2.1.2. Multiple Layered Fiber Mats

Multilayered fiber mats provide controlled release of a drug through the layer-by-layer stacking of a nanofiber sandwich, with drug loaded in between. This type of design is straightforward, easily controllable, and with a simple fabrication process as compared to the core/shell design. The drug release mechanism of multilayer fibrous mats can be controlled by adjusting the thickness of the outer layer, the amount of drug loaded, the porosity of the scaffolds, etc. The design of a core/shell structure is a complicated process, in one sense, due to the diverse electrical and rheological properties, such as conductivity and surface tension, of the core and shell polymer materials [43]. Hence, due to the difficulty of fabricating a core/shell design, electrospun fiber mats are not able to achieve sustained repeatability; additionally, controlled release of drug from the structure is difficult to be investigated efficiently. GeunHyung Kim [44] prepared polycaprolactone (PCL)-PEO-PCL layered fiber mats, and drug delivery was examined with various thicknesses of PCL outer layer. It was shown that burst release can be avoided by increasing the thickness of the PCL layer, as well as by incorporating antimicrobial peptide HPA3NT3, which does not lose its biological activities (Figure 3).

On the other hand, sustained release of the drug haloperidol was investigated by changing the hydrophobicity of the scaffolds. Therein, polyvinyl alcohol (PVA)-methylated b-cyclodextrin was incorporated with PLA and PLGA. The addition of b-cyclodextrin reduced the fiber degradation rate of PVA [45]. It was noted that when the hydrophobicity of the scaffold was increased, the release of the hydrophilic drug was sustained in a controlled manner, while polyester polymers released the drug by means of hydrolysis. The blending of the hydrophobic and hydrophilic drug will minimize the toxicity caused by the burst release of the drug. This type of combination can be applied for hydrophobic and heat-sensitive drugs, due to the simplicity of the process.

**Figure 3.** Schematic of the new drug release system consisting of two different electrospun mats. The inner and outer parts of the mat were PEO/rhodamine and PCL fibers, respectively. The red color shows that the rhodamine was well embedded in the PEO/rhodamine mat. Reproduced with permission from [44]. Springer Nature, 2010.

The drug delivery of ibuprofen from sandwich-layered fiber mats was studied, and its mathematical modeling was elaborated by using applying the power law, the Higuchi equation, and Fick's second law [46]. The mathematical modeling suggests that the thickness of the fiber

mats have a greater impact on drug delivery than the concentration of the loaded drug. Here, PLA was successfully electrospun by incorporating ibuprofen drug in between the two layers of PLA. Finally, according to the type of treatment, the drug loading can be changed by altering the thickness of the layers for controlled release of the drug. Dave Wei-Chih Chen et al. [47] studied drug delivery of vancomycin, gentamicin, and lidocaine for wound-healing applications. In their research, they successfully mixed PLGA/collagen on the outer layer and PLGA loaded with a drug in the middle layer. The drugs vancomycin and gentamicin were released in high concentrations from the biodegradable polymer scaffold. However, lidocaine showed a release time of up to 3 weeks. The bioactivities of the drug were shown to exhibit 40–100% efficiency, and it was concluded that this scaffold was suitable for boosting the wound-healing process in the initial stage of the wound.
