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. 2025 Sep 26;56(5):328. doi: 10.1007/s10735-025-10581-6

Morphological and histopathological study of edible bird’s nest on wound healing in mice

Min Li 1, Bo Liu 1, Man Yuan 2, Xiaoli Dai 1, Shuang Qiu 2, Xiangkui Zhang 1, Xiaoyang Zheng 1, Kai Chen 1, Chonggang Duan 1, Daizhou Zhang 1, Dongliang Wang 2,✉, Xiangjing Meng 1,✉
PMCID: PMC12474635  PMID: 41003813

Abstract

Edible bird’s nest (EBN) has a variety of pharmacological effects, such as improving immunity, antioxidant, promoting brain development, nerve prevention, degenerative diseases, and whitening and moisturizing skin, but its role in wound healing is still unknown. In this study, full-thickness excisional wounds were made on the back of mice to establish the wound model. The mice were treated with EBN, a positive drug, and 0.9% NaCl for 14 days. At days 3, 7, and 14 post-injury, the traumatic skin and intestinal contents of mice were collected. ELISA, western blot and quantitative PCR assay were used to evaluate the expression of inflammatory factor, protein, and mRNA. The damaged skin of the mice was analyzed by histopathology. Biochemical experiment was used to evaluate the content of hydroxyproline. Gas chromatograph was used to detect mouse intestinal contents. Results showed that EBN can narrow the wound area, reduce the expression of inflammatory factors, upregulate the expression of collagen and α-SMA, improve the damaged skin structure, increase the content of SCFAs and promote wound recovery rapidly. Current findings may suggest that EBN might serve as a potential effective substance for wound healing therapy either orally or externally.

Keywords: Collagen, Edible bird’s nest, Inflammatory factors, Mice skin, Wound healing

Introduction

As the largest and most important protective organ of the body, the skin is extremely vulnerable to external damage and infection by pathogenic bacteria, and even threatens the life and health of patients in serious cases (Proksch et al. 2008; Arda et al. 2014). When skin damage occurs, a variety of cells, including the epidermal layer, dermis subcutaneous adipose tissue, and cytokines, work together to allow the skin to heal (Baroni et al. 2012). Based on the healing time, wounds can be divided into acute and chronic wounds. A normal wound-healing process can be divided into hemostasis, inflammation, proliferation, and remodeling (Evans 1980; Reddy et al. 2002) Thus, skin healing is a dynamic and complex biological process. In recent years, therapeutic strategies used for wound healing include hydrogel wound dressings (Davoodi-Roodbordeii et al. 2019; Wang et al. 2022), oral or topical drugs, growth factors (Ou et al. 2022), autologous or allograft (Hosseini and Shafiee 2021), cell therapy and stem cells (Sharifiaghdam et al. 2022; Hassanshahi et al. 2019), plant extracts (Liang et al. 2020; Ramazanov et al. 2017) and others. After literature research and preliminary work accumulation, we found that bird’s nest may have the ability to promote wound healing.

EBN is a kind of natural nourishing food, the history of human use of EBN in China dates back about 1500 years ago. EBN contains many important nutrients, mainly including sialic acid, acidic mammalian chitinase, lysyl oxidase homolog, nucleobindin-2, calcium-binding protein, trace elements and glucose-regulated protein, etc. (Lai et al. 2021; Yuan et al. 2023). The biological activity of these component contributes to the main biological function of EBN. Recently, a study showed that EBN can enhance the mind’s core capabilities, relieve nerve damage by fighting ROS, play a protective role in neurons and promote brain development (Loh et al. 2022). ENB extract can reduce apoptosis and reduce damage from UV radiation (Masuda et al. 2022). EBN has anti-inflammatory, and wound-healing activities, these properties may contribute to the acceleration of wound healing process (Hwang et al. 2020). In the present work, we used a full-thickness defect wound model to investigate the influence of EBN on the skin wound healing process, and explore the potential mechanism between EBN and wound healing. Biochemical, molecular, and protein analysis were used to evaluate the wound healing ability of EBN. Results showed that oral and topical treatment of EBN had obvious ability to promote wound healing. Perhaps in clinical practice, EBN can be used as a material in the treatment of wound healing.

Materials and methods

Animals and treatment

Female BALB/c mouse of 6–8 weeks old, weight18–26 g were brought from the animal center of Shandong First Medical University (SDFMU, Jinan, Shandong, China). The experimental procedures were approved by the Animal Ethics Committee at Shandong Academy of Pharmaceutical Science (IACUC-2022-M023).

After an acclimation period, a skin punch was used to make a circular wound of 10 mm in diameter that excised the full thickness of the mice back skin (Xue et al. 2022). Next, the mice were randomly divided into seven groups of 6 animals, black control (BC): oral treatment water (40 mL/kg); negative control (NC): oral treatment water (40 mL/kg) and topical treatment of 0.9% NaCl; positive control (PC): oral treatment water (40 mL/kg) and topical treatment rhEGF (2000 IU/mL) 0.02 mL, and four treated groups (oral treatment EBN low dose (5 mL/kg), L; oral treatment EBN high dose (40 mL/kg), H; oral treatment EBN low dose (5 mL/kg) and topical treatment EBN 0.02 mL, L + T; oral treatment EBN high dose (40 mL/kg) and topical treatment EBN 0.02 mL, H + T).

Three mice from each group were euthanized by CO2 inhalation on days 3, 7 and 14.

Full-thickness skin samples from the wound were carefully excised and collected. One section of these samples was fixed in 10% neutral buffered formalin. The other was quick-frozen and stored at − 80 °C.

Preparation of EMB

Take EBN (Beijing Xiaoxiandun Biotechnology Co., Ltd. Beijing, China) 70 g, pour into a juice machine (Joyoung Co., Corp., Ltd, Hangzhou, China), and crush for 3 min before using.

Macroscopic observation

After treatment, the general status of the mice was observed and recorded every day, along with the inflammatory response, fluid exudation, and wound healing of each animal, and the images were photographed at 3, 7 and 14 days. The short diameter and long diameter of the skin lesion were measured in batches in 7 days and 14 days, and the area of the damaged area was calculated. Area (mm2) = short diameter (mm) × length diameter (mm).

Enzyme-linked immunosorbent assay (ELISA)

The skin tissues of mice in each group were homogenized with cooled phosphate buffer after grinding and liquid nitrogen freezing, centrifuged at 4 °C at 3500 rpm/min for 10 min, and the supernatant was taken out for sample analysis. The IL-6 and TNF-α in the supernatant were measured by ELISA kits (Boster Co., Ltd, Wuhan, China). The absorption was measured at 450 nm.

Evaluation of skin histopathology

The skin samples were taken out from 10% neutral buffered formalin and embedded in paraffin. 5 μm thick of paraffin sections were stained with Masson’s trichrome staining. Select10 random sections per slide were photographed by an optical microscope (Leica DMLB, Wetzlar, Hessen, GER).

Western blot analysis

The other skin tissues were processed in the same way to get skin homogenate. A BCA assay kit (Beyotime Co., Ltd, Shanghai, China) was used to quantify the protein concentration. Proteins were loaded onto 10% SDS-PAGE gels (Epizyme Biotech Co., Ltd, Shanghai, China) and then transferred to a PVDF membrane (0.45 µm, Millipore, Billerica, MA, USA). The membranes were blocked with 5% BSA (Beyotime) for 1 h at room temperature, and incubated overnight at 4 °C with primary antibodies: rabbit anti-α-SMA (1:1000, Proteintech Co., Ltd, Wuhan, Hubei, China), rabbit anti-β-actin (1:1000, Boster), After several washes with PBST (Solarbio), membranes were incubated with horseradish peroxidase-linked anti-rabbit antibodies (1:10,000, Boster) in 5% BSA (Solarbio) in PBST for 1 h at room temperature. Immunoblots were visualized using ECL (Beyotime) and analyzed using software Image J.

Quantitative PCR (qPCR) assay

Total RNA was prepared from whole skin tissue using Trizol ((TIANGEN, Life Technologies Corporation 92008, United States). Purifcation and reverse transcription RNA with TransScript One-Step gDNA Removal and cDNA Synthesis SuperMix (TransGen Biotech), PCR amplification with TransTaq DNA Polymerase High Fidelity (TransGen Biotech), all the steps are according to manufacturer’s protocol. Amplification and melting curves were recorded using aT100TM Thermal Cycler (Bio-Rad, USA). Relative expression level of the target mRNA was normalized to glycer-aldehyde 3-phosphate dehydrogenase (GAPDH) mRNA by the 2−ΔΔCT method.

SCFAs detection

0.2 g of intestinal content was mixed with 0.4 mL of 0.5 mol/L oxalate solution and fully reacted for 5 min. After centrifugation at 12,000 rpm for 10 min, the supernatant was filtered with a 0.22 μm millipore filter membrane (Millex, Billerica, MA, USA). A gas chromatograph (Agilent, Santa Clara, CA, USA) was used to survey concentration of SCFAs. The assay was performed as follows, the temperature of the injection block was 200 °C, the split ratio was 20:1, the temperature of the detector was 250 °C. And air, hydrogen, and nitrogen flows were 400, 40, and 25 mL/min, respectively. The column temperature was initially 60 °C, kept 5 min, then increased to 120 °C at 5 °C/min, kept 5 min, and finally increased to 180 °C at 30 °C/min and kept at this temperature for 2 min.

Statistical analysis

Data were expressed as the Mean ± SEM. Statistical analysis was performed with Origin 8 and GraphPad Prism 5 using one-way ANOVA followed by a post hoc Least Significant Difference test. P < 0.05 was considered statistically significant.

Results

Body weight and wound area

To confirm the role of EBN on cutaneous wound healing, the full thickness of the mouse’s skin wound was created on the back of the healthy mouse and monitored every day. Pictures of the macroscopic changes within 14 days in the wound site are displayed in Fig. 1A. Compared with the BC group, in L, H, L + T and H + T groups, the wound area was visually significantly reduced in 7 days. EBN may play a role in the early phase of wound healing and rapidly reduce the wound size. In Fig. 1B, compared with the BC group, the group of PC, L, H, L + T and H + T were significantly accelerated wound closure in 7 days. After treatment of EBN, one-two of closure was achieved by day 7 in L, H, L + T and H + T groups. On day 14, Compared with BC group, the wound areas of PC, L, H, L + T were closure, but had no significance, the wound area of H + T had significantly closure. The body weight of mice (Fig. 1C) had no significant differences in the treatment phase, it suggested that EBN had no negative effect on their health.

Fig. 1.

Fig. 1

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The changes of body weight and wound area. (A) Macroscopic picture of the mouse wound in 3 days, 7 days and 14 days. (B) The wound area of the mice after treatment with EBN in 3 days, 7 days and 14 days. (C) The mice body weight of each group in 3 days, 7 days and 14 days (Compared with group BC, *P < 0.05, **P < 0.01, ***P < 0.001. n = 3)

Inflammatory factors content

Inflammatory factors were measured by ELISA kits. Results showed that in the IL-6 experiment (Fig. 2A), compared with BC group, the expression of IL-6 was significantly decreased in L + T group at 3 days, in PC, L, L + T and H + T group at 7 days and in PC and H + T group at 14 days. In the TNFα experiment t (Fig. 2B), compared with BC group, the expression of TNFα as significantly decreased in H and H + T group at 3 days, in PC, L, H, L + T and H + T group at 7 days and in PC, H and H + T group at 14 days. Oral and topical using of EBN can reduce the expression of inflammatory factors in the wound skin, and thus play a role in promoting wound healing.

Fig. 2.

Fig. 2

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Inflammatory factors content in each group for 3 days, 7 days and 14 days. (A) IL-6; (B) TNFα. (Compared with group BC, *P < 0.05, **P < 0.01, ***P < 0.001. n = 3)

Histopathological study and hydroxyproline content

The damaged mouse skin structure gradually returned to normal as treatment time increased (Fig. 3A). We observed a lot of necrotic tissues, scab, and dermal connective tissue were closely bound. There were many inflammatory cells infiltration under the epidermis (Fig. 3A arrow IC) and no obvious difference in each group at 3 days. On day 7, the BC group had loose intercellular matrix structure and a thin epidermis began to appear. The subcutaneous blood cells were significantly reduced and the epidermis began to form. Small amount of collagen fiber filled the intercellular matrix in PC L, H, L + T and H + T groups (Fig. 3A arrow CF). On day 14, the cell interstitial structure of the BC group became more orderliness than 7 days. The group of PC, L, H, L + T and H + T had a lot of collagen fiber filling the intercellular substance (Fig. 3A arrow CF) and obvious new blood vessel formation (Fig. 3A arrow BZ).

Fig. 3.

Fig. 3

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Histological pictures and collagen characterization (A) Masson staining of full-thickness wound in central area skin at 3 days, 7 days and 14 days in each group (100×). The arrow IC points inflammatory cells. The arrow CF points collagen fiber. The arrow BZ points blood vessel. (B) Hydroxyproline content of each group at 3 days, 7 days and 14 days. (C) The expression of COL1A1 mRNA in different group at 3 days, 7 days and 14 days (Compared with group BC, *P < 0.05, **P < 0.01, ***P < 0.001. n = 3)

The increased collagen expression not only reflected by the pathological picture, but also hydroxyproline experimental and COL1A1 mRNA expression. In the hydroxyproline experiment (Fig. 3B), compared with BC group, the expression of hydroxyproline was significantly increased in PC, H, L + T and H + T groups at 3 days, in PC, L, H, L + T and H + T groups at 7 days and in PC, L, H, L + T and H + T groups at 14 days. The expression of COL1A1 mRNA was measured by the 2−ΔΔCT method (Fig. 3C). 2−ΔΔCT > 1, the expression of mRNA was significantly increased. Compared with BC group, the expression of COL1A1 mRNA was significantly increased in PC, L, H, L + T and H + T groups at 3 days, in PC, L, H, L + T and H + T group at 7 days. There was no significance in PC, L, H, L + T and H + T groups at 14 days, compared with BC group. The results showed that oral and topical using of EBN can promote collagen production.

α-SMA content

In the process of wound healing, myofibroblasts expressing α-SMA and produce a lot of actin stress fibers, which can make them contract and migrate, thus promoting the remodeling and repair of the wound tissue. In Fig. 4A, compared with BC group, we observed the expression of α-SMA was markedly increased in PC, L, H, L + T and H + T group in 3 days. In Fig. 4B, compared with BC group, we observed the expression of α-SMA was also markedly increased in PC, L, H, L + T and H + T group. We quantified the expression of the α-SMA protein in 7 days and 14 days (Fig. 4C, D), and the results were consistent with the observations. Indicating EBN and positive drugs can promote the expression of α-SMA and thus promote wound healing.

Fig. 4.

Fig. 4

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The expression of α-SMA protein at 3 days, 7 days in each group. Representative α-SMA protein in mice full-thickness wound area skin is analyzed using western blot in (A) 3 days; (B) 7 days. Relative α-SMA level at (C) 3 days; (D) 7 days in each group (Compared with group BC, *P < 0.05, **P < 0.01, ***P < 0.001. n = 3)

SCFAs content

As shown in Fig. 5, we analyzed the SCFAs content in the mouse intestinal contents at 14 days by gas phase. In Fig. 5A, compared with BC group, the content of propionic acid in PC, L, H, and H + T groups was significantly increased. In Fig. 5B, compared with BC group, the content of butyric acid in PC, H, and H + T groups were significantly increased. In Fig. 5C, compared with the BC group, the content of pentanoic acid in PC, H, and H + T groups were significantly increased. In Fig. 5D, compared with BC group, the content of acetic acid in L, H, and H + T groups were significantly increased. In Fig. 5E, compared with BC group, the content of isobutyric acid in PC, L, H, and H + T groups were significantly increased. In Fig. 5F, compared with BC group, the content of isopentoic acid in PC, L, H, and H + T groups were significantly increased. These results showed that after the skin damage, the intestinal contents of 6 SCFAs were increased in PC and ENB treatment groups, indicating that oral treatment EBN could promote the content of SCFAs, and the high dose group was better than the low dose group; the SCFAs content in the topic treatment groups were lower than the oral treatment group, which showed that the external application of the EBN helped to accelerate the repair of the damaged skin, making the intestinal flora secrete relatively few SCFAs.

Fig. 5.

Fig. 5

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Contents of the six SCFAs in the different groups in mice intestinal contents in 14 days. (A) Propionic acid; (B) Butyric acid; (C) Pentanoic acid; (D) Acetic acid; (E) Isobutyric acid; (F) Isopentoic acid (Compared with group BC, *P < 0.05, **P < 0.01, ***P < 0.001. n = 3)

Discussion

Wound healing is a complex and delicate process. In this study, different methods were used to treat a full thickness of the mice back skin wound model with a 10 mm diameter to evaluate the treatment effect. In our series of experiments, we found that EBN can reduce the wound area, promote wound healing and have no negative effect on the health of the mice. Most notably, EBN reduced damage to inflammation, increased the expression of collagen and improved the quality of healing.

The short period of hemostasis is followed by the inflammatory phase of the wound. The wounds in the inflammatory period directly affect the subsequent regeneration and repair of wound tissue, which is a crucial period for skin wound healing (Segal 2005). The extension of the inflammatory period reduces the expression level of neutrophil chemokines and adhesion factors, which leads to the delayed entry of neutrophils into the wound, increases the risk of infection, and promote the continuous release of inflammatory factors (Okonkwo et al. 2020; Vijayakumar et al. 2019). IL-6 and TNFα as the main proinflammatory factor in the inflammatory stage, it is one of the main monitoring targets of wound healing (Bakshi 2017). In this work, IL-6 and TNFα levels were increased after injury, EBN treatment markedly reduced the levels of these inflammatory factors in full-thickness skin wounds, with particularly pronounced inhibitory effects observed in the oral and topical treatment groups. These findings suggest that EBN may alleviate inflammatory responses by downregulating the expression of pro-inflammatory cytokines. Given that macrophages play a pivotal role in the inflammatory process, further investigation is warranted to determine whether EBN exerts its anti-inflammatory effects by modulating macrophages.

Collagen plays an important role in hemostasis, providing both strength and integrity to the wound matrix. Collagen is also necessary for re-epithelialization and cell–cell and cell–matrix interactions (Okur et al. 2018). Collagen can benefit the wound healing and the content of hydroxyproline is a sensitive biochemical indicator reflecting the degradation of collagen (Gorres and Raines 2010; Vasta and Raines 2018). Hydroxyproline is a unique amino acid in collagen, accounting for about 13.5% of the total collagen amino acids (Qiu et al. 2003). In the present work, Masson’s trichrome staining was shown the EBN treatment can promote collagen production in mice damaged area. As shown by the quantitative analysis of the mouse wound skin, the expression of hydroxyproline and COL1A1 mRNA was significantly increased in 3 days and 7 days after EBN treatment. Compared with BC group, the COL1A1 mRNA in 14 days in each group has no significant increased, the hydroxyproline expression was significantly increased in 14 days may be related to the transformation of the collagen protein. This assumption still needs our further research.

After the wound is created, letting the wound heal quickly is the first task (Chen et al. 2015a). We observed the area of wound healing and found that the degree of EBN treatment group wound healing was significantly higher than the other groups, so we examined the α-SMA associated with wound contraction. α-SMA is a specific marker of myofibroblasts. Upon wound healing, the abundant myofibroblasts in the granulation tissue promote the contraction of their cytoskeletal component α-SMA and close the wound margin, thereby closing the wound (Li and Wang 2011; Chen et al. 2015b; Liu et al. 2022). In 3 days and 7 days, after the treatment of EBN can enhance the expression of α-SMA protein. EBN may achieve the effect of promoting wound healing during early wound healing by reducing the area of the wound.

Gut microorganisms can affect the occurrence of skin diseases, and the mental state, gut microbial health condition can reflect the skin health condition (Zhang et al. 2008). Skin conditions can also be used as a reference for assessing mental status and gut microbial health (Zanvit et al. 2015; Bowe and Logan 2011). Short-chain fatty acids (SCFAs) as products of the gut microbes provide part of the energy needed by the human body and regulates the electrolyte balance, protects the intestinal mucosal barrier, promotes the absorption of nutrients, regulates lipid metabolism, regulates the pH value in the intestine, suppresses intestinal inflammation, antitumor effects, and regulates the immune response (Xiao et al. 2023; Trompette et al. 2022; Plöger et al. 2012). The SCFAs include acetic acid, propionic acid, butyrate acid, among which acetic acid, propionate and butyrate are the highest contents. Studies have shown that the short-chain fatty acid sodium butyrate can effectively regulate the skin immune system (Schwarz et al. 2017). This study demonstrates that in a full-thickness skin defect model, both oral administration and topical application of EBN significantly reduced the expression levels of inflammatory factors in skin tissue and induced marked alterations in SCFAs content, with particularly prominent effects observed in the HT group. These findings indicate that the combined oral-topical administration of EBN at appropriate concentrations not only effectively alleviates cutaneous inflammatory responses but may also mitigates wound damage, potentially through an SCFA-mediated gut-skin axis mechanism. Notably, as a multicomponent natural product, whether all bioactive components of EBN participate in the wound healing process requires further elucidation through component isolation and functional validation experiments. Subsequent investigations will focus on elucidating the molecular mechanisms by which EBN exerts its effects via the gut-skin axis.

Conclusion

The present study demonstrates that EBN exhibits significant wound-healing promotion in a mouse model. EBN can downregulation of inflammatory factor expression, enhancement of damaged skin tissue structure repair; and marked elevation of SCFAs levels. Western blotting analysis revealed significantly increased α-SMA expression at wound margins in EBN-treated groups, suggesting accelerated wound closure through enhanced myofibroblast contraction. Furthermore, compared with the control group, EBN treatment significantly increased collagen deposition at wound sites, further confirming its pro-healing efficacy. As this study did not comprehensively analyze EBN’s specific bioactive components, future research should employ chromatographic separation and mass spectrometry to identify its effective constituents, thereby elucidating the molecular mechanisms underlying EBN’s wound-healing properties.

Acknowledgements

We express sincere thanks to Beijing Xiaoxiandun Biotechnology Co., Ltd. for the supply of EBN samples.

Author contribution

Min Li and Bo Liu were responsible for data curation, Formal analysis and writing, Man Yuan and Xiaoli Dai for methodology, Shuang Qiu, Xiangkui Zhang and Xiaoyang Zheng for investigation, Kai Chen for validation, Chonggang Duan and Daizhou Zhang for project administration, Dongliang Wang for conceptualization and visualization, Xiangjing Meng for conceptualization, visualization and writing.

Funding

This research was funded by the Shandong Academy of Pharmaceutical Sciences [Grant Number HZ22004].

Data availability

The data are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical statement

Ethical committees, Internal Review Boards and guidelines followed Chinese standard GB/T 35892-2018 Laboratory animal-guideline for ethical review of animal welfare.

Consent to participate

Not applicable.

Consent to publish

The author confirms that the work described has not been published before and its publication has been approved by all co-authors.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Dongliang Wang, Email: dongliang.wang@xxdun.com.

Xiangjing Meng, Email: fredamxj@163.com.

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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 data are available from the corresponding author on reasonable request.

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