3.2.2. Surface Modification for Enhancing Biocompatibility

Surface modification via coating can improve the cell adhesion, proliferation, and differentiation; this reduces the risk of thrombosis and imparts bactericidal properties to the stent. In the literature, it has been shown that plasma surface treatment of L-PLA and PCL polymers improves the surface roughness, as well as reducing the surface free energy for better cell attachment of diverse cells to the surface of the polymer mesh [157]. Magnetron-sputtered polymer sheets offer reduced cytotoxicity and better cell viability for biomedical applications. The surface characteristics have been studied for polymer thin films, as well as for electrospun fiber scaffolds. For example, Staszek et al. [158] reported the cytotoxicity of glycerin sputtered with different noble metals such as Au, Ag, palladium (Pd) and platinum (Pt). The results suggested that they had prepared Au, Ag, Pd, and Pt NPs with sizes of 6.1 ± 1.0 nm, 4.2 ± 0.9 nm, 2.5 ± 0.6 nm and 1.9 ± 0.4 nm, respectively. In addition, Pt and Pd demonstrated great cytotoxicity for the 6 cells lines tested (human cells from hepatocarcinoma (HepG2), human keratinocytes (HaCaT), mouse macrophages (RAW264.7), mouse embryonic fibroblasts (L929 and NIH3T3), and cells from Chinese hamster ovary (CHO-K1)), and lower cytotoxicity was noted for Ag and Au after 24, 48 and 72 h.

Consequently, surface modification of hydrophobic polymers via plasma treatment can enhance wettability. E.N. Bolbasov studied the surface modification of PLA and PCL bioresorbable polymers via radio frequency thermal glow discharge plasma using hydroxyapatite as a target in the presence of Ar+ as plasma [127]. The results indicated that the PLA and PCL surfaces showed enhanced biocompatibility for cell line EA-hy926 attachment to the surface. Surface free energy and surface roughness were improved by long exposure to plasma treatment. In addition, plasma sputtering technology can enhance surface roughness, improving cell attachment onto the thin polymers fibers [159]. The PLLA polymer thin film was RF magnetron-sputtered with hydroxyapatite target. This coating led to an increase in biocompatibility with the cells of bone marrow multipotent mesenchymal stromal cells. This was mainly due to the increase in the surface roughness of the PLLA film resulting from the plasma coating, in addition to the enhancement of calcium and phosphorous caused by the hydroxyapatite target. Surface modification of polymer films enhances biocompatibility and reduces cell toxicity.

Furthermore, biodegradable PLA polymer was prepared via electrospinning, and surface modification was implemented by RF magnetron sputtering. The electrospun PLA scaffold was sputter-coated with hydroxyapatite (HAP), tricalcium phosphate (TCP), amorphous calcium pyrophosphate (CPP) and dicalcium phosphate dihydrate (DCPD) [134]. It was found that all prepared fibers showed cytotoxicity because of the production of a toxic compound on the fiber surface, as well as the fact that the fiber surface had been devastated due to the extended plasma treatment.

On the other hand, the same team of scientists worked on PCL scaffold fibers that were magnetron sputter-coated with titanium targets (Figure 8) [131]. They found that hydrophilicity improved with an increase in plasma treatment time. In addition, increasing the number of pores on the fiber structure did not affect the mean fiber diameter. As plasma treatment time was increased, the adhesion of cells improved. Consequently, cell viability decreased when plasma treatment time reached 9 min.

In another study, poly (L-lactic) acid (PLLA) scaffold was sputter-coated with titanium target under a nitrogen atmosphere [160]. The pure PLLA did not show any changes in its physiomechanical properties. Biocompatibility testing in in vivo rat models indicated that there was no severe tissue reaction after around three months for the implemented subcutaneous tissue. Finally, the replacement of scaffolds from the recipient tissue depends on plasma treatment time.

**Figure 8.** SEM images, fluorescent map of labeled cells (live green cells (acridine orange), orange nucleus of dead cells (ethidium bromide) and wettability for PCL samples that were (**a**) untreated; and treated in plasma for (**b**) 1 min; (**c**) 3 min; (**d**) 6 min; and (**e**) 9 min. Reproduced with permission from [131]. Elsevier, 2016.

#### 3.2.3. Tissue Engineering

Plasma technology has also emerged recently for use in tissue engineering applications such as vascular grafting, stem cell therapy, and artificial muscle sputter-coated with conductive Au. For this purpose, highly biocompatible polymers have provided a platform for cell adhesion, proliferation, and differentiation. To this end, stem cells are added to the polymer scaffold to provide a better tissue regeneration environment. Stem cell therapy is a new platform that may act as an alternative to many complicated surgical procedures. Stems cell-loaded materials have gained much attention recently [126]. Lee et al. [126] reported the use of PCL microspheres sputter-coated with Au as a platform for differentiating cardiomyogenic cells from human embryonic stem cells. They sputtered the PCL microspheres for 5 min, and then incorporated the human embryonic stem cells (hESCs). It was noted that these composites showed a higher cardiac differentiation, because Au acted as the mediator for gene expression on day 4 and day 14 [126].

Moreover, PLLA and PEG fibers were electrospun and sputter-coated with calcium phosphate for bone tissue engineering applications. Here, simple combination of the electrospinning and sputtering techniques is feasible for the fabrication of biopolymer scaffolds for biomedical applications [161].

Many novel composite materials have emerged due to the fusion of two valuable techniques, such as the electrospinning and sputtering techniques [162]. Innovative materials have been studied

for vascular tissue engineering. These composite materials were prepared using the electrospinning and sputtering technique. To this end, PCL and PHBV were incorporated at a ratio of 1:2 (*v*/*v*) and sputter-coated with Ti. Firstly, the sputtering process was optimized so that it would not damage the macrostructure of the scaffolds. The biocompatibility of the prepared composite mats was studied with hybridoma of the endothelial cells of the human umbilical vein and human lung carcinoma (EA.hy.926 cell line). The results showed that cell adhesion was improved for Ti-coated scaffolds, and that they exhibited better proangiogenic activity.

Furthermore, a novel approach was applied to process fibrous scaffolds for artificial muscles or human body smart devices by combining electrospinning and sputtering technologies [133]. A core/shell structure was made by first electrospinning the PMMA in optimized form to obtain a uniform fiber; later, the PMMA was coated with Au to induce conductivity and obtain suitable mechanical properties in the scaffolds. Subsequently, polyaniline (PANI) was coated onto the scaffolds via in situ electrochemical polymerization, starting with aniline and using sulfuric acid as an oxidizing agent (Figure 9). PANI-coated metalized fiber scaffolds in a structure similar to the core/shell structure showed fascinating electrochromic properties, in which color changes occurred when the applied voltage was switched from 0 to 1 V, and vice versa. In vitro biocompatibility testing revealed good cell adhesion, with a better result shown when tested on human amniotic fluid stem cells than on eukaryotic cells. Therefore, this type of web could be used to prepare smart artificial muscle devices via a versatile and straightforward preparation technique using electrospinning and sputtering.

**Figure 9.** Schematic representation of electrospinning and sputtering for muscle tissue engineering applications. Reproduced with permission from [133]. Elsevier, 2016.

### **4. Conclusions**

Throughout this review, new insights for biomedical applications have been addressed, focusing predominantly on the promising benefits of employing sputtered electrospun polymer-based nanofibers. It is evident from the number of ineffective conventional treatments that there is a desperate necessity for distinct and unique therapies. As addressed extensively in this paper, combining sputtering and electrospinning technologies has the potential to play a critical function in different biomedical applications such as antibacterial coatings, surface modification for enhancing biocompatibility, and tissue engineering. Investigated by means of various nanostructure studies, the above-mentioned concepts can be used in an attempt to strengthen overall therapeutic behavior. As represented through the numerous reports addressed, therapies including silver and copper nanoparticles have the potential to be applied directly in different biomedical applications. Overall, it is clear that the field of combined sputtering and electrospinning technologies is progressing at an incredibly fast rate, providing promising behaviors for various biomedical applications.

**Author Contributions:** H.K. and M.Z. wrote the manuscript; A.E. and T.A. supervised the writing and reviewed the manuscript.

**Funding:** This work was funded by Qatar University, grant number GCC-2017-007 and the publication of this article was funded by the Qatar National Library.

**Conflicts of Interest:** All authors of this review article declare no conflicts of interest.
