Light-Based Therapies for Treatment of Onychomycosis

1. Introduction

Onychomycosis (fungal nail infection), and particularly distal and lateral subungual onychomycosis (DLSO), is the most prevalent nail infection worldwide, making up about 90% of toenail infections globally [1]. This condition leads to nail discoloration, detachment from the nail bed (onycholysis), fragility, thickening, and accumulation of scales beneath the nail [1]. While dermatophytes are the primary cause of onychomycosis, non-dermatophyte molds and yeasts are also causative organisms, being dermatophytes responsible for over 60–70% of the cases. Among the different species of dermatophytes, Trichophyton rubrum is recognized as the most common pathogen [2]. Scopulariopsis brevicaulis, Acremonium spp., Aspergillus spp., Fusarium spp., and Neoscytalidium spp. are non-dermatophyte molds also responsible for some cases of the disease [2]. Candida albicans accounts for approximately 70% of yeast-related onychomycosis, although fungal nail infections caused by yeasts are rare [2]. Onychomycosis is acquired through direct contact of the nail with these species, as the nail lacks effective cell-mediated immunity [3]. Fungal invasion of the nail is aided by enzymes produced by fungi, which have proteolytic, keratinolytic, and lipolytic activities that promote the breakdown of keratin in the nail plate [3].

This disorder can negatively impact the quality of life of those affected. Onychomycosis is more likely to occur in toenails than fingernails, with the infection typically developing on the big toe first. It is rare for more than one nail to be affected without a concomitant infection in the toenail unless the patient has suffered trauma or is immunosuppressed [4]. Although its incidence is increasing across all age groups, it is still considered a disorder that primarily affects the older population [5]. Other factors that increase the risk of onychomycosis include persistent nail trauma, psoriasis, diabetes, poor peripheral circulation, HIV, immunosuppression, and smoking. Plantar tinea pedis and interdigital tinea are also risk factors for nail infections and often occur alongside onychomycosis [6]. The condition can be aggravated by moist environments, occlusive footwear, and genetic factors. These factors can also contribute to the recurrence of onychomycosis after treatment, making it a chronic and difficult-to-treat disease. Other risk factors for recurrence include >50% nail involvement at baseline, nail trauma, the presence of infectious organisms that are more difficult to eradicate (nondermatophytes, mixed infections), previous onychomycosis therapy, short-duration therapies, poor treatment success, and poor adherence to treatment [7].

In addition, the drawbacks of conventional therapeutic agents highlight the difficulty of treating this disease. Topical antifungal agents have a low ability to penetrate the nail and reach the infected nail bed, [8] whereas oral antifungals have the potential to cause systemic adverse effects, drug interactions, and the development of antifungal resistance, leading to patient non-adherence [9]. Since the growth of nails is slow, both oral and topical therapies involve longer durations of treatment, leading to poor patient compliance.

Laboratory confirmation is always necessary before treatment even though the diagnosis can be highly probable based on clinical criteria. Nail dermoscopy (onychoscopy) is a valuable, fast, noninvasive, and highly efficient tool that allows for the differential diagnosis of other non-mycotic nail disorders [10]. The current standards for diagnosing onychomycosis include direct microscopic examination with potassium hydroxide (KOH) preparation, which is best for prompt initial diagnosis; histopathologic analysis of the trimmed affected nail plate with a periodic-acid-Schiff (PAS) stain to identify the presence of fungi; fungal culture of collected subungual debris; or molecular detection by means of polymerase chain reaction (PCR) when the pathogen subtype needs to be specified. The ideal diagnostic test would be highly specific and sensitive, capable of assessing fungal viability and identifying the causative species while being easy to perform with a rapid result and low cost [11]. It is recommended to conduct at least two diagnostic tests to identify the infectious species to provide adequate information for determining the appropriate treatment plan.

Endpoints used in clinical trials to evaluate the action of new drugs/devices or strategies in the treatment of onychomycosis include mycologic cure, clinical cure, and complete cure [12]. Long-term treatment is generally required to successfully cure toenail onychomycosis, which can even extend beyond a year. Even then, achieving a complete cure, defined as both a clinical cure (nail clearing) and a mycological cure (negative microscopy and fungal culture), is often unattainable because of the slow growth rate of nails.

Digital images and direct observation can help the physician assess the severity of the disease or its improvement as treatment is applied. The severity of the disease should also be assessed before deciding on a treatment plan. A reproducible and objective numerical grading system called the Onychomycosis Severity Index (OSI), has been developed to detail the extent and involvement of distal and lateral subungual onychomycosis (DLSO). Points are given based on the percentage of nail area involved, the proximity of disease to the matrix, the presence or absence of dermatophytoma, and subungual hyperkeratosis >2 mm. The OSI can be used to predict responses to antifungal therapy. When cure rates are evaluated, nails with lower OSI scores (≤5) generally show better responses to conventional therapies, whereas nails with higher scores (such as 35) are accurately indicated as more challenging cases [13]. Another criterion for expected treatment success is the continued growth of the nail, with a growth rate of more than 0.5 mm per week [14].

Onychomycosis is a difficult-to-treat disorder with a high risk for recurrence that requires new approaches beyond pharmacological therapy. Due to their minimally invasive nature, avoidance of systemic side effects, drug interactions, the development of resistance, and the potential to restore clear nail growth, light-based therapies have become a popular option in the treatment of onychomycosis for both physicians and patients [15]. Light-based therapies are safe and can be considered as the first choice for people who cannot tolerate the invasiveness of the systemic antifungal agents. They may also be part of an adjunctive therapy, alongside topical or systemic antifungals, to presumably increase the likelihood of successful fungal elimination. In addition, for its implementation by the physician, an understanding of the light-nail structure interaction is essential. Table 1 below displays the light devices that are most frequently used in the treatment of onychomycosis.

The main concepts to understand light and nail interactions are wavelength, energy, power, fluence (energy density), and irradiance (power density). Tissue effects occur only when light is absorbed. Based on the wavelength of light, a particular chromophore (such as porphyrin, xanthomegnin, hemoglobin, melanin, or water) can be targeted and absorb that light. Mainly, the behavior of light in its interaction with tissue (nail) can be classified by its wavelength because molecular absorption depends on this parameter (Table 1) [16]. The light emitted by a light source can be measured in terms of both energy and power [17]. The intensity of the light beam on the nail is a function of the area of the nail over which it is spread (i.e., the spot size). The physician can adjust the exposure time, fluence, and irradiance of the light source according to the specific clinical requirements [16].

Early studies on the use of lasers (the acronym for Light Amplification by Stimulated Emission of Radiation) for treating onychomycosis began almost 30 years ago with the carbon dioxide laser (CO₂ laser); however, clinical use did not gain popularity until recent years. Additionally, the US Food and Drug Administration (FDA) has currently approved four lasers (long-pulsed Nd:YAG, Q-switched Nd:YAG, diode laser 870/930 nm combination, and 980 nm) for a “temporary increase in clear nail in patients with onychomycosis.” However, lasers have not been established for a cure, and the number of peer-reviewed literature discussing the subject is still too few [18]. Although bibliography evaluating the efficacy of light for onychomycosis are scarce, published studies include the application of a wide variety of therapies and types of devices, such as photodynamic therapy (PDT), intense pulsed light (IPL), CO₂ lasers, fractional ablative lasers, and the Nd:YAG and diode lasers (which have FDA approval). It is important to understand that FDA approval of medical devices used to treat onychomycosis differs from that for medications. While drugs are required to meet the medical endpoints of mycologic and complete cure, devices are required to show an esthetic endpoint of visual improvement [19].

The different types of light can be able to treat or improve the appearance of onychomycosis through different suggested mechanisms. For example, some exert their effect through a mechanism known as “selective photothermolysis” [20]. The energy is absorbed by a particular fungal chromophore, leaving the surrounding tissue undamaged. This is achieved using light with a wavelength within the absorption spectrum of the target chromophore and with pulse durations shorter than the thermal relaxation time of the target chromophore. This mechanism is, for example, achieved with the Q-switched Nd:YAG laser. Other light devices have a photothermal effect on fungi, meaning that the energy generated when light is absorbed by the fungus is converted to heat, reaching temperatures exceeding 50°C, which can directly lead to thermal killing. Fungal cells have a lower heat capacity than the surrounding human dermal cells, causing them to heat up more rapidly and retain heat better. This property helps inactivate the fungi while safeguarding the dermal cells. The near-infrared diode laser and long-pulsed Nd:YAG laser present this mechanism of action [21]. Alternatively, ablative fractional lasers represent a novel strategy that combines microablation with nail disinfection, promoting its reconstruction and healing. Lastly, in antimicrobial photodynamic therapy, the combination of a photosensitizer, light, and oxygen leads to the generation of reactive oxygen species (ROS), which trigger the death of the fungus responsible for the infection.

Published studies so far show lower cure rates of light-based therapies compared to conventional oral ones, so these treatments are still under development. Protocols (number of sessions, intervals between sessions, and adequate follow-up time) must be established, and the economic cost for the patient and the physician must be estimated as well. The therapeutic landscape is rapidly evolving with new light devices with novel mechanisms of action being investigated. Well-designed clinical trials are necessary to assess efficacy and establish the best treatment guidelines.

Finally, before administering a light-based treatment for onychomycosis, physicians should evaluate the effectiveness, side effects profile, and cost considerations of each option to ensure better patient compliance.

2. Carbon dioxide laser (CO₂ laser)

The carbon dioxide laser (CO₂ laser) was among the first gas laser systems to be developed. This system is the oldest of all laser therapies for onychomycosis. During the 1990s and the early 2000s, the CO₂ laser was the gold standard for skin resurfacing (skin vaporization to stimulate collagen production). This laser system produces a beam of infrared light at 10,600 nm that is selectively absorbed by water in skin cells. Initially, CO₂ lasers operated primarily in continuous-wave mode. With technological advances, the pulsed CO₂ laser was developed, introducing new possibilities in the therapeutic field. Pulsed ablative CO₂ lasers with shorter pulse durations than the thermal relaxation times provided greater precision in tissue vaporization, minimized thermal damage, and facilitated hemostasis [22]. Due to its ablative effects, this laser system was explored as a potential therapy for onychomycosis. CO₂ laser can increase localized temperature, gasify and decompose the infected nail, and have a sterilizing effect. However, the effectiveness of CO₂ devices was limited by their side effect profile. This laser system generates high temperatures and unpredictable thermal side effects, which can be difficult to control, particularly regarding the depth of laser penetration into the nail. This can lead to large wounds, the formation of a brown scab, and an increased risk of bleeding. It is counterproductive to excessively pursue curative outcomes when the treatment itself could cause significant clinical damage to the nail bed and to the plate [23]. Today, the availability of less invasive light treatment options has made the CO₂ laser a less preferred choice for treating onychomycosis.

3. Diode lasers and light-emitting diode (LED)

In addition to the diode laser, a light-emitting diode (LED) also generates light as a result of an electron–hole recombination. Both devices feature a PIN diode at their core, with an active zone, known as the Intrinsic (I) region, sandwiched between the Negative (N) and Positive (P) regions. Light is generated when electrons (negative charge) and electron holes (positive charge, due to the absence of electrons) recombine within the intrinsic region.

In an LED, the intrinsic region is larger than in a diode laser, which causes photon-producing recombinations to occur over a broader area. This promotes better heat dissipation and potentially enhances durability. In LEDs, any photons created escape immediately, emitting “normal” light (incoherent and multidirectional).

For laser light to be generated, population inversion is needed, which can only occur when the density in the upper state is sufficiently high. By making the edges of the intrinsic region smooth and mirror-like, photons are continuously reinjected into the active region. With population inversion, the intrinsic region becomes filled with excited atoms, allowing stimulated emission to occur, which effectively amplifies the reinjected photons. As these photons are repeatedly reinjected and reduplicated, they form a powerful laser beam. One side of the optical cavity (the output) is designed to be partially reflective, allowing the laser to escape. The light emitted here is coherent and unidirectional.

Bornstein et al. observed in an in vitro study that near-infrared diode laser reduces mitochondrial membrane potential and increases the production of ROS, which contributes to the photoinactivation of C. albicans and T. rubrum [24]. There are only a few clinical studies to treat onychomycosis using diode laser systems; however, all have shown positive outcomes. Combined long-pulsed 870/930 nm near-infrared diode laser treatment in patients with mild-to-severe onychomycosis achieved 65% clear nail growth [25]. Long-pulsed 980 near-infrared diode laser offers the advantage of contact-free homogeneous heating of the human nail while ensuring adequate temperature rises [26]. The suggested mechanism of action is similar to that of a long-pulsed Nd:YAG laser, where the fungi absorb light energy, leading to their heating and inactivation.

Recent studies show that the application of continuous-wave 405/635 nm dual-band diode laser in patients with mild-to-severe onychomycosis achieved 67% clear nail growth. This laser system acts through a non-thermal mechanism (blue light at 405 nm has antimicrobial effects, while red light at 635 nm promotes wound healing through a photobiomodulation process) [27].

In 1995, LEDs, originally developed for NASA’s plant growth experiments in space, were found to have the potential for delivering light deep into tissues of the body. These LEDs were significantly more powerful than the existing ones, with a stable output power, and, most importantly, a quasimonochromatic beam. This made them an excellent new source for phototherapy, offering biologically target-specific wavelengths. LED light sources have been built based on the same effective wavelengths used by diode lasers while benefiting from the inherent advantages of LEDs: they are highly efficient, versatile (able to be mounted in larger planar arrays to treat extensive body areas without hands-on involvement), and then offer a low-cost, less hazardous alternative to diode lasers.

Users of any LED system must select the correct wavelength for the intended target (such as fungal pigments, cytochrome C oxidase for photobiomodulation, or photosensitizers for photodynamic therapy) to ensure optimal absorption. This is crucial because, as the first law of photobiology states, without absorption, no reaction can occur. LED phototherapy at the proper wavelengths is safe, effective, easy to apply, free of pain and side effects, and well tolerated by patients of all ages. As indicated in Table 1, in the treatment of onychomycosis, LED lamps are now primarily used to induce the photoactivation of various photosensitizers in photodynamic therapy.

4. Nd:YAG laser

The Nd:YAG laser is a solid-state laser. It is made of a Y₃Al₅O₁₂ (yttrium aluminum garnet) crystal containing 0.1–1% of Nd³⁺ and emits light at a wavelength of 1.06 μm or sometimes at 1.32 μm, in the near-infrared region of the spectrum. This laser system can operate in short-pulse (Q-switched) or long-pulse mode as well as in continuous-wave mode. The Q-switched mode involves a variable attenuator, which stores the beam to maximize energy, delivering a pulse with peak power. This mode can be combined with potassium titanyl phosphate (KTP) crystal to double the laser’s frequency, generating laser light at 532 nm (visible green light).

The longer wavelength of the 1064-nm Nd:YAG laser is thought to penetrate tissue more deeply, effectively targeting fungal growth in the nail bed. The cell walls of Trichophyton species contain a considerable amount of melanin, which selectively absorbs this wavelength [28]. Furthermore, it is proposed that the 532-nm Nd:YAG laser is effective at targeting xanthomegnin (an endogenous fungal pigment), which has an absorption band ranging from 406 to 555 nm [28].

The Q-switched Nd:YAG laser generates high-energy peaks with numerous repetitions, resulting in minimal tissue warming and producing impact energy that mechanically and selectively damages only the fungi. The underlying mechanism, known as selective photothermolysis, depends on fungal chromophore, light characteristics, and pulse duration (which must be shorter than the “thermal relaxation time” of the target chromophore) [29]. Meanwhile, the absorption of light energy from the long-pulsed Nd:YAG laser by the fungus results in a general conversion of the energy into heat. Its microbiocidal effect has been associated with the resulting hyperthermia (as fungi are sensitive to heat above 55°C) and its ability to denature essential cellular proteins and structures [30].

The published results are controversial, with some studies showing positive outcomes, [31, 32] while others report no improvement [33, 34]. It remains uncertain whether the long-pulsed mode is more effective than the Q-switched mode, and no standardized laser protocol has been established yet. A common finding in all the published clinical studies is the high safety profile of this laser system, with no reports of severe or serious side effects. It has been observed, however, that higher energy density and a greater number of sessions tend to result in better clinical and mycological cure rates [35]. With regard to tolerability, patients usually experience mild burning or pain during irradiation sessions, but these sensations do not prevent them from continuing the treatment. Pain during irradiation is commonly reported and is therefore a key limiting factor when increasing laser power.

Valid conclusions have not been reached due to several factors, including the use of different laser protocols (different laser devices with different pulse durations, number of sessions, and intervals between the sessions), short follow-up periods, inadequate mycological diagnosis, recruitment of small and inhomogeneous study populations, and different types of onychomycosis and different causative fungal species. It should be noted that studies without significant results may discourage researchers from submitting their outcomes to prestigious journals. This is unfortunate, as negative results still offer valuable insights that could help redirect research focus toward more promising avenues.

5. Ablative fractional laser resurfacing (AFR)

Ablative fractional laser resurfacing (AFR) offers precise and deep tissue ablation with controlled depth of heating and vaporization. AFR was developed to maximize the safety of the ablative procedure while maintaining its effectiveness. Compared to traditional ablative resurfacing, AFR results in faster wound healing, fewer infections, and less post-operative downtime [36]. In AFR systems, the laser beam is divided into a pattern of microbeams, creating micro-holes due to the ablation and vaporization caused by the microbeams. The depth of the channels through the nail can be controlled by the applied wavelength, fluence, pulse duration, beam profile, and repetition rate.

The mechanism of action of AFR in onychomycosis is unknown. However, some studies suggest that the tissue ablation process induces a direct fungicidal effect. Fungi are highly sensitive to temperatures above 55°C; the photothermal effect of the fractional laser can increase the temperature of the target tissue, directly contributing to the destruction of the fungi in the affected nail. This effect might be further enhanced by alterations in the immune system or modifications in the local microenvironment caused by the micro-holes created through the vaporization of the tissue, ultimately leading to diffuse tissue remodeling and simultaneous destruction of the fungal growth environment [37].

Current AFR systems include erbium-doped yttrium aluminum garnet (Er:YAG) lasers (λ = 2,940 nm) and CO₂ lasers (λ = 10,600 nm). Both lasers operate in the mid-infrared range, where their wavelengths are absorbed by water (which represents 10–20% of the nail plate’s composition), ablating the nail in a fractionated pattern, creating microscopic vertical channels surrounded by a coagulation area [36]. CO₂ lasers penetrate deeper into the tissue due to their longer wavelength, enabling more heat deposition and a greater amount of tissue remodeling. In contrast, Er:YAG lasers emit at a wavelength closer to the water absorption peak (λ ~ 3,000 nm), offering a safe profile because most of the energy is absorbed by more superficial layers, resulting in better control over ablation depth and less thermal damage to underlying structures.

The creation of multiple micro-holes increases the contact area between the topical formulations (whose active ingredient can be an antifungal agent or a photosensitizer) and the nail surface, enhancing their diffusion through the nail plate to reach the nail matrix or bed [38]. Consequently, a reasonable number of studies support the benefits generated by AFR in the treatment of onychomycosis, used adjunctively with conventional topical antifungal therapy or photodynamic therapy [39, 40]. Figure 1 illustrates how an Er:YAG-based AFR system facilitates the diffusion of methylene blue through the nail, enhancing the effectiveness of photodynamic therapy. Additionally, applying a keratolytic agent like urea under occlusion before AFR irradiation increases the ablative and fungicidal effect. Urea, a hygroscopic agent, softens the nail plate and retains water (chromophore for AFR) at deeper levels, promoting ablation and remodeling of the nail or affected areas [41].

It has been demonstrated that combining platelet-rich plasma (PRP) with AFR systems is effective for skin rejuvenation and the treatment of atrophic acne scars. However, further research may be needed to explore its potential for treating onychomycosis. AFR systems enhance the penetration of topically applied PRP, exerting a synergistic effect that promotes faster healing and remodeling of damaged nails, as well as inhibiting microbial colonization.

6. Photodynamic therapy (PDT)

With the increasing development of resistance to antimicrobial agents, Photodynamic Therapy (PDT) has regained interest since the 1990s, as it represents a potential alternative for microbial eradication, although the emergence of resistance has not yet been described [42].

PDT is the most researched light-based treatment for onychomycosis, involving the use of a photosensitizing agent (photosensitizer, PS) followed by irradiation with light of a specific wavelength, enabling maximal absorption by the target and leading to the production of reactive oxygen intermediates. PDT relies on three basic elements: 1) the PS; 2) a light source: lamp, laser, or LED, with an appropriate wavelength and power suitable to activate the PS; 3) the presence of intracellular oxygen dissolved in the treated tissue. The success rate of PDT can be affected by the oxygen present in the tissue, the concentration of PS, the incubation time of PS, the time of application of light, and the number of treatment sessions [43].

PDT involves two distinct types of reactions. In the type I reaction, which involves redox (oxidation-reduction) reactions, the excited triplet state of PS interacts with the molecules of the diseased tissue, generating radicals that, in the presence of surrounding oxygen, give rise to ROS, mainly superoxide anion, hydrogen peroxide, and hydroxyl radical. These ROS can oxidize a wide variety of biomolecules. In the type II reaction, the excited triplet state of PS interacts with oxygen, resulting in the formation of singlet oxygen (oxygen in the excited singlet state), a highly reactive molecule that easily damages cells (Figure 2) [44]. The ratio of type I and type II processes is influenced by the PS and can happen either separately or together.

ROS produced during the photodynamic process can trigger fungal cell damage or death through three main mechanisms: cell membrane damage, inactivation of essential enzymes and proteins, and/or damage to DNA or RNA. PDT-induced photodamage can lead to significant changes in the morphology and function of microbial structures. Functional damage results from loss of enzymatic activities, protein oxidation, protein-protein cross-link formation, and inhibition of metabolic processes (e.g., DNA synthesis, glucose transport). Direct damage to the cell membrane causes the leakage of cellular contents and disrupts the membrane transport system (Figure 2) [45]. It is a selective action; the fungus absorbs the PS; then the damage is restricted to its structures without the surrounding healthy part of the nail being affected.

Several PS have been tested for this purpose: porfimer sodium, 5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), methylene blue (MB), flavin mononucleotide (FMN), rose bengal (RB), and curcumin (CU). The three most tested PSs to date for the treatment of onychomycosis are ALA, MAL, and MB. ALA and MAL are precursors of protoporphyrin IX, which is photoactivated by red light in the 630 to 700 nm range. Both of them, applied on the nail in occlusion for 2–5 hours and then exposed to a red light source at 630 nm with a fluence of 37 J/cm², have demonstrated effectiveness in the photodynamic treatment of onychomycosis [46]. MB is another increasingly popular PS. It absorbs light in the 550–700 nm region, with the maximum absorption at 664 nm. MB can induce the formation of type I radicals (ROS) and type II (singlet oxygen), which broadens its uses in PDT, and its widespread availability makes it a commonly used PS [47]. Research conducted with MB uses a concentration of 2% w/w, resulting in a blue discoloration of the nail that can persist for several months following treatment (see Figure 1).

For the photoexcitation of porfimer sodium, ALA, MAL, and MB, red light is used, as it is minimally absorbed by endogenous tissue chromophores like hemoglobin and has great penetration in most human tissues. In studies to treat onychomycosis via PDT, the fluence of the red light used typically ranges over the tens of J/cm², values that barely generate thermal effects and that are obtained using continuous low-power lasers, such as diode lasers (635 and 670 nm), and non-coherent light sources like LEDs. FMN and CU can be photoexcited with blue LEDs with a wavelength of around 450 nm [48, 49]. Blue light has less penetration than red light in biological tissue; therefore, for it to be effective, the exposure time is increased compared to the times used with red light. RB absorbs visible light between the wavelengths of 500 nm and 550 nm (encompassing the green light spectrum), so 532 nm solid-state pumped laser or green LED light at 532 ± 10 nm is typically used for RB photoexcitation [50].

For PDT, both coherent and incoherent light sources have been used. Non-laser light sources offer several advantages for topical PDT, including being cost-effective, operator-friendly, low maintenance, and capable of irradiating larger areas. Currently, there is no single light delivery system considered ideal for every indication for topical PDT, and each clinical situation should be assessed individually.

Published research on PDT for onychomycosis demonstrates its effectiveness in eradicating numerous fungal species, including its most common cause, T. rubrum. These studies highlight its safety in terms of the absence of systemic effects and only a low chance of local adverse effects reactions such as temporary pain, burning, and erythema [51].

Studies also suggest that for PDT to be more effective, pretreatment based on the application of 40% urea in occlusion 12 hours/day for 5–7 days before irradiation is advisable. This helps soften the nail and improves the diffusion of the PS, which can somewhat reduce the incubation time of the PS that requires it [52]. AFR with CO₂ and Er:YAG lasers can also be used for this purpose, facilitating the diffusion of PS through the created microchannels [40]. ALA and MAL require incubation times of 3 and 2 hours, respectively, while MB and FMN can be photoactivated immediately after application. For RB and CU, incubation times of 30 min and 1 hour, respectively, have been reported. When ALA, MAL, FMN, and CU are used, the treatment area can be examined with a Wood’s light after the designated incubation time to confirm the local accumulation of PS (Figure 3).

PDT cure rates for mild-moderate DLSO, affecting 20–50% of the entire nail, range from 40–70% [53]. These values are higher than those typically seen with standard topical antifungal agents, which have cure rates of 20–30% [54].

Although onychomycosis caused by non-dermatophyte fungi is not common in the Western world, the therapeutic management of these fungi is considerably more challenging than that of tinea unguium caused by dermatophytes. Some studies have demonstrated the efficacy of PDT in these cases [55].

To date, studies show that PDT is effective for treating mild–moderate DLSO, but they are still limited, making it difficult to draw definitive conclusions. A major disadvantage of treating onychomycosis with PDT is that it is still to be determined which PS is most effective depending on the infectious agent causing it, its optimal concentration, or the best delivery vehicle (liquid/semisolid) to achieve good penetration through the nail. This means that, to date, the only way to obtain good results and avoid recurrences is through the application of multiple PDT sessions, which may interfere with patient compliance.

Many studies using randomized clinical trials are needed to evaluate the efficacy of PDT treatments using a variety of PSs and to gradually delineate a standard protocol for the optimal PDT parameters. This includes determining the appropriate PS for the specific infectious agent (type, concentration, incubation time, administration method), as well as the ideal light source (wavelength, power, irradiance, pulse size, or irradiated area), the number of PDT sessions, and the interval between them, etc. The goal is to achieve the most effective therapeutic outcome based on the severity and type of onychomycosis. Ongoing investigations are focused on addressing these uncertainties.

7. Intense pulsed light (IPL)

This technology operates by emitting a high-intensity, pulsed, non-coherent, polychromatic light through a filter, which can be changed according to the desired target within the skin [56]. IPL devices use a xenon-flash lamp powered by capacitor banks controlled by microprocessors, allowing for adjustments to pulse duration. The wide spectrum of a flash lamp enables energy from multiple wavelengths (400–1200 nm) to be emitted, with pulse durations ranging from 2 to 200 ms. Filters and settings such as fluence, pulse duration, and pulse delay can be adjusted via software to treat different targets, making it a versatile tool [57]. Over the years, technical improvements have made this device safer and easier to use, broadening its clinical applications. Additionally, the large irradiated area per pulse allows for faster treatments. IPL is widely accepted for treating pigmented lesions, among other uses, and can be applied in the treatment of onychomycosis, as wavelengths between 500 and 600 nm can be absorbed by pigments like xanthomegnin found in fungi.

IPL has gained popularity as both a cosmetic and medical device for onychomycosis treatment. It is a safe and more affordable option compared to laser devices, both in terms of purchase price and maintenance. IPL and long-pulsed laser radiation have similar mechanisms for onychomycosis treatment, as both are absorbed by specific structures and chromophores, leading to their heating and destruction. While laser radiation is monochromatic and is only absorbed by a specific chromophore, IPL requires the practitioner to select the appropriate filter to ensure the emitted light is absorbed by the target chromophore.

A drawback in treating onychomycosis with IPL is that the procedure can be quite painful, though the discomfort is only felt during the irradiation. A water-based gel is recommended to reduce nail surface damage by decreasing the nail’s refraction index of light. This gel also provides a “heat-sink” effect and helps the handpiece glide more easily. The appearance of hematomas has also been reported [58]. Additionally, non-selective thermal damage is a risk, which can be increased when IPL is administered by untrained practitioners. An understanding of the mechanism and design of different IPL devices, along with knowledge of the appropriate parameters and indications, is key to ensuring safe and effective treatment.

There are very few studies on the use of IPL for onychomycosis. One small in vitro study using IPL at 420 nm on fungal biofilms developed on nail fragments showed promising results [59]. There is also a clinical study with 20 participants reporting an 80% complete cure rate 12 weeks after treatment, with the remaining 20% showing significant improvement, potentially treatable with adjunctive topical therapy [58]. Finally, IPL has also been used to photoactivate MB in PDT treatment using wavelengths between 560 nm and 700 nm [60].

8. Contraindications of light-based therapies

While light-based treatments are generally very safe, there are certain contraindications that must be taken into account: seizure disorders triggered by light, lupus erythematosus, light-sensitive disorder, gold therapy, peripheral neuropathy, and the use of medications that may induce photosensitivity.

9. Future directions

There is a clear need for additional research, particularly randomized controlled trials aimed at the eradication and cure of onychomycosis. Light-based therapies, which are noninvasive, are leading the way in addressing this need. Although these therapies are not FDA-approved for a cure, they are already being used in dermatology practices.

Although studies to date show acceptable cure rates only in mild-moderate cases, new devices must be continuously tested as they are introduced or developed for dermatological use, even if used in different contexts. In the field of PDT, new PSs and light sources need to be evaluated. It must be considered that elderly, diabetic, immunocompromised populations cannot tolerate the systemic side effects associated with oral antifungals (the most effective treatment to date). Therefore, light-based therapies should be considered a first-line treatment, not an alternative, for these groups to treat and prevent recurrences. Investing in these therapies will have a positive societal impact.

Acknowledgments

This work was supported by a grant from Fundación Eugenio Rodríguez Pascual (Madrid, Spain) and by the Spanish National Plan for Scientific and Technical Research and Innovation (PID 2023-149991NB-100). The authors also wish to acknowledge the support for open access by the CSIC Open Access Publication Support Initiative.

Conflict of interest

The authors declare no conflict of interest.