*3.4. Melt Electrospinning*

Melt electrospinning has gained more attention in the electrospinning field, where toxicity and solvent accumulation is a concern. In this process, polymer melt is used instead of a solution, which is transformed from liquid to solid to achieve the desired product on cooling, rather than through solvent evaporation [22]. The polymer melt flow rate and homogeneous polymer melt conditions must be controlled to produce high quality fibers of uniform morphology, but with a broad range diameter. Polymer blends [35] and additives [36] have been used to reduce the average diameter of the fibers. The effect of the melt temperature can affect the structure and function of drugs, proteins and bioactive molecules loaded in the fibers [37]. The flow rate and melt viscosity of melt electrospinning can influence the characteristics of the resulting fibers. The surface wettability of melt electrospun fibers has improved through the formation of hydroxyl or peroxyl and N-containing functional groups, respectively, by using oxygen and ammonia plasma [35,38].

#### *3.5. Gas Jet Electrospinning*

Gas jet electrospinning is an improvement on the conventional melt electrospinning technique, in which the conventional electrospinning setup is additionally equipped with a gas jet device. The major limitation of melt electrospinning is that it requires definite control over the temperatures and therefore multiple heating zones must be placed to maintain the polymer melt. This results in generation of thicker nanofibers compared to the solutions. In this technique, the co-axial jet is surrounded by a tube feeding the heated gas, which can provide sufficient heat near the nozzle and delay the process of polymer solidification. For example, Zhmayev et al. spun polylactic acid (PLA) and showed a decrease in the diameter of the nanofibers obtained by gas jet electrospinning compared to normal electrospinning. Interestingly, the heated gas flow-rate had a significant effect on the diameter of the nanofiber. The increased gas flow rate can offer additional drag force to the jet surface which can result in the development of thinner nanofibers. Zhmayev et al.'s result showed a significant decrease in the diameter of the nanofiber, from 350 nm to 183 nm, when the gas flow rate was increased from 5.0 L/m to 15.0 L/m [39,40].

#### **4. Therapeutics Delivery Systems**

Most conventional drugs are hydrophobic and suffer from poor bio-distribution, solubility and stability in the biological system. Moreover, these drugs do not have the desired active targeting capabilities, which can result in non-specific systemic toxicity or faster elimination from the body, without achieving the desired therapeutic efficacy. Drug delivery systems (DDS) are approaches, formulations and technologies for transporting therapeutic agents to the targeted therapeutic site in the body [41]. The developed DDS technologies not only encapsulate the target drug/biomolecule but also attune their absorption, distribution, release and elimination with higher loading efficacy and safety. The drug release from DDS carriers depends on diffusion, degradation, swelling and affinity-based mechanisms [42]. As mentioned above, electrospun nanofibers are gaining significant attention as promising therapeutic nanocarriers. In addition, their impressive characteristics, including biocompatibility, biodegradability, and high therapeutic payload capacity, meet the prerequisites for a good therapeutic delivery candidate [13]. Employing electrospun nanofiber scaffolds as a therapeutic nanocarrier, different routes of administration (ROA) are being investigated. Drugs/therapeutics can be administered to any region/organ in the body by way of common routes, such as oral, parenteral (subcutaneous, intramuscular, intravenous, and intrathecal), sublingual/buccal, rectal, vaginal, ocular, nasal, inhalation, and transdermal, using electrospun nanofibers (Figure 2). Here, we present the common routes of drug administration by electrospun nanofiber [43].

**Figure 2.** Types of electrospinning, different therapeutics-loaded nanofibers and their route of administrations.

#### *4.1. Oral*

Of all delivery routes, the oral route is considered the most preferable and convenient route of administration, which can overcome the problems associated with other routes of administration [44]. However, to achieve successful administration of therapeutics targeting the oral route of administration is a difficult task. Before designing a successful oral delivery system, scientists should consider the major key challenges, including the presence of acidic gastric juice in the stomach, along with proteases, mucosal barriers and intestinal retention, which can hamper the absorption of drug delivery systems into the body [45]. Electrospun nanofiber scaffolds offer a great opportunity to load and deliver both micro and macromolecules, targeting the oral route [46]. Some of the common features of electrospun nanofiber in oral drug delivery systems include targeted delivery of therapeutics, sustained release properties, high transfection efficiency, rapid onset of action and fascinating pharmacokinetic profiles. Another promising advantage of using electrospun nanofibers is that researchers can design any desirable release properties such as fast [47], controlled [48], biphasic [49] or delayed [50] releases of the drug. Various polymers are used for designing oral drug delivery systems utilizing electrospun nanofibers such as poly (lactic-co-glycolic acid) (PLGA), polyvinylpyrrolidone (PVP), poly(ethyleneoxide) (PEO), PVP/cyclodextrin, polyvinyl alcohol (PVA), polycaprolactone (PCL), PVP/ethyl cellulose, PVP/zein, Cellulose acetate, Eudragit L, hydroxypropyl methylcellulose (HPMC), Eudragit S, Eudragit S/Eudragit RS, and shellac [50].
