To the best of our knowledge, this work is the first to compare LLLT efficacy and safety to FCO2 and to combined both modalities in stria alba. The results of the present study show that LLLT is comparably effective to FCO2 in the management of stria alba in phototypes III-IV with an added benefit of lack of discomfort and downtime that are usually reported with FCO2 therapy. However, LLLT requires more frequent sessions, at least biweekly, for a minimum of 8 and a maximum of 12 sessions. The combination of both modalities, against our expectations, offers the least efficacy, but it also decreases the downtime of FCO2 laser (namely: erythema, edema, pigmentation, itching or peeling), although the difference does not achieve statistical significance.

The efficacy of LLLT, FCO2 and their superiority over combined both modalities was evidenced by the median patient GAI at three months after treatment (40%, 70% and 30% respectively), the median physician GAI (45%, 61.25% and 45% respectively) and the patient satisfaction score (50%, 77.5% and 40% respectively). Similarly, the intention-to-treat analysis for treatment success showed statistically comparable results between both LLLT and FCO2 groups, with again, better numerical values in the FCO2 group and the least numerical values in the combined group: marked to near-total improvement was reported by 30%, 80% and 10% of patients respectively and was documented by physicians in 20%, 70% and 20% of patients respectively, and highly satisfied patients were 50%, 80% and 20% of the patients respectively.

Two Brazilian comparative studies assessed the efficacy and safety of LLLT in the treatment of striae alba and reported significant improvement of the striae at one month after therapy in response to 660 nm [9], and less response to 830 nm in comparison to 660 nm [10], with no side effects reported [9, 10]. Both studies used Laserpulse (Ibramed®, Amparo, Brazil) adjusted at 30mW power, 4 J/cm2 energy density for 12 sessions over 4 weeks and used photographs with digital planimetry for quantification of surface area of stria. In fact, in vitro studies showed that, although both wavelengths are involved in wound healing, fibroblasts, the primary cell for collagen synthesis, respond better to 633 nm light, while the 833 nm light stimulates better the other cells of wound healing process (mast cells, neutrophils, and macrophages) [11]. This might explain why the LLLT arm using 808 nm diode in our study showed modest efficacy, and better results were demonstrated in the Brazilian studies by using the 660 nm LLLT in comparison to 830 nm [9, 10]. The beneficial effect of LLLT on wound healing was demonstrated by several in vitro and in vivo studies where positive actions were shown in tissue perfusion and stimulation to neovascularization, fibroblastic proliferation and keratinocytes, increased synthesis and deposition of collagen and hydroxyproline, decrease of inflammatory mediators such as IL-1β, IL-10, TNF-α and NF-κB, decreased stress oxidation and acceleration of tissue healing [10]. Both studies praised the convenience of LLLT as a safe and painless tool, as we could also demonstrate in our study.

The efficacy of the LLLT drastically depends on the use of the correct parameters. The Hormesis phenomenon states that too low or too high doses may result in insignificant effect or even inhibitory action. Therefore, adjusting the dose of LLLT application needs special attention [12]. Nevertheless, the dosing of LLLT for different indications is till now a matter of uncertainty [13].

Unlike LLLT, there are numerous reports about FCO2 in the treatment of stria alba; showing evidence for its efficacy clinically and histologically [13,14,15,16,17,18,19,20,21,22]. H&E and Masson-trichrome staining of biopsies showed greater average epidermal and dermal thickness after treatment of striae by FCO2 laser [14]. The number of sessions in these studies ranged from 4 to 5, the parameters used varied according to the device and patients’ skin phototype. The number of cases showing ≥ 50% improvement after 4 to 5 sessions varied between 20 and 47% [17,18,19,20,21,22,23].

A retrospective case series in Iran [22] studied the effect of four sessions of FCO2 (microxel MX700, Korea) in 24 female patients with skin type II-IV with the following parameters according to the skin type; frequency: 1000 Hz, duration: 130–200 s and energy: 40–60 J/cm2. Photos were obtained one month after the last treatment, and the authors reported 16.7% minimal improvement (in contrast to 20% in the fractional group in our study), 54.2% moderate improvement (in contrast to 10% in our study), 29.2% marked improvement (in contrast to 40% in our study), and no patients showed near total improvement (in contrast to 30% in our study), all based on physician’s global assessment of improvement.

Taking into consideration that the results of two sessions of FCO2 laser of the present study are comparable to those achieved by four sessions on similar skin phototype [22], with even higher percent of near-total improvement in the present study, the authors are confident that the dose regimen applied in the present study is a successful one to be recommended: combining a long pulse duration (800-1000us) with a moderate spacing (1 mm interdot) aimed at proper heating of the dermis for stimulation of neocollagenesis, while preserving the inter-dot tissue to allow for faster regeneration.

As regards the safety outcomes, the patients in the LLLT group experienced higher tolerability, as none of the patients suffered from side effects after the sessions, while the side effects after the FCO2 sessions included pain, during and after the procedure, edema, erythema, itching and peeling for variable durations each. This might explain the lack of dropouts in the LLLT group compared to the other 2 groups. Post-inflammatory hyperpigmentation that persisted after the first session of FCO2 group was reported by one patient from the combined group.

We hypothesized that the anti-inflammatory and analgesic effect of LLLT would palliate the side effects of FCO2 laser. Indeed, patients in the combined group showed a modestly shorter duration of the FCO2 reported side effects, in comparison to FCO2 alone group, although not reaching statistical significance. A cumulative anti-inflammatory effect along sessions was not observed in the combined group, as evidenced by the relative similarity of the duration of side effects between the first and second sessions of FCO2. This suggests that starting the LLLT earlier before the FCO2 laser session, instead of immediately after, would have probably not added more benefit. However, we suggest that the anti-inflammatory effect of LLLT was responsible for the dampened efficacy of FCO2 laser in the combined arm, where the least efficacy was recorded. The mechanism of action of FCO2 laser in management of stria alba is based on the formation of micro-thermal zones of injury leading to an inflammatory response, inducing the expression of heat shock protein 70 and type 1 procollagen by dermal dendritic cells along with enhancement of the antioxidant enzymes which induces the production of new collagen [16, 23].

Interestingly, 4 patients who underwent the LLLT reported at the EOS an unwanted pregnancy event, with two patients reporting previous history of infertility. This raises the question whether LLLT applied on the abdomen causes ovarian stimulation, and if confirmed such response might be of use in infertility issues but it suggests that unwanted pregnancy might be a warning to include in patients consent before receiving LLLT, particularly if performed over the abdomen and pelvis. It is known that LLLT may be contraindicated in cancer patients due to its hypothesized effect to stimulate the growth of cancer cells in cell cultures [24], but it is still unclear if there is a universal stimulatory growth effect on the whole body that contributed to the pregnancy of the four participants. This issue deserves further investigation.

This study is limited by its small number of participants, the lack of tissue samples to provide histopathological evidence of response, and, as data is sparse about the best parameters for LLLT in skin applications, the parameters used in this study were based on the investigator’s personal experience.

In conclusion, this randomized controlled trial shows that LLLT using Diode 808 nm is effective and safe in management of stria alba, comparable to FCO2 laser, in skin type III-IV. The lack of discomfort and downtime in the LLLT group reflected on patient’s satisfaction positively in disproportion to its modest efficacy. However, this is counterbalanced by the obligation to submit to frequent weekly visits for 8 to 12 sessions. The combination of both modalities, against our expectations, offers the least efficacy, but palliates the side effects induced by the FCO2, by shortening their duration. The systemic biostimulatory effect of the sessions can also be an advantage in favor of LLLT, as well as the anti-inflammatory and analgesic effect of LLLT that can be used as an adjuvant to other therapeutic modalities in cosmetology, provided that this modality does not depend on the wound response. Further studies are needed to define the adequate dosing regimens of LLLT in dermatological applications.