The Efficacy of Minimally Invasive Implantable Wireless Electrical Stimulation for the Treatment of Stress Urinary Incontinence in a Rat Model

Study Design

Experiments were conducted with 18 unfertilized female Sprague-Dawley rats, aged 12 weeks and weighing 290–350 g, provided by Nara biotech (Seoul, Korea). The rats were randomized and assigned to one of 3 groups: control, SUI rat model without stimulation (−ES group), and SUI rat model with stimulation (+ES group), with 6 rats per group. Before the experiment, rats were housed in appropriately sized spaces, at 22°C–24°C, 60%–65% humidity, and with proper ventilation on a 12:12-hour light–dark cycle. They received a nutritionally balanced diet and were acclimated in this clean environment for at least one week to minimize stress. All animal procedures were approved by the animal care and use committee at Soonchunhyang Medical University (SCH-S2025-03). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

SUI Animal Model

SUI was induced by VD as previously described in sham and ES group [15]. Rats were anesthetized with 1% ketamine (30 mg/kg) and xylazine hydrochloride (4 mg/kg). The 8F latex Foley catheter was inserted into the rat’s vagina, and 4.0 mL of sterile saline was slowly pushed into the balloon to expand the vagina. The catheter was sutured and fixed, and a 120 g weight was suspended in the drooping injection port. The catheter was removed after 4 hours of traction. VD was performed once weekly for 4 weeks (Fig. 1). After SUI induction, we performed conscious cystometry to confirm the reliable model of SUI.

Fig. 1.

Stress urinary incontinence model by mechanical dilatation of vagina. Establishment of the Rat Vaginal Distention and Traction Injury Model. An 8F latex Foley catheter was inserted into the rat’s vagina. 4.0 mL of sterile saline was slowly injected into the catheter balloon for vaginal distention. The catheter was secured by suturing and fixing, and a 120-g weight was suspended from the drooping injection port to induce traction. The catheter was removed after a total of 4 hours of sustained traction.

Device and Implantation

The device (SB Solution, Korea) implanted in the rats is primarily composed of a stimulator and a radio frequency (RF) cushion (Fig. 2A). The stimulator is cylindrical, measuring 3.5 mm in diameter and 21 mm in length, covered by a glass tube on its surface. The internal structure consists of 2 Ti-6Al-4V electrodes positioned at both ends, encased in polyetheretherketone packaging. The stimulator circuit was fabricated on a homemade 2 cm×4 cm, 100 μm thick, rectangular shaped homemade flexible printed circuit board. The internal components are hermetically sealed with medical-grade epoxy to ensure stable operation throughout the treatment duration. Silicon elastomer (Dragon skin 10 medium, Smooth-On) was used as the final encapsulation material, cured around the stimulator and transmitter in custom-made molds. The device operates wirelessly, delivering an output of 2.5 Vp-p. The hierarchical stimulation source was generated using a function generator (AFG1062, USA) and a relay module connected to a microcontroller (MEGA, Arduino, Italy).

Fig. 2.

(A) Specifications and operational parameters of the wireless neuromodulation device. The device measures 3.5 mm in diameter and 21 mm in length. It is constructed with 2 Ti-6Al-4V electrodes and is encased in polyetheretherketone packaging. The internal components are sealed with medical-grade epoxy to ensure stable operation over the treatment duration. The device operates wirelessly, delivering an output of 2.5 Vp-p. The electrical stimulation is characterized by a pulse duration of 300 μsec, a frequency of 1 Hz, and a duty cycle of 10 seconds. (B) Implantation of microwireless electrical stimulation.

The rats in +ES group underwent stimulator implantation. After identifying the pelvic space (approximately 0.5–1 cm outward from the perianal area), a 1-cm incision was made, and the stimulator was inserted into the pelvic floor muscle approximately 2 cm inward (with the anode end facing outward and the cathode end facing inward). The incision was then sutured closed. Successful implantation was confirmed by observing rhythmic contractions of the anus during stimulation testing (Fig. 2B).

Treatment Protocol

After SUI induction, the +ES group received ES twice weekly for 4 weeks. EMG and body weight were measured weekly throughout the 4 weeks treatment period (Fig. 3A). −ES group got midline incision and sutured. It receives electromagnetic signals from the RF cushion and generates stimulation current signals. Stimulation parameters were configured via the app and transmitted to the RF cushion. The ES was characterized by the following parameters: pulse duration of 300 μsec, frequency of 1 Hz, and a duty cycle of 10 seconds.

Fig. 3.

Treatment protocol and electrophysiological data acquisition. (A) Illustration of electrical stimulation (ES) therapy timeline and group allocation. Normal Sprague-Dawley (SD) rats are designated as a control group (control, n=6). Experimental group after 4 weeks of stress urinary incontinence (SUI) modeling phase is divided into 2 subgroups: −ES group (n=6) and +ES (n=6). (B) Electromyography (EMG) data processing flow: this panel illustrates the 4 key steps used to transform the raw EMG signals into quantifiable data. Step 1 shows the necessary baseline calibration to remove baseline drift from the raw EMG signal. Step 2 applies rectification to the signal, converting all values to a single (positive) polarity, which is essential for measuring the total muscle activity. Step 3 involves the collection of the maximum EMG peak from each individual data set, highlighting the point of strongest muscle contraction. Finally, Step 4 calculates the mean muscular activity by averaging the collected maximum EMG values across all data sets, providing a representative measure for group comparison.

To enable objective and reproducible assessment of neuromuscular function, we implemented a trigger-evoked EMG paradigm. Briefly, a trigger electrode delivered constant-current pulses and a separate sensing electrode recorded evoked EMG responses under anesthesia to minimize voluntary activity, and root mean square amplitude was used as the quantitative metric.

An electrophysiological data acquisition system composed of controller (RHS Stim/Recording controller, Intan Technologies, USA), head stage (RHS Stim/Recording headstages) and bundle software (Intan RHX). This system served as a trigger generation and EMG data acquisition platform. For the trigger technique, electrodes are connected to elec0 and ground port on headstage. A reference electrode was connected to Ref port. Triggers (amplitude: 1 mA, duration: 333.3 μsec) were applied on elec0 with regular time interval, and response EMG signals were recorded simultaneously with 20 kHz sampling rate. The raw data were processed in MATLAB using notch filter (59.5 to 60 Hz), bandpass filter (0.1 to 300 Hz), and RMS processing. At least 10 peaks of EMG were used to determine muscular activity by the trigger technique. The wireless ES, transmitter magnetically coupled with stimulator applying stimulation source. Function generator yielded 5.98-MHz source and integrated trigger system made 3-kHz on/off duty cycle. A relay module, which is controlled by microcontrollers, served as a scheduler of 5 seconds and 5 minutes on/off cycle. Current probe (TCP0030A, Tektronix) measurements demonstrated the highest power transmission efficiency at approximately 5.5 MHz for the wireless device. ES at this frequency were modulated into PRF 3 kHz and 30 Hz to cover regeneration efficacy from low and high frequency stimulation domain.

EMG was performed weekly throughout the 4-week treatment period to objectively quantify the changes in muscular activity induced by the ES. The raw EMG signals were processed and analyzed using MATLAB following a precise, 4-step methodology to obtain reliable and quantifiable data for muscular activity assessment. The recorded raw EMG signals underwent initial signal processing to perform baseline calibration. This critical step involved removing any electrical baseline drift or offset present in the signal, ensuring that subsequent amplitude measurements accurately reflect true muscular electrical activity. The calibrated signal was then subjected to rectification. This process converted all negative values to a single positive polarity, which is a standard procedure essential for determining the total integrated electrical activity generated by the muscle fibers over time. After signal rectification, the maximum EMG peak was collected from each individual data set. To ensure the reliability of the measurement, a minimum of 10 distinct peaks were analyzed using the trigger technique. This step specifically identified and quantified the point of the strongest muscle contraction achieved during the triggered stimulation. The final step involved calculating the representative mean muscular activity by averaging the collected maximum EMG peak values across all analyzed data sets. This mean value was used as the definitive, quantifiable measure of sphincter muscular activity for statistical comparison between the SUI groups (Fig. 3B).

Outcome Measure

Histo- and immunohistochemical analyses

After 24 hours of fixation in 4% paraformaldehyde, the urethra and the pubococcygeus muscle were harvested and cryoprotected in 30% sucrose for 24 hours, cut to 20-μm sections using a cryostat (Leica, Germany). The sections were stained by the hematoxylin and eosin (H&E) staining kit (ab245880, Abcam, UK). And the sections were stained using Masson trichrome (MT) staining kit (KH07007, Bioquochem, Spain). Sections were then imaged using microscope (IX70, Olympus, Japan). For each section, 3 random fields of view at ×200 magnification were photographed, ensuring that the tissue fully occupied the field and that background illumination remained consistent across all images. Images were analyzed using Image-Pro Plus 6.0 software (Media Cybernetics, Inc., USA) by applying a standardized blue threshold to identify collagen fibers. The software calculated the percentage of the collagen fiber area relative to the total tissue area for each image.

Statistical Analysis

Differences in the cystometric and histologic results were analyzed using the student t-test or 1-way analysis of variance with the Bonferroni post hoc test. We used GraphPad-Prism5.0 (GraphPad-Software, USA) to perform all analyses, and statistical significance was defined as P<0.05 or 0.01.

Cystometry

Conscious cystometric analysis showed that most rats in the SUI groups (+ES group and −ES group) exhibited lower LPP after 4 weeks of VD. SUI induction significantly reduced the LPP compared to the baseline (−37.7±7.4 cm H₂O vs. −38.5± 5.8 cm H₂O, P<0.001). When we measured the mean LPP, the SUI groups demonstrated lower LPP in comparison with the control group (25.0±6.9 cm H₂O vs. 62.6±4.1 cm H₂O, respectively; P=0.012).

Changes in LPP Among the 3 Groups in Control, −ES, +ES Groups

LPP after 4 weeks in +ES group and −ES group were 48.8±8.4 cm H₂O and 26.0±6.6 cm H₂O, respectively. In comparison with the SUI groups, at 4 weeks after ES treatment, the +ES group demonstrated significant increase in their mean LPP comparing −ES group (25.6±10.2 cm H₂O vs. 1.0±7.3 cm H₂O; P=0.002 and P=0.752, respectively). Furthermore, the increase observed in the +ES group was not significantly different from that observed in the control group at 4 weeks (P=0.043) (Fig. 4A and B).

Fig. 4.

Changes in leak point pressure (LPP) and urethral pressure (UP) among experimental groups. (A) Changes in LPP, mean LPP values measured in the control, −ES, and +ES groups at 4-week postintervention. SUI induction (4 weeks after vaginal dilatation [VD]) significantly reduced LPP in the SUI groups compared to the pre-SUI At 4-week postintervention, the +ES group demonstrated a significant increase in LPP compared to the −ES group. (B) The LPP improvement observed in the +ES group was statistically not significantly different from the LPP measured in the control group at 4 weeks. (C) Changes in UP, mean UP values measured in the 3 groups at 4-week postintervention. UP was significantly reduced following VD compared to the baseline. UP after 4 weeks of the +ES group did not improve significantly compared to the original baseline. Comparing the treatment groups, the +ES group showed no significant increase in mean UP compared to the −ES group. ES, electrical stimulation.

Changes in Urethral Pressure Among 3 Groups in Control, −ES, +ES Groups

Urethral pressures after 4 weeks of VD in SUI groups were 15.1±2.5 cm H₂O and 16.8±5.2 cm H₂O, respectively. Both were significantly reduced compared to the baseline (32.5±6.3 cm H₂O, P<0.001). Urethral pressure after 4 weeks ES treatment did not improve significantly compared to baseline (P<0.001), but it did not return to baseline levels. In comparison with the SUI groups at 4 weeks after ES treatment, the +ES group demonstrated no significant increase in their mean urethral pressure comparing −ES group (20.5±1.4 cm H₂O vs. 18.1±1.1 cm H₂O; P=0.070 and P=0.107, respectively) (Fig. 4C).

Trigger-Evoked EMG Functional Assessment

Trigger-evoked EMG recordings produced reproducible shortlatency responses (~100 msec duration) following stimulation, validating feasibility of the evaluation method. After SUI induction, RMS EMG amplitude was reduced in both experimental groups compared to controls, indicating deterioration of sphincter neuromuscular function. Following 4 weeks of ES, the +ES group demonstrated increased RMS EMG amplitude relative to the −ES group, suggesting enhanced neuromuscular responsiveness consistent with the observed improvement in LPP.

Histo- and Immunohistochemical Analyses

Compared with the control group, the muscle fiber fibrosis and inflammatory cell infiltration in bladder and urethra tissue were markedly found in the SUI group (+ES and −ES groups). ES treatment ameliorated the fibrosis of the muscle layer and the infiltration of inflammatory cells that was increased by VD. In H&E stain, the bladder and urethra tissues of the +ES group were significantly decreased fibrosis and inflammatory cell infiltration compare to −ES group.

MT staining of bladder and urethral tissues is shown in Fig. 5. The collagen fiber content in the SUI groups (−ES and +ES) appeared lower than that typically observed in normal control tissue, reflecting structural deterioration associated with the SUI model. After ES treatment, the +ES group demonstrated a tendency toward higher collagen fiber density compared with the −ES group in both bladder and urethral tissues. Quantitative analysis revealed that the mean collagen density in the bladder increased from 28.3%±5.2% in the −ES group to 32.5%±7.6% in the +ES group, although this difference did not reach statistical significance (P=0.292). Similarly, in urethral tissue, collagen density increased from 44.2%±8.6% in the −ES group to 51.7%±8.2% in the +ES group, but this difference also did not reach statistical significance (P=0.153). Compared with bladder tissue, the urethral tissue showed a more pronounced reduction in collagen density following SUI induction, suggesting that urethral structural damage may be more prominent in this model (Fig. 5B and C).

Fig. 5.

Histological evaluation of bladder and urethral tissues following electrical stimulation. (A) Representative hematoxylin and eosin (H&E) staining of bladder and urethral tissues from the −ES and +ES groups showing tissue architecture, muscle fiber structure, and inflammatory cell infiltration. Compared with the −ES group, the +ES group demonstrates improved tissue organization and reduced inflammatory cell infiltration. (B) Quantitative analysis of collagen fiber density in bladder tissue based on Masson trichrome (MT) staining. (C) Quantitative analysis of collagen fiber density in urethral tissue. Electrical stimulation showed a trend toward increased collagen fiber density in both bladder and urethral tissues compared with the −ES group, although the differences did not reach statistical significance. Bars represent mean±standard deviation. Images were obtained at ×200 magnification. ES, electrical stimulation.

Current Nonsurgical Treatment Landscape for SUI

The pathophysiology of SUI is rooted in the age-associated degeneration of the neuromuscular architecture of the urethral sphincter complex [16, 17]. Traditional surgical methods such as mesh-based midurethral slings and various reconstructive techniques have been used to re-establish urethral support [18, 19]. Nonetheless, these approaches often lack long-term durability and carry a risk of mesh-related complications.

Nonsurgical approaches, such as PFMT and ES, are often employed prior to surgery. These methods can provide therapeutic benefit and may be the only viable solution for patients for whom surgical treatment is contraindicated or difficult. SUI is primarily attributed to the weakening of the pelvic floor muscles and the urethral sphincter. Consequently, strategies aimed at strengthening these muscles through exercise have been developed, offering a fundamental and potentially long-lasting solution for SUI.

Mechanistically, the present device was designed to deliver spatial-upstream peripheral stimulation to the urethral sphincter complex, potentially enabling more localized activation of sphincter muscle and adjacent pelvic nerve branches than downstream (central) neuromodulation approaches. Importantly, our findings support functional augmentation rather than definitive regeneration, as molecular markers of myogenesis or neuromuscular junction remodeling were not assessed. The improvement in trigger-evoked EMG amplitude provides physiological support for enhanced neuromuscular recruitment as a contributor to the observed LPP improvement.

The Role of ES and PFMT

Pelvic floor ES is hypothesized to mimic natural nerve electrical activity, thereby promoting the activity of the pelvic floor muscle group, including the urethral sphincter. Recent meta-analyses have shown that PFMT is effective, with reported success rates in a certain percentage of patients compared to control groups who did not exercise. PFMT directly contributes to pelvic strengthening and helps induce histological changes in the muscle tissue [20, 21]. However, a significant limitation of PFMT is the difficulty for patients to accurately gauge the range of motion, which hinders effective exercise. Furthermore, the lack of sustained adherence often leads to suboptimal outcomes.

The drawbacks associated with conventional methods led to the introduction of ES therapy. This approach, specifically the application of functional ES to the pelvic floor muscles for treating incontinence, was first proposed by Caldwell in 1963 and has since been actively utilized in SUI treatment [22]. ES can simulate nerve electrical activity, thereby promoting the muscle tissue activity of the pelvic floor muscle group, including the urethral sphincter [23].

ES has been reported to be statistically more effective when used in combination with PFMT compared to PFMT alone. Moreover, it has also been reported to show significantly better efficacy when directly compared to PFMT as a standalone treatment. Compared to conventional training alone, ES shows significant advantages in improving clinical efficacy, and its effect is clearly superior to that of patients receiving no treatment or rehabilitation treatment only [23]. The main finding of this meta-analysis was that the combination therapy showed significant superiority over a single intervention in improving multiple outcome indicators of SUI, particularly in reducing incontinence episodes, decreasing the amount of leakage, and improving quality of life (QoL). The combined effect sizes showed statistically significant improvements in incontinence symptoms, pelvic floor muscle strength, and QoL in the intervention group with low heterogeneity, suggesting a high degree of concordance between the findings [21]. One Cochrane review suggested that ES might be more effective than sham ES or no intervention for women with SUI, although the effects of ES compared with other conservative treatments (PFMT and vaginal cone) appeared to show no statistically significant difference [24]. For subjective cure of SUI, we found moderate-quality evidence that ES is probably better than no active treatment (risk ratio, 2.31; 95% CI, 1.06–5.02) [24].

Evolution of Electrostimulation Devices for SUI

The ES devices for SUI treatment have progressively evolved. Recent models have been reported to exhibit greater convenience compared to the initially reported models, and the methods of application have also become simpler, enabling more sustained treatment. The earliest models presented several inconveniences for the patient, often requiring them to visit a clinic or hospital and disrobe for the procedure, which compromised long-term adherence. Subsequently, devices were developed that could be used while the patient was fully clothed or were designed for home use, allowing for continuous, longterm exercise. Three main types of ES (vaginal ES, surface ES, and electroacupuncture) are used in the treatment of women with SUI. Vaginal ES, with electrodes placed in the vagina, can stimulate the pudendal nerve, leading to a contraction of pelvic floor muscles and preventing involuntary urine leakage [25].

Existing studies mainly focus on evaluating the short-term effects of biofeedback ES treatment, with a lack of long-term monitoring of disease progression. Therefore, future research should pay attention to the long-term efficacy of patients receiving ES treatment and strengthen long-term tracking and monitoring. During the implementation of the treatment process, personalized assessment and parameter setting should be carried out according to the specific situation of the patient, and attention should be paid to the cooperation of home training to improve the treatment effect and the QoL of postpartum women. In the future, further in-depth research is still needed to optimize the treatment plan and provide better treatment options for more patients with postpartum urinary incontinence [10].

Efficacy of the Novel Wireless Implantable Electrical Stimulator

This study represents a pilot investigation into the efficacy of a wireless implantable ES device using a SUI rat model. The results of the animal experiments revealed that this device exhibits a therapeutic effect for the treatment SUI. Currently, studies on this specific type of technology remain limited. For instance, a notable previous report involves the NuStim implantable ES device from China, which presented a case report on 3 SUI patients following initial rat experiments [26]. As anticipated in that study, improvements were reported in both urodynamic parameters and the subjective evaluation of SUI.

In our current research, we investigated urodynamic parameters, including LPP and urethral pressure, in a rat model of SUI. Notably, studies directly monitoring urethral pressure following ES therapy remain limited. Histological analysis demonstrated structural alterations in bladder and urethral tissues following vaginal distension, including increased inflammatory cell infiltration and disruption of muscle architecture. ES showed a tendency to improve tissue organization and reduce inflammatory infiltration. In addition, quantitative analysis of MT staining revealed a trend toward increased collagen fiber density in the stimulation group compared with the nonstimulated group.

Although these histological differences did not reach statistical significance, the observed structural trends are consistent with the functional improvement in leak point pressure (LPP) observed in the stimulation group. These findings suggest that ES may contribute to partial remodeling of the urethral support structure in this SUI model. However, these findings should be interpreted cautiously. While histological observations suggested reduced fibrosis and improved muscle organization in stimulated animals, these changes likely represent adaptive remodeling or hypertrophic responses rather than definitive tissue regeneration. The discrepancy between improved LPP and the nonsignificant recovery of urethral pressure suggests that ES may preferentially enhance dynamic neuromuscular activation under stress conditions rather than restore baseline urethral tone. This mechanism may explain the improvement in continence function despite relatively modest structural changes observed histologically.

This study has several limitations. First, the sample size was limited, the present findings should be interpreted as preliminary and hypothesis-generating. Second, the vaginal distension model reflects an acute injury model and may not fully replicate the chronic multifactorial pathophysiology of human SUI. Third, long-term safety, durability, and potential tissue responses associated with the implantable device were not assessed in the present study. Future studies incorporating larger sample sizes, longer stimulation periods, and molecular analyses of neuromuscular remodeling will be required to clarify the regenerative potential of implantable ES in SUI.

In conclusion, minimally invasive microwireless implantable ES improved continence-related functional outcomes, particularly LPP, in a preclinical rat model of SUI. The findings are most consistent with functional enhancement of urethral sphincter neuromuscular activity, supported by trigger-evoked EMG changes, rather than confirmed tissue regeneration. Fur ther long-term mechanistic and safety studies are required before clinical translation.