Abstract
Background
Overactive bladder (OAB) is a common and burdensome condition characterized by urgency, frequency, and urinary incontinence. While tibial nerve stimulation (TNS) has emerged as a minimally invasive neuromodulation therapy for OAB, current systems are limited by external devices, frequent hospital visits, and inconsistent stimulation. This study aims to investigate the safety and efficacy of a novel implantable TNS system for treating OAB in pigs.
Methods
Three male Bama miniature pigs (25–28 kg) received bilateral implantation of a novel battery-free, wireless implantable TNS system. The right-side device was activated as the treatment side, and the left-side device remained inactive as a control. Postoperative observations continued for 30 days, including assessments of general health, body weight, and X-ray monitoring of device position. OAB was induced by intravesical infusion of 5% acetic acid. Bladder pressure-volume curves were measured under baseline, OAB-induced (control), and TNS-stimulated (experimental) conditions. Histological examination of tissues surrounding the implants was conducted using hematoxylin and eosin staining to assess inflammation.
Results
All pigs remained in good health throughout the study, with stable weight gain and no adverse events. The implanted devices showed no migration and maintained stable function. Compared with baseline, bladder capacity was significantly reduced in the control group after OAB induction (P<0.05), and significantly increased in the experimental group after stimulation (average improvement of 24.4%, P<0.05). Histological analysis revealed no significant inflammatory reactions at electrode contact sites or in surrounding tissues between the experimental and control groups (P>0.05).
Conclusions
The novel implantable TNS system demonstrated excellent safety, biocompatibility, and efficacy in reducing OAB symptoms in pigs. These findings support its potential as a convenient and effective long-term neuromodulation therapy for OAB.
Keywords: Overactive bladder (OAB), tibial nerve stimulation (TNS), neuromodulation, implantable device, pigs
Highlight box.
Key findings
• A novel implantable tibial nerve stimulation (TNS) system was evaluated in a pig model of overactive bladder (OAB).
• The TNS device demonstrated stable performance and biocompatibility throughout the 30-day study period.
• Bladder capacity significantly increased in the experimental group compared to controls, suggesting an inhibitory effect on OAB symptoms.
• These findings support the safety and efficacy of this implantable TNS system for potential clinical translation.
What is known and what is new?
• TNS is an established neuromodulation treatment for OAB. However, traditional systems rely on surface or percutaneous stimulation, requiring repeated hospital visits and showing variable compliance. Some implantable TNS devices, like eCoin and Revi, have shown promise but still face challenges including fixed stimulation modes, limited battery life, or insufficient personalization.
• This study introduces a novel battery-free, wirelessly powered, and programmable implantable TNS system. In a pig OAB model, the device maintained stable placement and function, improved bladder capacity by 24.4%, and showed no significant inflammatory response. These results demonstrate promising therapeutic potential and support further development toward clinical application.
What is the implication, and what should change now?
• This novel implantable TNS device may offer a more convenient and effective long-term treatment option for OAB.
• Future research should focus on optimizing stimulation parameters, evaluating chronic safety, and conducting human trials to validate its clinical utility.
Introduction
Overactive bladder (OAB) is a syndrome characterized by urgency, often accompanied by increased frequency, nocturia, and urgency urinary incontinence, after excluding other underlying causes such as infection or tumors (1). The global prevalence of OAB ranges from 8.6% to 16.9% (2), with prevalence rates in China reported as 19.5% in men and 22.1% in women (3). The incidence increases with age, reaching as high as 45% in individuals over 75 years old. With an aging population, the societal and economic burden of OAB continues to grow, making it a significant public health issue.
The 2024 American Urological Association-Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (AUA-SUFU) guidelines recommend personalized treatment plans for OAB, ranging from non-invasive behavioral interventions to invasive treatments, tailored to patient needs (4). However, the efficacy of behavioral therapy is limited by poor patient compliance, while pharmacological therapies are often associated with side effects such as dry mouth and constipation (5). Long-term use of muscarinic receptor antagonists may even increase the risk of cognitive impairment (6). Furthermore, approximately 42% of patients are unresponsive to pharmacological therapy and are classified as having refractory OAB (7,8). Therefore, alternative and more effective treatment approaches are needed. Minimally invasive therapies, such as botulinum toxin injections and neuromodulation therapies, have shown efficacy but also possess limitations (9). The overall efficacy rate of botulinum toxin injections is around 60%, with adverse effects (e.g., urinary retention and infection) occurring in 20–30% of cases (10).
Neuromodulation therapies for OAB primarily include sacral neuromodulation (SNM) and tibial nerve stimulation (TNS). While SNM demonstrates an overall efficacy of approximately 90%, its application is hindered by complex procedures and high costs (11). Compared to SNM, TNS is less invasive, safer, and more cost-effective. However, patch-based TNS therapy has shown limited efficacy (12), and percutaneous TNS requires regular hospital visits, leading to poor patient compliance. Recently, researchers have developed implantable TNS devices (e.g., eCoin and Revi) that are designed to be implanted subcutaneously with miniaturized designs, offering automated and continuous stimulation. These devices aim to reduce treatment frequency and improve compliance and therapeutic outcomes (13). eCoin features a built-in battery but has a relatively large size, fixed stimulation modes, and a limited lifespan, making it less efficient. Revi, a battery-free implantable TNS device, has demonstrated a 75% success rate at 36-month follow-up (14). While effective, its single-frequency mode may limit parameter personalization for individual patients.
Currently, commercially available implantable TNS devices remain in the early stages of research and development, with limitations such as short lifespans and low therapeutic efficiency. Compared with existing implantable TNS devices such as eCoin and Revi, our system features a smaller size, a battery-free wireless power supply, and programmable multi-modal stimulation, offering flexible and long-term neuromodulation tailored to patient needs. This preclinical animal study aims to evaluate the safety, biocompatibility, efficacy, and stability of the newly developed implantable TNS system. Future comparative studies are warranted to validate these advantages in clinical settings. We present this article in accordance with the ARRIVE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-245/rc).
Methods
Experimental animals
Three male, conventional-grade Bama miniature pigs, aged 12 months and weighing 25–28 kg, were selected for the study. The animals were obtained from Taizhou Taihe Biotechnology Co., Ltd. [SCXK (Su) 2022-0013]. Each pig received bilateral implantation of the TNS device: the right side was activated as the stimulation site (experimental group), while the left side remained inactive (control group). This self-controlled design minimized inter-subject variability and allowed intra-animal comparison of neuromodulation effects. Each pig was identified with an ear tag. The animals were housed under a 12-hour light/dark cycle, with a constant relative humidity of 40–70% and a temperature range of 20–26 °C. They were provided ad libitum access to feed (T/CALAS 36-2017 standard laboratory pig feed sterilized by 60Co irradiation) and water (GB 5749-2006 compliant tap water). Following a 1-week acclimatization period, the experiments were initiated. Experiments were performed under a project license (No. HB2403006) granted by Institutional Animal Ethics Committee of Hangzhou Hibio Technology Co., Ltd., in compliance with national guidelines for the care and use of laboratory animals in China. Every effort was made to minimize animal suffering.
Major experimental instruments and reagents
Instruments
The implantable TNS system, including the implantable TNS device and the tibial nerve stimulator programmer and transmitter, was developed by Hangzhou Shenluo Medical Technology Co., Ltd. (Figure 1). The experimental stimulation parameters were as follows: frequency, 20 Hz; pulse width, 200 µs; amplitude range, 3–10 mA. Bladder pressure measurement equipment: BL-420N Signal Acquisition and Processing System (TECHMAN Soft Co., Ltd. Chengdu, China).
Figure 1.
The implantable tibial nerve stimulation system.
Reagents
Hematoxylin (batch number: SLBN3249V) and eosin (batch number: 62R80915X) were purchased from Sigma (Sigma-Aldrich, USA).
Experimental methods
Surgical procedure
Three pigs were selected for the experiment and subjected to fasting for 12 hours and water restriction for 6 hours before surgery. Anesthesia was induced by intramuscular injection of Shutei 50 (dose adjusted based on body weight), followed by inhalation anesthesia to maintain the anesthetic state during surgery. After anesthesia, the pigs were placed in the lateral recumbent position, and standard surgical disinfection and draping were performed. The location of the tibial nerve (above the medial malleolus) was identified and confirmed under ultrasound guidance. The implantation site and puncture points were marked accordingly. A 5-mm skin incision was made at the puncture site using a scalpel. A tunneling tool was used to create a pathway to the tibial nerve, through which the stimulator was delivered using a fixation tool. The stimulator was implanted adjacent to the tibial nerve, and the core rod was withdrawn, leaving the stimulator in position. The accuracy of the implantation site was verified intraoperatively. During surgery, electrical stimulation responses from the stimulator were assessed, and the effectiveness of OAB-related electrical stimulation was evaluated. The incision was dressed to prevent infection, and the tunneling pathway was sealed with a bandage for at least 1 week. After the pathway closure was confirmed, the bandage was removed. Postoperatively, penicillin sodium was administered intramuscularly for five consecutive days to prevent infection.
Daily, the external control unit of the TNS system was placed on the skin over the right-side electrode implantation site and activated for 1 hour. The left-side electrode remained inactive throughout the 30-day observation period and served as an internal control. This unilateral stimulation design allowed comparison between active and inactive sides in the same animal. Additionally, during stimulator implantation, an X-ray-visible non-absorbable barium core suture was secured to the soleus muscle near the electrode implantation site as a reference marker for the stimulator’s position. X-ray imaging was performed immediately after surgery to document the stimulator’s position relative to the reference marker. The operational performance of the stimulator implantation procedure was also evaluated after surgery.
Tibial nerve electrical stimulation intervention (Figure 2)
Figure 2.
Tibial nerve electrical stimulation intervention. (A) Connecting the catheter; (B) implanting the stimulator; (C) implanting the stimulator; (D) postoperative activation of stimulation.
The right-side electrode was activated daily for 1 hour using the external control unit, while the left-side electrode remained inactive as an internal control. A radiopaque barium core suture was secured near the electrode site as a reference marker, and the stimulator’s operational performance was evaluated postoperatively, including impedance testing and bladder response assessment..
Evaluation metrics and detection methods in animal experiments
General condition assessment
From the day of implantation to the end of the experiment, the animals were observed daily, and their activity levels, coat condition, color, and mental state were recorded. Body weight measurements were taken and recorded weekly for all surviving animals.
X-ray examination and electrical stimulation response
Electrical stimulation responses were assessed immediately after implantation, at 1 week, 2 weeks, and 30 days (before anatomical dissection). Local muscle contractions and overall physical responses to stimulation were observed and recorded. X-ray imaging and stimulation response testing were conducted at the same time points under general anesthesia to ensure animal immobility and comfort.
Inflammation assessment at implantation sites
At the end of the experimental period, the animals were humanely euthanized, and the stimulators were removed. Tissue samples from the implantation site and sufficient unaffected surrounding tissues were collected according to the tissue sampling guidelines in the table above. The collected tissue samples were processed following histological evaluation standards, embedded in paraffin, and sectioned. Three sections were selected from each sample for hematoxylin and eosin (HE) staining. A semi-quantitative assessment of local histopathological responses was performed.
For each section, three random fields were selected under a high-power microscope (400×) for imaging and double-blind review. The average score for each indicator across three fields was calculated for each sample and recorded in the semi-quantitative evaluation table (Table 1). Representative section images were included in the report, and all slide content was preserved. A comprehensive analysis was conducted to determine whether there were significant differences in tissue inflammation and damage at the implantation site.
Table 1. Histological evaluation system.
| Inflammation/lesion | Score | ||||
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | |
| Polymorphonuclear cells | 0 | 1–2/phf | 5–10/phf | Severe infiltration | Full field of view |
| Lymphocytes | 0 | 1–2/phf | 5–10/phf | Severe infiltration | Full field of view |
| Plasma cells | 0 | 1–2/phf | 5–10/phf | Severe infiltration | Full field of view |
| Macrophages | 0 | 1–2/phf | 5–10/phf | Severe infiltration | Full field of view |
| Giant cells | 0 | 1–2/phf | 5–10/phf | Severe infiltration | Sheet-like distribution |
| Necrosis | 0 | Minimal | Mild | Moderate | Severe |
| Neovascularization | 0 | Mild capillary proliferation, focal lesions, 1–3 buds | Capillary proliferation in 4–7 groups, with auxiliary fibroblast structures | Extensive capillary proliferation, accompanied by fibroblast structures | Widespread capillary proliferation, accompanied by fibroblast structures |
| Fibrosis | 0 | Localized area | Moderately thick area | Thick area | Extensive area |
| Fat Infiltration | 0 | Minimal | Mild | Moderate | Severe |
Phf, per high-power field (400×).
In the event of adverse events such as infection or death, immediate dissection will be performed to examine the implantation site tissues and any visibly diseased organs. Pathological analysis will be conducted to determine the cause of the adverse event and its potential association with the device, and detailed records will be promptly documented.
Bladder pressure measurement
This experiment adopted a self-controlled design. The control group measured bladder capacity with the stimulator turned off, while the experimental group measured bladder capacity with the stimulator turned on. The control group evaluation was conducted first, followed by the experimental group. Bladder capacity under normal conditions was measured prior to OAB modeling and used as the baseline.
Baseline bladder pressure test
Before anatomical dissection following stimulator implantation, an 8-F double-lumen urinary catheter was evenly coated with lubricant on its tip and carefully inserted into the urethral opening. If resistance was encountered, the catheter was gently withdrawn, the angle was adjusted, and reinsertion was attempted. Successful catheterization was confirmed when the catheter passed the external urethral orifice without resistance and urine began to flow. The catheter was then secured to the urethra with ligatures.
One lumen of the catheter was connected to a peristaltic pump to infuse normal saline (NS) into the bladder at a rate of 30 mL/min, while the other lumen was connected to a pressure sensor to measure the bladder’s pressure-volume curve. The resulting curve was recorded as the baseline bladder pressure curve. This NS baseline test was performed once per pig to avoid excessive bladder irritation and maintain data consistency before chemical induction of OAB. The time from the start of infusion to the first sudden increase in bladder pressure was recorded.
Control group bladder pressure test
Before anatomical dissection following stimulator implantation, the animals were anesthetized, and an 8-F double-lumen urinary catheter was inserted, with the bladder emptied. The external control unit of the TNS system was placed on the skin over the electrode implantation site, but the stimulator was not activated.
OAB was chemically induced in the same pigs using 5% acetic acid (AA) infusion. Bladder pressure testing was then conducted with the stimulator turned off, serving as the control condition. The same animals were used for both control and experimental measurements to reduce inter-subject variability.
Experimental group bladder pressure test
After completing the control group test, the bladder was emptied. The TNS system’s external control unit was placed on the skin over the implantation site, and the stimulator was activated with the corresponding stimulation parameters adjusted.
OAB was induced in the three experimental pigs by infusing 5% AA into the bladder at a rate of 30 mL/min while recording the pressure-volume curve. The time from the start of infusion to the first sudden increase in bladder pressure was recorded. This process was repeated three times.
Statistical analysis
Data were analyzed using SPSS 20.0 software. All experimental data were expressed as mean ± standard deviation. Homogeneity of variance was tested, and comparisons between two groups were performed using Student’s t-test. For comparisons among multiple groups, one-way analysis of variance (ANOVA) was used, followed by pairwise comparisons with the LSD-t test. A P value <0.05 was considered statistically significant.
Results
General condition observation
The body weight of all experimental pigs showed a stable upward trend during the experimental period (Table 2). All pigs remained in good health, with normal mental states, regular activity, and no abnormalities in hair condition or color.
Table 2. Body weight changes (kg) by group in experimental pigs.
| Experimental period | Body weight (kg) | ||
|---|---|---|---|
| 693 | 765 | 778 | |
| Quarantine 1 week | 25.9 | 25.9 | 25.7 |
| Postoperative 1 week | 26.1 | 26.0 | 25.8 |
| Postoperative 2 weeks | 26.2 | 26.1 | 25.8 |
| Before dissection | 26.2 | 26.2 | 26.0 |
Data were analyzed using Student’s t-test. No statistically significant differences were observed between groups (P>0.05).
Implant stability
X-ray examinations of the implantation site conducted immediately after implantation, at 1 week, 2 weeks, and before anatomical dissection (Figure 3) revealed no displacement of the implant relative to the reference marker. The implanted device remained in its original position and operated normally throughout the observation period.
Figure 3.
X-ray examination of the implantation site at different postoperative time points. (A) Immediately after implantation; (B) 1 week after implantation; (C) two weeks after implantation; (D) before dissection.
Inflammatory response around the implant
There was no extensive inflammation observed in the tissues surrounding the stimulation contacts or the implant in either the control group (inactive stimulator side) or the experimental group (active stimulator side) (Figure 4). Figure 5 shows representative HE-stained sections at 400× magnification, demonstrating similar histological features between groups, with no evidence of necrosis or severe infiltration. The semi-quantitative inflammatory scores are summarized in Table 1. Compared to the control group, the experimental group showed no significant difference in the inflammation lesion scores of the tissues surrounding the stimulation contacts. While the inflammation lesion scores of the tissues surrounding the implant were slightly higher in the experimental group, the difference was not statistically significant (Table 3, Figure 5).
Figure 4.
Hematoxylin and eosin staining results. (A) Tissue surrounding the stimulation contact (control group 40×); (B) tissue surrounding the stimulation contact (control group 400×); (C) tissue surrounding the stimulation contact (experimental group 40×); (D) tissue surrounding the stimulation contact (experimental group 400×); (E) tissue surrounding the stimulator (experimental group 40×); (F) tissue surrounding the stimulator (control group 400×); (G) tissue surrounding the stimulator (experimental group 40×); (H) tissue surrounding the stimulator (experimental group 400×).
Figure 5.
Inflammatory lesion scores of each group. Stimulation contact: the electrode region in direct contact with the tibial nerve. Stimulator: the entire implanted device, including the housing and components beyond the electrode.
Table 3. Statistical results of inflammatory lesion scores.
| Groups | Inflammatory lesion scores |
|---|---|
| Tissue surrounding the stimulation contact | |
| Control group | 0.04±0.19 |
| Experimental group | 0.04±0.19 |
| Tissue surrounding the stimulator | |
| Control group | 0.07±0.27 |
| Experimental group | 0.15±0.36 |
Values are presented as mean ± standard deviation.
Improvement in OAB status
Compared to the baseline bladder pressure test results, the bladder capacity in the control group was significantly reduced (P<0.05). After activation of the TNS device, the experimental group showed a significant increase in bladder capacity compared to the control group (P<0.05), with an improvement of 24.4%. These results are visually depicted in Figure 6, which illustrates the average bladder pressure-volume curves across groups. Each data point represents the mean of three repeated measurements per condition (control and experimental) performed at the end of the 30-day study period, and numerically summarized in Table 4.
Figure 6.
The bladder pressure test pressure curves for the experimental groups. (A) Subject of 778; (B) subject of 693; (C) subject of 765. AA, acetic acid; NS, normal saline; TNS, tibial nerve stimulation.
Table 4. Bladder pressure test results.
| Groups | Bladder capacity (mL) |
|---|---|
| Baseline | 305.00±43.30 |
| Control group | 205.00±17.32* |
| Experimental group | 255.00±15.00* |
Data were analyzed using Student’s t-test. Values are presented as mean ± standard deviation. *, P<0.05.
Discussion
The primary neuromodulation therapies for OAB include SNM and TNS. The efficacy of SNM is highly dependent on the precise placement of the electrodes, making it a complex and costly procedure (15). In contrast, the novel implantable tibial nerve stimulator investigated in this study demonstrated advantages such as ease of operation, minimal invasiveness, and good tissue compatibility. It also reduces the reduction in bladder capacity observed in the OAB model, offering a low-risk and effective alternative for patients who are intolerant to or unresponsive to medications.
Previous studies have suggested that the tibial nerve shares partial neural root pathways with the pelvic nervous system controlling bladder function, making TNS potentially effective in regulating spinal nerves to modulate bladder activity (16). Low-frequency electrical stimulation can regulate afferent nerve activity and reduce involuntary detrusor contractions (17). Additionally, it may activate the prefrontal cortex to modulate bladder sensory pathways, thereby reducing the frequency of urgency perception (18). Previous animal studies have demonstrated the importance of optimizing stimulation frequency and neural targets. Li et al. [2017] reported that SNM at 15 Hz significantly increased bladder capacity in pigs with AA-induced overactivity, while higher frequencies provided no additional benefit, highlighting the value of frequency-specific modulation (19). In another porcine model, Li et al. [2017] showed that combined tibial and sacral nerve stimulation significantly improved bladder capacity (to 50.2% of baseline), outperforming either modality alone (20). These findings support the rationale for programmable multi-modal stimulation, as provided by our device, to achieve greater therapeutic flexibility and efficacy. Since the 21st century, TNS therapies, including percutaneous and surface electrode methods, have been progressively developed and approved by the U.S. Food and Drug Administration (FDA) for clinical use (21,22). Although earlier studies on patch-based transcutaneous TNS have shown mixed or limited efficacy, recent clinical evidence from wearable systems has demonstrated more promising results. For instance, the Vivally System (Avation Medical, California, USA), a non-invasive, wearable TNS device, was evaluated in the multicenter FREEOAB trial (23). Despite these advantages, wearable TNS systems still rely on consistent patient adherence and weekly usage protocols. More recently, implantable stimulators such as eCoin and Revi have further advanced treatment methods, achieving long-term automated stimulation via miniaturized designs and improving patient compliance (13). However, these devices still face challenges, such as short lifespans and limited treatment efficacy.
To address these limitations, we developed a novel implantable stimulator and validated its safety and efficacy through animal experiments. During the study, the general condition of all experimental pigs remained stable, with consistent weight gain. Histopathological examination revealed no significant inflammatory response or fibrosis around the stimulation contacts or adjacent tissues, indicating good biocompatibility and biosafety of the stimulator. These findings confirm the high tissue compatibility and safety of the newly developed implantable tibial nerve stimulator.
Using established protocols, the researchers successfully induced an OAB model in pigs (19). Bladder pressure tests showed that bladder capacity in the OAB control group was significantly reduced compared to normal bladder conditions. In contrast, the experimental group demonstrated a significant increase in bladder capacity after TNS stimulation, with a 24.4% improvement compared to the control group (P<0.05). These results suggest that tibial nerve electrical stimulation effectively alleviates bladder overactivity in the OAB model and improves bladder capacity, thereby addressing symptoms such as urgency and frequency. The findings also validate the efficacy of TNS in animal models, laying a foundation for its clinical application in OAB treatment.
Throughout the 30-day observation period following stimulator implantation, X-ray monitoring confirmed that the device remained securely in place without significant displacement and functioned normally. This highlights the stability of the stimulator’s design and implantation method, which is critical for clinical application, especially for long-term use. A stable device reduces the frequency of adjustments and postoperative management, enhancing patient compliance and supporting its potential application in humans.
This study has some limitations. The sample size was small, with only three pigs used in the experiments, which limits the statistical power and increases the risk of type I and II errors. Moreover, as this was a preclinical study conducted in a single species, the findings may not fully translate to human physiology.
While the control side (left tibial nerve) was kept inactive, we acknowledge the possibility of central nervous system involvement and partial crossover effects from unilateral stimulation. This could have influenced the contralateral bladder responses. Previous studies have shown that TNS typically exerts its primary effects ipsilaterally. Moreover, the control-side device remained entirely inactive throughout the experiment, and the stimulation was targeted and consistent, minimizing potential systemic or contralateral influence. Future studies with either crossover animal groups or separate untreated controls are needed to confirm the lateralized specificity of the stimulation effects.
Additionally, the experimental design did not include blinding procedures, and the same investigator conducted both the intervention and the outcome assessment. Although some objective outcomes (e.g., bladder capacity, histological scoring) were used, the lack of assessor blinding may introduce observer bias. Future studies should adopt blinded evaluations and assign different personnel for treatment and outcome assessment.
Furthermore, only a single set of stimulation parameters (20 Hz, 200 µs, 3–10 mA) was used without systematic optimization. This may not reflect the most effective settings, and further research is warranted to determine the optimal stimulation protocols tailored to different physiological conditions. Finally, the 30-day follow-up period does not fully reflect the long-term performance and tissue response to the implanted device. Extended follow-up studies are necessary to evaluate chronic biocompatibility and efficacy.
Conclusions
This study demonstrates that the implantable tibial nerve stimulator exhibits excellent safety, biocompatibility, stability, and efficacy in treating OAB in a pig model. It significantly improved bladder capacity and reduced bladder overactivity. The stimulator maintained stable performance throughout the experimental period, validating the structural stability of its design. These findings provide important evidence supporting the potential application of TNS in clinical OAB treatment.
Supplementary
The article’s supplementary files as
Acknowledgments
We would like to express our sincere gratitude to Hangzhou Shenluo Medical Technology Co., Ltd. for providing the animal housing facilities and assisting with data collection.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Experiments were performed under a project license (No. HB2403006) granted by Institutional Animal Ethics Committee of Hangzhou Hibio Technology Co., Ltd., in compliance with national guidelines for the care and use of laboratory animals in China. Every effort was made to minimize animal suffering.
Footnotes
Reporting Checklist: The authors have completed the ARRIVE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-245/rc
Funding: This research was supported by the Special Leading Plan of Zhejiang Provincial Major Science and Technology (No. 2024C03197), Zhejiang Province Health Major Science and Technology Plan Project (No. WKJ-ZJ-2401), and Key Project of Zhejiang Province Administration of Traditional Chinese Medicine (No. GZY-ZJ-KJ-24054).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-245/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-245/dss
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