Onychomycosis presents with nail discoloration (yellow or white, and brown in cases of heavy fungal burden), onycho- lysis, nail brittleness, nail plate thickening, and subungual hyperkeratotic debris. The condition can significantly impair the quality of life. It is a chronic fungal infection, and treatment typically requires prolonged therapy; however, recurrence remains a frequent challenge. Although oral systemic anti- fungal agents are the standard therapy for onychomycosis, cure rates are not high. Terbinafine achieves a mycological cure rate of approximately 70% and a complete cure rate of 38% in toenail infections, whereas itraconazole yields a mycological cure rate of 54% and a complete cure rate of 14%1. Furthermore, relapse or reinfection rates of approxi- mately 20-25% have been reported even after successful initial treatment1,2. Systemic conditions, including diabetes, impaired circulation, peripheral neuropathies, and immuno- suppression, as well as the type of causative fungus, are asso- ciated with poor treatment outcomes. The recent emergence of terbinafine-resistant Trichophyton indotineae has become a significant global concern. Although the optimal treatment for T. indotinea has not been established, increasing the dose and/or duration of antifungal therapy may help overcome resistance3. However, given the chronic, relapsing nature of infections caused by this organism, treatment with antifungal agents alone may be insufficient. Nonpharmacological treat- ments may provide an adjuvant effect by reducing fungal burden. In addition, biofilm formation may contribute to re- current infection and treatment resistance. Biofilms provide a protective barrier for organisms, conferring resistance to external insults and preserving a persistent infectious reservoir that promotes antifungal resistance4. Therefore, additional treatment options are needed to address the limitations of current therapies. In this review, we discuss nonmedical treatments for onychomycosis, including physical debridement and device-based treatments, with a focus on strategies to improve treatment efficacy.

Removing all infected keratin from a nail affected by onychomycosis can reduce the infectious load, similar to how drainage reduces the burden of an abscess. This approach has been shown to enhance mycological cure rates and may shorten the course of systemic treatment5.

2.1. Mechanical/Physical debridement

2.1.1. Recommended clinical subtypes

Physical debridement was suggested for some specific forms of onychomycosis6. In particular, surgical debridement may be beneficial in clinical subtypes in which systemic or topical antifungal therapies show limited efficacy. For instance, in cases involving a markedly thickened nail plate or dermato- phytoma, antifungal agents cannot adequately penetrate the dense keratin mass. In onycholysis, separation of the nail plate from the nail bed prevents systemic antifungals from reaching the nail plate via the nail bed, while topical agents cannot effectively penetrate from the nail plate to the nail bed. Similarly, antifungal treatment of lateral onychomycosis is often less effective because detachment of the nail plate from the nail bed impairs drug delivery6 (Table 1). Treatment of nondermatophyte molds (NDMs) is not well standardized, and these fungi respond poorly to systemic antifungal agents compared with dermatophytes7-10. In such cases, physical debridement combined with antifungal therapy is recom- mended as the first-line approach9,10.

2.1.2. Method for mechanical/physical/ chemical debridement

Mechanical/physical debridement does not require local anesthesia, and the procedure is noninvasive and safe for all patients, including those with peripheral vascular disease and diabetes. Curettage to remove subungual debris (hyponychial keratin) is particularly important, as this material is rich in fungal filaments6.

Chemical avulsion using 40% urea occlusion has long been used6,11. This selective method acts only on the infected keratin. Urea dissolves the bonds between the nail bed and the nail plate and also softens the nail plate6. After approxi- mately one week of occlusion, the infected part of the nail can be removed painlessly12.

Laser devices have emerged as therapeutic alternatives for onychomycosis. Unlike antifungal drugs, which require demon- strated efficacy in strict randomized controlled trials for approval by the US Food and Drug Administration (FDA), the 1,064-nm neodymium-doped/yttrium aluminum garnet (Nd:YAG) laser was approved by the FDA in 2010 for the "temporary increase in clear nail," an aesthetic endpoint that does not necessarily reflect fungal eradication13,14. Accordingly, evidence supporting the efficacy of laser devices remains limited compared with antifungal agents. Among clinical studies of laser device-based treatments, the Nd:YAG laser is the most commonly studied and has shown mixed outcomes, followed by the carbon dioxide (CO2) lasers14. This review focuses on Nd:YAG lasers, CO2 lasers, and the emerging modality of nonthermal atmospheric pressure plasma (NTAP).

3.1. Neodymium doped/yttrium aluminum garnet (Nd:YAG) laser

3.1.1. Proposed mechanism of action against fungi

The antifungal effect of lasers is thought to rely primarily on photothermal effects, in which fungal cells absorb laser energy and convert it into heat, leading to cellular damage6,14,15. This heat causes protein denaturation and inactivation of fungal cells16. Optimization of laser parameters must account for the thermal properties of the surrounding tissues to avoid damage to healthy human cells and ensure selective targeting of fungal cells14,16. Fungal cells have a lower heat capacity than surrounding human dermal cells, allowing them to heat up more rapidly and retain heat longer6,14. Thermal relaxation time (TRT), defined as the time required for cells to dissipate heat, determines pulse duration and intervals between pulses14,15. Both fungal hyphae and conidia have a TRT of less than 1 μs6. Based on selective photothermolysis, pulse duration should be shorter than the TRT of the target to allow heat accumulation6,15. Q-switched Nd:YAG lasers use nanosecond pulse durations but produce minimal ther- mal effect. Long-pulsed 1,064-nm lasers require continuous cooling to avoid severe pain and injury. Short-pulsed Nd:YAG lasers are considered advantageous. Fungal chromophores are an additional factor that can be used to induce a fungicidal effect by lasers, which can be explained by photomechanical/ acoustic phenomena6. An in vitro study showed that treat- ment with 1,064-nm Q-switched Nd:YAG laser and 532-nm Q-switched Nd:YAG laser resulted in a much lower growth rate of Trichophyton rubrum Rcolonies17. The 1,064 nm wave- length is absorbed by melanin in fungal cell walls, whereas the 532-nm wavelength is absorbed by xanthomegnin17. However, wavelengths that effectively penetrate the nail range from 750 to 1,300 nm18, making the short-pulsed 1,064-nm Nd:YAG laser the most widely used modality.

3.1.2. In vitro studies of the Nd:YAG laser

Vural et al.17 demonstrated significant inhibition of T. rubrum colony growth following treatment with both 1,064-nm and 532-nm Nd:YAG lasers, suggesting the potential utility of laser therapy for onychomycosis. Temperature of 55℃ are the lowest capable of killing dermatophytes via heat19. Carney et al.20 reported that the temperature of 50℃ inhibited T. rubrum colonies after 5 min and was fungicidal after 15 min. Conversely, direct Nd:YAG irradiation failed to demonstrate any effect on T. rubrum's growth while the temperature on agar plates peaked at 40℃. The authors concluded that a fungicidal effect was only achieved by heat; however, the necessary parameters (high degree of temperature and dur- ation of heating) could not be adapted for clinical practice because temperatures over 45℃, resulting in pain and necrosis in humans18,20.

3.1.3. Reported RCTs of short-pulsed 1,064-nm Nd:YAG laser monotherapy

In South Korea, the approved indication for laser-based treatment of onychomycosis is limited to patients who cannot tolerate oral antifungal therapy or have contraindications to it. Numerous clinical studies of laser-based treatments have reported variable and inconsistent efficacy in onychomycosis. However, RCTs evaluating short-pulsed 1,064-nm Nd:YAG laser monotherapy have failed to show significant treatment effects21-23 (Table 2). In an RCT by Hollmig et al.21, patients in the laser group underwent two sessions of 1,064-nm Nd:YAG laser treatment at 2-week intervals, using a fluence of 5 J/cm2, pulse width of 0.3 ms, spot size of 6 mm, and a repetition rate of 6 Hz to achieve a target temperature of 40-42℃. The results showed no significant difference in the percentage of patients with negative nail cultures between the laser and control groups (p = .49). Although patients treated with laser showed greater proximal nail plate clearance than controls (0.44 vs 0.15 mm, p = .18), this difference was not statistically significant. Moreover, the modest improve ment of proximal nail plate clearance seen in the laser group was not sustained. In another RCT, 20 patients (82 mycotic toenails) were randomized to a short-pulsed 1,064-nm Nd: YAG laser group or a control group22. The laser group received four treatments at 4-6-week intervals, with a follow-up period of 12 months. Neither group achieved mycological remission, and Onychomycosis Severity Index scores did not significantly differ between groups. The authors conclude that the short-pulsed 1,064-nm Nd:YAG laser shows no long-term efficacy as a monotherapy. Similarly, Sabbah et al.23 reported that three treatments with a 1,064-nm Nd:YAG laser administered at 3-month intervals were ineffective for the treatment of onychomycosis. In their study, 51 patients were randomized to receive three treatments (at weeks 0, 12, and 24) with either a short-pulsed 1,064-nm Nd:YAG laser or a placebo sham laser. No patients (0%) in the laser group achieved the primary outcome.

Numerous fungal spores have been identified within the infected nail plate, and a fungal biofilm surrounding a spore has also been observed24, contributing to the chronic infection course of onychomycosis. T. rubrum often produces arthro- conidia in vivo, and the arthroconidia are thought to be involved in pathogenesis and, in shed skin scales, act as a source of infection25. In vitro study revealed that arthroconidia formation of T. rubrum occurred optimally at 37℃ and pH 7.5 and was maximal at 10 days25. In the resting state, the toe skin temperature is approximately 27.8 ± 3.0℃26. When Nd:YAG laser treatment is delivered at suboptimal energy levels, the resulting temperature increase may fall within a range that favors arthrospore formation, potentially promoting rather than inhibiting spore production. A previous studies on the heat resistance of dermatophyte conidiospores has demonstrated that these spores exhibit high resistance to heat exposure at 80℃27. Therefore, even when nail plate temperatures approach 50℃ during the 1,064-nm Nd:YAG laser, fungal hyphae can be damaged or destroyed, whereas numerous viable spores may persist. RCTs have shown no significant therapeutic effect when treatment intervals exceed 1 month22,23. In contrast, laser treatments administered at 2-week intervals have demonstrated some clinical improvement; however, these effects were not sustained over time21. In this context, when treatment intervals are prolonged, residual fungal elements are more likely to contribute to fungal regrowth. Consequently, because the therapeutic mechanism of the Nd:YAG laser relies primarily on the photothermal effect, its efficacy as monotherapy is limited unless higher laser intensities and shorter treatment intervals are employed.

3.2. Carbon-dioxide lasers (CO2 lasers)

3.2.1. Reported clinical studies of CO2 laser

The CO2 laser represents the oldest laser-based approach for the treatment of onychomycosis28. It may be used as primary therapy or in combination with topical antifungals agents to enhance drug penetration through the nail plate into the nail bed29. The first study of ablative fractional CO2 laser combined with a topical antifungal reported a favorable clinical response after three laser sessions administered at 4-week intervals, along with once-daily amorolfine cream for 3 months. In that study, 50% of patients achieved a complete response, defined as negative microscopic findings, with no recurrence observed during the 3-month follow-up29. Similarly, studies evaluating fractional CO2 laser therapy in combination with topical antifungal creams have demonstrated efficacy in the treatment of onychomycosis30,31. Specifically, 33.33% of patients achieved a complete clinical response at 6 months of follow-up, and 80% were culture negative30. In another study, 69.6% of nails showed either complete or greater than 60% normalization in appearance, and 57.4% demonstrated negative fungal microscopic results31. In contrast to previous studies, a retrospective review literature reported a complete response (CR) rate—defined as 100% nail clearance of all treated toenails per patient—of only 15.6% after three or more fractional CO2 laser treatments administered at inter- vals of at least 4 weeks, in combination with topical anti- fungal agents32. This CR rate is comparable to or lower than that achieved with topical efinaconazole 10% (17.8% and 15.2%)33. Although results have been inconsistent, the CO2 laser emits light at a wavelength of 10,600 nm, at which water serves as the primary chromophore. Absorption of this energy leads to heat generation, which is thought to produce antifungal effects. In a study comparing fractional CO2 laser followed by topical antifungal treatment (ticonazole 28% solution) (Group A), fractional CO2 laser alone (Group B), and topical antifungal treatment alone (Group C), a significant difference in clinical response was observed among the three groups (p < .005)34. Complete clinical response was observed in 55% of patients in Group A, compared with 30% in Group B and 25% in Group C. Notable, CO2 laser monotherapy produced better clinical outcomes than topical antifungal therapy alone. Fractional CO2 laser treatment in a single session following 12% urea occlusion of the affected nail for 24 h showed excellent results35,36. Urea is a hygroscopic agent, and urea occlusion softens the nail plate and helps provide water chromophore at depth, thus enabling the accelerated fungicidal effect of a fractional CO2 laser36. Therefore, precise and selective delivery of high-energy laser irradiation to the infected nail plate is important in determining the therapeutic effect of CO2 laser treatment.

3.3. Nonthermal atmospheric pressure plasma

3.3.1. In vitro studies of NTAP

T. rubrum is the most common cause of nail infections, accounting for approximately 80% of all dermatophyte in- fections in humans37. Candida spp. and NDMs, i.e., Scopula- riopsis brevicaulis, Aspergillus spp., and Fusarium spp., can also be causative fungi. In addition, in untreated cases of onychomycosis, the nail plate may be completely destroyed, and infections with mixed bacteria and fungi may develop1,38. Nonthermal atmospheric pressure plasma (NTAP) is considered an attractive alternative option due to its surface disinfection and antimicrobial effect39. The antimicrobial effects of NTAP have been reported to include methicillin-resistant Staphylo- coccus aureus (MRSA)40, C. albicans41,42, dermatophytes39,43-45, and A. fumigatus46. Although the mechanism of NTAP is not fully understood, reactive oxygen and nitrogen species (ROS; RNS) generated by NTAP, rather than heat, are thought to play a key role in its antimicrobial effect47.

3.3.2. Reported clinical studies of NTAP

Despite numerous in vitro evidence of NTAP supporting antimicrobial effects, relatively few clinical studies48,49 have investigated their efficacy in the treatment of onychomycosis. The first pilot study reported overall clinical cure of 53.8%, and mycological cure of 15.4% after application to the dorsal layer of the nail plate48. However, the hyponychium is the primary site of dermatophyte entry into the nail, where abundant fungal elements are present50,51. In addition, the subungual space can serve as a reservoir for superinfecting bacteria and molds52. In this regard, applying NTAP after removing the nail plate can be a good strategy (Fig. 1). In addition, since the application of NTAP to damaged skin is generally tolerable53,54, it will be a suitable method for appli- cation to the nail bed without a nail plate. In another clinical study49, the combination of nail plate abrasion and NTAP resulted in better outcomes compared with NTAP combined with topical antifungal agents, with mycological cure achieved in 85.7% of patients in the case of nail plate abrasion with NTAP. In addition, all patients reported that the treatments were tolerable. Thus, with further validation in well-designed clinical trials, NTAP therapy has the potential to become an effective treatment modality for onychomycosis.

Figure 1. The nail plate acts as a barrier to NTAP, reducing its effectiveness (A). Nail removal exposes abundant fungal elements in the subungual area (B), thereby enhancing treat- ment efficacy by allowing fungal elements to be directly exposed to NTAP. NTAP: Nonthermal atmospheric pressure plasma

Modify Delete

Physical debridement and device-based treatments may serve as useful adjunctive options in the management of onychomycosis. However, achieving effective treatment inten- sity while avoiding injury to adjacent normal tissues remains challenging. Improved outcomes will depend on a thorough understanding of disease characteristics, as well as the benefits and limitations of available device-based treatments.