Wound healing after therapy of oral potentially malignant disorders with a 445-nm semiconductor laser: a randomized clinical trial

Oral potentially malignant disorders (OPMDs) are the most clinically relevant precursor lesions of the oral squamous cell carcinoma (OSCC). OSCC is one of the 15 most common cancers worldwide [1]. Two-thirds of all patients are men with a mean age at first diagnosis of 62 years, while women are diagnosed with a mean age of 66 years [2]. Women show an overall 5-year survival rate of 61% compared to 48% in men. The reason for that is mainly the higher rate of alcohol and tobacco consumption in men and the diagnosis at an earlier tumor stage in women. So one of three tumors is diagnosed at T1 stage in women but only one of four in men [2‐5]. Despite aggressive multimodal therapy options, the 5-year survival rate has improved only insignificantly over the past four decades. The prognosis of oral cancer is mainly determined by the stage of the tumor and the nodal status at the time of diagnosis. If oral squamous cell carcinoma is diagnosed and treated at an early stage, the disease-free survival rate is significantly more favorable compared to the late diagnosis. The therapy-associated functional limitations are also significantly lower, and the post-therapeutic quality of life is better [5].

The diagnosis and therapy of clinically relevant precursor lesions of the oral squamous cell carcinoma is one of the main parts of prevention of this malignant disease. Targeted therapy is one of the main challenges concerning an oncologically safe tissue removal without overwhelming functional and aesthetic impairment. Compared to the more invasive and bloody cold blade removal with scalpel, the 445-nm semiconductor laser could be a new functional less traumatic tool in the therapy of OPMDs.

Laser devices of a respective wavelength are able to cut or ablate tissue with synchronous hemostasis. Many interaction effects with the tissue have been described such as thermal, photochemical, or ablative effects [6].

Surgical devices with CO2 and Nd:YAG (neodymium-doped yttrium aluminum garnet) lasers have already been described for soft tissue dental surgery procedures [7]. Short-wave lasers have been described in several medical fields with the argon lasers in dermatology or ophthalmology where the use was limited by the high effort in inducing and controlling a surgical usable laser beam [8, 9]. With the evolving progress in optoelectronics, semiconductor lasers offer an increasing number of applications in research, industry, and medicine due to their compact structure, high optoelectronic efficiency, and reliability.

For oral applications recently, a 445-nm semiconductor laser device was introduced [10, 11]. One of the main benefits of the 445-nm blue laser compared to the standard red laser systems is its shorter wavelength, and the higher absorption in the target tissue leads to less deep penetration and less backscatter [10].

The reduced energy absorption in surrounding tissues from scattering may lead to less thermal side effects and promote better wound healing. Thus, the 445-nm laser technology should provide an auspicious instrument for a variety of applications such as surgical incision and ablative tissue surgery. Blue laser may offer a bloodless and clean cutting option with only few side effects in adjacent tissues basing on its special absorption properties [12].

However, there is no study that analyzed the effects of ablative tissue surgery in a randomized controlled trial. Furthermore, there is no extensive information about blue light laser cutting properties so far. Therefore, the aim of the present study was to establish and evaluate the short-term effects of laser coagulation of OPMDs with a novel 445-nm semiconductor laser, examining the assumption of a blue light laser being more effective and comfortable than conventional cold steel excision without increasing side effects.

Forty patients were randomized for one of the two groups. None of them presented adverse effects to the procedures or the laser application protocol. Table 1 shows the demographic characteristics of the patients. There were no significant differences in clinical parameters between the two groups at baseline. Figures 1 and 2 show representative photo documentation at the points in time examined in both groups.

Cold blade excision is the gold standard in the therapy of oral potentially malignant disorders but may lead to postoperative patient discomfort or functional impairing. Scar tissue formation after resection of the lesions may require surgical reconstruction. Conventional laser systems as CO2 lasers are technically sophisticated, are expensive, and are not feasible in many outpatient settings. Thus, an interesting alternative would be to minimize the negative impact of the cold blade excision without losing the positive therapeutic benefits. The aim of this study was the first evaluation of a recently established compact 445-nm semiconductor laser in this specific indication considering wound healing and patient discomfort in comparison to the standard cold blade excision.

The present study showed that wound healing after laser ablation with the 445-nm laser is favorable compared to the standard therapy. Remaining wound area after laser therapy shows a predictable continuous decrease over time with significantly smaller remaining wound areas in the laser group. No relevant wound area was measured after 4 weeks in the laser group. Tissue colorimetry showed comparable wound healing after laser and excision therapy without significant differences. This implicates a comparable predictability with a little shorter wound healing course in the laser group. There is a lot of literature supporting a wound healing propagation by laser light. Laser light of different wavelengths was shown to support wound healing in different intraoral an extraoral settings. Parker et al. describe in a recent systematic review on different short- and long-wave laser wavelengths for intraoral indications, positive effects of laser light on wound healing compared to scalpel treatment in 46%, and no difference in 46% of the included studies [15]. However, none of the included studies evaluated wound healing after the use of short-wave lasers (< 650 nm) comparing to a non-laser comparison group at a clinical level. Gobbo et al. describe excellent wound healing after excision of benign oral lesions with blue diode laser in comparison to infrared diode laser or quantic molecular resonance scalpel [16]. Dias et al. describe a positive effect of laser light on oral wound healing of free gingival and connective tissue grafts using a 660-nm diode laser [13]. Dawood et al. show a positive effect of short- and middle-wave laser light in a mouse model [17]. Fahimipour et al. also show a positive effect of laser light on oral wound healing in a mouse model [18]. Serrage et al. discuss different mechanisms of photobiomodulation by blue laser light promoting wound healing [19]. The modulation of the production of reactive oxygen species (ROS) is probably a central point. This is influenced by various signaling pathways of inflammation and regeneration, which include interleukin 6 (IL-6), transforming growth factor beta (TGF-β), and fibroblast growth factor 2 (FGF-2). Noda et al. showed the induction of osteocalcin gene in dental extraction sockets in rats leading to a significantly higher number of dividing cells in the early phase of wound healing and subsequently a higher bone density and bone volume after final wound healing using a 910-nm diode laser [20]. A widely known and published effect contributing to intraoral wound healing may the antibacterial effect of short-wave laser light [21, 22]. Lipovsky et al. show an antibacterial effect of short-wave laser light in terms of promoting and accelerating wound healing [23]. Further scientific studies are required to investigate other possible wavelength-specific effects.

After 1 week, the postoperative pain perception in the laser group was significantly lower than in the comparison group. Even if this can only be an indication in the context of an unblinded study and without recording the actual use of analgetics in the outpatient setting and its influence on the assessment of the pain intensity, this implies a possible analgesic effect of the laser treatment compared to the classical surgical approach. The scientific data on this is promising. Lopez-Jornet et al. were able to show reduced pain perception after treatment of oral leukoplakia using a CO2 laser in comparison to classic excision using a scalpel in a randomized controlled study [24]. Rocca et al. describe a positive effect of short-wave laser therapy on pain relief in oral aphthae treatment [25]. Likewise, Suter et al. describe a pain-relieving effect of laser therapy in oral aphthae [26]. Such effects could not only be described in the field of intraoral soft tissue surgery. In the field of endodontics too, there is a scientific consensus on the reduction of post-endodontic complaints through laser-assisted root canal decontamination [27‐29]. In the field of wisdom tooth surgery, there are indications of possible postoperative pain reduction through laser-assisted osteotomy and through postoperative low-level laser therapy [30, 31]. In addition, low-level laser therapy appears to have an overall positive effect on postoperative pain perception. Thus, D'Avila et al., for example, even demonstrate a positive effect of this treatment after bimaxillary osteotomy [32]. In addition, there are numbers of studies from all parts of the medical spectrum that show a positive effect of laser radiation, for example, on neuropathic pain in the context of diabetic foot syndrome [33, 34]. Cronshaw et al. discussed a photobiomodulation effect involving transmembrane uncoupling proteins promoting cellular heat stress response as a key factor in laser associated analgesia [35]. With regard to other physiological signal cascades involved, animal experiments have shown a possible influence on the endogenous opioid system and an associated reduced perception of pain after laser treatment [36, 37]. To date, however, there is no scientific consensus on the specific influence of different wavelengths, in particular on the short-wave lasers investigated here, although a possible wavelength-specific effect seems likely [38]. Further investigations, in particular double-blind randomized controlled clinical trials, are necessary.

Various wavelengths and protocols for the use of diodes, gas, and solid-state lasers have been published, but there is no uniform consensus regarding the optimal procedure, wavelength, and the time course of the energy deposition [39]. The current, widely recognized therapy standard in laser therapy for potentially malignant lesions of the oral mucosa is the use of CO2 lasers. With their laser wavelength of around 10,000 nm, these lasers are mainly absorbed in water, so that the tissue interaction is mainly vaporizing-thermal. Today, lasers that work in this way usually require an optical power of around 1–3 W. By using a short-wave diode laser around 450 nm in the blue visible spectrum whose absorption maxima are in the range of hemoglobin and melanin, this required optical output power can be reduced with the same cutting performance as systems operating with longer wavelengths [10, 40]. This may allow slimmer designs of the overall systems and of the intraoral applicators improving the handling and the clinical efficiency of the application in particular when treating awake patients who can only be positioned freely to a limited extent. The low laser wavelength with its absorption maximum in the area of hemoglobin and melanin can penetrate deeper into the tissue compared to the CO2 laser mainly absorbed by water [41]. It remains unclear if this can reduce the overall tissue load, particularly that of the surrounding tissue. Deeper penetration may lead to a potential therapeutic effect on deep-seated cells which could be desirable in the context of addressing possibly recurrent benign lesions of the oral mucosa and should be checked in further studies.

The duration of the intervention differed only slightly in both patient groups with only a minor, non-significant tendency to prolong the operating time through the use of laser coagulation. The laser coagulation of potentially malignant lesions of the oral mucosa using a 445-nm semiconductor laser, like the laser-based excision methods already described extensively in the literature, represents a time- and resource-efficient therapy method that can be easily integrated into the clinical process with little additional effort [42‐44].

Laser coagulation of OPMDs with the investigated 445-nm semiconductor laser is a safe, gentle, and predictable surgical procedure. The method should be further investigated with regard to the identification of further possible indications.