**1. Introduction**

With increased environmental awareness and an emphasis on eco-friendly products, the goal of research efforts is in the production of biocompatible, biodegradable and lowcost film-forming materials for biomedical applications [1–3]. Due to their biocompatibility,

**Citation:** Khan, M.U.A.; Yaqoob, Z.; Nainar, M.A.M.; Razak, S.I.A.; Raza, M.A.; Sajjad, A.; Haider, S.; Busra, F.M. Chitosan/Poly Vinyl Alcohol/Graphene Oxide Based pH-Responsive Composite Hydrogel Films: Drug Release, Anti-Microbial and Cell Viability Studies. *Polymers* **2021**, *13*, 3124. https://doi.org/ 10.3390/polym13183124

Academic Editor: Evgenia G. Korzhikova-Vlakh

Received: 27 June 2021 Accepted: 13 August 2021 Published: 16 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

nontoxicity, biodegradability, ease of availability and low cost, natural polymers have played an important role in producing biomaterials. CS, a natural biopolymer, is regarded as an outstanding candidate for film formation [4]. Alkaline de-acetylation is used to obtain a naturally occurring biopolymer (CS) with a poly-cationic structure from the chitin shells of shrimp and other crustaceans. It's a polysaccharide made up of *N*-acetyl Dglucosamine and D-glucosamine units linked by a (1–4) glycosidic bond that's abundant in nature [5]. CS has been widely used in biomedical and drug delivery applications. It possesses biocompatibility, low toxicity, mucoadhesive properties, antibacterial activities and permeation-enhancing characteristics [5]. However, on the other hand, CS has low mechanical properties that limiting its applications. Several methods have recently been developed to improve the mechanical properties of CS by using nanofillers, for instance, graphene and their derivatives [6]. GO is commonly used in biomedical applications and other carbon-based nanomaterials such as carbon nanotubes (CNTs). It has unique chemical properties, including such as high biocompatibility, low toxicity, a large surface area for effective drug binding, oxygen-containing functionalities and improved conductivity [7]. GO is graphite-derived two-dimensional (2D) carbon material. It has a long history of use as a precursor to chemically converted graphene. Many hydrophilic oxygenated functional groups in GO, such as hydroxyl (–OH), epoxy (–C–O–C–) and carboxyl (–COOH), enable it to disperse in water solution and be easily exfoliated into monolayer sheets [8]. Due to these functional classes, GO is amphiphilic with hydrophilic edges and hydrophobic basal planes. GO contains oxygen-enriched functional groups, which react with various polymers to form polymer-based graphene oxide nanocomposite [9,10]. The large surface area of GO is used to carry and distribute drugs through contact between GO functionalities and drug groups. The importance of GO-based hydrogels in drug release is well known [11], and GObased drug delivery systems have been extensively researched due to their pH-sensitive drug release behavior. By adjusting the pH of the GO-based hydrogel, controlled drug release was achieved [12]. Polyvinyl alcohol (PVA) is known as green material due to its nontoxicity and biocompatibility. PVA is biodegradable, chemically stable, biocompatible, eco-friendly, as well as water-soluble. It has been extensively researched in various fields and has several available hydroxyl groups (OH) on its polymeric chain [13]. As a result, PVA-based hydrogels find use in the pharmaceutical industry for managed drug delivery. Kim and Kim et al. [14] studied the relationship between the percentage of PVA and drug release time. They developed double-layered composite PVA beads for managed drug delivery. They found that as the amount of PVA increased, the release of therapeutic agents was delayed due to increased cross-linking. Crosslinking is used to enhance the resistance of hydrogel to disintegration in any solution [15]. TEOS is well-known cross-linker and has been widely used in biomedical applications. Several cross-linkers (TEOS, formaldehyde, acetaldehyde and glutaraldehyde, etc.) have been used to cross-link different polymeric chains to develop biomaterials. However, TEOS is an ideal cross-linker since it provides covalent bonding between inorganic and polymer chains [16].

Combining different polymers as a blend is a valuable strategy to create new materials with low cost and synergy in properties. For instance, CS/GO-based hydrogel has been developed without the addition of cross-linker by non-covalent interactions for the application of rapidly self-healing performance. The GO contains several oxygen-based functional groups that formed hydrogen bonds with an amino group of CS to improve the mechanical properties of hydrogel [17]. PVA/CS hydrogel is reported in the literature for its biomedical applications since it has appropriate biocompatibility and nontoxicity. Flexible and robust PVA/GO composite films were prepared with a layered structure by vacuum filtration [18].

Similarly, CS/PVA blended films cross-linked via glutaraldehyde for skin tissue repair are also reported in the literature. These hydrogels have potential applications in artificial muscle and controlled drug release [19]. Various research studies have demonstrated the excellent pH-sensitive ability of PVA and GO. These CS/GO composites films have other widespread applications for bone tissue engineering, drug delivery and water treatment [20]. CS/GO becomes a stable and biocompatible composite with excellent thermal and mechanical properties. Due to the strong hydrogen bonds and electrostatic attraction between negatively charged GO sheets and positively charged polysaccharides groups in CS. Under proper pH conditions, uniformly dispersed CS/ GO films could be fabricated. It is known that the amino group of CS interacts with oxygen functionalities of GO through hydrogen bonding, which results in improved mechanical properties [21].

In this work, a series of hydrogels were synthesized by blending the PVA/CS. The performing samples were selected for the suspension of GO. The prepared hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscope (SEM), Atomic Force Microscope (AFM) and contact angle. The hydrogels were also tested for their swelling capabilities in different media. The drug release profile was investigated in phosphate buffer saline (PBS) at pH = 7.4. Finally, antibacterial activity and cell viability data were obtained.
