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Article

Eco-Friendly Synthesis of Silver Nanoparticles by Nitrosalsola vermiculata to Promote Skin Wound Healing

by
Ahmed A. H. Abdellatif
1,2,*,
Osamah Al Rugaie
3,
Fahad A. Alhumaydhi
4,
Nahla Sameh Tolba
5 and
Ayman M. Mousa
6,7,*
1
Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
2
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al Azhar University, Assiut 71524, Egypt
3
Department of Basic Medical Sciences, College of Medicine and Medical Sciences, Qassim University, Unaizah 51911, Saudi Arabia
4
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
5
Department of Pharmaceutics, Faculty of Pharmacy, Sadat City University, Sadat City 32897, Egypt
6
Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
7
Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha 13511, Egypt
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2023, 13(12), 6912; https://doi.org/10.3390/app13126912
Submission received: 7 March 2023 / Revised: 31 May 2023 / Accepted: 5 June 2023 / Published: 7 June 2023
(This article belongs to the Special Issue Green Synthesis and Application of Silver Nanoparticles)
Browse Figures
Versions Notes

Abstract

:
Eco-friendly synthesis of silver nanoparticles (SN) by using a naturally occurring plant, such as Nitrosalsola (Salsola) vermiculata (SV), could be a novel way for appropriate wound healing. AgNO3 was reduced by SV to produce safe SN (SN-SV) extract and hasten the wound healing process. The obtained SN-SV were characterized by size, charge, wavelength, and surface morphology. The optimized formulation was dispersed in O/W cosmetic cream. Then, it was characterized in terms of pH, viscosity, homogeneity, and permeability. The ex vivo and in vivo studies have been conducted in a rat animal model to assess the potential of SN-SV cream on skin tissue regeneration. A skin punch biopsy was obtained to investigate the histopathological (HP) changes in the skin lesions of all rats by the H&E staining and PCNA immunostaining methods. The skin wounds in all subgroups were examined on days 5, 11, and 15 to analyze the effectiveness of SN-SV cream for treating surgical skin wounds. The prepared SN-SV had a particle size of 37.32 ± 1.686 nm, a charge of −1.4 ± 0.7 mV, non-aggregated SN-SV, and a λmax of 396.46 nm. The formed SN-SV cream showed a pH near the skin’s pH, with suitable viscosity and homogeneity and an apparent permeability of 0.009 ± 0.001. The HP changes in the SN-SV subgroups revealed a substantial reduction in wound size and improvement in wound granulation tissue formation and epidermal re-epithelialization (proliferation) compared to the healing in the SN subgroups. The current work revealed that SN-SV could be a novel skin-wound-healing agent with a practical application as a wound-healing platform.

1. Introduction

Wounds result from physical, chemical, or mechanical stress, and microbial infections impede the healing process by causing inflammation and tissue damage [1]. Normal skin regeneration is imperative for maintaining hemostasis in healthy individuals and patients with diabetes [2]. Wounds have been treated for decades using topically applied silver sulfadiazine, pentoxifylline, and psoralen, which may harm the skin [3]. These agents have side effects, such as allergic reactions, hyperosmolality, silver staining of the burn wound, and hemolysis [4]; therefore, there is a need to use a new technique that can overcome all these drawbacks. Nanoparticle formulations are promising dosages for wound healing, and silver has been reported to be used for treating pleurodesis and skin cauterization. Nanoparticles are considered safe, less staining, and more potent in treating disease than the previous drugs [5]. Silver nanoparticles (SN) are among the most commonly used engineered nanomaterials with medicinal, industrial, and agricultural applications [6]. They have exceptional physicochemical qualities (high surface to mass) and antibacterial capabilities, giving them an advantage against multidrug-resistant microbes [7]. The SN primarily acts by releasing silver ions (Ag ions), which are reported to exert potent antimicrobial activity [8]. Recently, green synthesized silver nanoparticles (G-SN) can be administered orally, parenterally, or topically for anticancer and wound healing effects [9]. Both Nitrosalsola (Salsola) vermiculata (SV) and Ag ions exhibit antioxidant action, facilitate enzyme detoxification and treat wounds due to their antibacterial activity affecting the fatty acid content of microbial cell walls [10]; therefore, using prepared SN and SV (SN-SV) may improve its stability and solubility and speed wound healing [11].
The SN and SN-SV are frequently employed in research (notably in biomedical fields) due to their physical and chemical characteristics, such as anticancer, antioxidant, and anti-inflammatory properties [12]. They may act as medication carriers and biosensing materials. Additionally, the SN has therapeutic applications and may be used to treat burns and infections [13,14]. At the same time, SV is considered a reducing agent, effectively synthesizing stable G-SN with minimal cytotoxicity [15]. This green technology approach is environmentally friendly and produces G-SNs of a consistent size [16]. The G-SN approach can inhibit bacterial and fungal growth, including E. coli and Bacillus subtilis [17,18]. The toxicity of chemically synthesized NPs is considered a substantial challenge that would be prevented by the production and use of G-SN [19]. We look for novel ways of synthesizing safe and friendly synthesized G-SN rather than relying on existing techniques [20].
In the current study, we incorporated the SN-SV in topical creams as a carrier for wound healing. Wound healing may also be sped up when the G-SN is applied topically to the affected areas due to the prevention of oxidative damage [21]. The cream is an oil-in-water (O/W) emulsion that helps the medicaments to penetrate the skin surface layer (stratum corneum) [22]. The present work aimed to eco-friendly synthesize the SN-SV and evaluate their particle size, surface charge, and morphology. As well, the in vivo anti-inflammatory and proliferative properties in an open wound incision can be used to assess the potential role of the SN-SV in hastening skin tissue regeneration in a rat animal model.

2. Materials and Methods

Nitrosalsola (Salsola) vermiculata (SV) was purchased commercially from a local vendor market (Riyadh, Saudi Arabia). Silver nitrate (AgNO3) (purity 99%), NaOH (purity 98%), and HCl (purity 99%) were obtained from Loba Chemie Pvt-Ltd. (Mumbai, India). All chemicals were of analytical grade. The present study was implemented on 45 male albino rats acclimatized in the Qassim University (QU) animal house for two weeks before experimentation. The rats, aged six weeks, weighed 120–180 g and were fed a routine chow diet with tap water ad libitum at 25 °C under a 12 h light–dark cycle. The study was approved by the Research Ethics Committee of QU/KSA (No. pharmacy-2020-1-3-I-10108, Project approval) according to the institutional guidelines on animal care and following the guidelines of NIH for the care and use of laboratory animals.

2.1. Synthesis of Silver Nanoparticles by Nitrosalsola Vermiculata (SN-SV)

For SN-SV synthesis, 1 g of fine powder Nitrosalsola (Salsola) vermiculata (SV) was dispersed in 100 mL of Millipore water and stirred for 24 h. The solution was filtered using Whatman 41 filter paper. To produce SN-SV, 5 mL of the SV extract was combined with 95 mL of distilled water, 17 mg of silver nitrate was added, and the mixture was stirred for 24 h [23]. The solution color changed from colorless to brown due to the reduction of AgNO3 by the SV. The obtained SN-SV were separated from the solution by centrifugation at 15,000 rpm using a centrifuge (Hettich, Tuttlingen, Germany). The precipitate was collected and resuspended in Millipore water as pure SN-SV and stored at four °C until further use [24].

2.2. Characterization of SN-SV

2.2.1. Size, Surface Charge, and Morphology

The particle size and surface charge (ζ-potential) of SN-SV were measured using a Malvern Zetasizer nano 6.01. In contrast, the surface morphology was assessed using a scanning electron microscope (SEM) (JEOL JSM-550, Tokyo, Japan). Briefly, 20 µL of SN-SV was dried on stubs, followed by sputter coating with platinum for 30 min. The stubs were then viewed under an accelerating voltage of 4–25 kV under argon gas [25].

2.2.2. UV-VIS Spectrophotometrically

Similarly, λmax was determined using a UV-VIS spectrophotometer (Kontron Instruments, Augsburg, Germany) in the 300–700 nm scanning range. Excel 2019 was used to create SPR peaks. Diphenyl picrylhydrazyl (DPPH) was used to assess the free radical scavenging activity of SN-SV.

2.2.3. Antioxidant Activities

A total of 2 mL SN-SV solution was mixed with 2 mL of 0.1 mM DPPH solution in methanol for 40 min [26]. Quercetin (50 mg/20 mL MeOH, 0.008 mol) was used as a positive control sample for antioxidant activity. Spectrophotometric measurements were taken at 517.5 nm to determine the absorbance, with methanol as a blank. The solution was mixed and stirred for 45 min in an amber-colored glass bottle at 25 °C. The developed violet-color absorbance was quantified spectrophotometrically at 518 nm, and the percentage of antioxidant activity was calculated using the following relation:
% A n t i o x i d a n t   1 A n t i o x i d a n t   2 × r a d i c a l   s c a v e n g i n g   a s s a y = A 0 − A 1 A 0 × 100
where A0 is the blank absorbance sample, and A1 is the absorbance of SN-SV.

2.3. Topical SN-SV Cream Preparation

The synthesized SN was then dispersed into an oil-in-water emulsion cream using a previously reported method [13]. Stearic acid, KOH, glycerine, propyl, and methylparaben were combined and heated to 65.5 °C to form a base cream. The emulsion cream was cooled to 50 °C with constant stirring until homogeneous, followed by adding a 2% SN-SV to form a drug-loaded topical formulation. The required amount of SN-SV was centrifuged at 1500 rpm, and the precipitated SN-SV was mixed with 50 g of the obtained vanishing cream (2%). The suspension and cream were mixed using a mortar and pestle until they become homogenous. The obtained color of the cream changed from creamy to a faint reddish color.

2.4. Characterization of SN-SV Cream

2.4.1. Evaluation of Emulsion Type

The SN-SV cream was evaluated for emulsion type using a previously reported method [7]. Briefly, 1 g of the cream was accurately weighed, diluted with 30 mL of Millipore water in a 100 mL beaker, and vortexed for 5 min. The homogeneity with water suggested an O/W emulsion and an SN-SV calibration curve was used to evaluate the cream.

2.4.2. Determination of the SN-SV Content

In brief, the quantity of SN-SV in cream was extracted using a mixture of water and methanol (1:1). Then, the SN-SV content was measured using a double beam UV-VIS spectrophotometer-1601 [23].

2.4.3. Cream Homogeneity and Skin Irritation Test

The cream was rubbed on five healthy rats aged two months without SN-SV sensitivity to score the degree of SN-SV erythema and edema from 0 to 4. The homogeneity of the cream was evaluated based on its look and on the behavior of the cream produced by pressing a small quantity of cream between the fingers (thumb and index) [27].

2.4.4. Evaluation of pH and Viscosity Measurement

A digital pH meter was used to determine the cream’s pH (Jenway, London, UK). The SN-SV and plain cream viscosities were evaluated at 28.0 ± 0.1 °C using spindle no. 4 (DV. Ultra, RVDV-111 U, Brookfield, MA, USA) [28].

2.4.5. Ex Vivo Study

Specific dissolving equipment was used for formulation creation and quality control under US pharmacopeias [29]. Six rats were used in this experiment. Dorsal skin samples were collected from each rat and used as a permeated membrane. A hair removal spray was used to remove the hair to facilitate the application of the SN-SV cream on the rat skin. The baskets were housed on the skin for in vitro dissolving tests and were immersed in citrate-phosphate buffer (pH 5.4) in a thermostatic shaker water bath maintained at 37.0 ± 0.5 °C for up to 5 h under continuous stirring at 50 rpm. The release of SN-SV from cream to dissolution buffer was examined spectrophotometrically using a dissolution tester. Samples of 1 mL aliquots were withdrawn regularly and replaced by an equal volume of fresh buffer. The samples were then analyzed spectrophotometrically at λmax 396.46 nm for dissolved content quantification [30].

2.4.6. Physical Stability

The stability of the cream was evaluated for three months in room-temperature storage at 25.0 ± 0.5 °C [31]. No sedimentation or particulate was observed visually, and the nanoparticle concentration was measured spectrophotometrically at λmax 396.46 nm.

2.5. Clinical Scoring of the Skin Lesions

Photographic pictures from all animal subgroups were taken on days 5, 11, and 15 using a digital camera of an iPhone 13 Pro mobile phone (Apple Inc., Los Angleles, CA, USA) and subjected to wound size analysis using the ImageJ software program.

2.6. In Vivo Experimental Study to Investigate the Wound Healing Activity

Forty-five adult male albino rats were randomly divided into three equal groups (n = 15), and each group was subdivided into three subgroups (n = 5) on days 5, 11, and 15 (subgroups 1, 2, and 3), respectively. The hair of the control group (GA), SN group (GB), and SN-SV group (GC) was shaved at day zero to apply the used creams on the skin of all rats. GB and GC were subjected to wound infliction from the dorsal skin surface of each rat at day zero under local anesthesia by a sharp punch biopsy to create a full-thickness surgical wound (0.8 × 0.8 cm) [32]. Vaseline cream was applied to the shaved skin of GA, whereas the wounded skin of GB and GC subgroups were treated with the SN and SN-SV creams, respectively. Another punch biopsy was excised from the dorsal skin of all rats after applying the creams for 5 days (GA1, GB1, and GC1), 11 days (GA2, GB2, and GC2), and 15 days (GA3, GB3, and GC3), respectively. The skin biopsies from all rats were investigated by the standard histopathological (HP) methods of hematoxylin and eosin (H&E) to evaluate the wound healing ability, and proliferating cell nuclear antigen (PCNA) immunostaining was used to evaluate the extent of epidermal re-epithelialization by the SN-SV cream in the GC subgroups compared to the SN cream in the GB subgroups following the skin injury [32,33]. The excised skin specimens (1 cm2) from all subgroups were preserved in 10% normal-buffered formalin and processed to obtain five µm-thick sections. One section from each rat was stained with H&E stain, and another section was stained with the PCNA immunostaining, then examined under a light microscope with a CMOS digital camera (Jinan, China). The skin wounds were subjected to wound size analysis using the ImageJ program and rated into scores (inflammatory cell numbers, amount of granulation tissue formation, and degree of epidermal re-epithelialization). The HP grading of skin wounds followed the reported classification of skin wound lesions by Sedighi et al. from 0 to 4 (none, minor, moderate, marked, and severe) [34].

2.7. Statistical Analysis

The data normality was tested using skewness and Kurtosis tests, revealing normal data distribution. One-way ANOVA test for intergroup comparisons and Student’s t-test for two-group comparisons were applied for statistical data analysis using the SPSS program (version 26). p-values ≤ 0.05 are statistically significant.

3. Results

3.1. Size and Zeta Potential

The SN-SV with reddish color were obtained. The reduction of AgNO3 to SN-SV was completed after 12 h at 25 ± 6 °C due to SV acting as a reducing agent for SN-SV. The diameter of SN-SV (Figure 1A) was recorded as 37.32 ± 1.686 nm. Furthermore, the obtained ζ-potentials of formulated SN-SV were recorded as a negative charge of approximately −15.4 ± 0.72 mV (Figure 1B). The PDI value was recorded as ≈ 0.121, confirming the preparation of a stabilized nanosystem for SN-SV.

3.2. SEM

SEM examination showed different shapes with different diameters. Some particles showed round, cubic, and irregular shapes. These SN-SV had sizes ranging from 60–200 nm (red arrow), while larger particles were around 1 µm (blue arrow) (Figure 2A).

3.3. UV-VIS Spectroscopy

The UV spectrum revealed a λmax of 396.46 for SN-SV (Figure 2B) and displayed a substantial peak in the visible region due to the recorded surface plasmon resonance (SPR) and the layer of SV coating the Ag0.

3.4. Scavenging Efficacy

The radical scavenging efficacy of SN-SV was evaluated against DPPH using quercetin as a control and aqueous (Figure 2C). SN-SV reduced the free radicals at concentrations ranging from 0.3 to 10 mg/mL. Compared to the control samples (quercetin and SV extract), all concentrations of SN-SV from 0.3 to 10 mg/mL exhibited a substantial increase in antioxidant activity. For concentrations of 10, 5, and 0.3125 mg/mL, the scavenging activities of SN-SV were significant (** p ≤ 0.01) compared to aqueous extract. Moreover, the scavenging activities of SN-SV were significant (* p ≤ 0.5) compared to the aqueous extract. The antioxidant activity of SN was improved upon reduction with SV while still lower than quercetin (the standard control).

3.5. Characterization of SN-SV Cream

The base (plain) cream was white, pearly, nongreasy, readily washed with water, and absorbed quickly by the skin. Wound-healing creams, including those containing SN-SV, can be easily applied to the skin. In addition, the cream containing SN-SV was analyzed to determine its type. It was confirmed to be an oil-in-water (O/W) emulsion, as it was easily soluble and washable. After scanning for the appropriate wavelength, SN-SV was calibrated using UV spectroscopy. The appropriate λmax for the prepared formula was 396.46 nm.
y = 0.0018 + 0.0584 ; R 2 = 0.95
The drug content of SN-SV creams was 2 ± 0.5% SN-SV, which was found to be acceptable. As a result, it was determined that the procedure used for cream compositions was appropriate.

3.6. Evaluation of the Formulated Cream

The base and SN-SV creams had skin-compatible pH values. The base and SN-SV cream pH values were 7.145 ± 0.14 and 6.99 ± 0.31, respectively. Additionally, compared to the base cream, the SN-SV creams exhibited much higher viscosity values, indicating that this formulation was better suited for transdermal absorption. Additionally, the base and SN-SV creams showed no lumps and excellent homogeneity. The consistency of both creams was consistent and homogenous regardless of whether it was examined visually or by pressing it between fingers. The cream was homogeneous and included no visible coarse particles or particulate matter. In addition, when administered, the cream formulation did not irritate the skin of five healthy rats, demonstrating that they were not sensitive to SN-SV. We found no evidence of erythema or edema on the palms and forearms of all rats; hence, our total score for these areas is 0. Furthermore, after eight hours, SN-SV permeated successfully across the abdominal skin at 104.36 ± 3.11 µg/cm2. Moreover, the steady-state flux and permeability coefficient was 1.915 ± 0.12 cm/h. The low cream permeability of SN-SV from the designed cream is due to the lower partitioning of the SN-SV cream in the stratum corneum, which promotes drug partitioning into the skin. The trans-epidermal osmotic gradient helps the SN-SV to cross the stratum corneum. Moreover, significant deposition showed that the cream might provide a skin drug reservoir to extend the impact of SN-SV between administrations (Table 1).

3.7. Physical Stability

The SN-SV revealed no color or morphological changes during the investigation. With SN-SV, particle sizes, and potentials did not vary significantly (p ≥ 0.05; ANOVA/LSD). The new SN has almost the same wavelength with only a minimal difference.

3.8. Macroscopic Clinical Scoring of the Wound Size

Wound diameters were measured on days 5, 11, and 15 after treatment with the used creams (Figure 3). The activity of SN-SV cream in wounds treated with the SN-SV cream (GC1, 2, and 3) revealed less wound area compared to the SN cream subgroups (GB1, 2, and 3), which received the SN cream on the same days. The SN-SV cream cured wounds in 15 days (GC3), but GB3 wounds took longer. On day 11, the wound size (31.42.9 mm) of the SN-SV group was statistically significant compared to the wound size (53 ± 1.8 mm) of the GB2. In contrast, the GC3 wounds were 7.2 ± 0.9 mm with normal epithelial tissue, and the GB3 wounds were 28.6 ± 2.5 mm on day 15, as presented in the histogram (H) of Figure 3.

3.9. Histopathological Wound Scoring on Days 5, 11, and 15

Figure 4 showed that GA subgroups (GA1, GA2, and GA3) exhibited normal skin on days 5, 11, and 15, respectively. In contrast, GB subgroups (GB1, GB2, and GB3) revealed inflammatory exudates and hemorrhagic granulation tissue filling the wound gap on days 5, 11, and 15, respectively. In contrast, the SN-SV subgroups (GC1, GC2, and GC3) showed intense inflammation of the wound gap and subcutaneous inflammatory cell infiltration, followed by mild inflammation with significant granulation tissue formation and skin wound re-epithelization on days 5, 11, and 15, respectively. Statistical analysis of the wound scores demonstrated no epidermal growth in the subgroups of day 11 (GB2 and GC2), with granulation tissue development in the GC2 subgroup (Figure 4). Interestingly, a significant improvement of the skin wound healing signs (minimal inflammation and better granulation tissue formation) was noticed in the GC3 subgroup compared to the GB3 subgroup on day 15. Additionally, Figure 5 shows substantial epidermal re-epithelialization (PCNA-positive cells) of the skin wounds in the GC3 subgroup compared to the GB3 subgroup on day 15.

4. Discussion

In the current study, we synthesized SN-SV by reducing Ag+ to Ag0. The silver ions Ag+ are reduced by SV through the loss of an electron, causing the nucleation of neutral silver atoms according to the following redox equation:
Ag+ + e− → Ag0
The SV is an appropriate and beneficial coating material for the adequate preparation of the SN-SV. The prepared SN-SV demonstrated better antioxidant activity and physical stability [35]. The particle size is appropriate for dermal penetration, which agrees with a study reporting that sizes under 100 nm are appropriate for deep skin penetration [36]. Furthermore, Patzelt et al. reported that particle sizes below 122 nm can penetrate significantly deeper into the skin [37]. The ζ-potentials of the prepared SN-SV have a highly negative charge of −15.4 ± 0.72 mV, confirming the solution’s stability. In this regard, it has been reported that higher ζ-potentials also make the particles highly stable. This result agreed with Kaufman et al., who reported that the particle charges play significant roles in the surface stabilization of the SN-SV [38]. Our results also agree with the study of Roto et al., which showed that NP stability could be expected at ζ-potential values of approximately +10 to −10 mV [39]. In contrast, the particles in our study have a charge of −15.4 ± 0.72 mV. The obtained PDI indicated the SN-SV distribution in the solution. It was reported that PDIs lower than 0.2 are ideal because they reveal a particle size distribution within a narrow range of sizes [40].
Herein, the SEM investigations verified the homogeneity of the SN-SV particles, which showed the nature and shape of the non-aggregated SN-SV nanoparticles; furthermore, the SN-SV showed most sizes around 60–200 nm with some nanoparticles around 1 µm. At the same time, the DLS estimates the average size to be 37.32 ± 1.686 nm. DLSs resulting values of the SN-SV sizes differ significantly from the SEM sizes, which are smaller than their sizes by the SEM. These results could be explained by the collapse of the hydrated layer of some particles of the SN-SV during their dryness in the high-vacuum chamber of the SEM. Additionally, our results are consistent with the SEM study of Tarrés et al. [41], who reported that the DLS size is smaller than the sizes of the SEM because the SV coating affects the density of the overall nanoparticles on the SN.
Furthermore, our findings agree with the recent study of Abdellatif et al. [7], which reported that the SN might be aggregated or displayed as an NP surrounded and coated by the SV. In contrast, the coated layer of SV has a larger size of SN-SV. The obtained SN-SV formed an irregular shape, making the particle larger than the rounded one. It was reported that the crystal shape of NPs depends on the distance from the thermodynamic equilibrium. In this regard, the polyhedral shape of SN-SV, such as octahedrons, cubes, and pyramids, has been demonstrated to develop a large size when the driving force for crystallization has increased [24].
SN-SV nanoparticles have scavenging activities and can reduce the free radicals at concentrations ranging from 0.3 to 10 mg/mL. Compared to SV extract as a control sample, all concentrations of SN-SV from 0.3 to 10 mg/mL exhibited powerful antioxidant activities. For concentrations of 10, 5, and 0.3125 mg/mL, the scavenging activities of SN-SV were significant (** p ≤ 0.01) compared to the aqueous extract. Moreover, the scavenging activities of SN-SV were significant (* p ≤ 0.5) compared to the aqueous extract. The antioxidant activity of SN was improved upon reduction with SV while still lower than quercetin (the standard control).
Biosynthesized SN-SV has more robust antioxidant properties than the aqueous root extract of SV. It showed higher inhibition than crude extract at different concentrations. Similar results were reported for the rhizome of Rheum austral, which was collected from Jammu and Kashmir, India, which showed higher antioxidant activity when extracted at ambient temperature compared to its aqueous extract [42]. The extract had a higher level of phenolic and flavonoid contents compared to the AgNPs, leading to an increase in the activity of the biogenic SN-SV nanoparticles [43]. Quercetin had the highest activity level (IC50 = 81.11 ± 2:29 μg/mL) and was used as a positive control. This result agrees with that reported by Khanal et al., who showed that the control antioxidant ascorbic acid still has higher antioxidant activities than other nanoparticles [44]. A separate study reported that biochemically synthesized. SV’s phenolics, flavonoids, terpenoids, and soluble proteins serve as agents for capping the synthesis of SN [45]. The polyphenols in plant extracts can donate electrons, which helps to reduce Ag+ to Ag0 and stabilize the resulting SN-SV [46].
Additionally, the SN-SV had a recognizable absorption peak at ~396.46 nm, likely due to the presence of free electrons that cause the SPR band to resonate, suggesting the activation of the SPR of the formed SN-SV [47]. The SN-SV cream was also applied ex vivo to verify SN-SV skin penetration. The obtained ex vivo skin permeation predicts in vivo research findings. The cream application showed skin penetration of more than 70%. These results imply that topical treatment with SN-SV might quickly ameliorate self-recognizable signs of some skin disorders, leading to morphological observations, such as improved skin texture and decreased wrinkles. Moreover, the SN-SV cream can promote skin smoothness and moisturization. Ortega et al. formulated a topical cream containing the SV extract only. The resulting cream had antibacterial activity against Staphylococcus aureus, Pasteurella multicoda, E. coli, and Bacillus subtills, which could make it an excellent wound-healing treatment [48]. Furthermore, the SV plant can treat wounds due to its potent antioxidant properties [49].
At the same time, the HP results of the present study showed clear improvements in the various stages of wound healing (inflammation, granulation tissue formation, and skin re-epithelialization) on days 5, 11, and 15 among the GC subgroups compared to the GB subgroups, indicating the potent anti-inflammatory and proliferative effects of the SN-SV cream on the wound healing process. These results were confirmed by prior research, which demonstrated increased NP aggregation and enhanced the wound-healing process [50]. Other studies reported that SN-SV synthesis could lead to more effective wound healing, as silver enhances wound-healing activity. The decreased NP-bacterial interactions result in the anti-inflammatory and proliferative effects of SN-SV against the hazards of skin-wound infection [51]. Additionally, the SN-SV combination could enhance wound healing by stimulating cell proliferation and fibroblasts migration during the wound-healing process [52]. It could reduce the activity of the myeloperoxidase (MPO) enzyme, which is involved in the induction of skin inflammation [53]. Overall, our findings could be related to the principal ingredients (carvone (49.9%), limonene, and linalool) of SV, which exhibit potent antioxidant, anti-inflammatory, proliferative, and antibacterial activity against Staphylococcus aureus and candidiasis [54].

5. Conclusions

Our current study revealed that using the green synthesis reduction approach of SV and SN formed functional nanoparticles (SN-SV), which showed a substantial antioxidant activity compared to the potent antioxidant activity of quercetin. The treatment regime of skin wounds in rats by synthesized SN-SV cream showed promising results for improving wound healing by reducing skin inflammation and enhancing good granulation tissue formation with full epidermal re-epithelialization. Hence, we proposed that the SN-SV cream could be a novel product for skin wound therapy.

Author Contributions

Conceptualization, A.A.H.A. and A.M.M.; data curation, F.A.A.; formal analysis, N.S.T. and A.M.M.; funding acquisition, A.A.H.A.; investigation, A.A.H.A. and N.S.T.; methodology, A.A.H.A., N.S.T. and A.M.M.; project administration, A.A.H.A., O.A.R. and F.A.A.; resources, A.M.M.; software, A.A.H.A., O.A.R. and F.A.A.; supervision, O.A.R. and F.A.A.; validation, A.A.H.A. and A.M.M.; visualization, O.A.R.; writing—original draft, A.A.H.A., F.A.A., N.S.T. and A.M.M.; writing—review and editing, A.A.H.A. and A.M.M. All authors have read and agreed to the published version of the manuscript.

Funding

The authors gratefully acknowledge Qassim University, represented by the Deanship of Scientific Research, on the financial support for this research under the number (10108-pharmacy-2020-1-3-I) during the academic year 1441 AH /2020 AD.

Institutional Review Board Statement

All animals were treated following the guidelines adopted by the US National Institutes of Health for the Care and Use of Laboratory Animals. Approval was granted by the Ethics Committee of Qassim University (10108-pharmacy-2020-1-3-I).

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available upon request from the corresponding author.

Conflicts of Interest

All authors declare that they have no conflict of interest.

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Applsci 13 06912 g001 550
Figure 1. (A) Particle size distribution of the prepared SN-SV, (B) ζ-potentials recorded as the charge of the formulated formed SN-SV.
Figure 1. (A) Particle size distribution of the prepared SN-SV, (B) ζ-potentials recorded as the charge of the formulated formed SN-SV.
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Applsci 13 06912 g002 550
Figure 2. (A) SEM image of prepared SN-SV. The size ranged from 60–200 nm (red arrow), while larger particles were around 1 µm (blue arrow). (B) UV-VIS spectroscopy of SN-SV, and (C) SN-SV scavenging activity (%) with DPPH. (#) Quercetin was higher compared SN-SV and the aqueous extract. (** p ≤ 0.01) SN-SV was significant compared to the aqueous extract. (* p ≤ 0.5) SN-SV was significant compared to the aqueous extract.
Figure 2. (A) SEM image of prepared SN-SV. The size ranged from 60–200 nm (red arrow), while larger particles were around 1 µm (blue arrow). (B) UV-VIS spectroscopy of SN-SV, and (C) SN-SV scavenging activity (%) with DPPH. (#) Quercetin was higher compared SN-SV and the aqueous extract. (** p ≤ 0.01) SN-SV was significant compared to the aqueous extract. (* p ≤ 0.5) SN-SV was significant compared to the aqueous extract.
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Applsci 13 06912 g003 550
Figure 3. Skin photographs from all rat subgroups, showing the mean skin wound size on days 5, 11, and 15. Histogram (H) presents all subgroups’ mean ± SD of the skin wound size. GB2 and GB3 vs. GC2 and GC3 reveal a significant difference (* p ≤ 0.5).
Figure 3. Skin photographs from all rat subgroups, showing the mean skin wound size on days 5, 11, and 15. Histogram (H) presents all subgroups’ mean ± SD of the skin wound size. GB2 and GB3 vs. GC2 and GC3 reveal a significant difference (* p ≤ 0.5).
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Applsci 13 06912 g004 550
Figure 4. Photographs from the skin sections of all rat subgroups, showing the parameters of skin wound healing (the inflammatory cells (IC) and the granulation tissue formation) on days 5, 11, and 15. GA1, 2, and 3 show normal skin epidermis (EP) and papillary dermis (PD) layers. Obvious improvement of the skin wound healing signs (minimal inflammation and better granulation tissue) is noticed in the GC2 and GC3 subgroups compared to the GB2 and GB3 subgroups. The histogram (H) presents the mean ± SD of the IC numbers and the scores of granulation tissue formation in all subgroups. *: GB2 and GB3 vs. GC2 and GC3 reveal significant differences (p ≤ 0.05).
Figure 4. Photographs from the skin sections of all rat subgroups, showing the parameters of skin wound healing (the inflammatory cells (IC) and the granulation tissue formation) on days 5, 11, and 15. GA1, 2, and 3 show normal skin epidermis (EP) and papillary dermis (PD) layers. Obvious improvement of the skin wound healing signs (minimal inflammation and better granulation tissue) is noticed in the GC2 and GC3 subgroups compared to the GB2 and GB3 subgroups. The histogram (H) presents the mean ± SD of the IC numbers and the scores of granulation tissue formation in all subgroups. *: GB2 and GB3 vs. GC2 and GC3 reveal significant differences (p ≤ 0.05).
Applsci 13 06912 g004
Applsci 13 06912 g005 550
Figure 5. Shows the skin wounds’ epidermal re-epithelialization (positive PCNA cells) on day 15. The histogram (H) presents the mean ± SD of the positive PCNA cells number/five HPF (high power field) in all subgroups. GB2 and GB3 vs. GC2 and GC3 reveal a significant difference (* p ≤ 0.05).
Figure 5. Shows the skin wounds’ epidermal re-epithelialization (positive PCNA cells) on day 15. The histogram (H) presents the mean ± SD of the positive PCNA cells number/five HPF (high power field) in all subgroups. GB2 and GB3 vs. GC2 and GC3 reveal a significant difference (* p ≤ 0.05).
Applsci 13 06912 g005
Table
Table 1. Ex vivo penetration of SN-SV from designed topical SN-SV cream, as well as formulation and assessments of SN-SV.
Table 1. Ex vivo penetration of SN-SV from designed topical SN-SV cream, as well as formulation and assessments of SN-SV.
FormulationpHViscosity
(cPs)		HomogeneityPermeated Quantities
(µg/cm2)		Flux
(mg/cm2/h)		Apparent Permeability Coefficient (cm/h)
Base cream7.11 ± 0.129801 ± 140Good0.46 ± 0.91.01 × 10 − 3 ± 0.0010.009 ± 0.001
SN-SV cream7.01 ± 0.3115,501 ± 320.01Good104.4 ± 3.1135.6 × 10 − 3 ± 0.0021.91 ± 0.12
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Abdellatif, A.A.H.; Rugaie, O.A.; Alhumaydhi, F.A.; Tolba, N.S.; Mousa, A.M. Eco-Friendly Synthesis of Silver Nanoparticles by Nitrosalsola vermiculata to Promote Skin Wound Healing. Appl. Sci. 2023, 13, 6912. https://doi.org/10.3390/app13126912

AMA Style

Abdellatif AAH, Rugaie OA, Alhumaydhi FA, Tolba NS, Mousa AM. Eco-Friendly Synthesis of Silver Nanoparticles by Nitrosalsola vermiculata to Promote Skin Wound Healing. Applied Sciences. 2023; 13(12):6912. https://doi.org/10.3390/app13126912

Chicago/Turabian Style

Abdellatif, Ahmed A. H., Osamah Al Rugaie, Fahad A. Alhumaydhi, Nahla Sameh Tolba, and Ayman M. Mousa. 2023. "Eco-Friendly Synthesis of Silver Nanoparticles by Nitrosalsola vermiculata to Promote Skin Wound Healing" Applied Sciences 13, no. 12: 6912. https://doi.org/10.3390/app13126912

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