**1. Introduction**

A wound is a type of injury caused by surgery, trauma, infection, diabetes, or other factors. Chronic wounds on the skin have become a life-threatening issue in recent years. According to reports, approximately 10 million people experience burning worldwide, leading to death if not handled properly [1]. Skin wounds of this nature necessitate immediate attention and treatment. Dehydration is caused by burning, which can lead to fatal complications. Choosing a suitable wound dressing is critical in caring for and the treatment of burn and chronic wounds. The material choice is crucial in facilitating quick wound healing and retaining fluidic contents with minimal dehydration [2,3]. An ideal wound dressing should have enough mechanical stability to support skin injuries, flexibility, water retention, antibacterial properties, and tear resistance, and be easily removable. It should also absorb a large amount of wound exudate from the wound surface, as the

**Citation:** Al-Arjan, W.S.; Khan, M.U.A.; Almutairi, H.H.; Alharbi, S.M.; Razak, S.I.A. pH-Responsive PVA/BC-*f*-GO Dressing Materials for Burn and Chronic Wound Healing with Curcumin Release Kinetics. *Polymers* **2022**, *14*, 1949. https:// doi.org/10.3390/polym14101949

Academic Editor: Ariana Hudita

Received: 16 April 2022 Accepted: 6 May 2022 Published: 11 May 2022

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exudate volume in burning wounds is usually relatively high [4,5]. It should protect against pathogens that cause severe disease by preventing their growth in the wound environment and surface. It should be biodegradable and easily removable to avoid skin peeling after application. Long-term drug delivery and growth factors should be easily swellable with controlled biodegradation. Various advanced wound dressings are commercially available for the care and treatment of skin-burning wounds. Ointment, cream, gels, natural oils, mists, gauzes, and bandages are among the wound dressings available [6,7]. Most chronic wound healing products are effective in wound healing, but their role in skin burns has yet to be determined.

Mechanical strength, swelling, water retention, and controlled therapeutic agent release are all problems with biomaterials. In addition, some of them are poor blood coagulators, while others lack antibacterial properties [8–10]. The non-biodegradability of these wound dressings is a significant issue, and most of the materials used in these dressings are also expensive. Taking all of this into account, developing an advanced dressing material with all of the necessary wound-healing and tissue engineering properties [11,12]. Hydrogel-based wound healing materials with all of the above properties can treat chronic and burn wounds. Hydrogels are typically made up of natural or synthetic polymers. However, they lack mechanical properties, biodegradation, and a low swelling ratio, limiting their clinical use as chronic wound dressings [13,14].

It is essential to develop composite hydrogels with enhanced functionalities to address these limitations. Bacterial nanocellulose is a biopolymer and polysaccharide that can retain enough biofluid. Water absorption, swelling, biodegradation, and long-term drug delivery properties make it a good candidate for biomedical applications. Cellulose is the most abundantly available natural polymer and is extensively used in several biomedical applications [15,16]. Graphene oxide is a potential material well-known due to its multifunctional behavior, and it has become popular with researchers due to its potential and versatility, including large surface area, π-π stacking, etc. The most widely credited material for developing next-generation biomaterials is graphene oxide (GO). On the basal plane and at the edge, GO has both hydrophobic and hydrophilic parts, with oxygen-containing functional groups like hydroxyl, epoxy, carbonyl, and carboxyl groups [17]. In addition, GO contains several oxygen-containing functional groups in biomedical applications and essential properties. Furthermore, GO-based materials have multifunctional properties [18].

We have reported the fabrication of composite hydrogels for burn and chronic wound healing applications. The bacterial nanocellulose and different graphene oxide amounts were functionalized via the hydrothermal method. Then, BC-*f*-GO was crosslinked with PVA using TEOS as a crosslinker to fabricate composite hydrogel. According to the best of our knowledge, these formulations have never been reported. The curcumin has been loaded into the composite hydrogel to determine its release behavior and kinetics. FTIR, SEM, water contact angle, and UTM determined the structural, morphological, wetting, and mechanical properties. The swelling was analyzed at different pH in PBS and aqueous media. The in vitro biodegradation and drug release analysis was conducted in PBS media. Antimicrobial were performed against Gram-positive and Gram-negative infection-causing pathogens to observe their antibacterial performance in burn and chronic wound healing.

#### **2. Materials and Methods**

#### *2.1. Materials*

A well-reported method was used to synthesize bacterial nanocellulose by a method by Saiful et al. [19], polyvinyl alcohol (PVA), Graphene oxide (CAS No. 763713-1G) tetraethyl orthosilicate (CAS No. 78-10-4), potassium persulfate (initiator), hydrochloric acid (CAS No. 7647-01-0), phosphate buffer saline (MDL No. 806552-1L) solution, and Sigma-Aldrich, Petaling Jaya, Selangor, Malaysia, supplied the ethanol. These chemicals were analytically graded and used as received.

#### *2.2. Hydrogel Fabrication*

The GO-functionalized-bacterial cellulose (GO-*f*-BC) was synthesized by the hydrothermal approach, in which bacterial cellulose (0.7 g) and various amounts of GO (0.01, 0.02, 0.03, and 0.04 mg) were placed in a 50 mL stainless-steel autoclave for 30 min. The stainless-steel autoclave was placed in the oven at 50 ◦C overnight to have BC-*f*-GO, and the stainless-steel autoclave was removed after the overnight reaction to obtain BC*f*-GO, which was then added in 25 mL double deionized water (DDW) and stirred at 55 ◦C for 1 h to have a homogenized mixture. PVA (0.3 g) was added in 10 mL DDW and dissolved at 80 ◦C. These were mixed and stirred at 55 ◦C for 1 h to have a homogeneous suspension. The crosslinker (TEOS (240 μL)) was added to 5 mL ethanol, added into the whorl of the mixture solution, and allowed to stir at 55 ◦C for another 2 h. Finally, 0.2 g of Potassium persulfate as initiator was dissolved into 5 mL of DDW, added to the solution as an initiator, and stirred at 55 ◦C for 3 h for successful crosslinking. After 3 h, we had a light yellowish color of the fabrication composite hydrogels and shifted the composite hydrogels into Petri plates. These Petri plates were oven-dried at 45 ◦C, and different codes (BSG-1, BSG-2, BSG-3, and BSG-4) were assigned to these composite hydrogels after a different GO amount (0.01, 0.02, 0.03, and 0.04 mg). The proposed chemical schematic of the composite hydrogel has shown in Scheme 1.

**Scheme 1.** The proposed chemical interaction of the bacterial cellulose, polyvinyl alcohol, GO, and crosslinked via TEOS.

#### **3. Characterizations**

#### *3.1. FT-IR*

The structural and functional group information was analyzed by Fourier transform infrared (FT-IR) Nicolet 5700, Waltham, MA, USA, spectrophotometer. FT-IR analysis was carried out at attenuated total reflectance (ART) mode with wavenumber (4000 to 400 cm<sup>−</sup>1) and 120 scans per sample.

#### *3.2. SEM*

The surface morphologies of well-dried hydrogels were examined (JSM-6701S, JEOL, Peabody, MA, USA). First, double-sided carbon tape was used to secure the hydrogels to

the aluminum stubs, which were then gold-sputtered. Then, micrographs were taken to examine their morphologies.

#### *3.3. Water Contact Angle*

The wetting behavior of composite hydrogels was studied using a water contact angle system (JY-82, Dingsheng, Chengde, China) to determine their hydrophilicity and hydrophobicity. We recorded wetting at zero and ten seconds to investigate wetting behavior over time.

#### *3.4. Swelling*

Swell tests were performed in PBS and aqueous media at various pH levels to determine their pH-responsive behavior. The sliced hydrogels were weighed (50 mg), and the initial weight (*Wi*) was taken. These hydrogels were submerged in PBS and aqueous media-containing beakers at room temperature. Hydrogels that had swelled were removed from the corresponding media. After 12 h, the extra surface media was carefully removed and weighed (*Wf*) as the final weight and swelling (%) were calculated using Equation (1).

$$\text{Swelling (\%)} = \frac{W\_f - W\_l}{W\_l} \times 100\tag{1}$$

whereas: *Wf* = Hydrogel final weight, *Wi* = Hydrogel initial weight.

#### *3.5. Biodegradation*

The hydrogels were tested in vitro in PBS buffer solution (pH 7.4, at 37 ◦C with 5% CO2) to see how they degraded. The squarely sliced hydrogels were carefully weighed (45 mg) and placed in PBS buffer solution to determine biodegradation behavior. Equation (2) was used to calculate the percentage of biodegradation.

$$Weight\,\,loss\,\,(\%) = \frac{W\_i - W\_t}{W\_i} \times 100\,\tag{2}$$

whereas: *Wt* = Hydrogel weight at "*t*", *Wi* = Hydrogel initial weight.

#### *3.6. Curcumin Loading and Franz Diffusion Release*

The dermatologic antibiotic curcumin prevents infection in partial-thickness and full-thickness chronic and burns wounds. However, it is still commonly used to treat third-degree burns. Curcumin (10 mg) was dissolved in ethanol (5 mL) and dropped into the polymeric mixture dropwise (BC 0.7 g, PVA 0.3 g, and GO 0.4 mg). The heterogeneous mixture was stirred for two hours at 55 ◦C, then crosslinked with TEOS (240 μL), and stirred for three hours at the same temperature. In vitro drug release was measured using the Franz diffusion transdermal method at three different pH levels (6.4, 7.4, and 8.4), as Saiful et al. [15] reported in PBS buffer solution at 37 ◦C. In addition, the calibration analysis was conducted to evaluate the release of Silver-sulfadiazine from hydrogel at different pH levels.

### *3.7. Drug Release Kinetics*

We used mathematical models to study drug release mechanisms (3–8) (zero order, first order, Higuchi, Hixson–Crowell, Korsmeyer–Peppas, and Baker–Lonsdale). In addition, data from Franz diffusion at various pH levels were used to evaluate drug release kinetics.

$$\text{Zero-order} \qquad M\_t = M\_o + K\_o t \tag{3}$$

$$\begin{aligned} \text{First order} \\ \qquad \log \text{C} = \log \text{C}\_0 - \frac{kt}{2.303} \\ \text{Higuchi model} \qquad \qquad ft = \text{Q} = \text{K}\_H \times t^{1/2} \end{aligned} \tag{4}$$

Hixson Crowell model *Wo* 1/3 <sup>−</sup> *Wt* 1/3 = *kt* (6)

Korsmeyer-Peppas model *ln Mt*

$$\frac{M\_t}{M\_o} = n\ln t + \ln K \tag{7}$$

$$\text{Baker-Lorsdale model}\qquad\qquad\qquad F\_t = \frac{3}{2}$$

$$F\_l = \frac{3}{2} \left[ 1 - \left( 1 - \frac{M\_l}{M\_o} \right)^{\frac{2}{3}} \right] \frac{M\_l}{M\_o} = K(t)^{0.5} \tag{8}$$

*Mt* = amount of drug release at "*t*", and *KH*, *K*, and *Ko* are constants.
