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. 2024 Apr 1;30(4):e13685. doi: 10.1111/srt.13685

The effect of hydatid cyst protoscolex somatic antigens on full‐thickness skin wound healing in mouse

Sajede Hosseinzade 1, Hossein Nourani 1, Hossein Kazemi Mehrjerdi 2, Narges Lotfalizadeh 1, Hassan Borji 1,✉
PMCID: PMC10982679  PMID: 38558086

Abstract

Background

Wound healing has evolved in recent years, resulting in diverse therapeutic options.

Objective

This study evaluated the effects of the somatic antigen of the hydatid cyst protoscolex on wound healing in mice with full‐thickness skin wounds.

Methods

Fifty‐four adult mice, weighing 25 ± 5 g and approximately 60 days old, were divided into three groups (A, B, and C), each further divided into three subgroups. Subgroups A1, A2, and A3 were assigned negative controls. B1, B2, and B3 received hydatid cyst somatic antigen tests at 10 µg/SC, whereas C1, C2, and C3 received somatic antigen tests at 20 µg/SC. Under general anesthesia, a wound biopsy puncture of 9.8 mm in diameter was performed on the mice's back and spine. In the experimental group, antigen and alum adjuvant were administered subcutaneously around the wound, while the control group received Phosphate‐Buffered Saline (PBS). Using digital images, a geometric assessment was conducted on days 0, 1, 3, 6, 9, 12, 15, 18, and 21 post‐wounding. The obtained images were analyzed by Image J software and after analyzing the data by SPSS software.

Results

A significant difference in terms of epithelization was observed in the antigen treatment group with a dose of 20 µg on days 3 and 6 (P < 0.05). Furthermore, the 20 µg antigen group was significantly higher than the 10 µg antigen group in terms of this factor on day 3 (P < 0.05). Skin samples were taken from all wounds on days 3, 10 and 21 for microscopic evaluation. Regarding epithelization, on day 10, a significant difference was observed in the treatment group with a concentration of 10 µg with the control group and the treatment group with a concentration of 20 µg (P < 0.05).

Conclusion

Based on the results of the present study, it can be concluded that somatic antigens of protoscolex hydatid cyst are dose‐dependent and antigens with a dose of 20 µg by subcutaneous injection accelerate wound healing and epithelialization.

Keywords: hydatid cyst, protoscolex somatic antigens, skin, wound healing

1. INTRODUCTION

Wound healing has always challenged clinicians. 1 , 2 In recent years, the knowledge of wound healing processes has increased significantly, leading to a wide range of treatment options. 3 , 4 The repair process that occurs after skin and soft tissue damage is called wound healing and includes a series of coordinated events that ultimately repair the damage and restore the integrity of the skin. 5 Wound healing requires the integration of complex cellular networks to restore tissue homeostasis and is classified into several stages that often overlap. 6 , 7 These stages include the hemostasis phase, inflammation, proliferation, tissue and rearrangement, and maturation. The epidermal cells’ proliferation and migration phase is the most important wound‐healing stage. The hemostasis and inflammation phase begins immediately after the injury and consists of creating a clot and recruitment of monocytes, neutrophils, lymphocytes, and macrophages. 8 By releasing growth factors, including Fibroblast Growth Factors (FGFs), Epidermal Growth Factor (EGF), and Platelet‐Derived Growth Factor (PDGF), macrophages cause the migration and proliferation of cells and enter the next phase, called the proliferation phase. In the repair phase, epithelialization, granulation tissue production and fibroblast proliferation are the most consequential events, as well as collagen organization and remodeling. 9

The location of the wound or infection may prevent suturing of the most traumatic wounds. 10 Therefore, factors that accelerate healing have always had special significance. Through the activation of innate and acquired immune cells, the immune system defends against foreign pathogens and promotes wound healing. 11 Cytokines and tissue growth factors, especially the Th2 cytokine pathway, produce IL4 and IL13 cytokines, essential mediators in wound healing and play a crucial role in wound healing by reducing inflammation. 12 , 13

The immune response against helminths includes several groups, which include, innate immune cells such as basophils, eosinophils, mast cells, M2 macrophages (which are known as alternatively activated macrophages), and the group innate lymphoid cells, and on the other hand, acquired immune responses with the action of Th2 cytokines including IL4, IL5, and IL13 as the main mediators. 14 , 15 The immune system's overall function may be greatly affected by helminth's strong anti‐inflammatory and wound‐healing pathways. 16 The expansion of immune regulatory mediators such as IL10 and arginase, control the destructive inflammatory reactions resulting from this disease in persistent worm infections. 17 , 18

The adult form of Echinococcus granulosus (Sensu Lato) is located in the definitive host's small intestine. 19 , 20 Gravid proglottids release their eggs into the feces, and a suitable intermediate host then ingests them. 21 , 22 The eggs hatch in the small intestine and release six hooked oncospheres, which can pass through the intestinal wall and migrate through the circulatory system to various organs, especially the liver and lungs. 23 , 24 A thick‐walled hydatid cyst forms from the Oncosphere's development. 25 The progressive growth of hydatid cysts leads to daughter cysts and protoscolices. 26 Considering that the innate immune system has a significant effect on wound healing, and on the other hand, parasitic infections trigger the innate immune response, probably the somatic antigens of the hydatid cyst can play an effective role in the development of wound healing. This study aims to investigate the role of somatic antigens of hydatid cyst protoscolex in the healing of an open wound by direct method and using local treatment.

2. METHODS AND MATERIALS

2.1. Ethical approval

All procedures were approved by the Animal Care Committee of Veterinary Medicine, Ferdowsi University, Mashhad, Iran. The principles of laboratory animal care were followed, and specific international laws were observed.

2.2. Study design

A total of 54 adult mice with an average weight of 25 ± 5 g and an age of about two months were used in the present study and divided into three groups A, B and C, and each group was divided into three subgroups of six. Subgroups A1, A2, and A3 were considered as control groups, subgroups B1, B2, and B3 were considered for hydatid cyst somatic antigen testing with a dose of 10 µg/SC, and subgroups C1, C2, and C3 were considered for hydatid cyst somatic antigen testing with a dose of 20 µg/SC. Every 2 days, the cages were completely emptied, washed, and disinfected to reduce the possibility of mortality and the risk of infectious diseases. The feeding and environmental conditions were the same for all mice. The mice of all groups were treated with anti‐parasitic treatment with Ivermectin (with a dose of 200 µg/kg) before the wounds creation and repeated 10 and 14 days after the treatment. Group A was injected with 0.4 mL containing 0.2 mL of phosphate‐buffered saline (PBS) solution, and 0.2 mL of alum adjuvant subcutaneously around the wound (a sterile insulin syringe was used for each mouse). Group B was injected with 0.4 mL containing 0.2 mL of antigen with a dose of 10 µg/mice, and 0.2 mL of alum adjuvant around the wound (a sterile insulin syringe was used for each mouse). Group C was injected with 0.4 mL containing: 0.2 mL of antigen with a dose of 20 µg/mice, and 0.2 mL of alum adjuvant around the wound (a sterile insulin syringe was used for each mouse).

2.3. Antigen preparation

Sampling was done in the Mashhad slaughterhouse, Iran. In the slaughterhouse, the liver and lungs of the slaughtered sheep were examined, the affected organs with hydatid cysts were separated, and immediately transferred to the Faculty of Veterinary Medicine parasitology laboratory. In the laboratory, the surface of the organs was washed with a phosphate buffer solution, and the isolated cysts were immediately transferred into a phosphate buffer solution. Hydatid cyst protoscolex was isolated and diagnosed by microscopic observation (Olympus, Japan). The protoscoleces were transferred into a sterile Falcon tube and sonicated in an ice bath: W176 several times for 25 s until completely crushed. In the next step, 1500 × g centrifugation was used for 5 min to separate the antigens. The Bradford method measured the protein concentration and read at 562 nm optical absorption. The concentration of the measured solution was 2 mg in 1 mL.

2.4. Wound creation

First, the mice were under general anesthesia with isoflurane, and the back area was shaved. Then, a biopsy punch created a full‐thickness wound with a diameter of 9.8 mm on the back area and the vertebral column. The wounds were examined over a period of 21 days. In this way, digital images of the wounds of the control and treatment groups were prepared on days 0, 1, 3, 6, 9, 12, 15, 18, and 21.

Each wound's crust was carefully removed in order to better observe the epithelial tissue formation. For this purpose, normal saline was poured on the wounds so the crust becomes soft and easily removed with tweezers. This work was done slowly and carefully so as not to damage the newly formed tissue and the cover. The ruler was placed near the wound, and then the pictures were taken by a digital camera perpendicular to the wound. Two measurements were taken in each photo. The first measurement included the wound's perimeter. That is, the distance between healthy skin and newly formed epithelial tissue was calculated. The second measurement included the perimeter of the inner area. The distance between the newly formed epithelial area and the newly formed tissue was measured. The area of ​​newly formed epithelial tissue and granulation tissue of each wound was measured by ImageJ software (Version 1.53).

To obtain a microscopic sample, on the third day, the mice of subgroups A1, B1, and C1 were euthanized by ether. Then, for histopathological study, a full‐thickness sample was taken from the wounds to include the entire wound area and some of the healthy skin area. The samples were placed in 10% buffered formalin containers. The same process was repeated on day 10 for the A2, B2, and C2 subgroups and on the day 21 for A3, B3, and C3 subgroups. The samples were processed through routine paraffin embedding technique, stained with Hematoxylin and Eosin (H&E), and observed under a light microscope (Olympus, Japan) and analyzed using Image J software (Version 1.8.0.).

2.5. Statistical analysis

According to the normal distribution of the data, repeated measure ANOVA was used to compare the macroscopic wound findings between the groups. Benferoni's test was used to compare the two‐by‐two means. In all tests, the significant level was considered P ≤ 0.05. The data related to the microscopic part had a non‐normal distribution, and then the Wallis‐Kruskal test was used to compare the groups, and the Whitney‐Mann test was used to compare the groups one by one.

3. RESULTS

3.1. Macroscopic findings

3.1.1. Wound contraction

In all three groups, the size of the wounds gradually decreased from day 1 to day 21. Between the antigen treatment group with a dose of 20 µg/mice and the control group, in terms of the percentage of wound contraction in all days, the antigen treatment group was higher than the control group. However, no statistically significant difference was seen (P > 0.05).

There was no statistically significant difference in wound contraction percentage between the antigen group with a dose of 20 µg/mice and the antigen group with a dose of 10 µg/mice on days 1, 3, 6, and 9 (P > 0.05). However, the antigen group with a dose of 20 µg/mice had slightly higher wound contraction percentages compared to the antigen group with a dose of 10 µg/mice.

When comparing the antigen group with a dose of 10 µg/mice to the control group, there was no statistically significant difference in wound contraction percentage (P > 0.05). However, the antigen group with a dose of 10 µg/mice showed higher wound contraction percentages on days 6, 12, 15, and 18 compared to the control group and lower percentages on days 1, 3, and 9.

3.1.2. Wound healing percentage

The results of the macroscopic examination found that in terms of wound healing percentage, the antigen treatment group with a dose of 20 µg/mice was higher than the control group on all days except day 9. Still, there was no statistically significant difference (P > 0.05). Furthermore, regarding the wound healing percentage factor, the antigen group with a dose of 20 µg/mice on days 1, 3, 6, 9, and 12 was higher than the antigen group with a dose of 10 µg/mice. Still, no statistically significant difference was seen (P > 0.05). Furthermore, comparing the results of this research between the antigen treatment group with a dose of 10 mice/µg and the control group, on all days except day 9, the antigen group with a dose of 10 mice/µg was higher than the control group, but no significant difference was observed (P > 0.05).

3.1.3. Percentage of epithelial tissue formation

During the macroscopic examination, it was observed that the antigen treatment group with a dose of 20 µg/mice had a higher percentage of epithelial tissue compared to the control group. This difference was significant on days 3 and 6, as well as on days 12, 15, and 18 (P < 0.05) and was not significant on other days (P > 0.05). In addition, regarding the percentage of epithelial tissue formation, the antigen group with a dose of 20 µg/mice on days 3, 6 and 12 was higher than the antigen group with a dose of 10 mice/µg, and this difference was significant on the day 3 (P < 0.05). On the other hand, comparing the results of this research, regarding the percentage of epithelial tissue formation in all days except day 9, the 10 µg/mice antigen group was higher than the control group. Still, there was no significant difference (P > 0.05). Figures 1, 2, 3 show the macroscopic images of wounds in the antigen treatment group mice with a dose of 20, 10 µg, and control on different days (Figures 1, 2, 3).

FIGURE 1.

FIGURE 1

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Macroscopic images of wounds in mice of the antigen treatment group with a dose of 20 µg on different days.

FIGURE 2.

FIGURE 2

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Macroscopic images of wounds in mice of the antigen treatment group with a dose of 10 µg on different days.

FIGURE 3.

FIGURE 3

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Macroscopic images of wounds in control group mice on different days.

3.2. Microscopic findings

3.2.1. Evaluation of the amount of inflammatory cells

After the formation of the wound in the first day, the infiltration of a huge number of inflammatory cells to the wound site indicated an acute inflammatory reaction. With time, the density of Inflammatory cells decreased. In the analysis of tissue sections stained with hematoxylin and eosin, and the evaluation of graphs depicting the density of inflammatory cells in the wound area, it was observed that the antigen group with a dose of 20 µg/mice had fewer inflammatory cells on day 3 compared to the control group. However, on days 10 and 21, the antigen group had a higher inflammatory cell density than the control group. These differences were not statistically significant on any day (P > 0.05).

Furthermore, the infiltration of inflammatory cells in the antigen group with a dose of 20 µg/mice on days 3 and 21 was lower than in the antigen group with a dose of 10 µg/mice. On day 10, the number of inflammatory cells was higher than the antigen group with a dose of 10 µg/mice. However, this difference was not significant (P > 0.05). In this study, the density of inflammatory cells in the antigen group with a dose of 10 µg/mice/ on days 10 and 21 was higher than in the control group, but no significant difference was observed (P > 0.05) (Figures 4, 5, 6).

FIGURE 4.

FIGURE 4

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Observation of inflammatory cells (asterisk) in the antigen treatment group with a dose of 10 µg per day 21 (×4, H&E).

FIGURE 5.

FIGURE 5

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The giant cell (asterisk) and macrophages (arrows) in the tissue sampled from the antigen group with a dose of 10 µg on day 21 (×40, H&E).

FIGURE 6.

FIGURE 6

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The presence of inflammatory foci (arrows) in the tissue, antigen treatment group with a dose of 20 µg on day 21 of sampling (×10, H&E).

3.2.2. Granulation tissue formation

It was found that on all sampling days, in the antigen treatment group with a dose of 20 µg/mice, the amount of granulation tissue formation was less than in the control group. However, the results of the statistical tests did not show a significant difference (P > 0.05) (Figures 7 and 8).

FIGURE 7.

FIGURE 7

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The pyogranulomatous reaction in the tissue and the complete re‐epithelialization in the antigen treatment group with a dose of 20 µg, on day 21 of sampling (×10, H&E).

FIGURE 8.

FIGURE 8

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Pyogranulomatous reaction (arrow) in the antigen treatment group with a dose of 20 µg day 21 of sampling (×40, H&E).

3.2.3. Evaluation of re‐epithelialization

On day 10, the antigen treatment group with a dose of 20 µg/mice showed less epithelial regeneration coverage compared to the other groups. However, this difference was not statistically significant (P > 0.05) compared to the other groups.

On the other hand, the antigen group with a dose of 10 µg/mice exhibited higher re‐formation of epithelial tissue on day 10 compared to the other groups. This difference was statistically significant (P < 0.05) (Figures 9, 10, 11).

FIGURE 9.

FIGURE 9

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The absence of re‐epithelialization (asterisk) at the wound site in the control group, day 3 of sampling (×10, H&E).

FIGURE 10.

FIGURE 10

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The re‐formation of epithelial tissue (arrow) in the control group, on the day 10 of sampling (×4, H&E).

FIGURE 11.

FIGURE 11

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Complete re‐epithelialization (arrow) in the antigen treatment group with a dose of 10 µg, day 21 of sampling (×4, H&E).

3.2.4. Amount of angiogenesis

In the descriptive analysis of tissue sections stained with hematoxylin and eosin, and the evaluation of graphs depicting the grading of angiogenesis in the wound area, it was observed that on day 3, the antigen treatment group with a dose of 20 µg/mice had a higher degree of angiogenesis compared to the control group. However, on day 16, the antigen treatment group with a dose of 10 µg/mice had a lower degree of angiogenesis compared to the control group. The statistical test results indicated a lack of significant difference (P > 0.05) (Figure 12).

FIGURE 12.

FIGURE 12

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Severe angiogenesis in the wound healing of control group on the day 10 of sampling (×40, H&E).

4. DISCUSSION

Wound healing is an important clinical challenge that requires effective management. 3 , 27 In wound care, many efforts have been made emphasizing the new therapeutic approach and the development of techniques for managing acute and chronic wounds. 3 , 28 In veterinary medicine, traumatic wounds cannot be sutured for various reasons and we often see the second type of healing. 29

In the macroscopic examination of the present study, a significant difference in terms of epithelialization was observed between the groups of the antigen treatment group with a concentration of 20 µg on days 6 and 3 (P < 0.05). Likewise, the 20‐µg antigen group was significantly different from the group in terms of epithelialization on day 3. However, no significant difference was observed in the treatment and control groups (P ≥ 0.05) regarding the percentage of wound contraction and wound healing.

In the microscopic examination of inflammatory cells penetration, flesh bud tissue, and angiogenesis, no significant difference was seen between the treatment and control groups (P ≥ 0.05). Still, in terms of re‐epithelialization, on the 10th day, there was a significant difference between the treatment groups and the control group (P < 0.05). The results of the present study show that using somatic antigens of hydatid cyst protoscolex with a concentration of 20 µg as subcutaneous injection accelerates the wound healing process and especially the production of epithelial tissue.

In a similar study, in 2017, Mohammadpour et al. investigated the effect of type 2 immune stimulation caused by parasitic infection on full‐thickness wound healing in a study on Marshalagia marshalli somatic antigens. In this study, based on the findings, 20 mcg somatic antigen of the Marshalagia nematode caused a decrease in inflammatory cells and a decrease in wound size on the 10th and 21st days after wound formation, and they concluded; Somatic antigens of M. marshalli nematode with a dose of 20 µg as subcutaneous injection probably accelerates the wound healing process. 30

In a study conducted by Bourke et al. in 2015, they concluded that Schistosoma mansoni sarkar and its excretory‐secretory products have a direct effect on epidermal keratinocytes, and by starting the repair function of the body's inherent defense barriers and pro‐inflammatory mechanisms, it causes epidermal wound healing. 31

Chen et al. in 2012, during a study related to contamination by Nippostrongylus braziliensis worm, it was shown that worm contamination with the presence of type 2 immune response activated the IL‐4R signal pathway, which led to an increase of 10 ‐IL and 1‐IGF, decreased IL‐17, and stimulate the development of M2 macrophages, which cause collagen synthesis and fibroblasts activity. They all play a role in wound healing. 32

Nilforoushzadeh et al. investigated the effect of allogeneic cord blood platelet gel on burn wound healing in 2023. Human patients with superficial and deep partial thickness burns were assessed using a novel topical dressing containing growth factors from umbilical cord blood platelet concentrates. The contexts and methodologies may differ, but both studies aim to improve wound healing by stimulating antigenic responses. 33

In terms of evaluating the efficacy of innovative treatment techniques in improving wound healing, Jin et al. demonstrated that platelet‐rich plasma (PRP) gel and umbilical cord mesenchymal stem cells (UC‐MSCs) gel were effective in treating diabetic ulcers at 2024. As such, it had a higher wound healing rate, a shorter healing time, a better symptomatic effect, and a more effective inflammation reduction impact. 34

Ultimately, wound healing continues to be a challenge, leading to the exploration of innovative therapeutic solutions. By implementing these strategies, it can be possible to improve wound care and patient outcomes.

5. CONCLUSION

Based on the findings obtained in this research, the somatic antigens of hydatid cyst protoscolex with a dose of 20 µg injected subcutaneously probably accelerated and improved the epithelialization process. It can also be concluded that this healing process was dose‐dependent and required a booster injection. Considering the results obtained and their comparison with the results of the antigen treatment group with a dose of 20 µg per mouse, more studies are needed on the doses of these antigens, and their effects should be compared.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

All procedures were approved by the Animal Care Committee of Veterinary Medicine, Ferdowsi University, Mashhad, Iran. The principles of laboratory animal care were followed, and specific international laws were observed. Ethical code: 2020.5.50140.

ACKNOWLEDGMENTS

We thank the research deputy of the Ferdowsi University of Mashhad for supporting us. Ferdowsi University of Mashhad. Funding Number: 50140.

Hosseinzade S, Nourani H, Kazemi Mehrjerdi H, Lotfalizadeh N, Borji H. The effect of hydatid cyst protoscolex somatic antigens on full‐thickness skin wound healing in mouse. Skin Res Technol. 2024;30:e13685. 10.1111/srt.13685

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Articles from Skin Research and Technology are provided here courtesy of International Society of Biophysics and Imaging of the Skin, International Society for Digital Imaging of the Skin, and John Wiley & Sons Ltd

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