinning is among the most useful techniques that is used for producing
promising nanofibrous scaffolds with above-mentioned criteria.
3
3. The background of electrospinning
Nanofibrous biomaterials take their origin in four main fields, namely, the biological applications, physics underlying Taylor cone
formation, material choices in electrospinning, and the impact of ambient conditions on the fabrication process. Nanofibers received
remarkable attention in biomedical engineering, especially in nanoscience and nanotechnology [60]. This relatively simple and
multipurpose method can make it possible to produce various fibers with beneficial features for regenerative medicine and tissue
engineering uses [61,62]. Formhals [63] reported using electrospinning technique for the first time in the 1930s [63]. However,
scientists and researchers alike paid attention to its applicability for biomedical applications five decades later [64]. This technique
benefits from the ability of applying a high electric field to produce ultra-fine polymeric fibers with micro- to nanometer diameters
[65,66]. A convoluted electro-physical activity between the polymer solution and the electrostatic force is the main mechanism
behind this technique [67]. In electrospinning, a high-voltage electric field is generated between the injection needle and the col
lecting screen using a power supply and electrodes [68]. After gradually forcing out of the polymer solution, a hemispherical polymer
solution droplet is shaped at the tip of the needle [69]. This polymer droplet lengthens into a conical shape, known as the Taylor
cone, and the surface charge on the polymer droplet increases with time by increasing the voltage [70]. A polymer jet starts to form
immediately after overcoming the surface charge of the polymer droplet. After vaporizing the solvent in the polymer jet, the surface
charge on the jet increases, which destabilizes the polymer jet [70]. The polymer jet is geometrically segregated, initially into two jets
and, eventually, into a large number of jets, to compensate for the instability [71,72]. The electrostatic force, which affects the
constantly splitting polymer droplets causes the nanofiber patterning [70]. In addition, a spinneret with a metallic needle, a syringe
pump, a high-voltage power supply, and a grounded collector are the major constituents of a standard electrospinning system (Fig. 1)
[73,74]. The processing plasticity of the electrospinning facilitates producing various polymeric fibers [75].
Researchers could successfully electrospun natural and synthetic polymers, such as chitosan, collagen, gelatin, polycaprolactone
(PCL) and poly(lactic-co-glycolic) acid (PLGA), as biomimetic and temporal substrates to regulate cellular and molecular activities
[76,77]. Moreover, by combining synthetic polymers (as the backbone material) with natural polymers (on the surface for improving
the cell adhesion) composite fibrous scaffolds with optimal mechanical and compatibility properties could be produced for biome
dical applications [78,79]. Doshi et al. [80] listed the internal and external parameters governing the structural morphology of the
electrospun nanofibers [80]. Environmental humidity and the temperature (as external parameters) as well as applied voltage,
working distance, conductivity, and viscosity of the polymer solution (as internal parameters) are the major factors [80,81]. In the
following sections, the effects of various parameters on the electrospinning efficacy are discussed in detail.
4. Parameters affecting the electrospinning efficacy
The diameter and the morphology of electrospun nanofibers are dependent on several parameters falling into three main cate
gories: innate properties of solution, processing, and environmental factors [82,83]. The innate properties of the solution (such as
concentration, viscosity, molecular weight, electrical conductivity, elasticity, as well as polarity, and surface tension of the solvent)
have a remarkable impact on the morphology and the ultimate diameter of the electrospun nanofibers. The concentration of the
solution is a key factor governing the electrospinning process, so that only a small amount of solution is needed to run the elec
trospinning device [84]. In addition, during electrospinning, ideal solution concentration is required to achieve smooth and uniform
nanofibrous biomaterials. When low-concentration solutions are used undesirable droplets may form, which could be caused by
surface tension effects [85]. However, at high concentrations, because of the high viscosity of the solution, the fiber construction
would be problematic. Additionally, the diameter of the fiber may increase with increasing the polymer concentration [86].
The viscosity of solution can also directly affect the fiber size and its morphology. Some investigators have demonstrated that
suitable viscosity is crucial for electrospinning, so that uniform and smooth fibers cannot be shaped in very low-viscosity solutions,
while a continuous jet makes producing fibers difficult in highly viscous solutions [85,87]. Changing the complex viscosity with ideal
solution concentration helps researchers to identify the best viscosity range suitable for the electrospinning. A polymer solution has
Fig. 1. A schematic representation of the electrospinning technique for designing fibrillar networks in synthetic scaffolds. Reprinted from [35], with
permission from Elsevier.
4
four regimes including i) dilute; ii) semidilute I; iii) semidilute II; and iv) concentrated solution. Under the dilute regime, polymer
chains in solution interact rarely with each other and the solution does not show viscoelastic behavior. Under semidilute I regime,
polymer concentration is higher than under the dilute regime, and the polymer chains interact at a critical concentration (C*), but
there is no major entanglement of polymer chains. Under semidilute II regime, polymer chains are entangled and exhibit a viscoe
lastic behavior. Polymer chains entangle very tightly in concentrated solutions [88]. The entanglement is vital for fiber formation
during the electrospinning. The concentration at which entanglement takes place is called entanglement concentration, Ce. As a
practical rule, the solution concentration should be higher than the Ce [89,90]. The oval blue area in Fig. 2 is the appropriate region
for viscosity selection. In the overlapping concentration region, polymer chains start to affect the viscosity, which can be calculated
using intrinsic viscosity as C* = 1 [60]. For core-shell electrospinning, the value of ηcore/ηshell largely determines the quality of
electrospun fibers. The concentration should be kept high enough to stretch the core by viscous drag [89]. A polymeric droplet
experiencing such high voltage becomes highly electrified under the influence of two major electrostatic forces, namely, electrostatic
repulsion of surface charges and coulombic force exerted by the external field. Under the influence of such forces, the droplet shape
changes from spherical to the conical (Taylor cone) after the voltage reaches a critical value. The minimum voltage needed for
electrospinning can be estimated by Eq. (1):
VC2 = 4(D 2 / Le 2 )(Ln(2Le /R) 3/2)(0.117 R) (1)
where Vc is the critical voltage; D is the distance between the capillary and the collector; Le is the capillary length; R is the capillary
radius; and γ is the surface tension [91].
The molecular weight of polymer can also play a key role in fine-tuning the fiber dimensions, as indicated by a remarkable change
in the rheological behavior of solution during fabrication [92]. Uniform and smooth nanofibrous constructs can be obtained by
choosing polymers with appropriate molecular weights. In low-molecular weight polymer solutions, beads may appear instead of
fibers, while high-molecular weight polymer solutions result in fibers with relatively increased average diameter [92,93].
Furthermore, suitable surface tension, which is a function of solvent nature, can impact the electrospinning process and fiber
fabrication [94]. In a solution with high surface tension, the formation of fibers can be limited because of an unstable jet and
dispersion of droplets [95]. Lower surface tension can facilitate the electrospinning process at lower electric fields [96].
Fiber diameter first increases and then decreases slightly when the electrical conductivity of the solution is increased [85,97,98].
Yang et al. demonstrated that the electrical field distribution has major effects on the fiber diameter. The strength of the electric field
increases with increase of voltage at the nozzle, which causes decreasing the fiber diameter because of the prolonged jet path and an
increased bending frequency. A uniform electric field provides an appropriate electric field distribution, enabling the formation of
thinner fibers as a result of higher bending speed, which stretches the fibers [91].
Processing parameters (such as voltage, distance between the spinneret and the collector, and feeding rate of the polymer so
lution) belong to another important category in the electrospinning process [82,83]. Electrospinning can generate fibrous scaffolds
only after overcoming the threshold voltage that causes substantial charge differences in solution during the process [99,100]. By
increasing the voltage and, subsequently, the charge value, the formation of droplets and beads in the fibers can be altered [101].
Another important factor with this regard is the flow rate of polymer solution. Decreasing the feed rate increases the time required
for solvent evaporation [102]. In electrospinning, a lower flow rate is usually applied to ensure complete evaporation of solvents from
nanofibrous scaffolds [103]. In addition, the distance between the tip of the syringe and the collector is a key factor that controls the
diameter of the round fibers and their morphology [104]. When the distance is small, the fibers do not have enough time to solidify
before reaching the collector; hence, fibers with larger average diameters will be formed. On the other hand, when the distance is
large, finer fibers may be formed [105]. Thus, choosing inappropriate solution concentration, applied voltage, and tip-to-collector
distance may result in bead formation.
The ambient parameters such as humidity and temperature of the environment when fabricating an electrospun sheet are also
vital, specifically when facing serious difficulties in obtaining uniform fibrous mats. High humidity is negatively correlated with the
Fig. 2. A schematic representation of four regimes suggested for polymer solutions: i) dilute; ii) semidilute I; iii) semidilute II; and iv) concentrated
solution. Regimes' characteristics are specified in Section 4.
5
solidification time, so that high humidity impedes the spinning process and prolongs charged jetting [106]. Some studies reported
that solvents can be completely removed by evaporation if the humidity is sufficiently low, while highly humid environments can
impair fibril formation [73].
Temperature is another factor affecting the morphology of the nanofibrous scaffolds. Two types of morphologies are observed
based on temperature differences: beads, which are formed at low temperatures, and condensed and flat fibers, which are formed at
high temperatures [107]. By increasing the temperature, the viscosity of the polymer solution decreases, leading to producing small-
diameter fibers [99]. Fig. 3 provides a phenomenological overview of electrospinning with main components, defined flow patterns,
and mass transfer equation governing the process. Table 2 also summarizes the effects of electrospinning parameters on the resultant
fiber morphology.
5. Electrospun nanofibrous scaffolds for biomedical applications
In the past few decades, many researchers have studied the applicability of different synthetic electrospun biopolymers for
biomedical applications to satisfy clinical needs [20,30,31,37,109]. Members of poly(α-hydroxy acid) family including glycolic acids,
lactic acids, and their copolymers with ε-caprolactone, are a key class of biodegradable polymers with a promising potential in the
biomedical field [110–112]. These biodegradable polymers can be degraded into nontoxic end-products by hydrolysis, and regulated
by some properties, including the morphology and the average molecular weight of these compounds [113]. Hence, by regulating the
electrospinning parameters, any biodegradable and biocompatible polymer can be electrospun for biomedical applications [113]. In
addition, electrospun nanofibers can potentially direct cellular and molecular responses after implantation [114–117]. For example,
Neves et al. [118] fabricated various fiber meshes based on poly(ethylene oxide) (PEO) and PCL, employing differently patterned
collectors with certain dimensions and forms to assess the resulting mesh features for biomedical applications (Fig. 4) [118]. Elec
trospinning technique has gained considerable attention of researchers and scientists in many areas of biomedical applications,
including regenerative medicine and agent delivery systems, which are described in detail below.
5.1. Electrospun nanofibrous scaffolds for tissue engineering applications
Tissue engineering, also known as regenerative medicine, is an emerging integrative field of study which benefits from the
principles of medicine, biology, and engineering fields to develop biological substitutes that restore, maintain, or improve tissue
functions [119,120]. Tissue engineering requires a scaffold that supports cells, regenerates ECM components, and/or provides a
vector to delivery biochemical factors [4]. The nanoscale structure of the native ECM-containing network of proteins and glycosa
minoglycans (GAGs) forms a boundary between tissues and a supportive meshwork around the cells to provide cell anchorage [121].
Fig. 3. A phenomenological overview of electrospinning, with the main components, defined flow patterns, and mass transfer equation that govern
the process.
6
Table 2
Effects of electrospinning parameters on the morphology of electrospun fibers [108]
Parameter Effect of parameter on fiber morphology
Applied voltage ↑ Fiber diameter ↓ initially, then ↑ (not monotonic)

Flow rate ↑ Fiber diameter ↑ (beaded morphologies occur if the flow rate is too high)
Distance between capillary and collector ↑ Fiber diameter ↓ (beaded morphologies occur if the distance between the capillary and collector is too short)
Polymer concentration (viscosity) ↑ Fiber diameter ↑ (within optimal range)
Solution conductivity ↑ At first fiber diameter ↑ then ↓ (broad diameter distribution)
Solvent volatility ↑
Fig. 4. a) SEM micrographs of meshes obtained using PEO (top) and PCL (bottom); b) PCL deposited on top of a flat copper collector (top) and in the
area around the flat copper plate (bottom); c) PCL fiber meshes deposited on the screw collector: close-up showing the mesh region corresponding to
the thread crest (top) and the region between two consecutive threads of the screw collector (bottom). Reprinted from [118], with permission from
Elsevier.
Hence, many researchers focus on designing scaffolds with similar properties to those of human tissue at the nanoscale level. Several
studies reported that using electrospinning loosely connected three-dimensional (3D) porous nanofibrous constructs with large
surface area can be produced to resemble the native ECM network [122–125]. For example, our research team designed novel
electrospun nanofibrous scaffolds by electrospinning various concentration of Bombyx mori silk fibroin solutions (10, 12, and 14%
Fig. 5. Morphology of normal human osteoblasts (NHOst) cells cultured for seven days on (a) PCL/osteo/gelatin/CaP and (b) PCL/osteo/gelatin/
CaP/PANI scaffolds. Reprinted from [142], with the permission from Elsevier.
7
w/v in formic acid), and evaluated their applicability for tissue engineering in vitro and in vivo [126]. The developed constructs allow
good cell adhesion and growth, with no adverse effect on cell viability or cytotoxicity. In addition, the nanofibers could not stimulate
foreign body responses; however, could enhance the total cell number in the implantation area. In the following sections, we discuss
the applications of electrospun nanofibrous scaffolds for engineering different tissues in detail.
5.1.1. Electrospun nanofibrous scaffolds for bone tissue engineering

Bone tissue engineering represents a dynamic strategy for designing scaffolds to deliver therapeutic agents and cells to the
damaged tissue for stimulating the neo-tissue formation [127–129]. Researchers should consider several critical factors when de
signing bone scaffolds including 1) the porosity size; 2) suitable mechanical strength and tunable biodegradation kinetics; 3) in
terrelated open porosity for growth factors; 4) sterile environment for cell growth and cell seeding [130–132]; and 5) scaffold
biocompatibility and biodegradability [128,133]. Using electrospinning many of the above-mentioned criteria can be achieved.
Electrospun nanofibrous scaffolds from various natural and synthetic polymers are used for bone engineering such as alginate,
chitosan, collagen, PCL, polyglycolic acid (PGA), PLA, and PLGA [28,128,134–136].
Hydroxyapatite (HA), which has a similar chemical structure to the minerals in the native bone, is one of the most important
biomaterials used for bone engineering applications [137,138]. HA can improve topographical properties of nanofiber surface to
achieve better cell adhesion and growth [139–141]. Rajzer et al. [142] established a new method for inkjet printing to generate
Fig. 6. A,B) SEM micrograph of hMSCs seeded on scaffolds, after 14 d [143]. C, D) Random and aligned electrospun nanofibers [poly(L-lactic acid)-
co-poly-(ε-caprolactone) (PLCL) synthetic biopolymer] influencing the direction of cellular spreading and elongation [144]. E) Core-shell structure
of silicon nanoparticles in interconnected hollow carbon fibers. F) Carbon matrix. Reprinted from [145], with the permission from Elsevier.
8
Table 3
An overview of key electrospun nanofibers for bone tissue engineering applications.
Materials composition Fibers diameter (nm) Studies Cells/ enzymes Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
(ml.h−1) distance (cm) size
M. Rahmati, et al.
(gauge)
nMP/PCL/HPG/nHA 725 ± 153, 783 ± 125, In vitro MG63 & hMSCs 9–13 500 µl/h−1 11 N/A Increasing swelling, biomineralization, [146]
535 ± 113 and 608 ± 120 nm for and breakages of fibers by adding nMP.
PCL, PCL/nHA, PHAMP, and Increasing cell viability, adhesion and
PGHAMP respectively. spreading by adding nMP.
miRNAs/PCL 538.574 In vitro iPSCs 16 0.4 18 N/A Increasing the expression of osteogenic [147]
markers by adding miRNAs.
PCL/CTS/Mg/HA 419–495 In vitro MG63 14–22 0.3&0.4 14 N/A Improved Cell viability and [148]
proliferation.
Improving bone mineralization through
introducing triazole rings on the
copolymer structure.
SPI/PEO 701.92 ± 315 In vitro rBMSC 23 9 µl/min 13 23 Neo-tissue formation can be detected [149]
for SPI/PEO electrospun nanofibers
with 7:3 concentration.
Improving bone formation in the
presence of rBMSC.
CNT 500 In vitro, In MSCs 13 0.007 ml/min 8 23 Coating nanofibers with CNT stimulates [150]
vivo the expression of angiogenic and bone
formation.
Collagen/ Catecholamines, 900 ± 150 In vitro hFob 17 0.8 13 27 The scaffolds has high mechanical [151]
9
Ca2+ properties with Young’s modulus close
to cancellous bone.
Improved cellular responses.
PLGA/HA1%/MWNTs 1055 In vitro BMSCs 0–45 0.2 13 N/A Depending average diameter of fibers [152]
on HA concentration.
Improved cellular responses.
CTS/HA/GP 335 ± 119 In vitro 7F2 15 1.2 15 N/A Increasing Young’s modulus by [153]
osteoblast-like crosslinking with genipin.
cells, ALP Increasing the osteoinductive
bioactivity.
Suitable for non-weight bearing bone
tissue engineering.
SF 411 ± 98 In vitro MC3T3-E1 12 N/A 10 22 3D NFS with high porosity has more [154]
cell adhesion and proliferation than 2D
NFS.
HA/PLA 1–2 µm In vitro MG63, ALP 25 0.1 15 N/A The surfactant-mediation method is [155]
operational in scattering the HA nano-
powder in the PLA Matrix.
Improved osteoblastic cellular
responses.
(continued on next page)
Table 3 (continued)
(gauge)
M. Rahmati, et al.
HA/PLGA 266.6 ± 7.3 In vitro MC3T3-E1, ALP 12 1 15 N/A Equally spreading HA on the fiber [156]
surface at a minor concentration.
Slowly increasing agglomerates by
increasing HA concentration.
Improved biomineralization.
A significant increase of cell viability
until day 7, and then decreasing to day
14.
Considerably high ALP activity in the
scaffolds.
Silk/PEO/nHA/BMP-2 520 ± 55 In vitro hMSCs 12 0.02 ml/min 21.5 N/A Significantly increasing bone formation [143]
through using BMP-2 and/or nHA into
the scaffolds.
PCL/Gel/calcium 1.2 µm In vitro MC3T3-E1 15 0.5 15 24 Improved homogeneous calcium [157]
phosphate phosphate coating in the presence of
gelatin.
Covering the fibers by a thin layer of
mineral deposition after two hours of
incubation.
The structure of the scaffold was a
mixture of dicalcium phosphate
10
dehydrate and apatite.
Improved cell proliferation.
The formation of a multilayered film of
cells on the scaffolds after seven days of
culture.
Improved cytocompatiblity in the
presence of gelatin and calcium
phosphate coatings.
CTS/HA 214 ± 25 In vitro hFOBs 17.5 20 µl/min 34 N/A Remaining the crystalline nature of HA [158]
and surviving the AA-dominant solvent
system.
Remarkable bone formation oriented
through using HA nanoparticles.
Collagen/PLGA/nHA Collagen = 353.8, In vitro N/A 12 1 12 N/A The surface functional groups [159]
Thin PLGA = 97.3, significantly affect the mineral
Thick PLGA = 320 formation.
Bonelike apatite formation is much
copious and constant over collagen
nanofibers than PLGA.
PCL/GT 312 In vitro BMSCs 20 2 18 N/A Inducing the BMSCs recruitment after [160]
In vivo adding SDF-1α to the fibers.

Table 3 (continued)
(gauge)
M. Rahmati, et al.
AP-g-GA/PLLA 200 In vitro MC3T3-E1 1.5 30–4 µl/min 24 N/A Improved thermal stability, [161]
biodegradation and biocompatibility.
Improved electroactivity and reversible
redox properties.
Improved cell differentiation.
Submicron bioactive glass 50–800 In vitro N/A 7–19 0.5 15 N/A The scaffolds have large surface area, [162]
fibers 70S30C high porosity and fine interconnected
pore network construction.
Improved elastic modulus.
PEOT/PBT/calcium 6.47 ± 1.46 µm In vitro, In hMSCs 12 15,20,25 15 20 The scaffolds could not display any [163]
phosphate vivo considerable change in ALP expression
when compared to uncoated scaffolds.
Stimulating osteogenesis.
PLLA/PBLG/Collagen 200–400 In vitro ADSCs 12 1 12 27 Introducing PBLG/n-HA on the [164]
polymeric nanofibers to adjust and
enhance specific biological functions of
ADSC into osteogenic lineage.
CTS/GP 144–154 In vitro SAOS-2 25 20 µl/min 15 20 Increasing the mechanical properties, [165]
preserve nanofibrous morphology, and
cellular proliferation using genipin.
The mats have adequate mechanical
11
properties, degradation rate and
cytocompatibility for GBR applications.
PHBV/nHA/ Bombyx mori 10–15 μm In vitro HOB 10,15 2,5 15 N/A Increasing fiber diameters and [166]
SF decreasing wettability by increasing
concentration of the co-phases within
the polymeric matrix.
Increasing Young’s modulus for
composites containing 2% wt of
ceramic and 2%wt of SF.
Decreasing Young’s modulus by
increasing the ceramic and proteic
phase’s concentrations to 5% wt.
A relative decreasing in compressive
secant modulus by increasing the
ceramic content.
The scaffolds were bioactive,
supporting bone like apatite crystals
growth after 28 days.
An appropriate topography mimicking
the ECM in the presence of HA.
Capability of the cells to infiltrate into
the scaffolds.
Table 3 (continued)
(gauge)
M. Rahmati, et al.
SF 200–400 In vitro, MC3T3-E1, ALP 13 N/A 20 22 Considerably increasing proliferation [167]

In vivo and ALP activity of osteoblasts.
Increasing expression levels of
activated adhesion-related proteins in
the P-ESF.
Improved new bone formation.
PLLA/collagen/HA 310 ± 125 In vitro hFOB, ALP 10,12 N/A 15 N/A Improved mineral deposition on [168]
scaffolds.
Providing cell recognition sites and HA
for cell proliferation and
osteoconduction in the presence of an
ECM protein, collagen and HA.
GTl/PCl/calcium 0.3–5 μm In vitro NHOst, ALP 30 1.5 15 N/A Improved mechanical properties of [169]
phosphate scaffolds.
Increasing the nucleation and growth of
apatite crystals on the surface in the
presence of calcium phosphate
nanoparticles.
Improved ALP activity and
mineralization.
PCL/SrBG 46.1 ± 16.6 μm In vitro MC3T3-E1 7 20 μl/h 6 19 Improving osteogenesis by adding [170]
12
SrBG.
Increasing ALP activity in MC3T3-E1
cells by adding SrBG.
PHB/HA 2.0 ± 0.2 μm In vitro preosteoblasts 10–30 2 20 N/A Increasing the fiber diameter by [171]
increasing the applied voltage and
solution concentration.
Positively encapsulating of NPs inside
the ultrafine fibers fabricated.
Improved cell viability and spreading
on the fibrous nanohybrids, and cell
metabolic activity by increasing
incubation time.
PHBV/PRP/nSrCO3 400–800 In vitro hMSCs, ALP 15 0.5 15 N/A Improving the osteogenic [172]
differentiation of hMSCs.
PLGA/PCL 0.36–2.4 μm In vitro BMSCs 13 3 12 N/A Affecting the morphology and [173]
orientation of cells by different
alignments of random PLGA and
aligned PCL fiber regions.
PCL//AV/SF/HA 133 ± 28 In vitro ADSC, ALP 13 1 10 21 ADSCs are appropriate cell therapeutics [174]
for bone regeneration.
The composite scaffold improves bone
regeneration.
Table 3 (continued)
(gauge)
M. Rahmati, et al.
PCL/PLGA 1.98 ± 0.51 μm In vitro, RBMCs 20 50 µl/min 15 18 Improved cell infiltration and cartilage [175]
In vivo matrix deposition.
Improved new bone formation over the
remodeling of the cartilage template
after 8 weeks of in vivo implantation.
HA/SF 350 ± 67 and 112 ± 89 μm In vitro, BMSCs 40 N/A N/A N/A Decreasing average pore diameters by [176]
In vivo increasing the SF concentration from
5% to 10%.
HA/SF-5% scaffold is a promising
candidate for improving cell adhesion
and biocompatibility of surface.
13
conductive patterns on electrospun scaffolds for bone tissue engineering. The authors printed conductive polyaniline (PANI) mi
cropatterns on PCL/osteo/gelatin/CaP scaffolds using an inkjet printer and demonstrated that calcium phosphate nanoparticles and
osteogenon could improve the bioactivity of hybrid scaffolds. Moreover, the morphology and proliferation of normal human os
teoblasts (NHOst) on PANI-modified surfaces improved compared to non-modified surfaces (Fig. 5) [142].
Li et al. [143] fabricated nanofibrous scaffolds containing silk fibroin, bone morphogenetic protein 2 (BMP-2), and HA nano
particles (nHA) [143]. After culturing human mesenchymal stem cells (hMSCs) for up to 31 days under static conditions on scaffolds
(silk/PEO/BMP-2, silk/PEO/nHA, and silk/PEO/nHA/BMP-2) and in control solutions (silk/PEO, silk/PEO extracted), the scaffolds
supported hMSCs growth and differentiation towards osteogenesis. The nHA particles were integrated into the scaffolds during
processing and enhanced bone formation. As depicted in the SEM micrographs shown in Fig. 6A and Fig. 6B, after 14 days cell
culture, the progression of cell growth on scaffolds in silk/PEO scaffolds was significantly lower than that of silk/PEO, PEO extracted
scaffolds. This could be because of the presence of PEO, which reduces the porosity of scaffold [143]. It was also reported elsewhere
that the alignment of grown cells largely depends on the randomness of the electrospun fibers. Comparing Fig. 6C and Fig. 6D, it
becomes apparent that highly oriented fibers (Fig. 6D) induce the stem cell growth in the direction of fiber alignment [144]. The fiber
geometry can also be adjusted by fine-tuning the electrospinning process, as illustrated in Fig. 6E and Fig. 6F. Table 3 provides a
comprehensive comparison of different types of electrospun fibers applied in bone tissue engineering.
5.1.2. Electrospun nanofibrous scaffolds for cartilage tissue engineering

Articular cartilage tissue is composed of tangential, transitional, radial, and calcified areas (specific cells and ECM), which reduce
friction and increase wear resistance of tissue [177]. Cartilage defects are among the most common crucial health issues [178,179].
Currently, an electrospinning technique that can be used to mimic the pattern features of the ECM has gained considerable attention
of scientists for applications in cartilage regeneration [180]. Wise et al. [181] developed electrospun oriented nano- and micro-fibrous
PCL scaffolds seeded with hMSCs for articular cartilage regeneration [181]. Their results indicated that an aligned ECM environment
for modulating cartilage arrangement could be achieved using this technique. Xue et al. [182] designed a novel electrospun fibrous
membrane based on GT/PCL, to engineer cartilage with the exact 3D network in a sandwich model. The authors fabricated a rounded
membrane and seeded it with chondrocytes. Macroscopic and histological analyses confirmed the possibility of cartilage regeneration
using these membranes (Fig. 7). Using an ear-shaped titanium alloy mold, the authors also created an ear-shaped cartilage in a
sandwich model. The in vitro and in vivo evaluations exhibited that the cartilage preserved its original shape, sharing up to 91.41%
similarity with the titanium molds [182].
Li et al. [183] designed some PCL nanofibrous scaffolds and then investigated their ability to promote in vitro chondrogenesis of
MSCs for cartilage regeneration. Their results indicated that the nanofibers were uniform and uniformly oriented, with a diameter of
Fig. 7. Engineering of ear-shaped cartilage. A) Tailored electrospun GT/PCL membrane; B) titanium alloy ear-shaped mold; C) gross view of ear-
shaped cell-scaffolds just after stacking (0 h); D) cell-scaffolds 2 weeks after in vitro culturing; E) subcutaneous implantation in nude mice; F–H)
engineered ear-shaped cartilage after 6 weeks of in vivo incubation; and I) similarity testing of the engineered ear and the titanium mold. Reprinted
from [182], with the permission from Elsevier.
14
Fig. 8. Immunohistochemical localization of cartilage-specific ECM molecules in day-21 nanofibrous fibroin scaffold (NFS) MSC cultures treated or
untreated with TGF-β1. Positive staining of collagen type II (A), cartilage proteoglycan link protein (B), and aggrecan (C) was observed in TGF-
β1–treated cultures but not in cultures without TGF-β1 exposure (D–F). Bar, 20 μm. Reprinted from [183], with permission from Elsevier.
700 nm. MSCs cultured in the scaffolds differentiated into cells with a chondrocytic phenotype, in the presence of transforming
growth factor beta (TGF-β)-1 (Fig. 8) [183]. Table 4 provides an overview of major nanofibrous scaffolds used for cartilage tissue
engineering applications.
5.1.3. Electrospun nanofibrous scaffolds for vascular tissue engineering

Vascular tissue engineering endeavors to reconstruct blood vessels consisting of endothelial and perivascular cells for clinical
applications [203]. High porosity and aspect ratio of nanofibers enhance nutrient and gaseous exchanges that lead to angiogenesis,
which is the main factor of vascular regeneration [204]. Blood vessels have three layers: the tunica (outer coat) intima, tunica media,
and tunica adventitia. The tunica intima is the innermost lining of a monolayer of non-thrombogenic endothelial cells, which can
induce platelet stimulation and thrombus formation. The second layer is the tunica media, which consists of a great number of
smooth muscle cells. The outermost layer, tunica adventitia, is composed of collagenous ECM and fibroblasts [205,206]. ECM is the
most important component of the vascular system; hence, the tensile stiffness, elasticity, and compressibility of a blood vessel are the
crucial features in designing vascular scaffolds [207]. The advances in nanotechnology ensure the capability of using electrospinning
not only for developing scaffolds but also for creating tubular scaffolds for vascular tissue engineering. Yazdanpanah et al. [208] used
electrospinning to fabricate nanofibrous scaffolds based on poly(L-lactic acid) (PLLA) and gelatin [208]. Tensile tests indicated that
the mechanical strength and estimated burst pressure of graded PLLA/gelatin scaffolds are better than those of layered PLLA/gelatin
and gelatin scaffolds.
Researchers seeded human aortic endothelial cells (HAECs) and human coronary artery smooth muscle cells (HCASMCs) onto
electrospun silk fibroin scaffolds [209]. Fig. 9 shows that HCASMC is a stromal support cell for HAEC, which undergoes alignment/
prolongation, while HAEC is a cell that forms cord-like network. Fig. 9 represents the appropriate alignment and prolongation of
HCASMCs on scaffolds five days after seeding, as well as the formation of enhanced cord-like networks on the surface. Because of
their superior mechanical properties, blood vessels require scaffolds with appropriate mechanical strength. Researchers suggest
developing multi-layer scaffolds for vascular tissue engineering to mimic the tissue while assuring the substrate has mechanical
strength in the range of targeted tissue [210–212]. Table 5 provides an overview of key nanofibrous scaffolds for vascular re
generation applications.
5.1.4. Electrospun nanofibrous scaffolds for cardiac tissue engineering

Cardiac tissue scaffolds should have high conductivity and elasticity to mimic cardiac functions (Fig. 10). Wang et al. [229]
fabricated conductive nanofibers based on PANI and PLA for cardiac regeneration. The nanofibers exhibited appropriate bio
compatibility, and enhanced cell-cell interactions and spontaneous beating of primary cardiomyocytes [229]. Further, Dippold et al.
[230] designed elastic nanofibers based on poly(glycerol sebacate) (PGS)-zein for cardiac engineering. Their results indicated that
zein enhance the mechanical properties of PGS, and the fibers exhibit appropriate biocompatibility as well as durability for cardiac
engineering applications [230]. In addition, researchers suggested using elastin to increase elasticity of nanofibers used in cardiac
tissue engineering [231,232].
Zong et al. [233] developed biodegradable non-woven PLGA-based scaffolds for cardiac tissue engineering using electrospinning
15
Table 4
An overview of key electrospun nanofibers for cartilage tissue engineering applications.
Materials composition Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
M. Rahmati, et al.
(gauge)
GAS/PCL 0.573–1.318 In vitro ACs N/A N/A N/A N/A Coaxial electrospinning can be used to [184]
load GAS in nanofibers.
Improving cell proliferation and growth
by adding GAS.
PCL/GEL/PEG 100–300 In vitro CP5 27 1.5 9 21 Improving cell attachment and [185]
proliferation by adding gelatin.
Increasing pore size and interconnectivity
of fibers by adding gelating.
PGS/PCL/KGN 617–738 In vitro hBMSC 20 50 & 180 μl/ 17 N/A Improving cell proliferation and [186]
min chondrogenic differentiation by adding
KGN into nanofibers.
PCL 0.4–1.4 μm In vitro hBMSCs 9 1 20 N/A The formation of new ECM components [187]
on the scaffolds.
PCL/CDM 0.56–0.58 μm In vitro hASCs 17, 25 1.2 20 21, 25 Stimulating sulfated GAGs synthesis and [188]
COL10A1 gene expression.
Higher cell infiltration and ACAN gene
expression in multilayer scaffolds than
single-layer constructs.
Lower elastic modulus in multilayer
scaffolds than single-layer constructs.
16
Improving homogeneous cell seeding,
and chondrogenesis-related bioactivity in
multilayer scaffolds.
Collagen/PLCL 295 ± 103 In vitro, Chondrocyte 16 1 12 N/A Stimulating more cartilage-like tissue [189]
In vivo with the extension of implantation time in
vivo.
Significantly increasing Young’s modulus
of the scaffolds by PLCL.
3,4,6-O-Bu3GlcNAc–loaded Thick fibers = 200 ± 20, Thin In vitro, Chondrocyte 11, 12 0.1, 0.4 11 22 3,4,6-O-Bu3GlcNAc not only hinders NF- [190]
PLGA fibers = 20 ± 2 μm In vivo B signaling, but also increases
chondrogenic and anti-inflammatory
properties on OA chondrocytes.
Stimulating cartilage tissue production in
3D in vitro hydrogel culture networks.
Pμ, PμPn, PμFn Fibers of Pμ = 10.1 ± 1.1 μm In vitro hMSCs 7,13,18 0.1, 0.4, 8 N/A N/A Preserving scaffold cellularity under [191]
Fibers of serum-free conditions and improving the
PμPn = 9.8 ± 1.4 μm, deposition of GAGs by nanofibers within
194.6 ± 45.9 nm a microfiber mesh.
Fibers of
PμFn = 8.8 ± 1.1 μm,
250 ± 50.2 nm
PEOT/PBT/PEG 268 ± 32 μm for 3DFESP, In vitro Primary bovine 15 0.39 15 N/A Providing structural integrity and [192]
10 ± 2.8 μm for 3DF articular mechanical properties by 3DF scaffold.
chondrocyte The ESP system acts as a “sieving” and
cell entrapment system and proposes
signals at the ECM scale.

Table 4 (continued)
(gauge)
M. Rahmati, et al.
The scaffolds improved cell entrapment,

an upper amount of ECM, and a
meaningfully greater GAG/DNA ratio
after 28 days.
A direct effect of fiber dimensions on cell
differentiation.
PLGA/HA/Collagen type I 421 ± 208 In vitro hMSCs 14.4 ± 0.4 1 14 N/A Improving the cell viability. [193]
Hypertrophic chondrocytes in the
scaffolds.
Collagen type I & II N/A In vitro hMSCs 13–30 0.3–1.5 N/A N/A Facilitating the differentiation of hMSCs [194]
by creating a biocompatible and
hydrophilic, chondroinductive scaffold
consisting of two types of collagen.
CTS/PVA/CaCO3 71.5–140.7 In vitro ATDC5 17 10 µl/min 15 N/A Increasing the diameter of fibers and [195]
Young’s modulus by increasing the
concentration of CaCO3.
CDPS/PLA N/A In vitro BHK-21 12 1, 4 10 N/A Improved biomechanical and [196]
hemocompatibility properties compared
to natural tissues.
PVA/PCL/BMSC 300–800 In vitro, MSCs 15 N/A N/A 17 Improving cell proliferation and [197]
In vivo chondrogenic differentiation in the
17
scaffolds.
Improving healing of defects by treating
with cell-seeded PVA/PCL scaffolds.
PLGA 0.79–0.92 In vitro L-929 0.56 N/A 25 18 The scaffold is mechanically stable. [198]
Faster degradation of the nanofiber
scaffold than a block-type scaffold.
Degradation of scaffold was Dependent
on the lactic acid/glycolic acid
concentration ratio and may be organized
by mixing ratio of blend PLGA.
increasing chondrocyte proliferation and
ECM formation by applying
Intermittent hydrostatic pressure to cell-
seeded scaffolds.
CTS/PEO N/A In vitro Chondrocyte N/A N/A 12–29 20 The fibers are aligned. [199]
Significantly higher elastic modulus,
Young’s modulus, and good chondrocyte
biocompatibility in the electrospun mats
than those of the cast films.
Slightly higher cell viability in the
electrospun mats than the cast films.
Solid cylindrical and 200–800 In vitro, N/A N/A N/A N/A N/A Fibrous tissue at the articular surface of [200]
cannulated tubular types of In vivo the scaffold two weeks postoperative.
PLGA The formation of cartilage at the articular
surface and bone at the subchondral area
and retained over postoperative week 24.

Table 4 (continued)
(gauge)
M. Rahmati, et al.
Considerably higher histologic scores in

the treated groups with the scaffolds than
those of control group.
PLGA/MSM 0.65–84 μm In vitro Chondrocyte 40 0.07–0.10 µl/ 20 N/A Improving cell proliferation and ECM [201]
min formation ability of the scaffolds.
Developing ECM formation, the cartilage
related gene expression of collagen type
II, aggrecan, and collagen type I, and
cartilage specific protein expression of
collagen type II in the 10 wt% MSM/
PLGA mats.
PLCL/CTS-QK 194 ± 65 In vitro HUVECs 19 0.4 16 N/A The scaffolds could effectively [202]
encapsulate QK peptide and keep its
secondary structure after release.
Accelerating the proliferation of HUVECs
by the release of QK peptide after nine
days.
GT/PCL 440 ± 63 In vitro, Chondrocyte 10 2 12 18 Using an ear-shaped titanium alloy mold, [182]
In vivo an ear-shaped cartilage can be created in
the sandwich typical.
The ear-shaped cartilage mostly preserves
18
their original form, after two weeks of
culture in vitro and six weeks of
subcutaneous incubation in vivo.
The engineered cartilage has good
elasticity and mechanical strength.
Fig. 9. Immunocytochemistry staining of HAECs on scaffolds on days 1, 5, 10, and 15. Reprinted from [209], with permission from Elsevier.
[233]. The scaffolds could improve the isotropic and anisotropic growth of cardiomyocytes [233]. Shin et al. [234] designed some
CM-electrospun nanofibers based on biodegradable PCL, by seeding neonatal rat CMs on electrospun meshes. The authors observed
good adherence of cultured CMs on scaffolds, with five even layers of cells without any core ischemia or synchronized beating
(Fig. 11) [234]. Castellano et al. [235] synthesized a number of different scaffolds based on polyhydroxybutyrate (PHB), PCL, silk,
PLA, collagen, and polyamide (PA), to compare their properties as electrospun nanofibrous scaffolds for cardiac regeneration. The
study demonstrated that PHB and PCL nanofibrous scaffolds could enable the maximum adhesion/growth of MSCs, cardiomyocytes,
and cardiac fibroblasts. Moreover, the in vivo studies exhibited that implantation of PCL, silk, PLA, and PA patches at the epicardial
surface of healthy rats could induce a traditional FBR, while collagen and PHB patches were mainly degraded. Although PHB-based
scaffold meaningfully induces angiogenesis, collagen, PCL, and PHB generally reduce tissue remodeling after implantation [235].
Table 6 provides a summary of major nanofibrous scaffolds used for cardiac engineering applications.
5.1.5. Electrospun nanofibrous scaffolds for nerve tissue engineering

Peripheral nerve injury is among the most common diseases in the world that may occur during traffic accidents, resections of
tumors and/or adverse iatrogenic effects of the surgery [245–247]. Over 500,000 cases of peripheral nerve injuries are annually
reported in Europe and the US [248]. An ideal scaffold for nerve tissue engineering should exhibit specific characteristics, such as
appropriate biological and physiochemical properties, excellent biocompatibility, biodegradability, oxygen and nutrient perme
ability, good mechanical characteristics, and suitable surface features [247,249]. Hence, researchers are paying increasing attention
to electrospinning as a technique for designing synthetic and natural nanofibrous scaffolds suitable for nerve tissue engineering
[250–252]. Our research team designed a novel laminin-incorporating PLCL scaffold for nerve engineering applications using co-axial
electrospinning and blend electrospinning approaches. We observed 78% increase of Schwann cell proliferation on the core-shell-
structured nanofibers after seven days in vitro culture [253]. Because of the neural action potential, conductive scaffolds are suitable
as neural substrates [254–256]. Tian et al. [257] electrospun conductively aligned nanofibers based on PLA and polypyrrole for
neural tissue engineering, in which aligned fibers could support the cell growth, proliferation, and neurite outgrowth than random
fibers. Neurite outgrowth was also enhanced by external electrical stimulation (40 mV) [257]. Fig. 12 provides a schematic re
presentation of bio-mimicking scaffold for peripheral nerve regeneration. Researchers used polymerized polypyrrole on PCL-PLA
electrospun fibers as a conductive nanofibrous conduit. Upon electrical stimulation, the performance of the conductive conduit is
significantly higher than that of an autografted non-stimulated PPY/PLCL conduit group [258]. Wang et al. [259] studied the effects
of fiber diameter on neural cell growth. The authors prepared three types of fibers with different diameters (1325-, 759-, and 293-
nm). The results indicated that neurite length on the intermediate-size substrate is greater than that of the other two substrates.
19
Table 5
An overview of key electrospun nanofibers for vascular tissue engineering applications.
Materials Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
composition (ml.h−1) distance (cm) size
M. Rahmati, et al.
(gauge)
PU/PEG 394 ± 106 In vitro HUVECs 20 0.6 15 21 The mechanical properties of the scaffolds are [213]
close to those of human and pig arteries.
Improved hemocompatibility by adding PEG.
Improved cell attachment and proliferation on
scaffolds.
LLA-TMC 2–5 μm In vitro SMCs 15 1 20 30 A middle TMC amount has the best [214]
electrospinning behavior.
The scaffolds could tolerate repetitive cyclic
loading, without meaningfully dropping
performance over the period of time tested.
Matching the mechanical properties of the
scaffolds to the stated range of human arteries.
A steady loss of modulus and strength by Bulk
degradation of scaffolds.
Supporting the cell growth and proliferation.
GT/Heparin 814 ± 201 for heparin 1% In vitro HUVECs 18 0.6 20 25 Decreasing in fiber diameter by increasing the [74]
heparin weight ratio.
Improving the tensile strength and elastic
modulus of crosslinked scaffolds.
A sustained release of heparin over 14 days from
20
the scaffolds.
Increasing the cell growth and proliferation by
adding the crosslinker.
Elastin/PU/Collagen 557.17 ± 113.33 In vitro SMCs 15–17 1, 2 10–12 N/A The scaffolds attain viscoelastic properties in the [215]
presence of elastin.
Improving cell proliferation in the presence of
collagen.
Supporting the cell growth and proliferation.
PCL/Collagen type I/ 4.85 ± 0.3 μm In vitro SMCs 20 10 15 18 Providing a mature smooth muscle layer that [216]
SMC expresses robust cell-to-cell junction and
contractile proteins in the presence of pre-
fabricated SMC sheets.
Increasing the growth and proliferation of Cells
by pulsatile perfusion bioreactor conditioning of
the cell sheet-vascular scaffold.
Bombyx mori SF 547 ± 132 and 555 ± 155 In vitro, In SMCs 24 1.1 10 N/A The expected compliance is similar or greater [217]
vivo than that of native rat aorta and
Goretex®prosthesis.
Improving the cell growth and proliferation.
The scaffolds cause a mild host reaction in rat
dorsal tissue.
PET/PU 2.1–2.8 μm In vitro Fibroblast 14–16 10 18, 25 N/A The incorporation of growth of vascular [218]
endothelial and SMCs into the scaffolds for
vascular regeneration should be studied.
TPU/GO 295–397 In vitro 3T3 fibroblast, 18–20 0.5 N/A 18 Cell viability for both types of cells is the utmost [219]
HUVECs at 0.5 wt% GO concentration.

Table 5 (continued)
Materials Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
(gauge)
M. Rahmati, et al.
Improved cell viability and attachment by

oxygen plasma treatment.
The scaffolds containing 0.5%GO have small
platelet adhesion and activation.
Cycloid PLA 800 μm-1 nm In vitro N/A 8, 20 1 3, 15 N/A The mechanical strength and Young’s module of [220]
the cycloid fibers are upper than those of
conventional tubular random ones.
PCL/PLLA/Collagen PCL = 127 ± 25, In vitro HUVECs 6,10 1, 5 12 27 The 3D scaffolds are more blood compatible [221]
PLLA = 1.2 ± 0.2 μm grafts than ePTFE grafts.
The 3D scaffolds can instantaneously hinder the
first thrombus formation and hasten
endothelialization.
Increasing vascular regeneration by the
nanofibrous structure of scaffolds.
PCL/Collagen N/A In vitro L929, ECs, 20 0.06,0.18 µl/ 15 N/A Substantial enhancement of tensile strength, [222]
SMCs min stitching strength, bursting pressure and
decomposition temperature by crosslinking the
scaffolds with genipin.
The scaffold has good biocompatibility and cell
affinity properties.
GT < 10 μm In vitro hSMCs 22.5 2.5 25 18 Improved cell growth and proliferation. [223]
21
PEU 422 ± 33 In vitro, In A-10 SMCs 10 1 15 23 Improved tissue remodeling in all type A grafts, [224]
vivo and occlusion over the time interval in the type
B grafts.
PCL-a cellular aortic 100–150 μm In vitro, In Endothelial 10 0.8 15 21 Improving the biomechanics of decellularized [225]
vascular vivo vessels.
The scaffolds could prohibit the occurrence of
vasodilation and aneurysm creation after
transplantation.
PLA/PCL combining 0.60 ± 0.08 μm In vitro, In HDFs, HUVEC 18 18 1 21 Improving the collagen remodeling and [226]
with HDFs, vivo biomechanical properties up to day 14.
HUVEC Increasing the cell growth and proliferation.
More infiltration of host cells and collagen
remodeling than those of the HDF-seeded grafts.
Thin constant layers of EC and SMCs could be
formed after 4 weeks.
PCL/ CORMs 1.84 ± 0.47 μm In vitro Rat SMCs 15 2 10 22 The scaffolds can be photoactivated and release [227]
CO.
Improved cell growth and proliferation.
PVA/GT/PCL 432.2 ± 37.9 and In vitro, In HUVECs 12 0.2 12,15 22,27 Quickly in vivo degradation of PVA fibers. [228]
400.1 ± 42.5 vivo Producing electrospun scaffolds with high
porosity.
Improved cell growth and proliferation.
Fig. 10. A schematic representation of various characteristics of cardiac fibrous scaffolds.
Fig. 11. (a) Hematoxylin and eosin staining. Cells have adhered by the entire mesh. Scale bar = 50 μm. (b) Immunohistochemical staining of F-
actin. Actin fibers traverse the entire thickness of the Cardiac nanofibrous meshes (CNM). Scale bar = 50 μm. (c) Immunohistochemical staining of
cardiac troponin I. Troponin-positive cells are found in the interior of the CNM. Scale bar = 50 μm (d) scanning electron microscopic (SEM)
micrograph of the CNM surface. The mesh is covered with multiple layers of cells. Scale bar = 100 μm. (f) SEM micrograph of a CNM cross-section.
Cells have attached to all fibers in the mesh. Scale bar = 50 μm. Reprinted from [234], with permission from Elsevier.
Further, Schwann cells extend proportionally with neurite extension on small and large fibers; however, this phenomenon delayed on
intermediate fibers [259]. Table 7 presents a summary of major nanofibrous scaffolds used in nerve tissue engineering applications.
5.1.6. Electrospun nanofibrous scaffolds for skin tissue engineering

Skin defects are among the main causes of morbidity and mortality around the world, which account for high socioeconomic costs
[274]. Depending on the duration of healing, these injuries can be acute or chronic [275]. Skin injuries are mainly caused by burns,
diabetes, trauma, surgical procedures, bedsores, aging, and congenital giant nevi [274]. Over the past few decades, researchers have
paid substantial attention to tissue engineering and biomaterials strategies for skin regeneration [109,276–278]. Autograft and
allograft are the two main approaches for skin regeneration [279,280]. Regardless of advances in auto/allografting, these approaches
have some drawbacks including health risks related to surgeries, imperfect donor sites, slow healing rate and scar formation
[281–283]. Biomaterials and interface tissue engineering fields have emerged with the aim of developing promising approaches
through combining biomaterials, engineering strategies and therapeutic agents to overcome these drawbacks [284,285]. The de
signed skin scaffolds can improve skin healing by protecting the tissue from dehydration and infection, as well as delivering growth
factors and matrix components to the wound sites [286–288]. In addition, by supporting ECM regeneration, scaffolds enable the cell
attachment, proliferation and migration, which eventually lead to the development of new skin [289]. Researchers should consider
some major points in designing skin scaffolds such as angiogenesis, gas exchange, moisture maintenance, and mass transport of tissue.
The biodegradability rate and mechanical properties of skin scaffolds should also match those of the native skin tissue [274]. Several
studies reported that because of the high surface area-to-volume ratio of an electrospun nanofiber, it can be a potential candidate for
22
Table 6
An overview of key electrospun nanofibers used for cardiac tissue engineering applications.
Materials Fibers diameter (nm) Studies cells Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
M. Rahmati, et al.
(gauge)
PCL 3.4–12.1 μm In vitro Myofibroblast 15–20 8–60 µl/min 15 N/A Improving the cell penetration by [236]
increasing fiber diameter.
Free delivery of cells, with the largest fiber
diameter (12.1 mm).
Homogeneous neo-tissue formation and
adequate matrix deposition.
PCL/GT Random fibers = 239 ± 37, In vitro Rabbit cardiomyocytes 12 1 10 27 Providing anisotropic wetting and [237]
aligned fibers = 269 ± 33 mechanical properties by the scaffolds.
Higher cell attachment and alignment on
aligned PG nanofibrous scaffolds compared
to PCL scaffolds.
PLCL/POC 412–490 In vitro cardiac myoblast 12 1 12 27 Regulating the mechanical and degradation [238]
properties of the scaffolds by changing the
concentration of POC blended with PLCL.
Increasing the cell growth and proliferation
on scaffolds after two and eight days by
increasing the concentration of POC.
PLCL/SF/AV 188 ± 16 In vitro Cardiomyocytes 18 1 12–13 27 The scaffolds are suitable for MI repair. [239]
Improved cardiac cell proliferation on
PLCL/SF/AV nanofibers.
23
The scaffolds have better cardiac expression
proteins myosin and connexin after nine
days cell culture.
Type I Collagen 200–800 In vitro Rat skeletal L6 17 0.6 23 21 The cells seeded onto the scaffolds can [240]
myoblasts preserve their contractile role for 17 days.
Using a new benign solvent, collagen I can
be electrospun without joining other
polymers.
PLGA/PCU PLGA = 280.4 ± 96.5 In vitro H9C2 cardiac myoblasts 20 0.5, 0.8 15, 18 N/A Improved cell growth and proliferation in [241]
PCU = 699.4 ± 201.1 anisotropic textile-templated scaffolds.
All cell-seeded PCU scaffolds had
mechanical properties similar to those of a
human heart.
PGS/zein 300–350 In vitro N/A 15, 20 0.5–2 15 N/A A physicochemically steady structure over a [230]
28-day time period by just a small drop in
pH after 28 days.
Table 6 (continued)
Materials Fibers diameter (nm) Studies cells Voltage (kV) Flow rate Needle–mandrel Needle Major outcomes Ref
(gauge)
M. Rahmati, et al.
GT 200–600 In vitro Myoblast 17 0.6 23 26 The scaffolds have 19.6 ± 3.6 kPa [242]
modulus, which is similar to natural human
myocardium tissue.
Good cell adhesion and proliferation.
Improved expression of contractile protein
desmin.
PCL 3.3 ± 0.8 μm In vitro, In MSCs N/A N/A N/A N/A The scaffolds provide an appropriate matrix [243]
vivo for MSC cardiac implantation.
The scaffolds could improve cardiac
function and weaken dilatation.
PGS/PCL 1.2 ± 0.2 In vitro C2C12 myoblasts, 15 1.6 15 20 Cell attachment over the first eight hours [244]
neonatal rat after seeding and aligning after 24 h.
cardiomyocytes Scaffolds could direct cell responses.
24
Fig. 12. A schematic representation of a bio-mimic scaffold for peripheral nerve regeneration application.
skin regeneration applications [109,276–278]. For example, Milan et al. [290] reported that 3D dermal substitutes fabricated using
collagen nanofibers provide a physiological environment for skin cell attachment and expansion [290]. Nanofibers can protect
damaged skin tissue from fluid and protein loss; facilitate elimination of exudates; and prevent invasion by exogenous micro
organisms [291,292]. Several natural and synthetic polymeric biomaterials can be successfully electrospun for skin regeneration
application. Hadisi et al. [293] demonstrated that a gelatin-oxidized starch nanofiber scaffold loaded with Lawsonia inermis (known as
henna) stimulates healing of second-degree burn wounds while reducing the inflammatory response and macrophage infiltration
[293]. Table 8 summarizes the major nanofibrous scaffolds used in skin tissue engineering applications.
5.2. Electrospun nanofibrous scaffolds for compound delivery
Many studies reported that scaffolds made of polymeric-based electrospun nanofibers can successfully deliver therapeutic agents
for biomedical applications, which is because of their unique functionality, high surface-to-volume ratio, nanoscale morphology, and
high pore connectivity [62,306,307]. The main drawbacks of classical delivery systems are toxicity at the release surface; reduced
drug potency; and costly long-term drug dosage [308]. Controlled and targeted delivery of agents using nanoparticle-based systems
offer more precise solutions to overcome such difficulties by fine-tuning of the drug eluting profile [309–312]. The drug release from
nanoporous 3D scaffolds is dependent on the polymer degradation rate and complex circulation pathway [313]. Various formulations
are suggested to improve the drug release profiles such as combining different polymers and designing polymers with various surface
coatings [314–317]. Electrospun hollow nanofibrous structures produced by coaxial electrospinning methods could be a promising
approach for encapsulating various drugs [318,319]. This method enables high drug loading capacity and enhanced solubilization of
some insoluble drugs [320]. Furthermore, several types of drugs such as anti-cancer drugs [321], antibiotics [310] and poly
saccharides [322] can be chemically or physically encapsulated in the mass phase of electrospun nanofibers or on their surface.
Kolambkar et al. [323] reported using electrospun PCL nanofibrous tubes loaded with a growth factor and a peptide-modified alginate
hydrogel injected into the tubes to sustain release recombinant bone morphogenetic protein-2 (rhBMP-2) for bone regeneration. The
authors reported that the designed delivery system allows consistent bone bridging of critical bone defects. However, in the absence
of rhBMP-2, the scaffolds are not robust enough to enhance the new bone formation. Fig. 13 shows that by controlling the growth
factor release, the system could improve lamellar bone formation, the tissue integration at interface, and formation of marrow spaces.
In addition, Diab et al. [324] evaluated the efficacy of a delivery system comprising an electrospun PCL nanofibrous mesh tube
and a silk fibroin hydrogel in a rat model for local delivery of BMP-2. Their results indicated that the system enables effective delivery
of BMP-2, which leads to better bone formation than control group (silk fibers) in rats post-surgery. The targeted release of BMP-2
also enhanced the overall biomechanical properties of the scaffold [324]. Hao et al. [325] could successfully develop electrospun
core-shell nano/micro fibers based on PU and cellulose acetate for intravaginal drug delivery [325]. Mendes et al. [326] designed
hybrid electrospun fibers based on chitosan/phospholipids for transdermal drug delivery [326]. The results indicated that fiber
morphology depends on phospholipid content. Additionally, the fibers are stable in phosphate-buffered saline (PBS) because of
chitosan amine groups and phospholipid side chains [326]. Tamayol et al. [327] fabricated elastic PGS/PCL-based nanofibers loaded
with an antibiotic for wound healing applications [327]. They reported that because of the porous structure of the electrospun fibers,
an initial burst release can be detected, which is not suitable for sustained and controlled release (Fig. 14). To address this problem,
various materials and/or methods are used, such as multilayer electrospun fibers, core-shell structures, nanocarriers, and coating
layers [312,319,328]. For example, researchers compared the unitial burst release of a polyester-based scaffold containing dex
amethasone with and without coating a layer of poly(3,4-ethylenedioxythiophene) (PEDOT). The drug has an initial burst release of
75% in the uncoated group. However, in the coated group, as an electro-responsive system, the initial burst release could be highly
controlled in tissue engineering applications [329].
25
Table 7
An overview of key electrospun nanofibers for nerve tissue engineering applications.
Materials Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle size Major outcomes Ref
composition (ml.h−1) distance (cm) (gauge)
M. Rahmati, et al.
PLGA N/A In vitro, In Schwann 12 1 10 N/A The scaffolds do not induce host responses. [260]
vivo Positive nerve regeneration for 5 out of 11 scaffolds, one
month after implantation.
The scaffolds are flexible, penetrable and exhibit no
swelling and tube breakage.
PCL/GT 113–189 In vitro C17.2 12 1 N/A N/A The PCL/gelatin scaffolds have the highest stability at [261]
70:30 proportion.
Improved cell differentiation and proliferation.
The cell direction is parallel to the direction of fibers.
PCL Nanofibers = 251 ± 32, In vitro, In N/A 8 1.5 N/A N/A The scaffolds could improve peripheral nerve [262]
Microfibers = 981 ± 83 vivo regeneration and functional recovery across a 15-mm
serious defect gap in rat models.
P(LLA-CL)/collagen 253 ± 102 In vitro C17.2 12 1 11 27 Fiber orientation, composition, and mechanical [263]
I/collagen III properties have critical roles in improving peripheral
nerve regeneration.
Improving cell proliferation on aligned nanofibers.
CTS 400 In vitro, In Schwann 25 2–8 10 N/A Increasing the tensile strength along the sheet’s axis. [264]
vivo Oriented fibrous sheets could display a Schwann cell
column.
Functional and electrophysiological recovery in the
oriented and the bilayered groups.
26
Sprouting of myelinated axons by axonal maturation in
the isograft, oriented and bilayered groups.
PLLA/PANi 195 ± 30 In vitro Nerve stem 15 1 15 27 The scaffolds presented a conductance of 3 × 10–9 S. [265]
cells Protracted neurite outgrowth compared to the cells
grown on non-stimulated scaffolds.
SF 290 In vitro, In RT4-D6P2T 10 N/A 10 22 Meaningfully increasing ASA in the SFNC group after 1, [266]
vivo Schwann 7 and 10 weeks implantation compared to the control
group (p < 0.05).
Increasing the average ASA in SFNC group after one
week implantation.
Reducing the onset and strictness of autotomy in SFNC
group.
PLCL/collagen 230 ± 31 In vitro MSCs 15 1 12 27 Increasing cell differentiation and proliferation using [267]
neuronal inducing factors such as b-mercaptoethanol,
epidermal growth factor, nerve growth factor and brain
derived growth factor in DMEM/F12 media.
PCL/SIS 0.32–0.47 μm In vitro PC-12 18 2 N/A N/A Increasing the alignment’s grade by increasing electrical [268]
conductivity of the original polymer solution.
Increasing mechanical properties, hydrophilicity and
cell proliferation on mats.
PLCL/Laminin PLCL = 350 ± 112, In vitro Rat Schwann 12, 15 1 11 27 Improving cell proliferation on laminin containing [253]
Laminin = 316 ± 110 core–shell PLCL scaffolds.
PAA 820 In vitro N/A 15 0.8 20 18 The length transition depends on the bathing NaCl [269]
amount and the operation temperature.
PHBV/collagen 386–472 In vitro PC12 15 1 12 27 Improved cell proliferation on aligned PHBV/Collagen [270]
50:50 nanofibers compared to aligned PHBV and PHBV/

Table 7 (continued)
Materials Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle size Major outcomes Ref
composition (ml.h−1) distance (cm) (gauge)
M. Rahmati, et al.
Collagen 75:25 nanofibers.

Aligned nanofibers provide contact guidance to direct
the cells along the direction of fibers.
PCLEEP/GDNF GDNF = 3.96 ± 0.14, In vitro, In GDNF 7.5–8 6, 8 5–6 N/A Randomly dissolving protein throughout the polymer [271]
PCLEEP = 5.08 ± 0.05 μm vivo matrix in an aggregate form, and sustained releasing for
up to two months.
Electrophysiological recovery was detected in 20%,
33%, and 44% of the animals in the EF-C, EF-L, and
EF–L-GDNF groups, respectively.
PCL/GT 0.548 ± 0.140 μm In vitro PC-12 1 0.5 N/A N/A Stimulating the essential biological pathways related to [272]
nerve regeneration including cell adhesion,
proliferation, the neurite outgrowth and differentiation.
PGS/PMMA/GT 225–631 In vitro Rat PC-12 10 1 15 N/A Increasing hydrophilicity and biocompatibility by [273]
adding gelatin.
Improved cell proliferation on the surface.
Elongated cell morphology and inducing nerve stem cell
differentiation.
27
Table 8
An overview of key electrospun nanofibers for skin tissue engineering applications.
Materials composition Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle size Major outcomes Ref
(ml.h−1) distance (cm) (gauge)
M. Rahmati, et al.
PLGA & PEO containing 280 for PLGA & 760 for PEO In vitro HSF 20 & 25 0.3 & 0.5 15 & 18 N/A Nanofibers have uniform morphology. [294]
rhbFGF& Similar mechanical properties to the human
rhEGF skin.
Improved cell proliferation.
Singular delivery of rhEGF plays a major
role in increasing collagen and elastin
expressions.
PLGA/gelatin gelatin = 175, In vitro HSF 12, 16, 20 0.4, 0.8, 1.2 10 21 Similar mechanical properties to the human [295]
PLGA = 630, skin.
PLGA/EGF = 390 A sustained release of EGF.
Improved blood clotting and platelet
adhesion.
Cell infiltration into the hybrid scaffold and
collagen synthesis.
Gelatin/ BDDGE 276–339 depending on the In vitro hDNF 11 0.4 12 15 Controlling both fiber diameter and [296]
content of BDDGE mechanical properties by BDDGE
concentration.
4% BDDGE has ideal mechanical properties.
No toxicity.
Coll/PCL/ gentamicinn 130 In vitro HDF 12 0,6 12 22 Good controlled release of drug. [297]
No toxicity.
28
Coll/bioactive glass 494 ± 153 In vitro, In HaCaTs, HDF, 16–18 1 10–15 N/A Improving the tensile strength of [298]
vivo endothelial cells. nanofibers.
Nanofibers have antibacterial properties.
Improved HaCaTs proliferation and
migration, secretion of COL-I and VEGF in
HDFs, as well as HUVECs proliferation.
The nanofibers induce skin regeneration
GelMA 1.36–2.18 In vitro, In HDF&HUVEC 20 4 15 N/A Improved cell adhesion, proliferation, [299]
vivo migration in vitro, and formation of 3D
vascular networks in vivo.
Controllable mechanical and degradation
properties.
SF/HAM 250 In vitro MEFs 15–20 0.2–1 ml/min 80 or 180 mm 12–15 Improved mechanical properties of bilayer [300]
scaffolds compared to amniotic membranes.
Additional oxygen plasma treatment
increased the surface wettability.
No toxicity.
PCL N/A In vitro, In N/A 18 1 15 20 Supporting fibroblast functions in vivo. [301]
vivo Increasing the speed of wound healing.
Formation of hydroxyl and carboxyl groups
on the membrane.
PCL/Coll 820 In vitro hEnSCs 24 0.5 20 21 The scaffold is a cost-effective, safe and [302]
angiogenesis stimulator.
High mechanical properties.
No toxicity.
689 ± 48 In vitro L929 18 1 N/A 18 [303]

Table 8 (continued)
Materials composition Fibers diameter (nm) Studies Cells Voltage (kV) Flow rate Needle–mandrel Needle size Major outcomes Ref
(ml.h−1) distance (cm) (gauge)
M. Rahmati, et al.
PLLA/COL/ aloevera/ The composite scaffold is an appropriate

coated with chitosan structure for sustained release of AV gel.
PCL/HA/ epidermal GFs 272 ± 38 In vitro, In HaCaT, fibroblasts 18 1 15 N/A Increasing the release of EGF by increasing [304]
vivo nanofiber Hydrophilicity through HA.
EGF and HA increase cell infiltration,
collagen and TGF-b1 gene expression as
well as the ration of collagen III to I.
Nanofibers induce epidermis regeneration
in the early phases of wound healing.
β-glucan butyrate/β- N/A In vitro, In 3T3, HaCaTs 30 2 μl/ min 15 18 The scaffold has an advanced structure, a [305]
glucan acetate vivo high degree of aqueous stability and water
holding capacity.
The scaffold has good mechanical
properties and cytocompatibility.
The scaffold accelerates wound healing in a
full thickness mouse model.
29
Fig. 13. Typical radiographs of reconstituted bones 4 and 12 weeks after implantation. Defects in Groups I (mesh alone) and II (mesh with alginate)
exhibited small amount of bone formation, and did not exhibit bridging, even after 12 weeks implantation. After 4 weeks implantation, defects in
Group III (mesh with alginate containing rhBMP-2) samples were filled with bone tissue, while Group IV (perforated mesh with alginate containing
rhBMP-2) samples showed the most robust mineralization. All samples in Groups III and IV were bridged with densely packed bone after 12 weeks
implantation. Reprinted from [323], with permission from Elsevier.
Fig. 14. A Schematic of controlling drug release using multilayer fibers and core-shell structures.
6. Surface modification of nanofibrous scaffolds
Several surface modification strategies are developed to improve the surface characteristics of electrospun nanofibrous scaffolds
[330–332]. Synthetic polymers require some modification to enhance their hydrophilicity and cellular attachment. There are specific
30
surface modification approaches available to change the chemical nature of the surface, improve surface hydrophilicity, and provide
a desirable environment for cellular adhesion as well as proliferation [333–335]. Plasma treatment, wet-chemical methods, surface
graft polymerization, and co-electrospinning of surface functionalization are the most common used approaches, which are discussed
in the following sections.
6.1. Plasma treatment
Plasma treatment is commonly used to immobilize polar groups, such as carboxyl or amine groups, to change the chemical nature
of surface and improve surface wettability [336]. Based on the plasma source different functional groups can be introduced to the
surface, which subsequently enables covalent immobilization of bioactive molecules [337–339]. Plasma treatment with ammonia,
oxygen or air can generate carboxyl groups or amine groups on the surface [340]. In addition, multiple ECM protein constituents,
such as collagen, gelatin, and fibronectin, can be immobilized by plasma treatment, which results in improved cellular adhesion and
proliferation [341–343]. For instance, researchers functionalized the surface of PLGA-based electrospun nanofibrous scaffolds by
plasma, oxygen or ammonia to enhance surface hydrophilicity and evaluated their biological performance [344]. The functionalized
surfaces could improve fibroblast adhesion and proliferation compared to non-functionalized surfaces [344]. Further, Chen et al.
[345] modified electrospun PLLA nanofibers with cationized gelatin to enhance their compatibility with chondrocytes, and under
lined the potential of such modified nanofibers as candidates for cartilage regeneration. They treated scaffolds with oxygen plasma to
introduce surface carboxylic groups. Then, using a coupling agent (water-soluble carbodiimide), they covalently grafted cationized
gelatin onto the fiber surface. The scaffolds improve the viability, proliferation and differentiation of rabbit articular chondrocyte
compared to untreated PLLA nano-fibrous membranes. In vivo studies indicated the formation of ectopic cartilage tissue 28 days after
implantation of the scaffolds (Fig. 15) [345].
6.2. Wet-chemical method
Surface-modified nanofibrous scaffolds are treated under acidic or basic conditions to generate reactive functional groups and to
improve surface wettability [346]. This method is based on random chemical breaking of ester linkages in the polymer backbone on
the surface, resulting in generating surface hydroxyl and carboxylic groups from degraded water-insoluble polymer fragments [347].
One research group demonstrated the benefits of wet-chemical surface modification for bone tissue engineering applications by
fabricating a novel electrospun PCL nanofibrous scaffold that was hydrolyzed with NaOH [344]. The researchers observed that the
modified fibers provide a better microenvironment for cell growth and proliferation than unmodified surfaces [344]. A variety of
molecules are used as surface-bioactive agents such as ECM proteins and ECM-derived peptides. One of the most common molecules
is collagen, which can be immobilized onto a nanofibrous scaffold using this surface modification method [348]. The surface
modification by immobilized collagen significantly improves the neural stem cell attachment and growth in neural tissue engineering
[349].
6.3. Surface graft polymerization
Grafting hydrophilic components on the surface of hydrophobic polymers results in improving the molecular and cellular re
sponses to the nanofiber surface [350,351]. Surface graft polymerization is used not only to increase surface hydrophilicity but also to
introduce multifunctional groups for covalent immobilization of bioactive molecules on the surface [352]. Surface graft
Fig. 15. Histological analysis of (a–d) control modified scaffolds and (e–h) chondrocyte-seeded modified scaffolds 4 weeks after implantation.
Sections were stained with hematoxylin and eosin (a, e), Alcian blue (b, f), or safranin O (c, g); and immunohistochemically, for collagen type II (d,
f). N, nanofiber; IC, inflammatory cells; ST, surrounding tissue. Scale bar = 100 μm. Reprinted from [345], with the permission from Elsevier.
31
polymerization begins with plasma and ultraviolet (UV)-irradiation treatment to produce free radicals [353]. In a typical reaction,
when acrylic acid is successfully grafted onto a PLCL scaffold by UV-irradiation, the modified layer creates a surface that is com
patible with hMSCs [354].
6.4. Co-electrospinning of surface-active agents and polymers
During the initial surface modification, it is possible to directly graft nanoparticles and/or functional polymers onto the nanofiber
surface. For instance, PLLA solution could be combined with HA nanoparticles by co-electrospinning, leading to the fabrication of
nanofibrous scaffolds containing HA nanoparticles on the surface [355]. Compared with pure PLLA nanofibrous scaffolds, these
composite nanofibrous scaffolds exhibit an extended degradation rate because of the ionic interactions between PLLA ester groups
and calcium ions of HA [356]. The aim of this method is to combine a range of electrospinnable functional polymers and polymers
conjugated with nanoparticles to yield bio-functionalized nanofibrous surfaces [357].
7. Innovative approaches to electrospinning
Electrospinning can be used to create nanofibrous scaffolds of various shapes, such as core-shell, hollow, porous, and honeycomb
[20,145,358–360]. The generated scaffolds are promising because of their structural similarities to the natural ECM. Nguyen et al.
[361] designed some 3D nanofiber-hydrogel systems for therapeutic agent delivery to direct axon regeneration for spinal cord injury
treatment [361]. The authors reported that the resulting nanofibers mimic the topographical properties of natural ECM more closely
than the hydrogels and micron-sized structures [361]. Because of the high surface area and porous structure, cells have a high
tendency to proliferate and differentiate on a nanofiber surface. In addition, the high surface area of such a nanofiber enables higher
surface adsorption of proteins and also promotes higher binding site formation. Using electrospinning, researchers are attempting to
develop nanofibrous scaffolds with different shapes and properties such as core-shell, highly porous, and multilayer nanofibers
[20,145,358–360,362]. Core-shell structures are used to make nanofibrous scaffolds [222,310]. This strategy allows the inclusion of
bioactive agents, such as bacteria, enzymes, drugs, viruses, and proteins, within the core, and controls their release kinetics
[363–365]. Coaxial core-shell electrospinning set-up is among the most common set-ups used for making such structures
[196,222,366]. This technique involves two separate solutions (generally, a hydrophobic polymer and a solution of water-soluble
bioactive factors) that can be co-electrospun without the need for direct mixing using two separate syringes [367].
Hollow nanofibrous scaffolds that are fabricated by direct coaxial electrospinning and chemical vapor deposition (CVD) could be
appropriate for special applications such as hydrogen storage and nanofluidic systems [359,368,369]. During coaxial electrospinning,
nanofibers are created by the same technique with which core-shell structures are produced. However, the core material is dissolved
in an appropriate solvent at the end of electrospinning process [370]. In addition, coaxial electrospinning is useful for creating highly
porous hollow nanofiber scaffolds for applications in the fields of optoelectronics, catalysis, nanofluidics, biosensor systems, drug
delivery, and tissue engineering [371,372].
Highly porous nanofibers are more useful for a variety of applications than the hollow nanofibers [373]. They can be fabricated
with specific topology by choosing either special solvents or polymer composites. These structures can also be electrospun using a
common solvent for immiscible polymers that is later dissolved yielding perfectly porous materials [374]. This method is grounded
on phase separation, which is dependent on the evaporation rate of the solution [375]. When generating 3D fibrous structures using
common electrospinning techniques, the longer the spinning time, the thicker the fabricated mat. This can yield 3D nanofibrous
structures with variable thicknesses [376].
The 3D fibrous structures can be designed by combining a nanofiber layer with another fibrous micro- or nanolayer (known as
multilayering-electrospinning) [31,328,377,378]. Some critical scaffold parameters can be controlled during multilayered electro
spinning process including blending, fiber diameter, layer porosity, and the number of electrospun fiber layers, which are all essential
for directing cellular responses [379].
Because of some drawbacks of traditional methods (low drug-loading efficiency, poor scalability, and inefficient incorporation of
hydrophilic drugs, etc.), many studies suggest combining electrospinning with electrospraying [380,381]. Electrospraying is an
advanced version of the electrospinning process, which can potentially be useful for the creation of nanofibrous mats and nano
particles [382]. Using this method, nanofibers can be synthesized by applying a solution of polymer and drug in an adequately
conductive solvent. Because of the fact that electrospinning and electrospraying methods share similar principles in regulating their
parameters, they could be combined to design highly advanced nanofibers. Electrospinning-electrospraying is a novel method that
can be used to fabricate multilayered scaffolds, by applying layer-by-layer deposition of different mats made of various polymers
[383,384].
In addition, by combining 3D printing with electrospinning, better micro- to nano-structured scaffolds/devices and flexible
electronics/flex circuits can be synthesized for controlled delivery of therapeutic agents as well as tissue engineering applications
[385–387].
8. Concluding remarks
Using advanced biomaterials, together with more promising engineering strategies opens the routes of innovation in the field of
tissue engineering and regenerative medicine. Electrospinning is one of the most adaptable and promising techniques for producing a
range of fibrous mats [82]. It can be used in different approaches to combine the material features with various morphological
32
characteristics for advanced tissue engineering uses. Nanofibrous scaffolds produced by electrospinning are biomaterials quite sur
prisingly similar to the ECM microstructure. Several studies demonstrated that these advanced nanofibrous scaffolds improve cell
attachment, differentiation, and proliferation. Considering these features, electrospun nanofibrous scaffolds are capable of providing
a wide range of functions needed for tissue engineering and biomedical applications in the near future [388]. Some novel techniques
are tested to generate electrospun 3D fibrous structures, including multi-layering electrospinning [389], self-assembly [390], using a
3D collecting template [380], and folding or accumulating 2D fiber films [391,392]. Among these techniques, consecutive elec
trospinning or multi-layering electrospinning emerged as the simplest and the most useful technique. It allows electrospun fiber
layers to be fabricated with a defined thickness and accurate 3D constructs, on a microscale range. By controlling some key para
meters of the electrospinning process, such as the polymer solution concentration, viscosity, ambient humidity, and electrostatic
field, a prompt growth of 3D nanofibrous structures could be achieved [393]. Nevertheless, further in vitro and in vivo studies are
necessary to characterize previously fabricated micro- and nano-scale fibers in detail. In addition, as outlined in the technical tables
of this review paper, some nanofibrous scaffolds are studied extensively in vitro, and we believe that it is time to focus on their
interactions with the native tissues in vivo. Instead of generally considering designed nanofibrous scaffolds for biomedical applica
tions, scientists are about to introduce specific applications for these scaffolds by precisely adjusting system features to match the
targeted cells and/or tissues. To enhance the properties of the produced electrospun nanofibrous scaffolds, a combination of natural
and synthetic polymers with surface modification might constitute another challenge. It is clear that these advanced 3D scaffolds will
be key players in the future of tissue engineering and regenerative medicine.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgement
Maryam Rahmati was supported by a project “Promoting patient safety by a novel combination of imaging technologies for
biodegradable magnesium implants, MgSafe” funded by European Training Network within the framework of Horizon 2020 Marie
Skłodowska-Curie Action (MSCA) grant number No 811226 (www.mgsafe.eu). The authors would like to thank Dr. Payam Zarrintaj
from the School of Chemical Engineering, Oklahoma State University, USA, for kind assistance with modification of the manuscript
and discussion on the compatibility mechanisms and the functions of polymers on tissues.
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Progress in Materials Science

Electrospinning for tissue engineering applications

ARTICLE INFO ABSTRACT

2. General requirements for designing biomaterials

3. The background of electrospinning

4. Parameters affecting the electrospinning efficacy

5. Electrospun nanofibrous scaffolds for biomedical applications

5.1. Electrospun nanofibrous scaffolds for tissue engineering applications

Applied voltage ↑ Fiber diameter ↓ initially, then ↑ (not monotonic)

5.1.1. Electrospun nanofibrous scaffolds for bone tissue engineering

(continued on next page)

SF 200–400 In vitro, MC3T3-E1, ALP 13 N/A 20 22 Considerably increasing proliferation [167]

5.1.2. Electrospun nanofibrous scaffolds for cartilage tissue engineering

5.1.3. Electrospun nanofibrous scaffolds for vascular tissue engineering

5.1.4. Electrospun nanofibrous scaffolds for cardiac tissue engineering

(continued on next page)

The scaffolds improved cell entrapment,

(continued on next page)

Considerably higher histologic scores in

5.1.5. Electrospun nanofibrous scaffolds for nerve tissue engineering

(continued on next page)

Improved cell viability and attachment by

Fig. 10. A schematic representation of various characteristics of cardiac fibrous scaffolds.

5.1.6. Electrospun nanofibrous scaffolds for skin tissue engineering

5.2. Electrospun nanofibrous scaffolds for compound delivery

(continued on next page)

Collagen 75:25 nanofibers.

(continued on next page)

PLLA/COL/ aloevera/ The composite scaffold is an appropriate

6. Surface modification of nanofibrous scaffolds

6.1. Plasma treatment

6.2. Wet-chemical method

6.3. Surface graft polymerization

6.4. Co-electrospinning of surface-active agents and polymers

7. Innovative approaches to electrospinning

Declaration of Competing Interest

engineering. Compos Part B: Eng 2016.

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