# Fibers by Electrospinning and Their Emerging Applications in Bone Tissue Engineering
## 4 Drug Delivery System
Figure 8: The illustration of a tricomponent delivery scaffold incorporating rhBMP-2, rhVEGF, and calcium phosphate nanoparticles by co-electrospinning. Reproduced with permission [46]. Copyright © 2021, The Royal Society of Chemistry. Apart from the blending process, several researchers reported their attempts on the surface chemistry of electrospun fibers. Drug carriers can be immobilized onto the modified surface for maximize utilization of the high specific surface area of fibers (Figure 10). [PERSON] et al. [81] modified electrospun PLA fibrous scaffold by surface grafting, and then BMP-2 peptide-loaded liposomes were immobilized. As observed by confocal laser scanning microscopy, the prepared scaffolds showed higher attachment efficiency of liposomes compared to those not modified. For further improvement of the effect of delivered drugs, the fabrication of drug-loaded carriers can be optimized by several technique. Microfluidic (MF) technique was selected to produce drug-loaded carriers with desired size and excellent cell viability. For example, [PERSON] et al. [93] prepared polyplexes nanoparticles loading BMP-2 plasmid DNA through MF platform (Figure 11). Compared to bulk prepared drug-loaded carriers, those fabricated by MF platform showed lower toxicity and higher cell viability due to the fine mixing reaction based on molecular diffusion. In addition, [PERSON] et al. [11] proposed combination of electrospinning and electrospraying for fabrication of fibrous scaffolds decorated with PLGA-BMP-2 particles (Figure 12). As a simple and low-cost approach, electrospraying can be used to prepare drug-loaded nanoparticles without significant phase separation, ensuring a stable release during bone regeneration [11]. Figure 10: Electrospun fibrous drug delivery system built by immobilizing drug carriers onto the modified surface [81]. Figure 9: Electrospun fibrous drug delivery system made by simply immersing drug carriers [27]. Moreover, by designing and optimizing electrospinning processing, the corresponding microstructure can be obtained to customize the desired drug release model. Coaxial electrospinning provides a strategy to fabricate core-shell structure nanofibers as a drug delivery system. It was reported that coaxial nanofibers exhibited lower release rates compared to that of uniaxial nanofibers, resulting in a prolonged release [156]. Recently,  
Figure 11: (**a**) Schematic representation of MF preparation of drug-loaded carriers and (**b**) scaffolds fabrication. Reprinted from [93] with CC-BY license. Copyright © 2021 [PERSON] et al. Figure 12: Fibrous drug delivery system prepared by electrospinning and electrospraying. Reproduced with permission [11]. © 2021 Elsevier Inc. All rights reserved. various drug delivery systems fabricated by coaxial electrospinning were reported. Generally, drugs are loaded in the core of coaxial nanofibers and continuously released for inducing bone regeneration [12; 14; 20; 21]. However, a few examples were reported in which the outer shell encapsulated drugs while the inner core part acted as mechanical support [19]. In order to achieve desired release pattern, several attempts focused on optimizing the structure of coaxial nanofibers. For example, [PERSON] et al. [67] developed BMP-2 loaded core-shell nanofibers with shish-kebab (SK) structure on the surface (Figure 13). After electrospinning, the prepared nanofibers were immersed in PCL solution and SK structure was obtained by polymer chain crystallization in a folded and periodic fashion with solvent evaporation. An in vitro drug release study showed that the SK structure nanofibers provided a gentler release than those of coaxial nanofibers without SK structure. [PERSON] et al. [17] incorporated redox-responsive nanogels into the outer shell of prepared coaxial nanofibers (Figure 14). The disulfide bonds of nanogels linked or disconnected under different concentration of glutathione (GSH), leading to the establishment or disappearance of nanochannels to release BMP-2.