Eugenol-Based Polymeric Materials—Antibacterial Activity and Applications

1. Introduction

Eugenol (4-allyl-2-methoxyphenol, EUG) (Scheme 1), a volatile naturally occurring phenol, is present in extracts of many botanical species. EUG has been identified in essential oils of cinnamon, bay and tulsi leaves, turmeric, nutmeg, and the most eugenol-rich clove Syzygium aromaticum (45–90% of 4-allyl-2-methoxyphenol) [1,2]. The antimicrobial, antifungal, antioxidant, anticancer, anti-inflammatory, analgesic, repellent, and insecticidal activities of this compound are well known. Because of those beneficial features, eugenol has been employed in food processing and biomedical industries and in a wide range of pharmaceutical, cosmetic, and dental care applications [1].

Bioactive compounds with antimicrobial activity, such as EUG, can be an alternative to antibiotics against many microbial pathogens, and thus reduce the increasing resistance of microorganisms to antibiotics. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of eugenol against selected pathogenic bacteria were found to be, respectively, 0.0312–8 μg/mL and 0.0625–16 μg/mL [3]. Eugenol showed significant antimicrobial activity against Escherichia coli (MIC = 0.125 μg/mL; MBC = 0.250 μg/mL). The time kill curve revealed a rapid reduction in E. coli to undetectable levels in the presence of EUG. It was postulated that the compound alters cell membrane permeability, leading to the leakage of intracellular contents. The disruptive action of EUG on the cytoplasmic membrane was demonstrated by measurements of intracellular ATP. The MIC value of eugenol was enhanced in the presence of divalent cations, and an increase in the bacterium membrane depolarization was observed. Microscopic studies proved morphological and physiological changes in E. coli caused by 4-allyl-2-methoxyphenol. After membrane disruption, eugenol may further interact with the intracellular organelles causing complete damage to bacterial cells (Scheme 2).

Interestingly, the effectiveness of antimicrobials (including eugenol) depends not only on their overall concentration but also on the time used to reach that concentration. Some microorganisms may become more tolerant when treated with lower concentrations of EUG. This may be particularly important for encapsulated antimicrobial systems, where the active substances are released gradually and their minimal lethal concentration (MLC) levels are only reached after a certain period of time. Adaptation to the environmental stressor involves membrane composition changes, which make the microbial cells more resistant.

The time between antimicrobial sublethal doses was shown to have a significant effect on the efficacy population dynamics of Staphylococcus carnosus, Listeria innocua, Escherichia coli K12, and Pseudomonas fluorescens exposed to MLC of eugenol (initially, or to half doses over time) [5]. As expected, complete cell reduction occurred after immediate exposure to the full MLC dose, regardless of the type of microorganisms. The high antimicrobial efficacy of EUG on E. coli K12 was independent of the timing of the two doses. For other tested strains, the effect of sequential dosing varied significantly. The effectiveness of EUG against S. carnosus and L. innocua was lower the later the second half dose was applied. In the case of P. fluorescens, a single MLC dose of EUG reduced the number of cells below the detection level, while the sequential application of two half doses had only a bacteriostatic effect. Less severely stressed microbial populations developed resistance to EUG. To minimize such an adaptation, two consecutive half-doses should be applied fairly quickly, and exposure to low levels of stress should be avoided.

The application of several different stressors (e.g., two different antimicrobials [6] or an antimicrobial and high/low temperature [7]) simultaneously or sequentially may be a solution to avoid the phenomenon of acquired resistance. For example, the application of two antimicrobials, eugenol and lauric arginate (LAE), against S. carnosus, L. innocua, E. coli K12, and P. fluorescens was most effective if they were added simultaneously at MLC and at the beginning of the incubation period [6]. The treatment with first eugenol and then LAE at half of their MLC was efficient against S. carnosus and P. fluorescens but no sequence effects were observed against L. innocua and E. coli K12. These results were attributed to the adaptation of cells after treatment with the first active agent, which provided better protection against the second antimicrobial.

Using temperature as a second stressor, the effectiveness of treatment with a sublethal dose of EUG against S. carnosus LTH1502 and E. coli K12 C600 depended on the timing and sequence of application [7]. Differences were observed between simultaneous and sequential treatments, and also according to the type of bacteria. Initial treatment with EUG followed by a temperature change was more effective than the first temperature/later EUG option, presumably due to temperature-induced adaptation processes in cell membranes. The combined treatment was also more effective against G- E. coli than against G+ S. carnosus.

4-Allyl-2-methoxyphenol contains three active sites in its structure: hydroxyl, allylic, and aromatic groups. It makes EUG an important starting material for the total synthesis of valuable natural products and novel drugs [1,8]. The phenol group endows eugenol not only with antimicrobial activity but also with the ability to scavenge reactive oxygen species. Apart from the bioactivity, eugenol also has significant potential as a natural, biobased building block in green technologies leading to sustainable materials. It can be obtained not only from essential oils but also from the depolymerization of lignin, and it has been used for the synthesis and modification of a wide range of polymers [9]. However, the application, processing, and storage of eugenol can be complicated due to its strong volatility, instability, and low solubility in water. The incorporation of EUG in macromolecular structures is an efficient strategy for the development and prolonged use of this volatile active substance. Polymers and composites with incorporated eugenol molecules include polyesters, polyurethanes, polyacrylates, epoxy, and polyolefins [10]. They often exhibit good barrier properties and thus have applications in the coating and packaging industries. Inexpensive, non-toxic, and environmentally friendly eugenol-based polymeric resins exhibit attractive properties such as thermal stability, water resistance, and flame retardancy [11]. Moreover, polymeric materials of different types (Scheme 3) can be used as carriers of EUG, either in their free form or bound to macromolecular structures. This article presents an overview of developments in the synthesis, pharmacological and antimicrobial properties, and applications and further perspectives of macromolecular systems containing or derived from eugenol.

2. Discussion

2.1. Eugenol-Based Polymers and Composites for High-Performance Antimicrobial Coatings

Polymers obtained with the use of eugenol are receiving growing interest because of their sustainability and enhanced physicochemical characteristics. The development of such polymeric materials designed to control bacterial biofilm growth is an important practical approach. They can be used to generate bacteria-repellent or antibacterial coatings aimed at preventing bacterial colonization. EUG-derived polymers can be used as coatings in a wide range of applications [13]. Excellent thermosetting materials were also obtained with monomers that are derivatives of eugenol [14,15]. For example, eugenol molecules were transformed into 4,4′-(butane-1,4-diyl)bis(2-methoxyphenol) by the Ru-catalyzed olefin metathesis coupling reaction [16]. The product was then converted into a polycyanurate thermoset resin that exhibited a glass transition temperature (T_g) of 186 °C and was thermally stable above 350 °C. The water uptake of the cured material was only 1.8% after immersion in hot water (85 °C) for four days. The high hydrolytic stability makes this polymer well-suited even for maritime environments. EUG molecules can also be transformed into other monomers suitable for the free radical polymerization reaction, including EUMA—eugenyl methacrylate, and thus particles of poly(DMA-co-EUMA) (DMA—dopamine methacrylamide) were obtained via precipitation copolymerization [17]. The antibacterial activity test against E. coli showed a >90% antibacterial rate of PD5E5 and PD3E7 particles (5:5 and 3:7 molar ratios of DMA to EUMA). Another derivative of eugenol—4-allylpyrocatechol—was used for the preparation of photocurable polymer networks of high macroscopic adhesion to glass, marble, aluminum, and steel [18]. Eugenol was also used for the synthesis of environmentally sustainable polybenzoxazines [19], polybenzoxazine-POSS nanocomposites [20], and analogues of urushiol [21] of superior adhesion, mechanical strength, and antioxidant properties. These polymerization processes are green and do not involve the evolution of volatiles.

Eugenol-derived polymers are also capable of self-healing, which is a very important feature regarding the stability of coating materials that affect their antimicrobial/antibiofilm performance. The process can be based either on thiol-oxidation reactions [22,23,24] or hydrogen bonding [25]. Interestingly, eugenol derivatives can take part in a self-healing process through mechanisms based on the formation of multiphase structures in polymer composites. A biobased molecular glass (ET-eugenol) obtained by thermochemical conversion of epoxidated eugenol and then incorporated into the matrix of polymerized soybean oil (p-ESO) can be an example [26]. The scratch damage on the surface of ET-eugenol/p-ESO (1:2 wt./wt.) composite was healed at 90 °C within 15 min or by UV radiation within 20″ effectively (efficiency up to 88%) and without a dimension change (Figure 1). Furthermore, the incorporation of ET-eugenol improved the mechanical properties of the p-ESO matrix as comparative tensile tests of these materials showed a 2.7-fold increase in ultimate stress.

Figure 1. (A) Atomic force microscopy images of the damaged surface of ET-eugenol/p-ESO sample (mass ratio of 1:2) and the process of its thermally induced self-healing with time and (B) proposed explanation of the healing mechanism via the diffusion-driven bonding of ET-eugenol near the damaged interfacial region. Reprinted with permission from [26]. Copyright {2020} American Chemical Society.

The synthesis reactions of some EUG-based polymers involved phenolic groups, which may inevitably lead to a partial loss of the antioxidant activity of eugenol. Nevertheless, several systems of this kind showed significant antimicrobial activity. For example, water-insoluble polyeugenol of a high molecular mass (~10 kg mol⁻¹, DP = 60) was synthesized by cationic polymerization and showed antibacterial activity with a slow response against E. coli and S. aureus [27]. Polyeugenol of a high molecular weight (~800–2200 kg mol⁻¹) was also tested against S. aureus and E. coli [28]. The antibacterial action was evaluated with the well diffusion method at 1, 2, 3, 4, and 5% concentrations to observe inhibition zones of 17.42, 17.76, 18.79, 21.42, and 22.55 mm for S. aureus and 15.87, 17.23, 17.56, 18.24, and 19.21 mm for E. coli. These results indicate that antibacterial activity was rather strong. It was supported by the strong antioxidant activity of the polymer indicated in the tests against free radical DPPH (2,2-diphenyl-1-pycrylhydrazyl), which resulted in an IC₅₀ value of 80.47 µg/mL.

Eugenol-derived polymeric films (EDF) can be deposited on stainless-steel surfaces using atmospheric pressure plasma discharge [26]. Scanning electron microscopy showed that the entire surface of the substrate was covered with circular structures of ~10–20 µm in diameter. FT-IR spectra showed that the hydroxyl and aromatic groups, which are key features for the antibacterial activity of native eugenol, were preserved. An increase in the hydrophilicity of the surface after the deposition was revealed. EDF deposits can be potentially of use in coating processes for biocompatible materials. The adhesion and proliferation of E. coli and S. aureus on EDF surfaces were inhibited by more than 78 and 65%, respectively, in comparison with control polystyrene plates (Figure 2).

Figure 2. Concentration of S. aureus and E. coli on (a) as-received stainless-steel supports, (b) immersed for 45 min in liquid eugenol, and (c) coated with EDF for 45 min (—bacteria concentration in the initial inoculum) [29]. Copyright (2021), with permission from Elsevier.

Eugenol was also used for the chemical modification of inorganic and organic polymeric materials. Hydrosilylation of the alkyl group in eugenol with hydrogen-containing MQ silicone resin (M: monofunctional and Q: tetrafunctional siloxane units) resulted in a hybrid bio-phenol MQ silicone resin (BPMQ) [30]. The thermal stability of BPMQ was significantly improved. The maximum degradation rate increased from 250 °C (MQ precursor) to 422.5 °C (BPMQ) due to the modification with EUG. The mass of residual yields left at 600 °C increased accordingly, from 2.0% (MQ) to 28.3% (BMQ). The resin was also investigated for its antibacterial properties against E. coli, markedly enhanced as a result of EUG grafting (Figure 3). Hybrid materials of this type can be used for biomedical silicone rubber products or pressure-sensitive adhesives.

Figure 3. Antimicrobial activity presented by changes in agar plate cultures: The blank group (a), HMQ (b), eugenol (c), and BPMQ (d) [30].

As an example of organic macromolecules grafted with EUG, the eugenol-methacrylate monomer with the free phenol group preserved was polymerized and copolymerized at different concentrations with 2-hydroxyethyl methacrylate (HEMA) [31]. The obtained amorphous homopolymer (pEUMA) and copolymers (pHEMA-EUMA) were equally thermally stable as pHEMA but much less swellable in water. Flexible pEUMA exhibited good elastic properties, even at high deformation frequencies (up to 80 Hz). Owing to the presence of phenol functions, the polymers acted as radical scavengers and showed antimicrobial activity towards Staphylococcus epidermidis. Bacterial growth was gradually reduced by increasing the EUMA content to 30% (~20% bacterial growth (BG) vs. 100% BG for the control sample and pHEMA). Nevertheless, higher amounts of the eugenol derivative did not bring further enhancement of the antimicrobial properties (~25% BG for pHEMA-EU50).

EUMA was also used for the preparation of a polymer for self-polishing antifouling coatings [32]. The self-cleaning process involved hydrolysis of the phenolic ester group with the release of eugenol molecules. As a result, the surface energy of the coating increased as the hydrophobic surface was transformed into hydrophilic. EUG was released from the coating most rapidly at the beginning of immersion in artificial seawater, but after 15 days, the process had stabilized (0.48 μg·cm⁻²·day⁻¹ and 0.14 μg·cm⁻²·day⁻¹, respectively, observed for the sample with the highest release rate). The resin has good antibacterial and anti-algae properties. Coatings with high eugenol content were also avoided by mussels Mytilus edulis.

Essential oils (EO), such as eugenol, can be also physically blended with various polymers. The structural stability of such materials and their antimicrobial performance are limited by the phase separation phenomena, especially if there are no specific interactions between EUG and the polymer matrix. For example, poly(ethylene-co-vinyl acetate) copolymer (EVA) films containing citronellol, eugenol, and linalool were prepared and evaluated for their antimicrobial and antibiofilm action against Listeria monocytogenes, S. aureus, Staphylococcus epidermidis, E. coli, and P. aeruginosa (mono- and dual-species tests) [33]. The addition of the essential oils influenced the mechanical properties of EVA (15% elastic modulus decrease, 30% tensile strength decrease, 10% elongation at break increase). EVA/citronellol and EVA/eugenol at 7 wt% of the essential oils content showed the best inhibition of bacteria growth (30–60% and 15–30%, respectively, after 24–48 h of incubation). However, in both cases, the inhibition decreased after 240 h of incubation. Antibiofilm action of the composites was strong, even after prolonged incubation time. A 40–70% decrease in the bacterial biomass of L. monocytogenes, S. aureus, and E. coli was found for the EVA/EO composites in comparison with the pure EVA control. Interestingly, better results were achieved with EVA/eugenol than EVA/citronellol when inoculated simultaneously with combinations of S. aureus and E. coli. The biomass accumulated was higher (EVA + citronellol) or lower (EVA + eugenol) than that in monoculture biofilms. Similar findings were obtained with measurements of the metabolic activity of viable cells with 2,3-bis [2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide assay.

Eugenol can be also used to modify natural biopolymers or green synthetic polymers obtained from renewable resources, such as chitosan, with well-known antimicrobial and therapeutic activity. A chitosan-based polybenzoxazine monomer was synthesized in water and then crosslinked by thermal treatment via ring-opening polymerization to form free-standing polymer films [poly(E-Ch)] [34]. Hydrogen bonding interactions between chitosan and polybenzoxazine macromolecules resulted in an enhancement of the thermal and mechanical properties (T₁₀ of ~260 °C; ε′ of ~3.6 GPa; and T_g of ~135 °C). The poly(E-Ch) was found to be effective in preventing bio-film-associated infections (S. aureus and Candida albicans). Films made of chitosan and poly(vinyl alcohol) (PVA) (ratio 30/70 w/w; 9 wt%) were prepared by the solvent casting and phase inversion method and then supplemented with 1 and 10 wt% of EO [35]. The film thickness and degree of swelling increased with the EO content. The chitosan films alone exhibited antimicrobial properties and were able to eradicate P. aeruginosa within one hour. Yet, chitosan/PVA films loaded with EUG showed significantly improved antimicrobial action within 2 h of contact, particularly against S. aureus, compared to the corresponding unloaded samples. Such materials could potentially be used in the treatment of chronic wounds.

Eugenol was also grafted to the copolymer of carboxymethyl cellulose (CMC) and cysteamine hydrochloride (CYST) by the thiol-ene click reaction between the allyl group of EUG and mercapto-groups of CYST [36]. The resulting amphiphilic polymer (CMC-CYST-EUG) showed a 7.8-times longer duration of antimicrobial activity compared to pure EUG under the same environmental conditions. Cytotoxicity tests show that the polymer is safe at low concentrations. CMC-CYST-EUG can also increase the shelf life of fruits and vegetables owing to their good adhesion. The efficacy of CMC-CYST-EUG in pest control was significantly higher than that of EUG.

In summary, inorganic and organic macromolecular systems functionalized with eugenol, both as a building block and as a doping additive, show interesting physicochemical, mechanical, and antimicrobial properties. This approach increases the potential contact time of eugenol with pathogenic micro-organisms and increases the efficiency of their inactivation. Of particular interest is the possibility of using eugenol for antimicrobial modification of ‘green’ biopolymers.

2.2. Eugenol-Based Materials for Food Packaging

Bioactive and biodegradable hybrid materials are a very interesting solution for, e.g., environmentally friendly food storage [4,37,38]. Packaging technologies have to meet growing demands regarding the extended shelf-life and good quality of products, especially fresh or low-processing food. The improvement of food preservation via the design of new technologies incites growing interest in biocompatible and preferably biodegradable antimicrobial/antibiofilm materials. The process of making “green” polymeric materials for active packaging is related both to the type of matrix and the incorporated additives.

It was shown in the tests performed with selected bacterial strains isolated from dairy products (E. coli, S. aureus; Bacillus pumilus, Bacillus subtilis, Bacillus tequilensis, and Stenotrophomonas maltophilia) that biodegradable polymer films of poly(lactic acid) (PLA), poly(butylene adipate-co-terephthalate) (PBAT), and poly(butylene succinate) (PBS) have a varying propensity for biofilm growth [39]. Neat PLA was less prone to biofilm settlement than PBS. The antimicrobial activity and the reduction in biofilm formation on polymer films were improved upon the inclusion of thymol and eugenol into these materials. Biofilm formation was not detected on polymer films with incorporated antimicrobial compounds.

On the other hand, polylactide-based materials covalently grafted with eugenol did not exhibit high antimicrobial action [40]. The polymers were synthesized by homopolymerization reactions of eugenol-bearing L-malic acid-derived O-carboxyanhydride (L-MalOCA) or its copolymerization at two different ratios with the L-lactic acid-derived OCA (L-LacOCA) monomer. The thermal properties of the resulting polymers depended on the content of L-MalOCA. The antimicrobial activity of the hybrid materials against common food-related bacteria, namely E. coli, Pseudomonas aeruginosa, S. aureus, and B. cereus, was tested. The action of the eugenol-rich poly(L-MalOCA) product was detected against S. aureus and B. cereus, and to a minor extent, against P. aeruginosa. No inhibition was found in tests against E. coli.

Eugenol, cinnamaldehyde (CIN), and carvacrol (CAR) were added to enhance the antimicrobial properties of zein-based materials [41]. Polyethylene glycol (PEG) and oleic acid (OA) were used as plasticizers to improve the mechanical properties of zein. Compared to OA, PEG efficiently improved the tensile strength and elongation (%E) of zein films but induced weaker water barrier properties. The EO-embedded zein films demonstrate a gradual release of EO (up to 96 h) and showed even better antimicrobial effects against S. aureus and E. coli than neat EO in a filter paper sample (FPS). This can be explained by the difference in release rates for EO in zein-PEG and FPS. The chemical associations lead to a controlled release of EO. EO interacts with zein through weak chemical bonds and their molecules are chemically entrapped in the zein film, thus the evaporation rate is low. The strongest antimicrobial effect was noted for CIN (16.67 mm inhibition zone against S. aureus for zein/PEG with 5% CIN and 4.67 mm for pure CIN). CAR was active only at a concentration of 3% in zein-PEG, and it was comparably effective toward both bacteria. Unfortunately, EUG showed no inhibitory effect against S. aureus and E. coli at the 1% and 3% concentration levels, respectively. Tests at 8% of EUG indicated that the G- bacterium E. coli was more sensitive to EUG than G+ S. aureus, either entrapped in zein-PEG or in pure form in FPS.

Eugenol was also added to improve the antimicrobial properties of a blend of PLA and zein of improved mechanical and barrier properties (elongation, tensile strength, water vapor, and gas permeabilities) [42]. EUG significantly inhibited the growth of both S. aureus and E. coli. The migration tests of eugenol from the polymer composites into distilled water and three food simulants (10% (v/v) ethanol simulating hydrophilic food, 50% (v/v) ethanol for lipophilic products, and 3.0% (w/v) acetic acid solution for acidic hydrophilic products with pH < 4.5) were conducted (Figure 4). Interestingly, the results illustrated the different actions of various types of food on the migration rates of eugenol. The EUG migration rate was controlled by zein. In the case of hydrophilic food, it was generally faster for materials with a higher content of PLA, and transport of EUG in this case was slowed down by zein nanoparticles. EUG molecules moved most rapidly in the environment simulating lipophilic products. In such systems, hydrophobic interactions of both zein and eugenol with the stimulant exist. The migration of lactic acid (LA), that is the degradation product of PLA, to water and three different food simulants depended on the content of PLA, but the amount was generally low (<2.5 mg/dm² in 5 days). This demonstrates the lack of degradation of the polylactide by eugenol.

Figure 4. EUG migration from the PLA/zein films to (A) deionized (DI) water, (B) 3.0% (w/v) acetic acid solution, (C) 10% (v/v) ethanol, and (D) 50% (v/v) ethanol; compared to lactic acid (LA) migration under the corresponding conditions: (E) DI water, (F) 3.0% (w/v) acetic acid solution, (G) 10% (v/v) ethanol, and (H) 50% (v/v) ethanol. Ref. [42] Copyright (2022), with permission from Elsevier.

Gelatine (GL)/chitosan (Ch)-based active, biodegradable, and edible films and coatings containing eugenol and oregano (Origanum vulgare) essential oil (OEO) in different OEO:EUG ratios were designed for food preservation [43]. Retardation of the oxidative processes and the growth of pathogenic microorganisms (S. aureus and E. coli) on the surface of food (e.g., fresh cheese) could be achieved. The optimal activity of systems containing 0.50% EUG  +  0.50% OEO and 0.25% EUG  +  0.75% OEO is attributable to the synergistic antimicrobial effect of EUG, OEO, and Ch. The water vapor barrier properties in OEO-containing films were markedly enhanced despite a slight phase separation in the hybrid materials, especially with the high OEO:EUG ratio. The observed higher moisture content and water solubility values can be related to the morphology of those coatings. The optimal film structure (a sample with 0.5% wt/wt of OEO  +  0.5% wt/wt of EUG content) correlated with preservation properties of coatings that were tested on fresh cheese during 14 days of storage at 4 °C. However, none of the tested coatings prevented WL (freshness) in the cheese samples.

The eugenol content of physical blends with biocompatible polymers is not high since larger amounts of EUG cannot be retained by the polymer matrix. It is thus desirable to introduce an ingredient that traps the eugenol molecules. For example, eugenol can form inclusion complexes with β-cyclodextrins (βCD). The formation of host-guest interactions was exploited for the preparation of a water-absorbent antibacterial mat, made of electrospun fibers composed of polylactic acid-β-cyclodextrin/eugenol (PLA-β-CD/EUG), a super absorbent polymer (SAP), and filter paper [44]. The mats were shown to restrain the growth of S. aureus, E. coli, P. aeruginosa, L. monocytogenes, Bacillus pyocyaneus, and Salmonella typhimurium. Comparative EUG release tests from PLA-β-CD/EUG and PLA-EUG fiber membranes demonstrated that the maximum release time for the latter was 4-fold lower. Stable release profiles were then observed for both samples over a period of up to 40 min. The slower and steady EUG release profile of PLA-β-CD/EUG fiber membranes can be attributed to host–guest interactions between EUG and β-CD. In addition to the demonstrated inhibitory effect on both G+ and G- bacteria, the water-absorbent antibacterial PLA-β-CD/EUG mats had a longer-lasting EUG release effect in different food simulants. The slowest eugenol delivery was found for oily food, which may be promising in meat preservation.

Fish gelatine mats containing cinnamaldehyde (CEO), limonene (LEO), and eugenol at 1, 3, and 5% with β-cyclodextrins at an equimolar ratio were prepared from electrospun fibers [45]. It was expected that the diverse structure of EO molecules (aldehyde, terpene, and phenol derivatives) would cause different interactions with βCD. The presence of essential oils did not disturb the morphology of fibers (defect-free) but reduced their mechanical properties (tensile strength and elongation at break), despite the improvement in the gelatine melting temperature by 3 to 13 °C. Although all three types of gelatine mats showed similar antifungal activity at 5% concentration of essential oils, their antibacterial properties depended on the type of EO additive. The highest radical scavenging activity (96.5%) was obtained with EUG, while cinamaldehyde resulted in the highest inhibition zone (27.73 mm). The functional stability of the developed mats and a slow release of EOs for 60 days at ambient temperature were noted, which indicates the applicative potential as active antimicrobial packaging for low-to-intermediate moisture foods.

Packaging materials with EUG molecules built into the macromolecular system were also obtained. Polymacrolactones with pendant eugenol moieties were prepared via the functionalization of poly(6HDL-co-PDL) copolymers of random structure that were obtained in ring-opening copolymerization of ω-6-hexadecenlactone (6HDL) and ω-pentadecalactone (PDL) carried out in the presence of a pyridylamidozinc(II) complex [46]. Eugenol was converted into 4-(3-mercaptopropyl)-2-methoxyphenol (TE) and then grafted by thiol-ene addition to the unsaturated C=C bonds of 6HDL units in poly(6HDL-co-PDL). The structure and thermal properties of the final products were modulated by the amount of eugenol-derived side groups. The antimicrobial activity of TE-functionalized copolymers against E. coli was also dependent on the content of TE units in the films.

Copolymers of eugenol-trithiol methylenebisacrylamide (E3TMBA) and eugenol-trithiol, allyl eugenol (E3TAE) of high thermal stability (5.0% mass loss at 179 °C for E3TMBA and 255.9 °C for E3TAE) were synthesized via solvent-free photopolymerization of eugenol and trithiol with methylenebisacrylamide (MBA) and allyl eugenol (AE) as crosslinkers [47]. E3TMBA and E3TAE were moderately hydrophilic (contact angle values (θ) of 74° and 58.4°, respectively). They exhibited glass transitions at 48 °C and 30 °C, respectively. The trend correlated with their mechanical properties (tensile strength of 0.463 MPa and a 6% elongation recorded for E3TMBA and 0.378 MPa/33% for E3TAE). The antibacterial activity against E. coli (12/24 h inhibition values: 46.65%/77.04% (E3TMBA) and 55.7%/83.04% (E3TAE)) and S. aureus (12/24 h inhibition values: 64.11%/82.06% (E3TMBA) and 68.8%/80.04% (E3TAE)) was good, which is promising for their food packaging potential.

Eugenol and three dithiols of various structures were used for the preparation of macromolecular antioxidants (MAOs), subsequently applied as additives to poly(vinyl alcohol) (PVA) [48]. The polymer main-chain morphology and properties were tuned by the structure of dithiols. Mono-phenolic and catechol moieties from EUG were distributed along the polymer backbone, with coexisting thioethers, oxyethers, or vicinal diol groups. Macromolecules with catechol groups and vicinal diols exhibited a synergistic effect to enhance the anti-oxidation storage stability. Solution-cast hybrid films exhibited enhanced mechanical strength and toughness. Excellent scavenging of DPPH radicals was noted for PVA containing ≥5% MAO (at 7.5% MAO complete scavenging after 3 min).

For packaging applications, eugenol can be also used in the neat form, for physical modification of polymeric materials. Their final properties depend on the processing conditions. For example, EUG was added to linear low-density polyethylene (LLDPE) films under conditions of supercritical CO₂-assisted impregnation [37]. The effect of this process can be modulated by the pressure and depressurization rate. Binary mixtures of EO containing thymol, carvacrol, citral, and eugenol were also introduced into polypropylene (PP)/polyamide (PA)/nanoclays composite blends processed into thin films [49]. Their release kinetics were studied in correlation with their capacity to inhibit the growth of E. coli and fungi over time. The inhibition of fungal growth on food samples for over 50 days indicated the potential use of the developed EO-loaded films as active food packaging.

The above examples prove that the application of eugenol for chemical and physical modification of various polymeric materials of synthetic and natural origin can yield prolonged beneficial antimicrobial activity. These hybrid compositions can be used for packaging applications (thin films and adsorbent mats). Despite previous observations of bacterial adaptation to the low concentration of eugenol, such effects were not retained on an experimental time scale in polymeric materials that release EUG slowly.

2.3. Encapsulation of Eugenol in Polymeric Materials for Biomedical Applications

Increasing antibiotic resistance of bacterial strains necessitates the development of new antibacterial agents and therapies to prevent uncontrolled disease-causing pathogenic microorganisms. The increasing resistance of bacterial strains to antibiotics requires the development of new antimicrobial agents and therapies to prevent pathogenic microorganisms from causing disease uncontrollably.

Nano-based and combinatorial strategies offer solutions for reducing the use of antibiotics. The toxicity of various inorganic and organic antibacterial compounds has caused increasing interest in medicinal plant extracts with biocompatible and potent antibacterial characteristics. Such green antimicrobials are volatile and most often insoluble in water; thus, their bioavailability is rather poor. Nano-scale technologies provide a range of solutions to the problem of their poor bioavailability as well as oxygen sensitivity. As an additional result, the therapeutic potential of the active compounds may be enhanced [50,51,52,53,54]. Bioactive phytochemicals can be encapsulated or entrapped within inorganic or organic hydrophilic capping agents to improve their solubility and stability. Various nanocarriers, including nanoemulsions, dendrimers, micelles, liposomes, solid lipid nanoparticles, and nanoparticles of biodegradable polymers, can be employed for delivery of the active agents. For example, zein, sodium caseinate (NaCas), and pectin were exploited as polymeric matrices to formulate colloidal complex nanoparticles for the encapsulation of eugenol [55]. Small (~140 nm under optimized conditions), uniform, and stable particles were obtained. The process was affected by synthetic conditions and, preferably, pH 6.6 corresponding to the isoelectric point of zein should be maintained.

Analogously, pH-responsive biopolymeric nanocapsules containing essential oils of Thymus vulgaris, Rosmarinus officinalis, and Syzygium aromaticum were formed with the use of chitosan, alginate-chitosan, guar gum-chitosan, xanthan gum-chitosan, and pectin-chitosan [56]. The average encapsulation efficiency in nanovessels of 100–500 nm was 60% while the loading efficiency was 70%. Essential oil release kinetics were determined in pH = 3, 5.6, and 7.4. The best results were obtained for nanocapsules built from a chitosan-guar gum structure. The chitosan-guar gum and chitosan-pectin nanocapsules released 30% of essential oils (similar release kinetics for thymol, eugenol, and α-pinene) at pH 3 and 80% at pH = 7.4 during 3 h. Growth rates of S. aureus and E. coli, as well as their minimal inhibition concentration values, were estimated. The MIC of Thymus vulgaris and Syzygium aromaticum essential oils ranged from 0.025 to 0.5%.

Release kinetics of thymol, cinnamaldehyde, and eugenol encapsulated in liquid lipid nanoparticles (LLN) or solid lipid nanoparticles (SLN) were studied as a function of the lipid structure and carrier particle concentration in pullulan-based films [57]. The EO significantly reduced the crystallization temperature of SLN, and their release rate from SLN films was twice as high as that of LLN films. The release rate also depended on the type and amount of active compound (thymol > eugenol > cinnamaldehyde).

Eugenol and linalool were also encapsulated in polylactic acid [58]. Their antimicrobial activity against E. coli, Salmonella enterica, S. aureus, and Listeria monocytogenes was studied, and their minimum inhibitory concentration and minimum bactericidal concentration were evaluated. MBC values of these strains were, respectively, 0.39%, 3.13%, 0.78%, and 1.56% (for eugenol) and 0.39%, 12.50%, 0.39%, and 12.50% (for linalool). Inhibition zones of relevant size were detected for EUG against E. coli (60 mm) and linalool against Salmonella (32 mm). The capsules have prolonged efficiency, continuing to release the active species for up to 40 days. Such bio-based antimicrobial systems can be potentially applied as active food packaging.

The slow release of natural antimicrobials from nano-vessels can also improve the performance of bacteria-repellent polymer coatings. A hemocompatible interpenetrating network designed to repel bacteria was prepared with the use of poly(lauryl acrylate) nanocapsules containing eugenol [59]. The vesicles were entrapped within the network and EUG was slowly released. A significant reduction in surface-bound Klebsiella pneumoniae and methicillin-resistant S. aureus (MRSA) was achieved with this system (Figure 5) when the hybrid material was coated on a catheter and an endotracheal tube.

Figure 5. Normalized relative luminescence intensity of (A) media containing surface-bound MRSA and K. pneumoniae from monoliths of the control blank-network, EUG-containing network, and porous poly(methyl methacrylate-co-dimethylacrylamide) (PA13); and (B) BacTiter-Glo™ assay of surface-bound MRSA and K. pneumoniae on the surface of uncoated endotracheal tube, control and EUG-network. Reproduced from Ref. [59] with permission from the Royal Society of Chemistry.

Eugenol can be also incorporated into cross-linked polymer nanocomposite “sponges” [60]. In this form, it was applied for the treatment of bacterial biofilms of E. coli (CD2), P. aeruginosa (CD1006), and the E. cloacae complex (CD1412). This method was found to be very effective at delivering phytochemicals containing phenyl hydroxyl groups, such as eugenol and carvacrol. The results indicated that encapsulating EUG and other phytochemicals (methyl eugenol, carvacol, linalool, (+)-limonene, p-cymene, and α-pinene) effectively eliminated biofilms while demonstrating low cytotoxicity against mammalian fibroblast cells. It makes the NC sponges a promising direction to address wound biofilm infections. MICs (v/v%) of neat eugenol against these bacterial strains were 16, whereas, in the nanocomposites, it was reduced to 4. Similar results were obtained for carvacol, whereas the action of other phytochemicals was much more reduced when incorporated into NC “sponges”. NCs loaded with eugenol (log P: 2.49) were able to kill 90% of bacteria in the biofilms at approximately 12 v/v%. Similar results were obtained in the case of EUG for MRSA (CD489) (MIC of 16 v/v% for neat eugenol was diminished to 4 for EUG-NCs), whereas no reduction in antimicrobial activity was noted for (+)-limonene, p-cymene, and α-pinene after their incorporation into NCs.

Silica nanoparticles capped with triblock copolymer Pluronic F-127 were also used as nanocarriers of eugenol [61]. Results obtained with dynamic light scattering (DLS) and zeta-potential measurements suggested that in such particles, eugenol molecules are dispersed between the polymer chains of Pluronic F-127, most likely in the region of poly(propylene oxide) blocks. Nanocarriers obtained in Pluronic F-127 emulsions were only stable in aqueous medium under conditions in which the ratio between the weight fractions of Pluronic F-127 and eugenol > 1.5. For other stoichiometries, phase separation appeared within 48 h after their preparation. The weight fraction of silica nanoparticles must be low to obtain a stable emulsion. The potential application of these nanocarriers in the development of new formulations for pest control was studied. The formulation was tested as an insecticide (up to 60% mortality of Pediculus humanus capitis after application of the water emulsion of EUG/silica/F-127).

3. Conclusions

This review article presents the current state-of-the-art design and advantages of eugenol-based materials for antimicrobial applications. The use of polymeric nanocarriers not only can improve the stability, bioavailability, and cellular uptake/internalization of natural compounds but also reduce their toxicity. There are a number of EUG delivery methods using polymeric materials (in the form of nanocapsules, liposomes, microemulsions, micelles, and dendrimers). Such methods have been used to prepare drug delivery systems for various types of medical treatment, including anticancer therapies. Modern systems of EUG delivery for skin and wound treatment are based on hydrogels and electrospun nanofibers. The effect of eugenol is often enhanced by the presence of active nanoparticles of metals and metal oxides (ZnO).

The prospects for the development of EUG-based macromolecular systems in the broader biomedical field are very promising, as there is a great need to develop new therapies in view of the rapidly increasing incidence of life-threatening bacterial, fungal, and viral infections. The research focused on solutions that involve incorporation of biologically active natural substances into hybrid, multicomponent polymeric nanoparticles with antimicrobial/antiviral activity systems has a great potential.

The availability of eugenol from reproducible natural sources and the general low tendency of bacteria to develop resistance to the bactericidal effects of eugenol-based polymeric materials are two strong pillars for future applications of the antimicrobial solutions presented in this review. Specific properties of eugenol and the possibility of obtaining synergistic therapeutic effects from the use of EUG combined with other bioactive agents are also of great importance. This approach may, in the future, allow the precise design of novel efficient drug delivery systems, including targeted anti-cancer therapies.

References

1. Abdou, A.; Elmakssoudi, A.; El Amrani, A.; JamalEddine, J.; Dakir, M. Recent advances in chemical reactivity and biological activities of eugenol derivatives. Med. Chem. Rev. 2021, 30, 1011–1030. [Google Scholar] [CrossRef]
2. Mandal, D.; Sarkar, T.; Chakraborty, R. Critical Review on Nutritional, Bioactive, and Medicinal Potential of Spices and Herbs and Their Application in Food Fortification and Nanotechnology. Appl. Biochem. Biotechnol. 2023, 195, 1319–1513. [Google Scholar] [CrossRef] [PubMed]
3. Jeyakumar, G.E.; Lawrence, R. Mechanisms of bactericidal action of Eugenol against Escherichia coli. J. Herbal. Med. 2021, 26, 100406. [Google Scholar] [CrossRef]
4. Basavegowda, N.; Baek, K.-H. Synergistic antioxidant and antibacterial advantages of essential oils for food packaging applications. Biomolecules 2021, 11, 1267. [Google Scholar] [CrossRef]
5. Manrique, Y.; Gibis, M.; Schmidt, H.; Weiss, J. Antimicrobial efficacy of sequentially applied eugenol against food spoilage micro-organisms. J. Appl. Micobiol. 2016, 121, 1699–1709. [Google Scholar] [CrossRef] [PubMed]
6. Manrique, Y.; Gibis, M.; Schmidt, H.; Weiss, J. Influence of application sequence and timing of eugenol and lauric arginate (LAE) on survival of spoilage organisms. Food Microbiol. 2017, 64, 210–218. [Google Scholar] [CrossRef]
7. Manrique, Y.; Suriyarak, S.; Gibis, M.; Schmidt, H.; Weiss, J. Survival of spoilage bacteria subjected to sequential eugenol and temperature treatments. Int. J. Food Microbiol. 2016, 218, 6–16. [Google Scholar] [CrossRef]
8. Kaufman, T.S. The multiple faces of Eugenol. A versatile starting material and building block for organic and bio-organic synthesis and a convenient precursor toward bio-based fine chemicals. J. Brazil. Chem. Soc. 2015, 26, 1055–1085. [Google Scholar] [CrossRef]
9. Morales-Cerrada, R.; Molina-Gutierrez, S.; Lacroix-Desmazes, P.; Caillol, S. Eugenol, a Promising Building Block for Biobased Polymers with Cutting-Edge Properties. Biomacromolecules 2021, 22, 3625–3648. [Google Scholar] [CrossRef]
10. Kerosenewala, J.; Vaidya, P.; Ozarkar, V.; Shirapure, Y.; More, A.P. Eugenol: Extraction, properties and its applications on incorporation with polymers and resins—A review. Polym. Bull. 2023, 80, 7047–7099. [Google Scholar] [CrossRef]
11. Kumar, B.; Agumba, D.O.; Pham, D.H.; Kim, H.C.; Kim, J. Recent progress in bio-based eugenol resins: From synthetic strategies to structural properties and coating applications. J. Appl. Polym. Sci. 2022, 139, 51532. [Google Scholar] [CrossRef]
12. Montoya, C.; Roldan, L.; Yu, M.; Valliani, S.; Ta, C.; Yang, M.; Orrego, S. Smart dental materials for antimicrobial applications. Bioactive Mater. 2023, 24, 1–19. [Google Scholar] [CrossRef] [PubMed]
13. Shelton, M. Eugenol: Biosynthesis, Toxicity and Uses; Nova Science Pub Inc.: Hauppauge, NY, USA, 2019; pp. 1–1251. [Google Scholar]
14. Caillol, S.; Boutevin, B.; Auvergne, R. Eugenol, a developing asset in biobased epoxy resins. Polymer 2021, 2233, 123663. [Google Scholar] [CrossRef]
15. Kouznetsov, V.V.; Vargas Méndez, L.Y. Synthesis of eugenol-based monomers for sustainable epoxy thermoplastic polymers. J. Appl. Polym. Sci. 2022, 139, 52237. [Google Scholar] [CrossRef]
16. Harvey, B.G.; Sahagun, C.M.; Guenthner, A.J.; Groshens, T.J.; Cambrea, L.R.; Reams, J.T.; Mabry, J.M. A high-performance renewable thermosetting resin derived from eugenol. ChemSusChem 2014, 7, 1964–1969. [Google Scholar] [CrossRef]
17. Xu, H.; Zhang, D.; Li, J. Antibacterial Nanoparticles with Universal Adhesion Function Based on Dopamine and Eugenol. J. Biores. Bioprod. 2019, 4, 177–182. [Google Scholar] [CrossRef]
18. Donovan, B.R.; Cobb, J.S.; Hoff, E.F.T.; Patton, D.L. Thiol-ene adhesives from clove oil derivatives. RSC Adv. 2014, 106, 61927–61935. [Google Scholar] [CrossRef]
19. Thirukumaran, P.; Parveen, A.S.; Sarojadevi, M. Eugenol-Based Polybenzoxazines. In Advanced and Emerging Polybenzoxazine Science and Technology; Elsevier: Amsterdam, The Netherlands, 2017; pp. 523–531. [Google Scholar] [CrossRef]
20. Thirukumaran, P.; Parveen, A.S.; Sarojadevi, M. Synthesis of eugenol-based polybenzoxazine-POSS nanocomposites for low dielectric applications. Polym. Comp. 2015, 36, 1973–1982. [Google Scholar] [CrossRef]
21. Watanabe, H.; Takahashi, M.; Kihara, H.; Yoshida, M. Biobased coatings based on eugenol derivatives. ACS Appl. Bio Mater. 2018, 1, 808–813. [Google Scholar] [CrossRef]
22. Cheng, C.; Zhang, X.; Chen, X.; Li, J.; Huang, Q.; Hu, Z.; Tu, Y. Self-healing polymers based on eugenol via combination of thiol-ene and thiol oxidation reactions. J. Polym. Res. 2016, 23, 110. [Google Scholar] [CrossRef]
23. Cheng, C.; Li, Y.; Zhang, X.; Li, J. Eugenol-based non-isocyanate polyurethane and polythiourethane. Iran. Polym. J. Eng. Ed. 2017, 26, 821–831. [Google Scholar] [CrossRef]
24. Cheng, C.; Li, J.; Yang, F.; Li, Y.; Hu, Z.; Wang, J. Renewable eugenol-based functional polymers with self-healing and high temperature resistance properties. J. Polym. Res. 2018, 25, 57. [Google Scholar] [CrossRef]
25. Rahim, E.A. Synthesis, Properties, and Function of Self-Healing Polymer-Based on Eugenol. Ind. J. Chem. 2022, 22, 922–928. [Google Scholar] [CrossRef]
26. Li, C.; Chen, Y.; Cai, X.; Yang, G.; Sun, X.S. Eugenol-Derived Molecular Glass: A Promising Biobased Material in the Design of Self-Healing Polymeric Materials. ACS Sustain. Chem. Eng. 2020, 8, 3553–3560. [Google Scholar] [CrossRef]
27. Prasetya, N.B.A.; Ngadiwiyana; Ismiyarto; Sarjono, P.R. Synthesis and study of antibacterial activity of polyeugenol. IOP Conf. Ser. Mater. Sci. Eng. 2019, 509, 012101. [Google Scholar] [CrossRef]
28. Rahim, E.A.; Istiqomah, N.; Almilda, G.; Ridhay, A.; Sumarni, N.K. Indriani Antibacterial and antioxidant activities of polyeugenol with high molecular weight. Ind. J. Chem. 2020, 20, 722–728. [Google Scholar] [CrossRef]
29. Getnet, T.G.; Kayama, M.E.; Rangel, E.C.; Duarte, I.C.S.; da Silva, G.F.; Cruz, N.C. Atmospheric pressure plasma deposition of eugenol-derived film on metallic biomaterial for suppression of Escherichia coli and Staphylococcus aureus bacterial biofilm. Thin Solid Film. 2021, 73430, 138833. [Google Scholar] [CrossRef]
30. Ji, J.; Ge, X.; Liang, W.; Liang, R.; Pang, X.; Liu, R.; Wen, S.; Sun, J.; Chen, X.; Ge, J. A simple preparation route for Bio-Phenol MQ silicone resin via the hydrosilylation method and its autonomic antibacterial property. Polymers 2019, 11, 1389. [Google Scholar] [CrossRef] [PubMed]
31. Di Consiglio, M.; Sturabotti, E.; Brugnoli, B.; Piozzi, A.; Migneco, L.M.; Francolini, I. Synthesis of sustainable eugenol/hydroxyethylmethacrylate-based polymers with antioxidant and antimicrobial properties. Polym. Chem. 2023, 14, 432–442. [Google Scholar] [CrossRef]
32. Sha, J.; Yu, J.; Chen, R.; Liu, Q.; Liu, J.; Zhu, J.; Liu, P.; Li, R.; Wang, J. Eco-friendly self-polishing antifouling coating via eugenol ester hydrolysis. Progr. Org. Coat. 2022, 172, 107077. [Google Scholar] [CrossRef]
33. Nostro, A.; Scaffaro, R.; D’Arrigo, M.; Botta, L.; Filocamo, A.; Marino, A.; Bisignano, G. Development and characterization of essential oil component-based polymer films: A potential approach to reduce bacterial biofilm. Appl. Microbiol. Biotechnol. 2013, 97, 9515–9523. [Google Scholar] [CrossRef] [PubMed]
34. Thirukumaran, P.; Parveen, A.S.; Atchudan, R.; Kim, S.-C. Sustainability and antimicrobial assessments of bio based polybenzoxazine film. Eur. Polym. J. 2018, 109, 248–256. [Google Scholar] [CrossRef]
35. Antunes, J.C.; Tavares, T.D.; Teixeira, M.A.; Teixeira, M.O.; Homem, N.C.; Amorim, M.T.P.; Felgueiras, H.P. Eugenol-containing essential oils loaded onto chitosan/polyvinyl alcohol blended films and their ability to eradicate staphylococcus aureus or pseudomonas aeruginosa from infected microenvironments. Pharmaceutics 2021, 13, 195. [Google Scholar] [CrossRef]
36. Lv, N.; Zhao, M.; Hao, L.; Zhou, X.; Chen, H.; Zhou, H. Eugenol and carboxymethyl cellulose derived nanocoating with insect repellent and long-term antibacterial activity. Ind. Crops Prod. 2022, 190, 115902. [Google Scholar] [CrossRef]
37. Muratore, F.; Goñi, M.L.; Strumia, M.C.; Barbosa, S.E.; Gañan, N.A.; Martini, R.E. Eugenol As An Active Component in Food Packaging Materials. In Eugenol: Biosynthesis, Toxicity and Uses; Nova Science Pub Inc.: Hauppauge, NY, USA, 2019; pp. 1–481. [Google Scholar]
38. Malhotra, B.; Keshwani, A.; Kharkwal, H. Natural polymer based cling films for food packaging. Int. J. Pharm. Pharmaceut. Sci. 2015, 7, 10–18. [Google Scholar]
39. Pleva, P.; Bartošová, L.; Máčalová, D.; Zálešáková, L.; Sedlaříková, J.; Janalíková, M. Biofilm formation reduction by eugenol and thymol on biodegradable food packaging material. Foods 2022, 11, 2. [Google Scholar] [CrossRef] [PubMed]
40. Gazzotti, S.; Todisco, S.A.; Picozzi, C.; Ortenzi, M.A.; Farina, H.; Lesma, G.; Silvani, A. Eugenol-grafted aliphatic polyesters: Towards inherently antimicrobial PLA-based materials exploiting OCAs chemistry. Eur. Polym. J. 2019, 114, 369–379. [Google Scholar] [CrossRef]
41. Yu, H.; Huang, X.; Zhou, L.; Wang, Y. Incorporation of cinnamaldehyde, carvacrol, and eugenol into zein films for active food packaging: Enhanced mechanical properties, antimicrobial activity, and controlled release. J. Food Sci. Technol. 2023, 60, 2846–2857. [Google Scholar] [CrossRef]
42. Huang, X.; Ge, X.; Zhou, L.; Wang, Y. Eugenol embedded zein and poly(lactic acid) film as active food packaging: Formation, characterization, and antimicrobial effects. Food Chem. 2022, 3841, 132482. [Google Scholar] [CrossRef] [PubMed]
43. Reyes Méndez, L.M.; Méndez Morales, P.A.; López-Córdoba, A.; Ortega-Toro, R.; Gutiérrez, T.J. Active chitosan/gelatin-based films and coatings containing eugenol and oregano essential oil for fresh cheese preservation. J. Food Process. Eng. 2023, e14396. [Google Scholar] [CrossRef]
44. Wang, C.; Wu, L.; Zhang, Y.; Xu, M.; Saldaña, M.D.A.; Fan, X.; Sun, W. A Water-absorbent Mat Incorporating β-cyclodextrin/eugenol Inclusion Complex for Preservation of Cold Fresh Mutton. Food Biophys. 2022, 17, 437–447. [Google Scholar] [CrossRef]
45. Mahmood, K.; Kamilah, H.; Karim, A.A.; Ariffin, F. Fabrication and Characterization of Electrospun Fish Gelatin Mats Doped with Essential Oils and β-Cyclodextrins for Food Packaging Applications. Food Biophys. 2023, 18, 186–197. [Google Scholar] [CrossRef]
46. Naddeo, M.; Vigliotta, G.; Pellecchia, C.; Pappalardo, D. Synthesis of bio-based polymacrolactones with pendant eugenol moieties as novel antimicrobial thermoplastic materials. React. Funct. Polym. 2020, 155, 104714. [Google Scholar] [CrossRef]
47. Ngadiwiyana, N.; Merinah, M.; Bima, D.N.; Ismiyarto, I.; Sarjono, P.R.; Christwardana, M. Synthesis and characterization of Eugenol-Trithiol-Methylenebisacrylamide and Eugenol-Trithiol-Allyeugenol copolymers for antibacterial food packaging. Polym. Plast. Technol. Mater. 2023, 62, 1728–1743. [Google Scholar] [CrossRef]
48. Wang, J.; Huang, S.; Yan, K.; Shi, J.; Shi, S.; Jin, Y.; Yuan, L. Sustainable macromolecular antioxidants from eugenol with synergistically enhanced storage stability for active PVA packaging. React. Funct. Polym. 2023, 191, 105671. [Google Scholar] [CrossRef]
49. Moshe Dvir, I.; Weizman, O.; Weintraub, S.; Ophir, A.; Dotan, A. Antimicrobial active packaging combining essential oils mixture: Migration and odor control study. Polym. Adv. Technol. 2019, 30, 2558–2566. [Google Scholar] [CrossRef]
50. Mei, L.; Zhang, Z.; Zhao, L.; Huang, L.; Yang, X.-L.; Tang, J.; Feng, S.-S. Pharmaceutical nanotechnology for oral delivery of anticancer drugs. Adv. Drug Deliv. Rev. 2013, 65, 880–890. [Google Scholar] [CrossRef]
51. Trifan, A.; Luca, S.V.; Greige-Gerges, H.; Miron, A.; Gille, E.; Aprotosoaie, A.C. Recent advances in tackling microbial multidrug resistance with essential oils: Combinatorial and nano-based strategies. Crit. Rev. Microbiol. 2020, 46, 338–357. [Google Scholar] [CrossRef]
52. Chiriac, A.P.; Rusu, A.G.; Nita, L.E.; Chiriac, V.M.; Neamtu, I.; Sandu, A. Polymeric carriers designed for encapsulation of essential oils with biological activity. Pharmaceutics 2021, 13, 631. [Google Scholar] [CrossRef]
53. Stan, D.; Enciu, A.-M.; Mateescu, A.L.; Ion, A.C.; Brezeanu, A.C.; Stan, D.; Tanase, C. Natural Compounds with Antimicrobial and Antiviral Effect and Nanocarriers Used for Their Transportation. Front. Pharm. 2021, 126, 723233. [Google Scholar] [CrossRef]
54. Ghosh, S.; Nandi, S.; Basu, T. Nano-Antibacterials Using Medicinal Plant Components: An Overview. Front. Microbiol. 2022, 1222, 768739. [Google Scholar] [CrossRef]
55. Veneranda, M.; Hu, Q.; Wang, T.; Luo, Y.; Castro, K.; Madariaga, J.M. Formation and characterization of zein-caseinate-pectin complex nanoparticles for encapsulation of eugenol. LWT 2018, 89, 596–603. [Google Scholar] [CrossRef]
56. Skalickova, S.; Aulichova, T.; Venusova, E.; Skladanka, J.; Horky, P. Development of pH-responsive biopolymeric nanocapsule for antibacterial essential oils. Int. J. Mol. Sci. 2020, 21, 1799. [Google Scholar] [CrossRef] [PubMed]
57. Tonyali, B.; McDaniel, A.; Amamcharla, J.; Trinetta, V.; Yucel, U. Release kinetics of cinnamaldehyde, eugenol, and thymol from sustainable and biodegradable active packaging films. Food Pack. Shelf Life 2020, 24, 100484. [Google Scholar] [CrossRef]
58. Silva, C.G.; Yudice, E.D.C.; Campini, P.A.L.; Rosa, D.S. The performance evaluation of Eugenol and Linalool microencapsulated by PLA on their activities against pathogenic bacteria. Mater. Today Commun. 2021, 21, 100493. [Google Scholar] [CrossRef]
59. Venkateswaran, S.; Henrique Dos Santos, O.D.; Scholefield, E.; Lilienkampf, A.; Gwynne, P.J.; Swann, D.G.; Dhaliwal, K.; Gallagher, M.P.; Bradley, M. Fortified interpenetrating polymers-bacteria resistant coatings for medical devices. J. Mater. Chem. B 2016, 4, 5405–5411. [Google Scholar] [CrossRef]
60. Li, C.-H.; Chen, X.; Landis, R.F.; Geng, Y.; Makabenta, J.M.; Lemnios, W.; Gupta, A.; Rotello, V.M. Phytochemical-Based Nanocomposites for the Treatment of Bacterial Biofilms. ACS Infect. Dis. 2019, 5, 1590–1596. [Google Scholar] [CrossRef]
61. Sánchez-Arribas, N.; Guzmán, E.; Lucia, A.; Toloza, A.C.; Velarde, M.G.; Ortega, F.; Rubio, R.G. Environmentally friendly platforms for encapsulation of an essential oil: Fabrication, characterization and application in pests control. Coll. Surf. A Physicochem. Engin. Asp. 2018, 555, 473–481. [Google Scholar] [CrossRef]
62. Padhy, I.; Paul, P.; Sharma, T.; Banerjee, S.; Mondal, A. Molecular Mechanisms of Action of Eugenol in Cancer: Recent Trends and Advancement. Life 2022, 12, 1795. [Google Scholar] [CrossRef]
63. Jaganathan, S.K.; Supriyanto, E. Antiproliferative and Molecular Mechanism of Eugenol-Induced Apoptosis in Cancer Cells. Molecules 2012, 17, 6290–6304. [Google Scholar] [CrossRef]
64. Costa, A.; Bonner, M.Y.; Arbiser, J.L. Use of Polyphenolic Compounds in Dermatologic Oncology. Am. J. Clin. Dermatol. 2016, 17, 369–385. [Google Scholar] [CrossRef] [PubMed]
65. de Meneses, A.C.; dos Santos, P.C.M.; Machado, T.O.; Sayer, C.; de Oliveira, D.; Hermes de Araújo, P.H. Poly(thioether-ester) nanoparticles entrapping clove oil for antioxidant activity improvement. J. Polym. Res. 2017, 24, 202. [Google Scholar] [CrossRef]
66. Li, Z.; Veeraraghavan, V.P.; Mohan, S.K.; Bolla, S.R.; Lakshmanan, H.; Kumaran, S.; Aruni, W.; Aladresi, A.A.M.; Shair, O.H.M.; Alharbi, S.A.; et al. Apoptotic induction and anti-metastatic activity of eugenol encapsulated chitosan nanopolymer on rat glioma C6 cells via alleviating the MMP signalling pathway. J. Photochem. Photobiol. B Biol. 2020, 203, 111773. [Google Scholar] [CrossRef]
67. Thakur, K.; Sharma, G.; Singh, B.; Chhibber, S.; Katare, O.P. Current state of nanomedicines in the treatment of topical infectious disorders. Recent. Pat. Anti-Inf. Drug Discov. 2018, 13, 126–150. [Google Scholar] [CrossRef]
68. Zlotnikov, I.D.; Ezhov, A.A.; Petrov, R.A.; Vigovskiy, M.A.; Grigorieva, O.A.; Belogurova, N.G.; Kudryashova, E.V. Mannosylated Polymeric Ligands for Targeted Delivery of Antibacterials and Their Adjuvants to Macrophages for the Enhancement of the Drug Efficiency. Pharmaceuticals 2022, 15, 1172. [Google Scholar] [CrossRef] [PubMed]
69. Barradas, T.N.; Senna, J.P.; Cardoso, S.A.; Nicoli, S.; Padula, C.; Santi, P.; Rossi, F.; de Holanda e Silva, K.G.; Mansur, C.R.E. Hydrogel-thickened nanoemulsions based on essential oils for topical delivery of psoralen: Permeation and stability studies. Eur. J. Pharm. Biopharm. 2017, 116, 38–50. [Google Scholar] [CrossRef] [PubMed]
70. Park, J.; Nabawy, A.; Doungchawee, J.; Mahida, N.; Foster, K.; Jantarat, T.; Jiang, M.; Chattopadhyay, A.N.; Hassan, M.A.; Agrohia, D.K.; et al. Synergistic Treatment of Multidrug-Resistant Bacterial Biofilms Using Silver Nanoclusters Incorporated into Biodegradable Nanoemulsions. ACS Appl. Mater. Interfaces 2023, 15, 37205–37213. [Google Scholar] [CrossRef]
71. Bartošová, L.; Sedlaříková, J.; Peer, P.; Janalíková, M.; Pleva, P. Antibacterial and Antifouling Efficiency of Essential Oils-Loaded Electrospun Polyvinylidene Difluoride Membranes. Int. J. Mol. Sci. 2023, 24, 423. [Google Scholar] [CrossRef]
72. Somsap, J.; Kanjanapongkul, K.; Chancharoonpong, C.; Supapvanich, S.; Tepsorn, R. Antimicrobial activity of edible electrospun chitosan/cellulose acetate/gelatin hybrid nanofiber mats incorporating eugenol. Curr. Appl. Sci. Technol. 2019, 19, 235–247. [Google Scholar]
73. Sethuram, L.; Thomas, J.; Mukherjee, A.; Chandrasekaran, N. Eugenol micro-emulsion reinforced with silver nanocomposite electrospun mats for wound dressing strategies. Mater. Adv. 2021, 2, 2971–2988. [Google Scholar] [CrossRef]
74. Nabawy, A.; Makabenta, J.M.; Schmidt-Malan, S.; Park, J.; Li, C.-H.; Huang, R.; Fedeli, S.; Chattopadhyay, A.N.; Patel, R.; Rotello, V.M. Dual antimicrobial-loaded biodegradable nanoemulsions for synergistic treatment of wound biofilms. J. Control. Release 2022, 347, 379–388. [Google Scholar] [CrossRef] [PubMed]
75. Safdari, F.; Gholipour, M.D.; Ghadami, A.; Saeed, M.; Zandi, M. Multi-antibacterial agent-based electrospun polycaprolactone for active wound dressing. Progr. Biomat. 2022, 11, 27–41. [Google Scholar] [CrossRef] [PubMed]
76. Campa-Siqueiros, P.I.; Madera-Santana, T.J.; Castillo-Ortega, M.M.; López-Cervantes, J.; Ayala-Zavala, J.F.; Ortiz-Vazquez, E.L. Electrospun and co-electrospun biopolymer nanofibers for skin wounds on diabetic patients: An overview. RSC Adv. 2021, 11, 15340–15350. [Google Scholar] [CrossRef] [PubMed]
77. Chummun, I.; Bekah, D.; Goonoo, N.; Bhaw-Luximon, A. Assessing the mechanisms of action of natural molecules/extracts for phase-directed wound healing in hydrogel scaffolds. RSC Med. Chem. 2021, 12, 1476–1490. [Google Scholar] [CrossRef]
78. Comini, S.; Scutera, S.; Sparti, R.; Banche, G.; Coppola, B.; Bertea, C.M.; Bianco, G.; Gatti, N.; Cuffini, A.M.; Palmero, P.; et al. Combination of Poly(ε-Caprolactone) Biomaterials and Essential Oils to Achieve Anti-Bacterial and Osteo-Proliferative Properties for 3D-Scaffolds in Regenerative Medicine. Pharmaceutics 2022, 14, 1873. [Google Scholar] [CrossRef]
79. Chaves, P.; Oliveira, J.; Haas, A.; Beck, R.C.R. Applications of polymeric nanoparticles in oral diseases: A review of recent findings. Curr. Pharm. Des. 2018, 24, 1377–1394. [Google Scholar] [CrossRef]
80. Rajendra Suryawanshi, V.; Ramashray Yadav, H.; Chatur Surani, H. Formulation & characterization of anti-microbial property of herbal oral in-situ gel. Mater. Today Proc. 2022, 51, 2339–2347. [Google Scholar] [CrossRef]
81. Markowitz, K.; Moynihan, M.; Liu, M.; Kim, S. Biologic properties of eugenol and zinc oxide—Eugenol. A clinically oriented review. Oral Surg. Oral Med. Oral Pathol. 1992, 73, 729–737. [Google Scholar] [CrossRef]
82. Lee, J.-H.; Lee, H.-H.; Kim, K.-N.; Kim, K.-M. Cytotoxicity and anti-inflammatory effects of zinc ions and eugenol during setting of ZOE in immortalized human oral keratinocytes grown as three-dimensional spheroids. Dent. Mater. 2016, 32, e93–e104. [Google Scholar] [CrossRef]
83. Lee, J.-H.; Lee, H.-H.; Kim, H.-W.; Yu, J.-W.; Kim, K.-N.; Kim, K.-M. Immunomodulatory/anti-inflammatory effect of ZOE-based dental materials. Dent. Mater. 2017, 33, e1–e12. [Google Scholar] [CrossRef]
84. Estrela, C.; Estrada-Bernabé, P.-F.; de Almeida-Decurcio, D.; Almeida-Silva, J.; Rodrigues-Araújo-Estrela, C.; Poli-Figueiredo, J.-A. Microbial leakage of MTA, Portland cement, Sealpex and zinc oxide-eugenol as root-end filling materials. Med. Oral. Patol. Oral. Cir. Bucal. 2011, 16, 418–424. [Google Scholar] [CrossRef]
85. Hemasathya, B.; Mony, C.M.B.; Prakash, V. Recent advances in root end filling materials: A review. Biomed. Pharm. J. 2015, 8, 219–224. [Google Scholar] [CrossRef]
86. Aragão, A.C.; Pintor, A.V.B.; Marceliano-Alves, M.; Primo, L.G.; Silva, A.S.; Lopes, R.T.; Neves, A.A. Root canal obturation materials and filling techniques for primary teeth: In vitro evaluation in polymer-based prototyped incisors. Int. J. Paediatr. Dent. 2020, 30, 381–389. [Google Scholar] [CrossRef] [PubMed]
87. Almaroof, A.; Niazi, S.A.; Rojo, L.; Mannocci, F.; Deb, S. Influence of a polymerizable eugenol derivative on the antibacterial activity and wettability of a resin composite for intracanal post cementation and core build-up restoration. Dent. Mater. 2016, 32, 929–939. [Google Scholar] [CrossRef]