Abstract
Objective
This retrospective study evaluated the clinical efficacy, safety profile, and long-term recurrence rate of honeycomb interval puncturing using high-frequency ion therapy combined with saturated saline soaking for multiple plantar warts, compared with saturated saline monotherapy.
Methods
A total of 74 patients with clinically diagnosed multiple plantar warts were enrolled between January and December 2024. The observation group (n=42) received standardized honeycomb micropuncturing (hole spacing: 1.5–2.0 mm; pore diameter: 0.3–0.5 mm; puncture depth limited to stratum corneum and superficial dermal papillary layer), followed by room-temperature saturated saline soaking (30 minutes daily for 6 weeks) beginning 24 hours post-procedure. The control group (n=32) received identical saline soaking alone. Wart clearance, Visual Analogue Scale (VAS) pain scores, adverse events, and 12-month recurrence rates were assessed. Statistical analyses employed Chi-square and independent t-tests.
Results
Baseline characteristics were comparable between groups (all P>0.05). At week 6, the observation group demonstrated significantly superior outcomes: complete wart clearance (95.0% vs 77.0%), complete patient remission (88.1% vs 65.6%), and overall effective rate (95.2% vs 75.0%). Mean time to therapeutic response was significantly shorter in the observation group (2.1±0.7 vs 3.8±0.9 weeks; P<0.05). Postoperative VAS score for local distending pain was 2.3±0.6. Pinhole scabs developed in 21.4% of patients and resolved spontaneously within 7–10 days. No wound infections, scar formation, or severe adverse events occurred. The 12-month recurrence rate was 2.70% in the observation group versus 14.29% in the control group.
Conclusion
High-frequency ion-mediated honeycomb interval puncturing effectively disrupts the hyperkeratotic barrier and relieves intralesional pressure, enhancing saturated saline penetration. This combined regimen achieves faster responses, superior clearance, minimal trauma, and lower recurrence compared with monotherapy, representing a safe, cost-effective, and outpatient-friendly treatment modality for multiple plantar warts.
Keywords: multiple plantar warts, high-frequency ion therapy, honeycomb puncturing, saturated saline, soaking therapy, therapeutic efficacy
Introduction
Plantar warts are benign epithelial proliferations caused by human papillomavirus (HPV), predominantly genotypes 1, 2, and 4.1 These lesions typically manifest on weight-bearing surfaces, where chronic mechanical compression and friction induce severe hyperkeratosis and mosaic configurations. The propensity for multiple clustered lesions, accompanied by significant tenderness and autoinoculation to adjacent skin, renders plantar warts notoriously refractory to treatment, with chronicity and recurrence posing substantial clinical management challenges.1
Current first-line therapeutic modalities, including salicylic acid keratolysis, liquid nitrogen cryotherapy, carbon dioxide laser ablation, and surgical curettage, are predominantly destructive in nature.2 While these approaches can achieve single-session lesion removal, they are associated with significant procedural pain, prolonged wound healing, increased risk of dyspigmentation and scarring, and considerable recurrence rates. For patients with extensive, confluent, or long-standing plantar warts, repeated interventions are frequently required, substantially compromising patient compliance and escalating healthcare burden.2
Saturated saline soaking has recently gained recognition as a non-invasive therapeutic alternative for recalcitrant plantar warts.3 The hyperosmotic microenvironment generated by saturated saline induces dehydration and functional inactivation of HPV-infected keratinocytes, while concurrently modulating local immune responses through regulation of inflammatory cytokines including IL-37 and IL-18.4 This treatment modality offers distinct advantages including painlessness, absence of scarring, and suitability for home-based administration. Previous clinical investigations have confirmed that 8-week saturated saline monotherapy achieves favorable clearance and remission rates in refractory plantar warts with reliable short-term safety.3,4 However, the markedly thickened stratum corneum characteristic of multiple plantar warts constitutes a dense physical barrier that impedes deep saline penetration, thereby attenuating hyperosmotic effects and resulting in delayed efficacy and suboptimal outcomes in challenging cases.
To overcome these limitations, we adopted honeycomb interval puncturing using high-frequency ion therapy as a minimally invasive pretreatment strategy. Distinct from conventional radical electrocautery, which completely ablates verrucous tissue, this technique creates uniform micropores on lesion surfaces to disrupt the keratin barrier, enhance saline permeability, release intralesional pressure, and expose sequestered HPV antigens to activate local cellular immunity. Previous studies have validated that high-frequency ion pretreatment significantly improves the efficacy of subsequent targeted cutaneous therapies.2 Accordingly, this retrospective controlled investigation comprehensively evaluated the clinical efficacy, safety profile, and 12-month recurrence rate of this combined regimen, aiming to establish an optimized therapeutic protocol for multiple plantar warts.
Materials and Methods
Study Design and Population
This retrospective comparative study was conducted at the Dermatology Outpatient Department of Qingpu Branch, Zhongshan Hospital, Fudan University. We reviewed consecutive cases of clinically diagnosed multiple plantar warts treated between January and December 2024.
Inclusion criteria: (1) Clinically confirmed multiple plantar warts with disease duration ≥3 months; (2) ≥5 lesions distributed on weight-bearing plantar and heel regions with demonstrable local tenderness; (3) Pronounced surface hyperkeratosis; (4) Complete follow-up and treatment documentation.
Exclusion criteria: (1) Concurrent active bacterial foot infection, skin ulcers, vesicular or interdigital tinea pedis; (2) Diabetic peripheral neuropathy, lower extremity vascular disease, or other conditions impairing wound healing; (3) Immunodeficiency disorders or chronic immunosuppressant use; (4) Pregnancy or lactation; (5) Cryotherapy, laser treatment, or topical corrosive therapy within 1 month prior to enrollment; (6) Allergy to metal treatment materials or sodium chloride.
All enrolled patients were clinically diagnosed with multiple refractory plantar warts by professional dermatologists. Group assignment was determined according to patient treatment willingness and clinical conditions: patients who consented to combined physical puncture plus saturated saline soaking were assigned to the intervention group, whereas patients who received saturated saline soaking alone were allocated to the control group. Baseline demographic and clinical characteristics were well balanced between the two groups, which effectively reduces potential selection bias.
Notably, the current study focused on evaluating the clinical efficacy and safety of the combined treatment regimen, and we did not systematically collect or record patients’ previous treatment history. Therefore, relevant data on prior interventions is unavailable in this retrospective cohort.
As a retrospective observational study analyzing existing de-identified clinical data, this investigation involved no invasive interventions or additional experimental procedures on patients. The study protocol received formal approval from the Institutional Ethics Committee of Qingpu Branch, Zhongshan Hospital Affiliated to Fudan University (Approval Number: Qingyi 2025–090), which also waived the requirement for written informed consent. All patient data were fully anonymized prior to analysis. Eligible patients were allocated to the observation group (n=42, combined treatment) and control group (n=32, saline monotherapy).
Treatment Protocols
Honeycomb Interval Puncturing (Observation Group Only)
All target warts and surrounding skin (within 2 cm margins) underwent routine disinfection with iodophor, followed by sterile draping. For patients with heightened pain sensitivity, compound lidocaine cream was applied topically with occlusion for 30 minutes to achieve superficial local anesthesia.
A multifunctional high-frequency ion therapeutic instrument (Model GX-III) was utilized in short-fire touch mode with output power set at grades 2–4 (8–15 W). The device was pre-calibrated to generate only superficial epidermal whitish vaporization without tissue carbonization or deep dermal injury.
The standardized honeycomb interval puncturing procedure was executed as follows: uniform micropores (diameter: 0.3–0.5 mm) were created along the long axis of each wart at 1.5–2.0 mm intervals. Puncture depth was rigorously confined to the stratum corneum and superficial dermal papillary layer (visual depth ≤1 mm). The needle was immediately withdrawn upon superficial epidermal vaporization to prevent deep tissue injury. The number of puncture points corresponded to lesion area (5–7 micropores for 5 mm diameter warts). The procedural objective was barrier disruption and pressure relief, not complete tissue ablation.
Post-procedure, sterile gauze was applied for mild hemostasis. A thin layer of erythromycin or mupirocin ointment was applied to the puncture area, covered with sterile adhesive dressing. The operative field was maintained clean and dry for 24 hours to prevent infection.
Saturated Saline Soaking (Both Groups)
The observation group commenced daily room-temperature saturated saline soaking 24 hours post-puncture. The control group initiated soaking directly on the first day of enrollment. Saturated sodium chloride solution was prepared using GB 2721 standard refined salt and room-temperature purified water, with salt continuously added until undissolved crystals precipitated, achieving a stable saturated solution (mass concentration: 26.0%–26.4%).
All patients immersed the affected foot for 30 minutes daily over 6 consecutive weeks. Following each session, the local skin was rinsed with clean water and thoroughly dried. Concomitant use of topical adjunctive therapies (including salicylic acid, imiquimod, cantharidin, etc) and mechanical curettage was strictly prohibited throughout the treatment period.
Outcome Measures
Primary endpoints: (1) Lesion-level complete clearance rate (number of completely cleared warts / total baseline warts) at week 6 (descriptive only); (2) Patient-level complete remission rate (100% regression of all baseline lesions) at week 6.
Secondary endpoints: (1) Lesion partial regression rate at weeks 2 and 4 (descriptive only); (2) Postoperative pain Visual Analogue Scale (VAS) score; (3) Mean time to therapeutic response.
Safety endpoints: Incidence of local adverse reactions including erythema, exudation, infection, hemorrhage, blistering, scarring, pigmentary abnormalities, and systemic adverse events.
Long-term recurrence: Monthly clinical follow-up examinations were conducted for 12 months post-treatment. Recurrence was defined as reappearance of typical verrucous lesions or characteristic black dot signs in previously cleared areas.
Efficacy Evaluation Criteria
Cured: Complete regression of all verrucous lesions; normal plantar skin texture; complete resolution of local tenderness. Markedly effective: Lesion regression >80%. Effective: Lesion regression 50%–80%. Ineffective: Lesion regression <50%. Overall effective rate: (Cured + Markedly effective) / Total cases × 100%.
Therapeutic response: Defined as the first-documented clinical improvement characterised by measurable reduction in verrucous hyperkeratosis, flattening of lesion surface, and partial resolution of local plantar tenderness. Mean time to response was defined as the average interval from treatment initiation until the first observation of therapeutic response according to the above criteria.
Statistical Analysis
All statistical calculations were performed using SPSS software (version 27.0). Continuous variables that followed a normal distribution are reported as means with their corresponding standard deviations (Mean ± SD), and between-group comparisons were conducted via independent-samples t-tests. For continuous data that did not meet the assumptions of normality, the Mann–Whitney U-test was applied for intergroup analysis. Categorical variables are presented as frequencies with percentages, and differences among groups were evaluated using either the Chi-square test or, when expected cell counts were insufficient, Fisher’s exact test. For all statistical inferences, a two-tailed probability value below 0.05 was regarded as denoting statistical significance. Because multiple warts from the same patient are not statistically independent, lesion-level clearance data were not subjected to inferential statistical testing. Primary efficacy comparisons were performed at the patient level, where each patient contributed exactly one observation. Lesion-level clearance rates are presented descriptively only. This approach avoids treating individual warts as independent observations and prevents inflation of Type I error due to within-patient clustering.
Results
Baseline Characteristics
A total of 74 patients were enrolled, comprising 42 in the observation group and 32 in the control group. Baseline characteristics were well-balanced between groups (all P > 0.05), confirming comparability (Table 1).
Table 1.
Baseline Demographic and Clinical Characteristics
| Characteristic | Observation Group (n=42) | Control Group (n=32) | P-Value |
|---|---|---|---|
| Sex (Male/Female) | 26/16 | 19/13 | >0.05 |
| Age (years, Mean±SD) | 38.2±12.7 | 37.6±11.9 | >0.05 |
| Disease duration (months, Mean±SD) | 12.5±8.2 | 11.8±7.9 | >0.05 |
| Total baseline warts (n, mean per patient) | 329 (7.83) | 251 (7.84) | >0.05 |
Primary Efficacy Outcomes at Week 6
At week 6, the observation group demonstrated significantly superior patient-level outcomes compared with the control group: complete patient remission (88.1% vs 65.6%) and overall effective rate (95.2% vs 75.0%) (both P < 0.05; Table 2). Lesion-level complete wart clearance was 95.0% in the observation group versus 77.0% in the control group; this outcome is reported descriptively because multiple lesions per patient violate the assumption of independence. No inferential statistical testing was performed on lesion-level data. Representative clinical images of the treatment process and outcomes are shown in Figure 1. Pre-treatment, multiple hyperkeratotic verrucous lesions were present on plantar weight-bearing areas with obvious epidermal thickening and local tenderness (Figure 1A). Intra-treatment, standardized honeycomb micropores were evenly created on lesion surfaces with minimal trauma and no obvious bleeding, while normal intervening skin was well preserved (Figure 1B). At week 6, complete resolution of verrucous lesions and hyperkeratosis was observed, with restored normal plantar skin texture and full relief of tenderness, confirming the favorable efficacy and safety of the combined regimen (Figure 1C).
Table 2.
Comparative Efficacy Outcomes at week 6
| Efficacy Indicator | Observation Group | Control Group |
|---|---|---|
| Complete wart clearance (n/%) | 313/329 (95.0%) | 193/251 (77.0%) |
| Complete patient remission (n/%) | 37/42 (88.1%) | 21/32 (65.6%) |
| Overall effective rate (n/%) | 40/42 (95.2%) | 24/32 (75.0%) |
| Mean time to response (weeks, Mean±SD) | 2.1±0.7 | 3.8±0.9 |
Figure 1.
Representative clinical images of multiple plantar warts treated with high‑frequency ion‑mediated honeycomb interval puncture combined with saturated saline soaking. (A) Pre‑treatment: Multiple hyperkeratotic verrucous lesions located on plantar weight‑bearing areas, with obvious epidermal thickening and local tenderness. (B) Intra‑treatment: Standardized honeycomb micropores were evenly created on lesion surfaces with minimal trauma and no obvious bleeding; normal intervening skin was well preserved. (C) At week 6: Complete resolution of verrucous lesions and hyperkeratosis, with restored normal plantar skin texture and full relief of tenderness, confirming the favorable efficacy and safety of the combined regimen.
Safety Profile
Adverse events were mild and transient in both groups (Table 3). Postoperative distending pain in the observation group was well-tolerated (mean VAS: 2.3±0.6), requiring no additional analgesia. Pinhole scabs developed in 21.4% of patients and resolved spontaneously within 7–10 days without residual scarring. Mild plantar desquamation occurred in 7.1% of observation group patients and 15.6% of control group patients, all self-limiting. No wound infections, hypertrophic scarring, pigmentary abnormalities, or serious adverse events were observed in either group during treatment or follow-up.
Table 3.
Safety Outcomes
| Safety Indicator | Observation Group (n=42) | Control Group (n=32) |
|---|---|---|
| Postoperative VAS score (Mean±SD) | 2.3±0.6 | – |
| Pinhole scab formation (n/%) | 9 (21.4%) | – |
| Wound infection (n/%) | 0 (0%) | 0 (0%) |
| Scar formation at 12 months (n/%) | 0 (0%) | 0 (0%) |
| Plantar desquamation (n/%) | 3 (7.1%) | 5 (15.6%) |
| Serious adverse events (n) | 0 | 0 |
Long-Term Recurrence Rates
According to study definitions, recurrence should only be calculated among subjects who attained complete patient remission (all warts cleared) at week-6 endpoint. As shown in Table 2, 37 of 42 patients in the observation group and 21 of 32 patients in the control group achieved complete patient remission. The 12-month follow-up demonstrated significantly lower recurrence in the observation group (2.70%; 1/37) compared with the control group (14.29%; 3/21), confirming the sustained therapeutic benefit of the combined regimen.
Discussion
This retrospective comparative study suggests that high-frequency ion-mediated honeycomb interval puncturing combined with saturated saline soaking may represent a potentially cost-effective, minimally invasive therapeutic option for multiple plantar warts. In our cohort, this combined regimen achieved favourable efficacy outcomes, accelerated therapeutic response, and promising long-term remission. The present findings highlight the therapeutic potential of integrating physical barrier disruption with physicochemical antiviral modulation in dermatological practice, although these observations require confirmation in larger prospective cohorts. Furthermore, this sequential approach may lessen reliance on repeated destructive interventions and lower treatment-related burden for refractory cases. Potential benefits in healthcare resource utilization are suggested by the possibility of home-based saline soaking, yet these cannot be definitively concluded from the current retrospective dataset and warrant further health-economic evaluation.
Despite the extensive array of therapeutic options for plantar warts, no single modality has demonstrated comprehensive effectiveness across all clinical presentations. Conventional destructive approaches—including cryotherapy, laser ablation, electrocautery, and surgical excision—frequently entail procedural pain, scarring, dyspigmentation, and delayed healing, with substantial recurrence rates. A systematic review and network meta-analysis reported that cryotherapy achieves a mean cure rate of only 45.61%, with the highest odds of recurrence among all treatment modalities.2 Laser therapy offers cure rates ranging from 53% to 96% (mean 79.36%) but carries recurrence rates of 10.87% to 52%.2 A recent Bayesian network meta-analysis incorporating 33 randomized controlled trials further questioned the efficacy of traditional first-line options, demonstrating that salicylic acid and cryotherapy were not superior to no treatment in achieving complete response.5 Even 5-aminolevulinic acid photodynamic therapy (ALA-PDT), despite its targeted antiviral activity, is constrained by high costs, repeated visits, and insufficient penetration through hyperkeratotic layers, often resulting in incomplete clearance and residual viral persistence.6 The persistent therapeutic challenge posed by treatment-refractory and recurrent warts thus remains a significant clinical conundrum in contemporary dermatology.
Research on noninvasive treatment modalities for plantar warts remains limited. Saturated saline immersion has emerged as a promising non-invasive therapy, with a landmark open-label trial reporting 98.3% lesion clearance and 88.2% patient remission after 8 weeks of daily soaking.4 However, the markedly thickened stratum corneum characteristic of multiple plantar warts constitutes a dense physical barrier that impedes deep saline penetration, thereby attenuating hyperosmotic effects and leading to delayed efficacy and suboptimal outcomes in challenging cases. In our control group, saturated saline monotherapy achieved only 77.0% lesion clearance and 65.6% patient remission at week 6, underscoring the inherent limitation of passive saline penetration through unmodified hyperkeratotic surfaces.
The unique potential advantage of our combined regimen lies in its use of superficial micropuncturing—rather than tissue ablation—to breach the keratin barrier. The standardized honeycomb interval puncturing (hole spacing 1.5–2.0 mm, pore diameter 0.3–0.5 mm, depth ≤1 mm) creates uniform micropores that may facilitate even and deep infiltration of saturated saline into the lesion core, while intact interpore skin islands promote rapid wound repair and minimize scarring.7 The procedure was well-tolerated within this cohort, with a mean postoperative VAS score of only 2.3±0.6, and pinhole scabs, when they occurred (21.4%), resolved spontaneously within 7–10 days without sequelae. Patients could conveniently perform daily soaking at home (30 minutes daily for 6 weeks), which may reduce the frequency of required clinical visits. Owing to its minimal side-effect profile, this treatment generally imposes few activity restrictions, in contrast to destructive treatment modalities that may cause post-procedure pain and functional impairment, with limited demand for specialized post-treatment care. It appears affordable and safe within our observed population, as no serious complications such as hemorrhage, cauterization, or wound infection were recorded. This barrier-disruption strategy parallels the rationale of microneedling-assisted therapies, which have demonstrated enhanced therapeutic outcomes in plantar warts in other published studies.
A randomized clinical trial comparing microneedling with topical bleomycin versus cryotherapy for refractory hand and foot warts found that the bleomycin microneedling group achieved superior clearance rates (69.6% vs 54.2% for foot lesions) with few adverse effects, whereas cryotherapy was associated with local pain, blisters, and scars.8 The network meta-analysis by Xu et al further identified microneedles plus bleomycin (MNB) as one of only three treatments significantly superior to no treatment, alongside cantharidin–podophyllotoxin–salicylic acid (CPS) and intralesional bleomycin.7 The multipuncture technique, first described by Falknor in 1969, induces a controlled inflammatory process that allows the immune system to identify viral proteins and generate antibodies to eliminate virus-infected cells.7
The clinical observations—no deep tissue injury, no hemorrhage, no scar formation, and intact dermal architecture—suggest that the combination may work through synergistic mechanisms. First, micropuncturing may release intralesional mechanical tension, providing rapid pain relief, and expose sequestered HPV antigens to activate local cellular immunity.1 Second, the hypertonic saline environment exerts direct antiviral and immunomodulatory effects. The precise mechanism underlying the treatment effect, however, remains incompletely elucidated. Previous work has proposed that hypertonic sodium chloride solution therapy for plantar warts operates through synergistic pathways centered on restoring endogenous antimicrobial peptide activity and enhancing immunity. Studies have demonstrated that low NaCl concentrations can inhibit the activity of LL-37 and other antimicrobial peptides.4 LL-37 is a 37-amino-acid antimicrobial peptide derived from cathelicidin, playing a critical role in innate immune defense against bacterial, viral, and fungal infections.4 Beyond its direct antimicrobial functions, LL-37 also acts as an immunomodulator with emerging roles in autoimmune disease pathogenesis.4
This study was not designed to interrogate underlying molecular mechanisms; the following represent plausible hypotheses inferred from previously published literature rather than findings directly demonstrated by our clinical data. It has been hypothesised that hypertonic sodium chloride solution may restore LL-37 expression levels. Upregulated LL-37 could exert direct antiviral effects against human papillomavirus-16, as reported elsewhere.4 Furthermore, LL-37 might potentially activate the host immune system by inducing the proliferation of natural killer cells, B lymphocytes, and dendritic cells.4 Concurrently, hypertonic saline may promote IL-18 secretion4. Elevated LL-37 and IL-18 could synergistically form a robust antiviral network. Crucially, human papillomavirus-infected keratinocytes may exhibit heightened vulnerability specifically under hypertonic conditions.4 Collectively, these proposed effects — direct viral inhibition mediated by restored LL-37, immune activation involving enhanced IL-18, and the intrinsic susceptibility of infected cells to hyperosmolarity — may cooperatively contribute to wart clearance. Our combined puncture-soaking regimen, which creates skin-barrier disruption, is hypothesised to facilitate improved saline penetration and possibly augment the above-mentioned putative pathways, while potentially preserving normal skin integrity. Future translational investigations will be required to experimentally verify these mechanistic conjectures.
The favourable efficacy observed in our observation group—95.0% lesion clearance, 88.1% patient remission, and 95.2% overall effective rate at week 6—compares favourably with other combination regimens reported in the literature. Notably, the mean time to therapeutic response in our observation group (2.1±0.7 weeks) was significantly shorter than in the control group (3.8±0.9 weeks), indicating that barrier disruption not only improves ultimate clearance rates but also accelerates the onset of therapeutic benefit within our cohort. This rapid response has potential implications for patient compliance and quality of life, as prolonged treatment courses frequently lead to dropout and suboptimal outcomes. A previous study reported that warm saturated saline combined with liquid nitrogen cryotherapy achieved an 81.7% overall effective rate, surpassing cryotherapy alone (65.0%).4 However, cryotherapy-based combinations risk unpredictable freeze-thaw injury to normal tissue, require specialized equipment, and show variable real-world performance. Our honeycomb puncturing approach may mitigate these drawbacks by offering more controllable operative parameters and faster pain relief, though reproducibility across different operators and settings remains to be formally evaluated.
Notably, among patients achieving complete patient remission at week 6, the 12-month recurrence rate was 2.70% (1/37) in the combined-treatment group versus 14.29% (3/21) in the saline-monotherapy group; these outcomes compare favourably with recurrence rates reported for conventional therapies. A study evaluating CO2 laser combined with ALA-PDT for periungual and plantar warts reported a 3-month recurrence rate of 2.00% in the combination group versus 10.87% in the CO2 laser monotherapy group.8,9 Intralesional bleomycin injection, while achieving cure rates of 16–97% depending on administration method, has been associated with 3-month recurrence rates of 3.3% to 15.78%.10,11 The low recurrence rate observed in our cohort might arise from several hypothetical factors: improved saline penetration that may help target deeper viral reservoirs, the controlled micropuncture-induced inflammatory response that may activate local HPV-specific cellular immunity, and intact interpore skin islands preserving plantar epidermal structure to theoretically reduce the risk of reinfection via micro-defects. These proposed explanations cannot be confirmed by our present dataset.
Safety analyses from this retrospective cohort suggest a favourable tolerability and safety profile for the combined therapeutic regimen.4 All adverse events observed throughout treatment and the 12-month follow-up period were mild, transient, and self-limiting, with no permanent clinical sequelae or severe systemic complications. Postoperative pinhole scabbing (21.4%) and slight local distending pain (VAS 2.3±0.6) represent routine physiological responses to controlled superficial microtrauma, which resolve spontaneously within 7–10 days without additional clinical intervention.4 The lower incidence of plantar desquamation in the observation group (7.1% vs 15.6%) is primarily attributed to accelerated lesion regression after combined treatment within our study population.
Barrier-disruption pretreatment may facilitate early clearance of HPV-infected lesions, shorten the duration of hyperosmotic stimulation on perilesional healthy skin, and potentially reduce osmotic irritation and adverse cutaneous reactions.4 Given its minimal invasiveness and encouraging safety findings in this cohort, this sequential regimen may offer an alternative option for patients poorly tolerant to conventional destructive interventions, including cryotherapy, carbon-dioxide laser ablation, and surgical excision, potentially expanding the therapeutic armamentarium for plantar warts.1,4,6 Unlike bleomycin-based therapies, which may cause significant injection-related pain and carry risks of local necrosis,10,11 our approach appears to avoid these safety concerns in the present series.
Persistent lesions occasionally seen in immunocompromised patients, such as individuals receiving disease-modifying therapies for rheumatoid arthritis, suggest that prolonged treatment durations or additional sessions may be required for clearance in immunosuppressed populations, as immune competence remains a critical determinant of therapeutic success.4
Study Limitations
This study has several limitations. First, although the number of lesions was substantial (329 in the observation group), lesion-level data were analyzed descriptively only because multiple warts per patient violate the assumption of independence. Primary efficacy analyses were therefore performed at the patient level. The modest patient sample size (N = 74) constrains the robustness and generalizability of findings. Formal clustered analyses such as generalized estimating equations (GEE) or mixed-effects models were not performed because the required software modules were not available to us; future studies should incorporate these methods to account for within-patient clustering. Second, as a single-center retrospective study with a non-randomized design, the evidence is not as strong as that from a prospective randomized controlled trial with a concurrent control group; selection bias cannot be entirely excluded. Third, while the 12-month follow-up provides meaningful recurrence data, extended observation (≥18 months) would strengthen long-term efficacy assessment. Fourth, optimal puncture parameters for different lesion subtypes, including variations in wart size, depth, and degree of hyperkeratosis, remain to be standardized. Fifth, the immunomodulatory mechanisms hypothesized (including effects on LL-37, IL-18, and HPV-specific T-cell responses) were not directly investigated and merit further mechanistic exploration. Sixth, ethnic diversity was limited, and HPV genotyping was not performed, precluding analysis of genotype-specific responses.7 Finally, patient-reported outcomes beyond pain, such as functional impairment and treatment satisfaction, were not systematically captured and should be included in future prospective studies. As the gold standard for causal inference, randomized controlled trials provide robust efficacy and safety data; when integrated with real-world evidence, they further validate long-term safety and rare adverse events, yielding more reliable clinical evidence for dermatological practice. Future multicenter, prospective, randomized trials with standardized protocols and comprehensive immunological assessments are warranted to confirm these promising findings and refine the treatment algorithm for multiple plantar warts.
Conclusion
High-frequency ion-mediated honeycomb interval puncturing combined with saturated saline soaking effectively overcomes the limitations of saturated saline monotherapy by disrupting the physical barrier of hyperkeratotic plantar warts, enhancing drug penetration, and relieving intralesional pressure. This combined regimen achieves significantly superior patient-level therapeutic outcomes, including faster response times, higher complete patient remission rates, minimal adverse effects, and lower long-term recurrence compared with monotherapy, although lesion-level clearance was reported descriptively only. Featuring low economic cost, standardized and simple operation, and suitable for large-scale outpatient clinical promotion, the regimen is suitable for large-scale outpatient clinical promotion and home-based auxiliary maintenance treatment. It provides an optimized, safe, and efficient alternative for the standardized clinical management of multiple and mosaic plantar warts, substantially enriching the current therapeutic armamentarium for recalcitrant cutaneous HPV infections.
Acknowledgments
The authors express sincere gratitude to all patients who participated in this retrospective clinical observation. We also thank all nursing staff in the dermatology outpatient department for their assistance in patient follow-up and data recording.
Funding Statement
This research received no external funding.
Abbreviations
ALA-PDT, 5-aminolevulinic acid photodynamic therapy; CI, confidence interval; CO2, carbon dioxide; CPS, cantharidin–podophyllotoxin–salicylic acid; HPV, human papillomavirus; IL-18, interleukin-18; LL-37, cathelicidin antimicrobial peptide LL-37; MNB, microneedles plus bleomycin; OR, odds ratio; SD, standard deviation; VAS, Visual Analogue Scale.
Data Sharing Statement
The raw clinical datasets generated and analyzed during this retrospective study contain sensitive patient medical information. To strictly comply with medical privacy protection regulations and institutional data management rules, the original identifiable medical records cannot be publicly shared. De-identified aggregated statistical data supporting the findings of this manuscript are available from the corresponding author upon reasonable and formal written request, subject to institutional data access review procedures.
Ethics Statement
This retrospective clinical observational study was based on routinely collected clinical data from Qingpu Branch, Zhongshan Hospital Affiliated to Fudan University. The study protocol was reviewed and formally approved by the Institutional Ethics Committee of Qingpu Branch, Zhongshan Hospital Affiliated to Fudan University (Approval Number: Qingyi 2025-090; Approval Date: January 21, 2025). As this study involved only retrospective analysis of existing de‑identified clinical data without any invasive interventions or additional experimental procedures on patients, the Institutional Ethics Committee waived the requirement for written informed consent from individual participants. All patient information was fully anonymised and de‑identified prior to data analysis, including the removal of all personally identifiable information (name, ID card number, medical record number, and contact information), in strict compliance with national ethical guidelines and institutional regulations for retrospective observational studies. The study was conducted in accordance with the principles of the Declaration of Helsinki.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no competing interests.
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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 raw clinical datasets generated and analyzed during this retrospective study contain sensitive patient medical information. To strictly comply with medical privacy protection regulations and institutional data management rules, the original identifiable medical records cannot be publicly shared. De-identified aggregated statistical data supporting the findings of this manuscript are available from the corresponding author upon reasonable and formal written request, subject to institutional data access review procedures.