Nanofibers: A current era in drug delivery system

Abstract

Nanofibers have a large area of surface variable 3D topography, porosity, and adaptable surface functions. Several researchers are researching nanofiber technology as a potential solution to the current problems in several fields. It manages cardiovascular disorders, infectious diseases, gastrointestinal tract-associated diseases, neurodegenerative diseases, pain treatment, contraception, and wound healing. The nanofibers are fabricated using various fabrication techniques, such as electrospinning, phase separation, physical Fabrication, and chemical fabrication. Depending on their intended use, nanofibers are manufactured using a variety of polymers. It comprises natural polymers, semi-synthetic polymers, synthetic polymers, metals, metal oxides, ceramics, carbon, nonporous materials, mesoporous materials, hollow structures, core-shell structures, biocomponents, and multi-component materials. Nanofiber composites are a good alternative for targeted gene delivery, protein and peptide delivery, and growth factor delivery. Thus, nanofibers have huge potential in drug delivery, which enables them to be used for various applications and can revolutionize these therapeutic areas. This review systematically studied nanofibers' history, advantages, disadvantages, types, and polymers used in nanofiber technology. Further, polymers and their types used in the preparation of nanofibers were summarised. Mainly review article focuses on the fabrication method, i.e., electrospinning and its types. Finally, the article discussed the applications and recent advancements of nanofabrication technology.

Graphical abstract

List of abbreviations

Term

Full-Form

1D

One-dimensional

TiO₂

Titanium dioxide

CNT

Carbon nanotubes

CNFs

Carbon nanofibers

PAN

Polyacrylonitrile

USFDA

US Food and Drug Administration

PVA

Polyvinyl alcohol

PVD

Physical vapor deposition

CVD

Chemical vapor deposition

HAR

High aspect ratio

PVP

Polyvinylpyrrolidone

EE

Encapsulation efficiency (EE%)

TEVG

Tissue-engineered vascular graft

PCL

Poly (caprolactone)

PLLA

Poly (l-lactic acid)

FGF

Fibroblast growth factor

NGF

Nerve growth factor

BBB

Blood-brain barrier

ICV

Intracerebroventricular

TMOs

Transition metal oxides

APCVD

Ambient pressure chemical vapor deposition

MEMS

Microelectromechanical systems

LIGA

Lithographie, Galvanoformung and Abformung

FITC

Fluorescein isothiocyanate

LPD

Luteal phase defect

ECM

Extracellular matrix

HEC

Hydroxyethylcellulose

1. Introduction

One-dimensional (1D) nanomaterials called nanofibers have become famous for various scientific and industrial uses. Nanofibers have a thousand times the smaller diameter of human hair and more excellent mechanical qualities (such as stiffness and tensile power) than any other commonly used base material. They also have a large area of surface variable 3D topography, porosity, and adaptable surface functions. Various materials can be utilized for manufacturing nanofibers, such as carbon-based, composite nanomaterials, metals, metal oxides, and natural and synthetic polymers [1]. Manufacturing and handling of nanomaterials are as shown in Fig. 1. Nanofiber at the nanoscale have two identical exterior dimensions but a third dimension that is much larger. The nanofibers are classified according to their rigidity, composition, nature, and structure [2]. Nanofiber's high aspect ratio, wound healing activity, tissue engineering, and capacity to build 3D-network architectures are used in different applications [3]. The next objectives are the enhanced control of the nanofibers' alignment during the deposition, the creation of a more complex architecture to improve cellular adhesion, the increment in the thickness of the mats, the incorporation of bacteria, multistage release matrices, overcome of the limits of electrospinning by producing multi-layers nanofibers stacked for both Drug delivery and TERM purposes.

Fig. 1.

Manufacturing and handling of nanomaterials.

Nanofiber biomedical applications are possible, including nanomedicine, wound dressings, tissue engineering scaffolds, different diagnostic instruments, in vivo models, and filters. Nanofibers can make pharmaceutical compounds from BCS classes II and IV more soluble and permeable. Due to nanofibers' more extended-release profile, high loading capacity, and high encapsulation effectiveness enhance therapeutic effects, minimize adverse effects and toxicity, and make alternative administrations easier. Nanofibers are used in tissue engineering because of their capacity to build scaffolds that are aligned and resemble the extracellular matrix. To replicate the nanoscale characteristics of human tissues, consideration must be given to the nanofibers' diameter, pore size, and orientation. Nanofibers used in medical devices and medication delivery systems serve many purposes. They are used to prevent, diagnose or treat diseases, detect, measure, restore, correct or change the body's functioning for health purposes. Adhesive bandages, dentures, more complex devices, and cardiac pacemakers are applications for nanofiber medical devices.

1.1. History

More than four centuries ago, electrospinning was used to create the first nanofibers. William Gilbert's creation (around 1600) pioneered the electrospinning technique. Gilbert's study is the first instance of a liquid being attracted electrostatically. Louis Schwabe developed some methods for spinning silk and producing synthetic fibers in 1845. Hughes and Chambers first patented for creating of carbon nanofibers in 1889. The first electrospinning machine was patented in 1902 by American inventor John Francis Cooley as an “Apparatus for electrically distributing fluids.” Rozenblum and Petryanov-Sokolov created electrospun fibers in 1938, which they then utilized to develop “Petryanov filters,” or filter materials. Radushkevich and Lukyanovich invented hollow graphitic carbon fibers 1952, and Harold L. Simons patented a machine 1966 that could create patterned fiber fabrics. By creating fibers from various polymers with sizes ranging from 50 nm to 5 m microns and a range of cross-sectional morphologies, Doshi and Reneker (1995) popularized the term “electrospinning” [1].

The electrospinning nanofiber process is preferred over other processes because nanofibers produced by these processes have a high surface area to volume ratio and a more significant number of inter/intra pores. The competition between laboratory-scale equipment has increased due to ongoing electrospinning research. With various spinning and collecting electrode accessories, the market activity was restarted. Many organizations have attempted to address low productivity by creating novel production techniques based on traditional electrospinning [4].

1.2. Advantages

• i.A high surface-to-volume ratio

Due to its nanoscale dimension, nanofiber naturally has a high surface area-to-volume ratio. The surface area to volume ratio increases as the radius of the nanofiber decreases. This quality is highly desirable in applications like sensors and affinity membranes where a large surface area is desired. Nanofiber membranes have advantages over cast film due to their enormous surface area. Where rapid drug release is desired, the greater surface area of nanofibers permits faster dissolution. The nanofiber composite with a high surface area to volume ratio can support cell attachment, proliferation, drug loading, and mass transfer processes.

• ii.Nanofibers are made using different materials and polymers. Molecular weight, solution viscosity, electrical, mechanical, thermal, electrical conductivity, charge carrier mobility, tensile modulus and tensile strength, wettability, thermal stability, and degradation are critical physicochemical properties of materials and polymers [5,6].
• iii.Nanofibers are made using different materials and polymers.
• iv.Ease of fiber functionalization: A simple polymer solution can be blended before spinning; surface functionalization can be done after spinning or utilizing core-shell electrospinning.
• v.Combining materials is easy: Different materials could be easily used for electrospinning, with low requirements for creating fibers.
• vi.Relatively low startup cost: A basic electrospinning system typically costs around $3,000 to $4,000. A setup can be self-built using store-bought parts in a lab setting.
• vii.Easy to learn the technique: Within a few weeks, with the help of a mentor and some familiarity with electrostatics and polymers, a person may grasp the fundamentals of electrospinning.
• viii.Ease of fiber deposition onto other substrates.
• ix.Electrospun fiber deposition necessitates a lower static charge on the collecting surface.
• x.Electrospun fibers are frequently deposited on metal, glass, micro-fibrous mats, and water.
• xi.A variety of nanofibrous structures have been constructed. The creation of tubular nanofibrous structures, yarns, and three-dimensional blocks of nanofibers has been made possible by electrospinning setup and modification in the procedure.
• xii.Mass production capability: There are also commercially accessible electrospinning systems for producing nanofibers in large quantities.
• xiii.Commercial applications: Several commercially accessible goods have been built using the electrospinning technique.

1.3. Disadvantages

Since the widely used electrospinning techniques have certain limitations,

• i)The challenges in achieving in situ deposition of nanofibers on different substrates,
• ii)It provides a low yield and needs a high working voltage.
• iii)Production of nanofibers with these features on a large scale remains complex. The electrospinning method is shown in Fig. 2.
• iv)Few quantities of material are deposited in terms of thickness, high electrical dispersion with high-conductive blends, and challenges with aqueous solutions and biomaterials.

Fig. 2.

Representation of the electrospinning method.

1.4. Types

Over the past 20 years, nanoscience and nanotechnology have produced numerous distinct forms of nanoparticles; nanofibers, nanorods, nanowires, and nanosheet nanomaterials. The dimensions of the nanostructure and its constituent parts are used to evaluate and categorize various nanostructured materials. This classification identifies nanofibers as 1D nanomaterials with less than 100 nm diameter. The nanofibers and nanofibrils are categorized according to their size, form, and content (for example, metals, metal oxides, ceramics, polymers, carbon, nonporous, mesoporous, hollow, core-shell, bicomponent and multi-component) [7].

1.4.1. Inorganic nanofibers

CuO, ZnO, SnO₂, BaTiO₃, and ZnS nanofibers are oxide and sulfide nanofibers, whereas TiO₂/Bi₂WO₆ and LiCl/TiO₂ nano-multicomponent nanofibers are examples of composite nanofibers. The metal nanofibers like Cu, Ni, and Ag are examples of inorganic nanofibers. Several inorganic nanofibers have been produced using electrospinning, followed by the calcination step [8]. The photocatalysis has prepared inorganic nanofibers from a few metal oxides, including TiO₂, ZnO, Fe₂O₃, SnO₂, CeO₂, and WO₃. According to the current study, using nanofibers is the most effective manner to lessen the toxicity and dangers associated with using nanoparticles in healthcare products, particularly sunscreen [9,10].

1.4.2. Carbon nanofibers

One-dimensional (1D) nanomaterials, carbon nanofibers (CNFs), are primarily carbon-based. Carbon nanotubes (CNTs) are structurally more complex systems than CNFs. Due to their characteristics, CNFs have lately undergone innovation in various sectors. The orientation of the carbon layers influences the mechanical characteristics of CNFs. CNFs are linear, sp2-based dis-continuous filaments with one double bond and two single bonds with an aspect ratio of more than 100. Recent studies showed that most carbon nanofibers' layers of graphitic planes are typically not aligned along the fiber's axis [11,12]. Ideally, carbon nanotubes are cylinder-shaped nanofibers coated with layers of graphene. Carbon nanofibers that have been electrospun or vapor-grown are cylindrical nanostructures with stacked graphene layers that have the forms of cones, cups, or plates [13]. Carbon nanofibers (CNFs) have been an exciting area of research due to important characteristics like high electrical conductivity, excellent mechanical strength and promising morphological properties [14]. The significant surface area can adsorb different sensing and therapeutic agents in diagnosis and therapy [12].

1.4.3. Polymer-based based nanofibers

Polymer-based fibers are used in different areas, such as garments, fishing nets, cigarette filters, air conditioner filters, surgical masks, heart valves, and vascular grafts. Typically, micro-sized fibers manufactured of various polymers are used in these applications. Electrospinning has produced ultrafine fibers from more than 50 polymers ranging from 3 nm to 1 m in diameter. Nanofibers with various forms and structural traits were produced by enhancing the spinneret design and collecting system. Many polymer nanofiber morphologies, like flat, branching, split, and ribbon nanofibers, have been reported in the literature [15]. It is necessary to conduct polymer melt electrospinning in a vacuum. The metal-collecting screen and the capillary tube must be enclosed in a vacuum. Due to the requirement for highly complicated and advanced device technology, melt spun a few industries are only exploring split nanofibers. The most popular organic fibers are nanofibers made of polyacrylonitrile (PAN). The catalytic fiber's degradation function is good when polyacrylonitrile nanofibers are used as carriers. PAN nanofibers are also used to make electrodes, antifungal medications, and adsorbent materials [16].

1.4.4. Composite nanofibers

Multiple phases of various chemical structures or components are commonly used to formulate composite nanofibers. The characteristics of composite nanofibers are a large surface area, small pore size, resistance to high temperatures, exceptional conductivity, and high cycle stability. This type of nanofibers has been used in numerous fields because of their improved physical and chemical characteristics.

The desired material is produced by thermally or chemically processing composite nanofiber mats. By electrospinning nanoparticle-containing polymer solutions, composite nanofibers can be made. Composite nanofibers are produced using polymer template processes. Composite nanofibers are produced using polymer template processes. Composite nanofibers have been created using polymer template techniques. The dis-advantages of this technology include the prolonged processing time and the inability to control the amount of substance absorbed into the fibers.

2. Role of polymers in nanofiber technology

Nanofibers can be spun from natural, synthetic polymers, polymer blends and other composite materials. Polymer selection is crucial to prepare nanofibers with properties particular to a specific application. The optimal polymer for biomedical applications should be suitable for mechanical strength, biodegradability, safety, and mild hydrophilicity. The origin of the polymers used in the Fabrication of nanofibers can range from natural to synthetic polymers [17], each of which has a unique set of benefits and drawbacks. The adequate preparation and use of polyblend nanofibers in regenerative medicine (as tissue engineering scaffolds, wound dressings, and vascular grafts) resulted in long, spaghetti-like masses of thin polymeric mixes. It is also employed for the local delivery and release of biological agents (such as proteins and nucleic acids) and small-molecules. These nanofibers are made from various combinations of polymer components to control the mechanical and biological properties of fibers. These structures have high surface area-to-mass ratios, which result in nanofibrous mats with high pore volumes and varied pore diameters. As a result, nanofiber scaffolds are given significant mechanical characteristics while still being extremely low-density [18]. The most popular types of polymers used in biomedical applications are categorized in Table 1.

Table 1.

Polymers used in various nanofiber.

Type of Polymer	Example	Encapsulated Drug (s)	Solvent	Manufacturing Technique	Reference
Natural Polymers	Collagen	N-acetylcysteine •	Hexafluoroisopropanol (HFIP)	Dissolution process Electrospinning (Physical)	[19]
	Gelatin	–	Acetic acid	Electrospinning (Physical)	[19]
	Hyaluronic acid (HA)	Naproxen	–	Electrospinning Cross-linking Freeze drying (Physical/Chemical/Mechanical)	[19]
	Alginic acid	Moxifloxacin HCl	–	Dissolution process Cross-linking Electrospinning (Physical)	[19]
	Chitosan	Ampicillin sodium	Trifluoroacetic acid (TFA)	Electrospinning Cross-linking via Glutaraldehyde (Physical)	[19] [19] [19]
		Curcumin		Electrospinning (Physical)
		Ascorbic acid		Coaxial and monolithic Electrospinning (Physical)
	Silk fibroin	Curcumin	Formic acid	Electrospinning (Physical)	[20]
		Doxorubicin hydrochloride
Semi-synthetic polymer	Cellulose nitrate	Diclofenac sodium	Water	Chemical crosslinking (Chemical)	[21]
		Penicillamine-D
		Phosphomycin
Synthetic Polymers	Polyethylene oxide (PEO)	Teicoplanin	Water	Electrospinning (Physical)	[22]
		Doxorubicin hydrochloride
	Polyimide (PI)		N, N-dimethylace tamide (DMAC)	Electrospinning (Physical)	[22]
	Polyurethane (PU)	Donepezil hydrochloride	N, N-dimethylformamide	Electrospinning (Physical)	[23]
	Poly(3-hydroxybutyric acid-co-3-hydroxy valeric acid) (PHBV)	Metformin hydrochloride	Water	Electrospinning (Physical)	[23] [24]
		Metoprolol tartrate
	Nylon-6	5,5-Dimethyl hydantoin	Water	Modified Electrospinning (Mechanical)	[25]
	Polyacrylonitrile (PAN)	Diclofenac sodium	N, N-Dimethylformamide (DMF)	Electrospinning (Physical)	[26]
	Polyvinyl pyrrolidone (PVP)	Donepezil hydrochloride	N, N-dimethylformamide	Electrospinning (Physical)	[23]
	Polyvinyl alcohol (PVA)	Ofloxacin	Water	Chemical crosslinking (Chemical)	[27]
	Polylactic acid (PLA)	Paclitaxel	1,1,1,3,3,3-hexafluoro-2-propanol	UV-induced grafting method (Mechanical)	[28]
	Poly (ε-caprolactone) (PCL)	Simvastatin	Tetrahydro furan (THF)	Electrospinning (Physical)	[29]
		5-Fluorouracil	Chloroform		[30]
		Methotrexate	Chloroform		[29]
	Poly (D, l-lactide-co-glycolide (PLGA)	Amphotericin B	2,2,2 Trifluoroethanol	Electrospinning (Physical)	[31]
	Polyethylene glycol (PEG)	Simvastatin	THF	Electrospinning (Physical)	[29]

2.1. Polymers

The polymers used in nanofiber technology are proteins, cellulose, and silk, which are present in nature, many others, like nylon, polystyrene, and polyethylene, can only be made synthetically. Polymers with high extension characteristics under ambient conditions frequently produce elastomers.

Natural fibers like cotton, wool, and silk can be effectively replaced with synthetic fibers, namely nylon and polyester. Commercially available plastic resins can have two or more polymers and a range of fillers and additives. These enhance processability, thermal or environmental stability, and mechanical properties [32].

2.1.1. Types of polymers

2.1.1.1. Natural

Nanofibers made using natural and synthetic polymers can be explored for transdermal drug delivery. Due to the excellent properties of natural polymers, like biodegradability, biocompatibility, and low toxicity, natural polymers are preferred compared to synthetic polymers-based nanofibers. Polysaccharides and proteins are the most frequently used natural polymers to prepare nanofibers using electrospinning [19].

Electrospun polysaccharides containing cellulose, alginate, and chitosan derivatives can be made into nanofibers and employed as a delivery mechanism. d-glucose amine and N-acetyl-d-glucose amine are linear co-polymers that combine to form chitosan. Cellulose is a polymer in plant cell walls, despite having a porous structure and being extremely strong and stiff mechanically. By combining polyvinyl alcohol (PVA), and cellulose acetate, hybrid electrospun nanofibers were produced to encapsulate the fungus that offered the removal of water tainted with aflatoxin B2 [33].

In the medical device sector, hyaluronic acid (HA) and its derivatives are frequently employed in implant materials, drug delivery systems, and tissue engineering scaffolds due to their outstanding biocompatibility and biodegradability. A thiolated-HA derivative (for instance, 3,3′-dithiobis (propanoic dihydrazide)-modified hyaluronic acid; HADTPH) were created and electrospun to create nanofibrous matrices, which were then used to replicate the structure of the natural extracellular matrices. There may be applications for HA-DTPH nanofibrous matrices in cell encapsulation and tissue regeneration, given that NIH 3 T3 fibroblasts adhered to the matrix and distributed throughout it with an enlarged dendritic architecture [34].

Noorani et al. formulated a chitosan and gelatin-containing nanofibrous scaffold having a mean diameter of 180 nm. They showed that adding gelatin improved chitosan's hydrophilicity and breakdown with lessened mechanical properties. The lower tensile strength and Young's modulus were observed for samples with higher gelatin amounts. The scaffold comprising gelatin/chitosan (50/50) showed the highest tensile strength 6.93 + 0.63 MPa, and the 30% chitosan-containing scaffold showed 3.51 ± 0.45 (p < 0.05) tensile strength. The nanofibers prepared using gelatin/chitosan in 70/30 and 50/50 ratios indicated Young's modulus of 1.05 and 2.24 mPa, respectively. Thus, scaffolds with excellent biological and mechanical characteristics were developed by adding gelatin to chitosan [35].

2.1.1.2. Semi-synthetic

Natural polymers retrieved in their valuable forms through chemical procedures are known as semi-synthetic polymers. Cellulose, a natural polymer, is the starting point for semi-synthetic polymers. Thermoplastic polymers are another name for semi-synthetic polymers. The method of making cellulose is known as acetylation; acetic anhydride and sulfuric acid are used to prepare cellulose diacetate. Typically, this material is used to develop thread-like film spectacles. Examples of semi-synthetic polymers include gun cotton and cellulose nitrate etc. [36].

Fawalet al. prepared a PVA/Hydroxyethylcellulose (HEC) scaffold comprising fluorescein isothiocyanate (FITC) encapsulated ethosomes for transdermal use. The transdermal permeability and release study of FITC encapsulated ethosomes was studied by the Franz diffusion method and FITC-eluting technique. The study results showed a burst release in the first 12 h and 33.2%, 39.5%, and 43.5% release for 5, 10 and 15 μg/ml of FITC encapsulated ethosomes, which was more (26.5%) than the control group. The results also indicated increased mobility and deformability of the ethosomes via rat skin due to ethanol. The FITC passage via the skin cells is direct diffusion through the cytomembrane because of lipids in ethosomes structure. It results in membrane fusion during endocytosis, aiding the cellular uptake of the drug-encapsulated ethosomes [[37], [38], [39], [40], [41]].

2.1.1.3. Synthetic

Synthetic polymers comprise most materials used to create nanofibers with biological components. The most common synthetic polymers used to create nanofibers are PEO, PVA, PCL and its co-polymers, polyvinylpyrrolidone, and polylactic acid. These have received US Food and Drug Administration (USFDA) approval for use as tissue engineering scaffolds or drug delivery systems. These polymers can be mixed with other synthetic and natural polymers or utilized independently. Hydrophilic, biocompatible, and non-toxic polymer polyethylene oxide is commonly used in tissue engineering and drug delivery. Polyvinylpyrrolidone, polycaprolactone, and polylactic acid comprise most nanofiber compositions. Additionally, using methylmethacrylate and methacrylic acid polymers, nanofibers have been electrospun. Fig. 3 shows polymers used in nanofiber technology [42].

Fig. 3.

Polymers used in nanofiber technology.

Fu et al. used an extracellular matrix to optimize the surface characteristics of poly (l-lactic acid) (PLLA) nanofibers. Initially, MC3T3-E1 cells were cultured and permitted to grow on nanofibers prepared by electrospinning to deposit extra cellular matrix. Cellular components were eliminated by decellularization after 14 days. Cell adhesion and osteogenic differentiation of cells were significantly enhanced than PLLA nanofibers without extracellular matrix [43].

3. Fabrication methods of nanofibers

Even though there are several techniques for creating nanofibers, including phase separation, self-assembly, and others, very few can successfully produce nanofibrous structures for systemic gene transport and inclusion phenomena. An effective delivery system based on nanofiber composites for targeted gene delivery is developed using electrospinning and coaxial electrospinning. In addition to providing experimental examples, the following sections briefly describe some of these methods [44].

3.1. Electrospinning

Electrospinning is the process used most frequently to fabricate nanofibers. It is possible to trace the development of electrospinning as a practical method for creating nanofibers with a formula 1934 patent upon making artificial suits utilizing a strong electric field.

The research was based on how the electrostatic force affects liquids. A cone-shaped, electrically charged item forms when it gets close to a liquid droplet in a tiny capillary. When the charge density gets very high, tiny jets can be produced from the cone's tip.

During electrospinning, the fibers were deposited on a grounded collector. After deposition, the charge on the fibers is quickly dissipated through the ground collector. Due to the low conductivity of the solution, a measurable amount of residual charge remains on the surface of the collected fibers [45]. According to the process for making the polymer, the electrospinning technique is classified into solution and melt electrospinning [46]. Electrospinning is the most widely used technology because it is easy, repeatable, economical, and scalable. The high gene loading and a sustained release distribution throughout extended periods are made possible by the massive, linked, porous network that electrospun fibers form. Both natural (such as zein and collagen) and synthetic polymers (including polycaprolactone (PCL) and poly (lactide-co-glycolide) (PLGA)) have been utilized successfully for gene transfection [47].

The factors affecting the characteristics of nanofibers are divided into three groups: process parameters, material parameters and environmental parameters such as temperature and humidity. High voltage, flow rate, and the distance from the Taylor cone to the collector are process variables that impact the nanofibers' morphology. The material attributes include molecular weight, polymer concentration, surface tension, conductivity, and solvent volatility. The polymer impacts the electrospinning liquid's charges. Electrospinning cannot dissolve the very low conductivity polymer because there is no charge on the liquid droplet's surface for the electric field to act on. The utilized polymer's concentration and molecular weight affect the polymer solution's viscosity. The liquid's viscosity get enhanced due to higher molecular weight and concentration [48,49].

The size of the droplet generated and the force the crack needs to drive the melt out depend on the amount of polymer melt escaping, which is indicated by the nozzle. If the nozzle is too small, the polymer solution will be too viscous, and the melt cannot be pushed out. Therefore, different nozzle types should be used [50]. The different nozzles used in electrospinning are shown in Fig. 4. An essential component of electrospinning is the surface tension, which depends on the solvent composition of the solution. The different solution shows different surface tension. Pearl fibers can become smooth fibers because the surface tension of the solution was lowered by the concentration of fixed [50]. Solvents play a crucial role in determining the mechanical properties of the nanofibers. Two important considerations are the solvent's boiling point and the solubility of the polymer in the solvent. Nanofiber mats' mechanical strength can be increased with solvent vapor treatment without appreciably altering the membrane's morphology or dimensions [51]. The nanofiber collector in electrospinning is electrically grounded, showing the stable potential difference between the source and the collector. Variability of collectors are available for electrospinning, e.g., different diameter rotating drugs, parallel electrodes, rotating wire drum collector, rotating tube collector with knife-edge electrodes, disk collector, arrangement of counter electrodes, rotating drum with sharp pin inside, and placed ring collector parallel to. The homogeneity of the deposit is an essential issue for the productivity of technical electrospinning. The homogeneity of electrospinning depends mainly on the electrospinning setup and the choice of dope and substrate. The modified electrode design significantly improves the homogeneity [52]. The post-spinning modification not only changes the properties of the nanofiber but also improves the mechanical properties of the nanofiber. Post-spinning modification is vital for controlling processing parameters and precursor quality. The post-spinning modification can help decrease the activation energy of cyclization, reduce the stabilization exotherm, increase the speed of the cyclization reaction, improve the alignment of molecular chains in the nanofibers, and decrease sheath-core formation in stabilized nanofibers [53].

Fig. 4.

Different types of nozzles used in electrospinning.

3.1.1. Coaxial electrospinning

Coaxial electrospinning is primarily used to produce nanofibers with a core-sheath structure. Using this method, one can create nanofibers with drugs embedded in their cores, resulting in sustained and controlled drug release. These kinds of nanofibers have a three-dimensional network and a sizable surface area. Coaxial nanofibers for drug delivery have been effectively integrated with proteins, growth hormones, anti-biotics, and other biological agents. The core-shell structure of the loaded molecule is protected by this method with maintaining the biological activities of the pharmaceuticals. When the biomolecule is inside the jet during the electrospinning process, its functionality is increased, and the polymer solution is outside the jet, protecting the biomolecule. This is one of the essential benefits of coaxial electrospinning. In this method, the polymer shell aids in preventing direct contact between the biomolecule and the outside world. The core-shell approach maintains unstable biological agents' ability and prolongs g drug release [54].

Due to the distinctive architecture of coaxial electrospun nanofibers, coaxial electrospinning is an improved electrospinning method for manufacturing composite nanofibers for effective gene delivery. This approach produces multilayer structures, such as nuclear (internal) and envelope (external) structures, which enable many genes to be delivered under controlled conditions, thus increasing the genes' bioactivity. Coaxial electrospun nanofibers protect the encapsulated gene from adverse core/shell structure circumstances. Developing tissue-engineered frameworks enabling gene delivery that are excellent at extending and pinpointing cellular viral transduction during the past two decades has been an intriguing strategy for preventing unchecked systemic viral transmission. To transduce viral genes into RAW 264.7 cells, an in vitro method utilizing the coaxial PCL/PEG nanofiber [55].

3.1.2. Multi-jet electrospinning

Multi-nozzle electrospinning systems were designed for manufacturing large nanofibers to boost output and coverage. Multi-needle electrospinning has reportedly been utilized to develop skin-core structures. It comprised two steps for creating nanofiber filaments: spinning and drawing together. When the auxiliary electrode was inserted during the formation of spun nanofiber filaments, the electrostatic field interference between needles decreased, leading to either a reduction in beam offsets or an enhancement in Taylor cone and beam stability. An electrospinning apparatus with several or fewer nozzles can produce electrospun nanofiber jets [56]. Using a multiJet electrospinning apparatus, multicomponent polymers can be electrospun to create an amalgamation of nanofiber mats with a consistent thickness and sufficient dispersibility. Using this method, it is also possible to create mixed nanofiber mats that comprise multipolymers. CNR-ISMAC has created an electrospinning system with many nozzles that are bottom-up. It has a 50 cm wide metal collector with 31 to 62 nozzles. The configurations created overlapping deposition zones to achieve a uniform deposition of nanofibers on the collector [57].

3.1.3. Emulsion electrospinning

Emulsion electrospinning is a quick, cost-effective and potential method for fabricating electrospun core-shell nanofibers. It is a versatile and prospective technology for encapsulating diverse pharmaceuticals in nanofibers. Metformin hydrochloride (MH) or metoprolol tartrate (MPT) were added to the fibers of poly (ϵ-caprolactone) (PCL) and poly (3-hydroxybutyric-co-3-hydroxy valeric acid) (PHBV) using emulsion electrospinning. Emulsion electrospinning was a more effective method in this study than mixed electrospinning, particularly for modifying the pace at which drugs are released by controlling the water and oil phases of the emulsions to achieve the desired drug release. PCL demonstrated superior drug transport capabilities compared to PHBV [58]. The biomolecule-laden stage can be disseminated throughout the fiber for low molecular-weight drugs. A core-shell fibrous architecture may be formed if macromolecules combine with an aqueous phase [59].

3.1.4. Bubble electrospinning

A revolutionary technique called bubble electrospinning has just been included in the family of highly sophisticated electrospinning techniques. Electrospinning uses electrical forces to break the surface tension of the resultant bubbles. With moving air, these bubbles develop on the polymer solution's surface. Taylor cones are created by electrical forces, which are used to create fibers. The shape and size of the bubble impact the surface tension [60]. The surface tension of vesicles can be described using the following equation (1).

$$\text{Young}-\text{Laplace}\text{equation}:=1/4\text{rP}$$ 1

Where, P-Pressure difference,

• r-Vesicle's radius

There are several challenges involved in the electrospinning process. On the solution's surface, the formation of a bubble takes place. Nevertheless, this phenomenon is unaffected by the characteristics like morphology or profitability of the process used to produce industrial fibers [61]. Nanofibers having a diameter of 100 nm are created using aqueous solvent bubble electrospinning. Eco-friendly nanofibers have a minimum diameter of only 46.8 nm and are produced using polyvinyl alcohol (PVA) and water as the solvent [62].

3.1.5. Roller electrospinning

A needleless electrospinning device developed by Jirsak et al. known as a nano spider, is sold by Elmarco Co. (Czech Republic). It uses rollers and cylinders for the preparation of fiber. The roller electrospinning apparatus has a rotating cylinder electrode partially submerged in a reservoir of polymer solution [63]. The polymer solution is put onto the top roll surface as the roll turns slowly. The electrospinning method produces several jets of solution from the surface of the revolving spinning electrode simultaneously whenever a high voltage is applied, thus increasing fiber productivity [64]. In needle and roller electrospinning, the effect of polyvinyl butyral solution concentration on process efficiency and fiber characteristics was examined. In roller electrospinning, polymer throughput would be a dependent parameter controlled through both the material and process factors, but in needle electrospinning, it becomes an optionally independent parameter [65]. In both methods, increasing concentration results in larger fiber diameters. Unlike roller electrospinning, needle electrospinning produces fibers with lower diameters [66].

3.1.6. Electrospinning by a porous hollow tube

In this technology, an electrospinning process is made more effective using a porous wall tube. Beads are created as an outer layer by pushing the polymer solution through the pores of a cylindrical tube with a thick wall. Applying air pressure to the top of the tube makes the polymer solution sufficiently pressurized to force the polymer to flow through the drilled holes. Each hole in the solution produces a jet upon charging; these jets escape from the droplets to form several electrospun threads [44]. Although this technology stands out for its high productivity, it suffers from complicated equipment design drawbacks [67].

Varabhas et al. created a porous hollow polytetrafluoroethylene tube to make electrospinning nozzles. The pores on the tube wall have an average diameter of 2040 mm. The wall has holes that have been partially drilled, and the bottom of the tube is lined up with its horizontal axis. The holes are 1.0 mm deep and 0.5 mm in diameter [68].

3.1.7. Melt blowing

When a polymer melt is extruded via tiny nozzles surrounded by fast-moving gas, the output is typically 2-m diameter microfibers. On the other hand, individual sub microfibers/nanofibers were created employing an idealized of an estimated average jet. Similarly, electrospinning can be scaled up by adding more nozzles; melt blowing may be scaled up by adding nozzles to reduce costs. However, melt-blown fibers are arbitrarily arranged into nonwoven layers, in contrast to electrospinning, which might result in aligned fibers. The Laval spinning procedure, an offshoot of the melt-blowing method, uses airflow to extract fiber from the nozzle. However, the air is accelerated by the geometry of stretched Laval die, which makes the procedure more effective than conventional melt blowing. A cold air flow also replaces the hot air flow of the traditional approach. The nozzle is entered from behind by the laminar airflow. The airflow and fiber are accelerated to supersonic speeds by the nozzle's narrowing right behind the polymer entering channel. The essential advantage over traditional melt-blown is the possibility of a substantially bigger nozzle diameter, which allows whirling with a relatively high throughput per nozzle [69].

3.2. Physical fabrication techniques

The manufacturing of nanofibers has been researched using a variety of physical, chemical, and biological procedures, such as milling, physical vapor deposition (PVD), laser ablation, and spin fabrication methods. In addition, mechanical processing, refining cellulosic-based materials like wood or tunicates, produces parts with 50 nm to 3 m with 5–50 nm diameters.

3.2.1. Physical vapor deposition (PVD) techniques

Vapor or bottom gas phase deposition are the two most used processes for producing carbon and metal oxide nanoparticles. Recently, vapor-phase deposition methods, including chemical vapor deposition (CVD) and PVD, have been used to build highly structured metal oxide and carbon nanofibers.

• i)The two most popular PVD techniques are plasma sputtering and electron beam evaporation.
• ii)Plasma sputtering involves bombarding the material with electrons to heat and create a vapor that can be used to deposit nanofibers.
• iii)Vacuum arc deposition, in which the arc vaporizes the target material in a vacuum before re-depositing it to produce nanofibers;
• (iv)Pulsed laser deposition involves the formation of nanofibers on a solid substrate following high-power laser ablation of the material. Recently, the possibility of creating polymeric materials with nanostructures resembling fibers has been investigated using PVD [70]. Typically, CVD is used to create carbon nanofibers. Carbon nanofibers are produced by mixing a carbon feed (such as CO or a hydrocarbon gas) with catalyst particles of transition metals like Fe, Ni, Co, Pt, and Cu at temperatures between 500 and 1200 °C.

Nanofibers are used as a template in atomic layer deposition, where materials are deposited before removal. The stencil can only be partially removed without harming the fibrous structure. Among the most conforming deposition methods at low temperatures is atomic layer deposition (ALD). Several materials have been utilized as nanostructured growth templates for ALD. The most often documented are polymer nanofibers, employed frequently to synthesize oxide nanotubes [71].

3.2.2. Laser ablation method

Venkatakrishnan et al. directly ablated silica glass that used a femtosecond laser with a repetition rate of 12.4 MHz and a pulse width of 214 fs; this produces densely packed and randomly oriented silica nanofibers. Nanofibers come in four shapes and diameters, from tens to hundreds of nanometres. This study offers a straightforward, one-step method for producing densely fused silica nanofibers with interwoven, randomly oriented architectures with little sample preparation and quick processing time. Densely packed fibers ranging from millimeters in length and 10 nm to several hundred nanometres thick were created by applying a femtosecond laser towards the surface of quartz glass. Pulsed laser ablation of the dielectric sample indicates that nanosecond and microsecond lasers can create fibers as 150 nm as small and 100 m as large [72]. Deniz et al. formulated PVP nanofibers incorporating gold nanoparticles using laser ablation and electrospinning methods. The laser ablation approach provides some benefits over chemical and thermal procedures, including low cost, variability, a clean process, and rapid and broad applicability for developing a variety of NPs [73].

3.2.3. Mechanical fabrication techniques

For synthesizing CNF from natural materials like pulp, physical manufacturing procedures (top-down approaches) like grinding, ball milling, cryo crushing, and high-pressure homogenization are frequently used. By altering the milling media, speed, material, milling state (dry or wet), duration, and energy transfer between the milling media and material, it is possible to control the size and shape of nanofibers [1]. Additionally, the CNFs made have particularly poor mechanical properties due to their low crystallinity, aspect ratio, and degree of polymerization. To solve these issues before the mechanical process, chemical treatments such as acid hydrolysis, alkaline acid pre-treatment, and oxidation pre-treatment are used. These modifications lower energy requirements, promote bulk material breakdown and boost nanofibril yields [74].

3.3. Chemical fabrication technique

Nanofibers' most popular wet chemical fabrication methods are hydrothermal synthesis, electrochemical deposition, sol-gel processes, phase separation, polyol synthesis, and microemulsion. Metallic nanofibers like polycarbonate and anodic alumina membranes are typically produced through electrochemical deposition with hard porous templates. Once more, the requirement to remove the template without damaging the fibrous structure is a crucial constraint. For the Fabrication of nanofibers, soft templates like polymers and surfactants have been combined with electrodeposition methods. For illustration, Nam et al. used an aqueous solution of Triton X100 to create Sn nanofibers using cathodic electrodeposition. Electrochemical techniques can create nanotubes with a diameter of 100 nm and a length of several micrometers from metal and metal oxide surfaces [75].

3.3.1. Chemical vapor deposition (CVD)

In the flexible chemical vapor deposition (CVD) process, reactive gas-phase molecules are broken into film or particle-growing reactive species. The CVD technique can deposit various conductors, semiconductors, and insulators. Controlled manufacturing of nanomaterials in porous hosts, such as zeolite nanochannels, has been a recent focus of the CVD technique. One of the benefits of CVD procedures is the capacity to consistently establish thin films of material, also on irregular shapes [76]. Catalytic chemical vapor deposition is of interest in improving the commercial synthesis of carbon nanofibers [77]. Wang et al. used a simple electrospinning technique to create a MnO/carbon nanofiber (MnO/CNFs@G) membrane, which was then subjected to an ambient pressure chemical vapor deposition (APCVD) procedure [78].

3.3.2. Template-assisted synthesis

The templated method is a cutting-edge bottom-up method for creating highly crystalline mesoporous transition metal oxides (TMOs). Hard-template, soft-template, and template-assisted synthetic approaches can be broadly categorized, with colloidal templates emerging as a vital component of the synthetic approach. Soft templates such as surfactants, block polymers, or flexible organic molecules. Complex templates are mainly made of inorganic materials, with silica being the most significant. Soft matrices are chosen over complex matrices because they are less expensive and easier to synthesize rapidly for template removal processes [79]. According to Deeney et al. many beverage-related precursors react with nitrogen-rich polyethyleneimine to produce luminous carbon nanofibers (CNFs) with the help of microwave heating. Under moderate temperature conditions (250–260 °C) and a quick reaction time (6 min), strong luminous resilient carbon fibers with a length of 10–30 m and a diameter of 200 nm were produced. The fibers with a high aspect ratio exhibited wavelength-dependent emission that is simple to observe using epifluorescence. There are several possible applications for fabricating these multi-emissive one-dimensional (1D) carbon nanomaterials [80].

3.4. Electrochemical deposition method

Although it is seldom used in the wet-chemical technique, electrochemical deposition is an effective way to create metal nanoparticles. This method has numerous benefits, especially regarding short synthesis periods, lack of chemical reductants or oxidants, and undesired by-products. However, it occasionally has certain restrictions regarding nanomaterial dimensions and permitted morphologies. Additionally, improved adhesion is possible when the modifier layer is directly put on the electrode [81]. Many micro-scale metal devices with intricate geometries were created in the early stages of microelectromechanical systems (MEMS) research by electroplating metals onto a thick PMMA mold that had been formed using the Lithographie, Galvanoformung and Abformung (LIGA) (lithography, electroforming, molding) technique [82].

3.5. Hydrothermal method

To create nanofibers, chemical reactions must occur in water under various pressures and temperatures (ranging from ambient to exceptionally high). SrTiO₃/TiO₂ nanofibers were created by Cao et al. utilizing easy in situ hydrothermal processes. Cao et al. reported a single-step hydrothermal process for efficiently fabricating WO₃ nanofibers with specific dimensions (diameter: 100 nm; length 10 μm). The main advantages of hydrothermal methods are the more moderate reaction conditions and the excellent crystallization of the generated material [83]. Simpraditpan et al. developed titanate nanofibers by hydrothermal processing using a naturally occurring mineral (ilmenite) as the initial raw material [84].

3.6. Sonochemical synthesis

By substituting ultrasonic irradiation for mechanical stirring, Jing et al. developed polyaniline nanofibers with dimensions as small as 50 nm and lengths ranging from 200 nm to several microns [85]. Intense ultrasonic irradiation is used for the chemical reaction of molecules during sonochemical synthesis. Using this technique, the molecules are heated to high pressures, resulting in a range of nanostructured materials example, polyaniline nanofibers [86].

3.7. Microwave synthesis

A quick and easy way to create carbon nanofiber coatings on various substrates is microwave synthesis of CNFs. With this method, CNF development can frequently begin shortly after microwave irradiation, leading to processing periods of under a minute and minimum environmental heating. It is crucial to comprehend the processes and pinpoint crucial parameters to regulate and optimize these rapid synthesis processes [87]. Active TiO₂ nanoparticles are created by microwave synthesis and modified with platinum by Drunka et al. Raw materials used in this study included 10 M KOH solution and anatase nanopowder. TiO₂ nanofibers and nanowires with a 10 nm diameter but a defined surface area within 70–150 m²/g can be created using microwave-assisted synthesis [88,89].

The electrospinning nanofiber process is preferred over other processes because nanofibers produced by these processes have a high surface area to volume ratio and a more significant number of inter/intra pores. The level of competitiveness amongst scalability devices in laboratories has increased as a result of ongoing research in the field of electrospinning. The market movement was revived with various spinning and collecting electrode devices and accessories. There is a large selection of scalable laboratory equipment in the market. Many companies have attempted to address low productivity by creating novel production techniques based on traditional electrospinning [4].

4. Applications of nanofibers

Nanofibers offer a significant benefit for administering pharmaceutical substances with numerous biomedical uses. Recent developments in nanotechnology could make it simple to produce nanofibers with different shapes and release characteristics [90]. Among the most potential biological applications are those related to tissue engineering, cardiovascular disorders, infectious diseases, GIT-associated diseases, neurodegenerative diseases, pain management, contraception, dentistry, and other biological conditions [6].

4.1. Cardiovascular diseases

A WHO report states cardiovascular disease is the leading cause of mortality worldwide. According to forecasts, around 17.9 million deaths worldwide are anticipated in 2019, accounting for 32% of all fatalities. Heart attack and stroke mortality accounted for 85% of these deaths [91]. Electrospinning has been used to fabricate nanofiber scaffolds for cardiac ventricular tissue engineering applications using a variety of synthetic and natural biomaterials [92]. A new era of immune-suppressed tissue regeneration has arrived thanks to nanofiber scaffolds harboring stem cells. Nanofibers have undergone several modifications, including coaxial electrospinning, layer-by-layer production, and a phase separation technique to increase their efficiency as stem cell transporters. The ability of nanofibers containing stem cells to cure cardiovascular diseases like atherosclerosis and cardiomyocyte regeneration has also been demonstrated [93].

4.2. Drug delivery

Because of the numerous distinctive feature and parameters of the porous nanostructure include high encapsulation efficiency (EE%), high drug loading, improved therapeutic index, markedly reduced side effects, potential to integrate drug release, and control over the solution and processing conditions. Hence the biomedical application of nanofiber in drug delivery systems is expanding rapidly. Electrospun fiber's properties include composition, swelling, diameter, porosity, form, geometry, and thickness, affecting drug release. A combination of drug solubility, polymer breakdown, drug partitioning in polymers, and diffusion is believed to be responsible for drug release from fibers [94].

4.3. Bone regeneration

In bone tissue engineering, biomaterials and cells are combined to produce biosynthetic bone grafts that effectively mineralize the healing of broken or damaged bones. The bone matrix's aligned collagen and hydroxyapatite components give bone stiffness, strength, and toughness. The electrospinning technique's versatility has prompted researchers to look into other ways to build bone healing and repair scaffolds. The optimum substance must be bioactive and biocompatible to stimulate osteogenesis and lead to bone regeneration. Several researchers from the medical field have used electrospun scaffolds to create bone grafts, speeding up bone regeneration by including bioactive chemicals that help osteoblasts proliferate and mineralize [95]. A biocompatible, biodegradable scaffold with appropriate mechanical characteristics for the bone environment should be used for bone tissue engineering. To address these objectives, silver nanoparticles, transforming growth factor-3 (TGF-3), bone morphogenetic proteins (BMP), and VEGF are added to nanofibers [96].

4.4. Wound healing

Skin trauma from exogenous laceration results in a wound. Compared to chronic wounds, which take longer to heal and are thus more prone to bacterial infection, acute wounds recover more quickly. Hemostasis, inflammation, proliferation, and remodeling are the four stages of wound healing. Researchers studying skin tissue engineering have recently become interested in drug-loaded nanofiber scaffolds due to their flexibility, drug release effectiveness, and biocompatibility, allowing damaged tissue regeneration [97]. To create drug-loaded nanofiber scaffolds, many nanofibers manufacturing processes, including melt blowing, rotary jet spinning, hand spinning, pressured gyration, and electrospinning, have been developed. The previous strategy for treating wounds was therapeutic. Drugs are mixed with polymers and spun into nanofibers, enabling more efficient drug release than conventional therapy. Nanofibers have a high level of resistance to germs until these drugs were chosen for their qualities, such as anti-biotic, anti-bacterial, and anti-inflammatory. Some even trigger healing events such as vasodilation [98].

Collagen electrospun nanofiber scaffolds are the most biomimetic substitute for skin because they encourage cell development and penetration into the constructed matrix. Hybrid poly scaffolds or mixed poly nanofibers prevent the “fishnet effect” compared to electrospun scaffolds of single polymers. Chitosan-graft-poly electrospun nanofibrous mats have special cell attachment and proliferation capabilities, making them a suitable replacement for skin tissue engineering [99].

4.5. Contraceptives

Recently, nanofibers have become a viable option for systemic and loco-regional drug delivery. In recent years, many researchers have shown a strong interest in developing vaginal nanofibers for diseases like cancer and infection [100]. Pharmaceutical drugs are frequently applied to the human vaginal area as pills, capsules, lotions, creams, ointments, rings, films, foams etc., for local and systemic effects. Most medications for use in the vaginal area have been utilized to treat diseases that are directly related to women's reproductive and sexual health. The most typical applications for hormonal contraception include the treatment of vaginal infections (using different azole as antifungals), cervical ripening to facilitate labor (using dinoprostone or misoprostol), bacterial vaginosis (using metronidazole or clindamycin), luteal phase defect (LPD), and bacterial vaginosis (progesterone) [101]. In recent years, nanofiber platforms have been used successfully to deliver drugs directly through the vaginal mucosa to prevent sexually transmitted diseases (STDs) and as a contraceptive for unintended pregnancy. The nanofiber mats may be shaped into specific shapes for the best implantation since they are flexible and free of sharp edges. Compared to intravenous cisplatin injection, treatment with nanofiber mats dramatically decreased the size of the excised cervical tumors.

4.6. Tissue engineering

Organ transplantation is increasingly in demand due to the rising incidence of tissue damage and organ failure. The most common techniques for nanofibrous structures are electrospinning, self-assembly and phase separation [33]. As a fundamental building block of tissue engineering, electrospun nanofiber scaffolds have potential uses in various tissues, including vascular, bone, neuron, cartilage, etc. A form mimics the fibrous structure of the natural extracellular matrix, ease of surface functionalization, a high surface-to-volume ratio, and tunable porosity are just a few of the characteristics of electrospun nanofiber scaffolds for tissue healing that are similar to those of natural tissue [102]. Nanofiber-based scaffolds are used for various tissue engineering procedures, including the tissue engineering of bones, cartilage, ligaments, skeletal muscles, skin, blood vessels, and neural tissue [103].

4.6.1. Vascular tissue engineering

The migration of stem and progenitor cells is critical for organ development and wound healing in the adult body. They are also necessary for the movement of stem and progenitor cells, the circulation of nutrients and oxygen, with the elimination of metabolic waste products. Autologous vessels' biological and mechanical characteristics should be replicated by a tiny diameter, tissue-engineered vascular graft (TEVG) [104]. The scaffolds' porosity, pore size distribution, and structural characteristics can be modified using the electrospinning technique's precise control over fiber alignment [33].

4.6.2. Bone tissue engineering

The primary connective tissues of the human body that carry weight are bones. They are highly susceptible to deterioration. Bone abnormality is the most challenging and has been an important research topic. Recently, the study of scaffolds for bone, cartilage, and osteochondral tissue engineering is becoming more advanced and getting more attention [105]. The natural extracellular matrix of the bone should be replicated in the scaffold so the cells to develop and differentiate into specific tissues as they would have in nature. To endure the dynamic remodeling of the designed bone in vivo, an ideal scaffold should also possess specific qualities. These attributes include biocompatibility, exceptional mechanical strength, high porosity, high surface area, and high pore interconnectivity. Among all the scaffold fabrication techniques, the electrospun nanofiber is the most successful technique that fabricates the most identical nano fibrillar components, i.e., collagen [106]. The studies show that natural polymers like gelatin, collagen, silk, and chitosan have been used as scaffolds for bone tissue repair and regeneration [107].

4.6.3. Skin tissue engineering

Skin is the body's outermost layer and the largest organ of the integumentary system. Skin tissue engineering is a novel method for repairing and regenerating injured skin [108]. The extracellular matrix (ECM) provides an advanced context for many cellular functions and aids cell adhesion and proliferation. There has been a lot of recent research on biomimetic nanoparticles that can help to regenerate injured tissues. Phase separation, template synthesis, drawing, self-assembly, and electrospinning are techniques utilized for making nanofibers. The electrospun nanofiber is the most successful of all the scaffold fabrication techniques. Collagen, elastin, and reticular fibers comprise most of the ECM [109].

4.6.4. Cartilage tissue engineering

The primary cause of disability is cartilage disintegration, which can be brought on by trauma or common joint conditions like osteoarthritis. Cartilage has a less vascular network, showing limited regeneration potential. Traditional treatment involves surgery for cartilage degeneration; however, this deliberately results in the fibrous repair of tissues. Articular cartilage's ability to regenerate is constrained by the fact that it is a circulatory, neural, and lymphatic tissue in contrast to many other tissues. Nanofibers are vital in managing cartilage tissue regeneration [110,111]. The application of nanofiber in various diseases is shown in Fig. 5, and nanofibers in clinical trials are shown in Table 2.

Fig. 5.

Applications of nanofiber in various diseases.

Table 2.

Nanofibers in clinical trials.

Sr. No.	Study Title	Condition/disease	Interventions/treatment	Sponsors	Reference
1.	Rotator cuff healing using a nanofiber scaffold in patients greater than 55 years	Rotator cuff tears	Device: Nanofiber scaffold	Atreon Orthopedics	[112]
2.	Antimicrobial effect of modified antibiotic nanofibers for regenerative endodontics procedures	Necrosis, Pulp	Procedure: electrospun TAP nanofibers	Cario University	[113]
3.	Evaluation of marginal integrity of hydroxyapatite nanofiber reinforced flowable composite versus conventional resin-based flowable composite in initially demineralized pits and fissure: a one-year, randomized clinical trails	Marginal integrity of hydroxyapatite nanofiber reinforced flowable composite	Other: Conventional resin-based flowable composite Other: Hydroxyapatite nanofiber reinforced flowable composite	Cario University	[114]
4.	The retention rate of hydroxyapatite nanofiber reinforced flowable composite versus conventional	The retention rate of flowable composite in demineralized pits and fissures	Other: Hydroxyapatite nanofiber reinforced flowable composite Other: conventional resin-based flowable composite	Cario University	[115]
5.	To investigate the feasibility and efficacy of a novel biomimetic poly-l-lactide (PLLA) nanofiber membrane in repairing anterior urethral strictures.	Urethral stricture	Underwent urethral reconstruction using a biomimetic PLLA membrane	Shanghai Sixth People's Hospital	[116]
6.	Clinical study of functional electrospun nanofibers capturing circulating tumor cells from patients with ovarian cancer to predict the efficacy and prognosis of patients with ovarian cancer	Ovarian Cancer	CTC device The CTCs of ovarian cancer patients at different stages were captured by electrospinning nanofibers	Xinhua Hospital, Affiliated with the Medical College of Shanghai Jiaotong University	[117]
7.	Clinical study of new liposome nanofibers patches for transdermal drug delivery containing ebracteolata Hayata in treating actinic keratosis.	Actinic keratosis	Drugs for external use	Shuguang Hospital, affiliated with the Shanghai University of Traditional Chinese Medicine	[118]
8.	A novel drug delivery system using acyclovir nanofiber patch for topical treatment of recurrent herpes labialis: a randomized clinical trial	Herpes Labialis	Acyclovir nanofiber patch	Esfahan University of Medical Sciences	[119]

5. Recent advancements in nanofiber technology

5.1. Gene delivery

Gene delivery enables the modification or exploitation of specific genes through exogenous stimulation of the intended population of cells to achieve a range of outcomes, including the differentiation of specific receptors into specialized cells, stimulation of apoptotic indicators among tumors, secretion of autocrine or paracrine factors inside body tissue, and the development of cellular therapies [120]. Electrospun nanofiber composites have been investigated as spatial frameworks to precisely replicate natural ECM structures or properties [110]. These nanofiber composites may work incredibly well as interfaces for transmitting genetic traits to the relevant cells in the body since they preserve cellular morphologies [121]. As an example, it was found that short interfering RNA (siRNA) was successful at transfecting mesenchymal stem cells (MSCs) for neural development when it was physically adsorbed onto a poly (caprolactone) (PCL) nanofiber scaffold. Simple techniques like electrospinning and coaxial electrospinning are used to develop electrospun nanofibers [122]. Electrospun nanofiber composites are frequently created by combining them with polymer or ceramic-based components. Genes can also be transferred using nanofibers by immobilizing the desired gene with nanofibers after electrospinning them or blending the desired gene with a solution that forms fibers before electrospinning them [123].

One method for delivering bone morphogenetic protein (rhBMP-2) plasmid DNA successfully uses electrospun poly (l-lactic acid) (PLLA)/collagen nanocomposite fiber. This caused ectopic bone development and the expression of the BMP-2 protein. Due to the benefits of such porous composite architectures, it is practically possible to introduce plasmid DNA (pDNA) into cells to encourage the in-cell production of desired encapsulating growth factors, signaling molecules, and other bioactive substances. Recent research has demonstrated the potential of nanofiber composites as spatiotemporally controlled delivery systems across various biomedical uses, including regenerative medicine and tissue engineering [124].

Non-viral gene vectors, such as DNA/polyplexes or naked plasmid DNA, have undergone substantial research and are being inserted into and fastened to electrospinning for usage in the Fabrication of nanofiber hybrids enabling targeted gene delivery. This nanostructure may be simpler to build over viral-based carriers and can better preserve the characteristics of the genetic material. Additionally, it has been shown that integrating viral-based vectors with the desired gene loaded into their viral capsid with electrospun nanofibers can improve the efficiency of gene transport and extend the period that a gene is produced [125].

5.2. Protein and peptide delivery

Peptides and proteins are macromolecules with a large molecular mass composed of amino acid chains associated with peptide bonds. Due to the peptide-protein propensity for degradation, there are critical factors to consider while generating fiber from the components. To prevent protein breakdown and denaturation, ambient and electrospinning conditions must be maintained at their ideal levels [126]. This can be accomplished by changing the environmental circumstances, such as pH and temperature. To increase spinnability and enhance solubility, these substances are frequently blended with organic solvents such as ethanol, dimethylformamide, hexafluoro isopropanol, and trifluoroacetic acid [127]. The destruction of the peptide/protein structures is the main issue to be concerned about when combining these medications with organic solvents; as a result, the procedure should be meticulously followed, and every step should be examined and monitored. Accurately comprehending the structures of peptide-proteins is another technique to solve these issues. Proteins and peptides, for instance, must have their tertiary structures broken down and their beta chains stabilized to be converted into fiber [128]. Peptides and proteins can be combined with various natural and synthetic polymers, such as Eudragit®, poly-l-lactic acid (PLA), polycaprolactone (PCL), chitosan, etc., to improve mechanical properties [129].

Soy protein is obtained from a plant that has received interest in the biomedical field due to its low cost, abundance, biocompatibility, processability, and biodegradability. It is generated from soybean (dissolved soybean flakes) [130]. The electrospinning process used soy protein and PEO to create nanofiber crosslinked with carbodiimide. When this fiber's biocompatibility was tested using human mesenchymal stem cells, the fiber produced acceptable levels of cell growth. The produced fiber was discovered to have the potential for tissue regeneration. Nanofibers made from soy protein may one day serve as a scaffold in tissue engineering [130]. Vancomycin was embedded into sodium alginate-soy protein-PEO nanofibers that were created by Wongkanya et al. The indirect cytotoxicity test performed on this biomaterial with dermal fibroblast cells revealed that it is both biocompatible and non-cytotoxic. Finally, the study's findings reveal that this fiber is used in tissue engineering as a scaffold [131].

Similarly, gluten, a plant protein found inside the endosperm of gluten grains soluble in alcohol but insoluble in water. It comprised of accounts for 85% e proteins in wheat. Furthermore, it attracts attention in biomedical applications due to its convenient accessibility and environmentally safe [132]. Gluten-free films are more affordable and mechanically less resistant than those made from synthetic polymers. The gaps created by fibers from plant-derived proteins like zein and soy protein are filled in by fibers derived from gluten.

5.3. Growth factor delivery

The electrospinning technique's adaptability makes it possible to incorporate protein growth factors into polymer nanofibers, which might subsequently cause the formation of the growth factor's continuous and regulated release. Proteins have been integrated into these nanofibers' centers by coaxial electrospinning, which modifies the electrospinning technique by employing two concentric needles. This method allows for the electrospinning of a protein solution while shielding it from the organic solvent used to dissolve the outer polymer layer. Although attempts to incorporate growth factors into nanofibers have been made in the past, studies on coaxial electrospinning have mainly focused on model proteins such as albumin and lysozyme, with just one study incorporating a growth factor [133].

Soluble proteins, called growth factors, are naturally used as transient intercellular signaling molecules. These are frequently utilized in tissue engineering and nanomedicine to regulate cells and encourage repair because they stimulate cell survival, proliferation, and differentiation. Despite their apparent value, their effective therapeutic delivery is difficult due to their comparatively large size compared to traditional drug molecules and intrinsic instability. Growth factors have brief half-lives in vivo due to enzymatic degradation; for example, the primary fibroblast growth factor (bFGF) has a half-life of just 3 min, while the nerve growth factor (NGF) has a half-life of 45 min [134]. The electrospun commercial products could be used for different applications enlisted in Table 3.

Table 3.

Commercial products of electrospun nanofiber.

Product Name	Brand Name	Manufacturer	Reference
Face Mask	SWASA face mask	E-EPin NanoTech Pvt. Ltd., India	[135]
	SWASA surgical Mask
Surgical Implant and Wound products	AVflo	Nicast, Israel	[136]
	PK Papyrus	Biotronic, Germany	[137]
	Surgiclot	St. Theresa, USA	[138]
	NanoCare	Nanofiber Solution™, USA	[139]
	Phoenix Wound Matrix RenovoDerm
	Zeus Bioweb	Zeus Industrial Product, USA	[140]
	REBOSSIS	Ortho ReBirth, Japan	[141]
	ReDura	MEDPRIN, China	[142]
	HealSmart	PolyRemedy, Inc. USA	[143]
	3D Inert PCL	3D Biotek, USA	[144]

6. Conclusion and future perspectives

Nanofibers showed various advanced such as huge surface area, variable porosity, and other unique properties, including high conductivity, superior electrochemical activity, increased mechanical strength, structural stability, etc. The review addressed ambient, solution, and process properties and the capacity to shape-change the nanofiber. It has several applications in the healthcare industry, such as biosensors, wound healing, tissue regeneration, and medication delivery. Similar challenges have arisen in electrospun nanofiber-based energy device applications. These include higher energy densities, reproducibility, extended shelf life, better durability, inefficient inhibition, a lack of efficient and long-lasting redox stimulation, and stability.

Along with these, each field also contains application-specific defects. Nanofibers offer distinctive qualities, yet they have poor biodegradability in medical applications, poor cell or drug penetration into scaffolds, a consistent incompatibility with the bone extracellular matrix, etc. Energy device applications based on electrospun nanofibers have faced similar issues. Among these is the requirement for increased energy densities, reproducibility, extended shelf life, improved durability, ineffective inhibition, a lack of efficient and long-lasting redox stimulation, and stability.

The current problems and difficulties have evolved into the conceptual framework for upcoming research projects. Future research will prioritize commercialization and supplying the market with nanofiber technology to facilitate the transition from the lab to the market. Nanofibers' brittleness will also influence future research, a fundamental limitation for many applications. This study will concentrate on the Fabrication of very flexible continuous fibers. The insertion of nanofillers into the fiber matrix to obtain complementing chemical and physical properties has emerged as another key research field for biological and energy-related applications. It is critical to investigate the cytocompatibility of fibrous scaffolds for cell adhesion, proliferation, and differentiation, particularly in bioengineering, wound dressing, and drug carriers. Furthermore, it is critical to focus on research that uses in vivo animal/human investigations and clinical trials to establish how effectively the device or scaffold will operate in real-world scenarios. This review seeks to provide a comprehensive overview of nanofibers and their cutting-edge applications by evaluating recent research in technology and healthcare.

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Data availability statement

No data was used for the research described in the article.

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.