Pomegranate (Punica Granatum L) and Wound Healing: A Review of Experimental Studies

The wound healing process involves cellular and molecular events that culminate in repairing damaged tissues [1]. The process is composed of hemostasis, inflammation, proliferation, and remodeling. Hemostasis is performed by blood coagulation, while inflammation protects the host from pathogen invasion and promotes proliferation [2,3].

Proliferation results in wound re-epithelialization, angiogenesis, fibroblast, and extracellular matrix (ECM) formation. Remodeling is the final stage of wound healing and tissue maturation [4]. However, wound healing can be impaired due to infection, underlying diseases, or malnutrition. Therefore, there is growing interest in developing new therapies to enhance wound healing [4,5]. One promising approach is using natural products such as Roma, a plant with potential wound-healing properties. Punica granatum L., commonly known as Pomegranate, has been used for centuries in traditional medicine due to its medicinal properties [6]. Several studies have reported the beneficial effects of Pomegranate in wound healing, which has drawn the attention of researchers in recent years 4-6.

The fruit of Punica granatum L. contains polyphenols, flavonoids, and tannins, which have been shown to have antioxidant, antiinflammatory, and antimicrobial properties2. These compounds contribute to wound healing by reducing oxidative stress, inflammation, and infection. In addition, pomegranate extract stimulates fibroblast proliferation and collagen synthesis, which are essential processes in tissue repair [3]. Hayouni et al. demonstrated that applying pomegranate extract on excision wounds in rats increased wound closure rate, epithelialization, and collagen deposition, accelerating wound healing compared to the control group [1]. Similarly, Niknam et al. showed that topical application of pomegranate extract on burn wounds in rats decreased wound size, inflammation, and bacterial load compared to the control group [2].

Moreover, studies have also investigated the effect of pomegranate extract on diabetic wound healing, which is a challenging condition. Albahri et al. demonstrated that applying pomegranate peel extract on diabetic wounds in rats accelerated wound closure rate, re-epithelialization, and angiogenesis compared to the control group [3]. Yan H et al. investigated the effect of pomegranate peel polyphenol gel on wound healing in diabetic rats. The gel promoted wound healing, angiogenesis, and inflammation by elevating collagen deposition [4].

In this sense, the pomegranate peel polyphenol gel proved to be an effective alternative in recovery regarding the association of wounds and diabetes. Although the results of animal studies are promising, clinical studies are needed to confirm the efficacy and safety of pomegranate extract in wound healing [5,6].

Karim et al. observed the effects of a gel based on the methanolic extract of pomegranate peels on wound healing in diabetic rats. The section accelerated wound closure and promoted collagen deposition, suggesting the potential of pomegranate peel extract as a natural wound healing agent, especially in diabetic patients were delayed healing is shared [5].

In summary, using pomegranate extract in wound healing has shown promising results in animal and clinical studies. The bioactive compounds in Pomegranate may contribute to wound healing by reducing oxidative stress, inflammation, and infection and stimulating fibroblast proliferation and collagen synthesis [6,7]. Further studies are needed to investigate the optimal dosage and duration of treatment and to assess the long-term safety and efficacy of pomegranate extract in wound healing. Nonetheless, pomegranate extract has excellent potential as a natural and safe alternative for wound healing therapy [8,9].

This review aims to summarize the current knowledge regarding using Punica granatum L in the context of cutaneous wound healing. We will discuss the available evidence from animal studies, the potential mechanisms of action, and the challenges and opportunities for future research in this field. In addition, the possible mechanisms underlying the beneficial effects of Pomegranate on wound healing were discussed. Finally, we will highlight the potential clinical applications of Pomegranate in treating human cutaneous wounds and its limitations and challenges.

This cross-sectional, observational, and integrative study consists of a review of Pomegranate (Punica granatum L.) use, without restriction regarding the parts of the plant used or the pharmaceutical form applied, and its activity in healing cutaneous wounds, infected or not, in animal/experimental models. A search for studies was carried out in the PubMed/Medline, Scopus, Scielo, Embase, and Web of Science databases, in addition to Google Scholar, considered a source of gray literature, as it does not contain peer-reviewed articles. Studies related to the topic were selected using the following search strategy: “Nano-PSO” [Supplementary Concept] OR Pomegranate OR Pomegranates OR Punica granatum”; Wound Healing OR Wound Infection; “Models, Animal” OR Animal Model OR Animal Models OR Model, Animal OR Laboratory Animal Models OR Animal Model, Laboratory OR Animal Models, Laboratory OR Laboratory Animal Model OR Model, Laboratory Animal OR Models, Laboratory Animal OR Experimental Animal Models OR Animal Model, Experimental OR Animal Models, Experimental OR Experimental Animal Model OR Model, Experimental Animal OR Models, Experimental Animal. Cohort studies, systematic reviews, case-control, cross-sectional studies, case series studies, and randomized clinical trials were included. Experimental studies on skin wounds and the effect of Punica granatum were used as inclusion criteria, complete and published articles with no date limit. Duplicate reports were excluded using the Rayyan software— Reviewer. Analysis, review, and selection of the studies were made by peers unthinkingly, from reading the title and summary of the study, with a third reviewer in case of disagreement between the other two reviewers.

In recent years, several studies have investigated the effects of pomegranate on wound healing in animal models [1]. The woundhealing properties of pomegranate extract may be attributed to flavonoids and triterpenoids, which possess antioxidant, antiinflammatory, and antimicrobial activities. These compounds modulate the proliferation, migration, and differentiation of cells [6]. In addition to its potential therapeutic effects, pomegranate is relatively safe and well-tolerated, with minimal side effects reported in animal studies [7-9].

Dkhil et al. investigated pomegranate peel extract’s anticoccidial, anthelmintic, and antioxidant activities. The pomegranate peel extract exhibited anticoccidial and anthelmintic activities, suggesting an alternative to synthetic anticoccidial and anthelmintic agents [8].

Additionally, Scappaticci et al. use green and chemical silver nanoparticles (AgNPs) and pomegranate formulations to treat infected wounds in diabetic mice. Diabetic rats with infected wounds were treated with different formulations containing green and chemical AgNPs and pomegranate extract. Researchers assessed healing progress by measuring wound size, bacterial counts, and tissue histology [9]. It was noted the group treated with green AgNPs and pomegranate extract had a faster and more efficient healing process. Histological analysis revealed a reduction in inflammatory cells in the treated group compared to the control group10.

Following the same line of research, Wasef et al. analyzed the effects of silver nanoparticles (AgNPs) on burn healing in a mouse. In the model, mice treated with AgNPs and P. granatum extract reduced wound size, better histopathological characteristics, and reduced oxidative stress markers in the treated group. It was concluded, therefore, that the combination of AgNPs and P. granatum extract can be used as an effective therapeutic option for healing burns [9,10].

Devanesan et al. synthesized silver nanoparticles from pomegranate peel extract and evaluated their antimicrobial and cytotoxic effects in humans. The results demonstrated potent antimicrobial activity against gram-negative and grampositive bacterial and fungal pathogens, with low cytotoxicity for human cells [11]. Likewise, Nasiriboroumand et al. found that the nanoparticles exhibit good stability and biocompatibility, suggesting their potential as a safe and effective agent for various biomedical applications [12]. Mahmood et al. analyzed the chemical composition of Punica granatum L. (pomegranate) bark extract using high-performance liquid chromatography (HPLC). They evaluated its antimicrobial activity against a variety of microorganisms. The authors extracted the bark using methanol and identified ellagic acid, gallic acid, and quercetin [13].

The pomegranate peel extract exhibited antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. The results suggested that pomegranate peel extracts are a natural alternative for treating microbial infections. However, more studies are needed to evaluate its effectiveness and safety in clinical settings [12-14].

Do Nascimento et al. develop a bio-interactive gelatin dressing based on Punica granatum Linn extract. Dressings containing gelatin have biocompatibility, biodegradability, and the ability to absorb wound exudates [14]. The pomegranate peel extract incorporated into the gelatin dressing potentiated healing, rapid closure, and increased collagen production associated with inflammatory reduction. In this sense, the present study’s findings are significant for developing new effective and safe dressings for clinical practice [14-16].

Some studies focus on the fruit itself, while others analyze fruit extracts in the form of nanoparticles, associated or not with silver, and the potential therapeutic properties of Punica granatum in the treatment of various health conditions, whether in the healing of wounds, infections, and other illnesses [17]. Bakkiyaraj et al. investigated the anti-biofilm potential of pomegranate extract against human bacterial and fungal pathogens. They found that it has inhibitory properties against the growth of these harmful agents [15]. Likewise, Swaroop et al. summarized the pomegranate’s potential mechanisms of action in wound healing, emphasizing the activity of polyphenols and flavonoids [16].

Lukiswanto et al. demonstrated the wound-healing potential of P. granatum whole fruit extract on skin burns in rats compared to silver sulfadiazine. Wound contraction, histopathology, and hydroxyproline content were analyzed as healing parameters. More significant collagen deposition, increased angiogenesis, and reduced inflammation were observed [17]. In turn, Mousavi et al. analyzed the effect of pomegranate seed oil on wound healing in mice with burns, in which it was possible to observe a reduction in healing time, wound size, and elevation of local collagen [18]. The effects of pomegranate flower extract on burn skin lesions in rats were observed by Nasiri et al., reduced inflammation, favoring angiogenesis and collagen deposition [13-15].

Akbari et al. studied the wound-healing potential of pomegranate in streptozotocin-induced diabetic rats. They observed efficacy in wound healing associated with increased collagen deposition and reduced oxidative stress, corroborating the results of Cho et al [19,20]. The efficacy of Punica granatum (pomegranate) in promoting wound healing has been investigated by several studies [2-4]. Kim et al. demonstrated that pomegranate extract accelerates wound healing by modulating hypoxia-inducible factor 1α (HIF-1α), and IL-6 expression in mice [21]. Similarly, Alimoradian et al. observed improved wound healing in rats treated with Punica granatum seed extract, attributed to increased growth factor expression and reduced inflammation [22].

Celik et al. demonstrated the effectiveness of pomegranate seed oil in wound healing, as evidenced by increased growth factor expression and reduced oxidative stress. The benefits of pomegranate peel extract in wound healing were further supported by Hoseny et al. and Ragab et al. in rat and rabbit models, respectively [23-25].

These studies highlighted the extract’s ability to enhance collagen synthesis, increase growth factor expression, and reduce inflammation, all contributing to improved wound healing outcomes [24-26].

Moreover, Cho et al. investigated the impact of pomegranate extract on surgical skin wounds in rats, revealing a significant acceleration of wound healing. This effect was attributed to the promotion of granulation tissue formation, re-epithelialization, and the antioxidant activity of the extract [20]. In the context of excisional wounds, Akbari et al. found that pomegranate peel extract effectively accelerated wound healing in rabbits by reducing wound size and increasing collagen deposition [19]. Furthermore, Murthy et al. investigated the wound-healing activity of P. granatum peel in rats, demonstrating higher hydroxyproline content in the treated group compared to the control group [27].

Notably, Ragab et al. developed a chitosan-based hydrogel containing pomegranate peel extract to treat chronic wounds. This hydrogel formulation exhibited improved cellular antennas, angiogenesis, and collagen deposition, highlighting its potential as a natural remedy for chronic wound management [25]. Collectively, these studies provide scientific evidence supporting the effectiveness of Punica granatum in promoting wound healing through various mechanisms, including modulation of growth factors, reduction of inflammation, stimulation of collagen synthesis, and antioxidant activity. However, further research is required to fully elucidate the underlying mechanisms of action and evaluate potential side effects associated with using Punica granatum for wound healing.

In summary, a body of research has demonstrated the potential of Punica granatum L., or Pomegranate, and its extracts as promising agents for promoting wound healing in various animal models. The observed effects involve the modulation of critical biological processes such as collagen deposition, inflammation reduction, oxidative stress mitigation, and growth factor expression.

Nevertheless, additional investigations are warranted to determine the optimal dosing regimens and administration routes for pomegranate extracts in wound healing. Given its inherent antioxidant, anti-inflammatory, and antimicrobial properties, Punica granatum L. holds promise as a natural therapeutic option for cutaneous wound treatment.

Despite the promising results obtained in animal models, further research is needed to determine the efficacy and safety of pomegranate extract in human clinical trials. Moreover, the mechanisms underlying the wound-healing effects of Româ need to be elucidated to optimize its use in wound care. This review provides a comprehensive overview of the current knowledge on the use of Pomegranate in the healing of cutaneous wounds in animal models. The information presented in this review may help to inform the development of new therapies and strategies to enhance wound healing in humans.

None.

No conflicts of interest.

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