Clinical endpoints of needle-free jet injector treatment: An in depth understanding of immediate skin responses.

OBJECTIVES: Needle-free jet injectors have been used in dermatological practice for many years. However, predefined clinical endpoints that guide physicians to choose optimal device settings have not been clearly defined. Here, we evaluate immediate skin responses as clinical endpoints for needle-free jet injector treatments. METHODS: We injected methylene blue in ex vivo human skin using an electronically-controllable pneumatic injector (EPI; 3-6 bar, 50-130 µl; n = 63), and a spring-loaded jet injector (SLI) with fixed settings (100 µl; n = 9). We measured the immediate skin papule (3D-camera), residual surface fluid (pipette), dermal dye distribution by estimating depth and width, and subcutaneous dye deposition. RESULTS: EPI with 4 bar and 100 µl resulted in the largest skin papule of 48.7 mm3 (35.4-62.6 mm3 ) and widest dermal distribution of 8.0 mm (5.5-9.0 mm) compared to EPI with 6 bar and 100 µl (p < 0.001, p = 0.018, respectively). The skin papule volume showed a significant moderate to high positive correlation with the width and depth of dye distribution in the dermis (rs = 0.63, rs = 0.58, respectively; p < 0.001 for both correlations). SLI showed high variability for all outcome measures. Finally, a trend was observed that a small skin papule (≤7 mm) and little residual surface fluid (≤10% of injection volume) were warning signs for subcutaneous deposition. CONCLUSIONS: The immediate skin papule and residual surface fluid correspond with dermal drug deposition and are relevant clinical endpoints for needle-free jet injector treatments in dermatological practice.

Enhanced topical cutaneous delivery of indocyanine green after various pretreatment regimens: comparison of fractional CO2 laser, fractional Er:YAG laser, microneedling, and radiofrequency.

Different devices have been used to enhance topical drug delivery. Aim of this study was to compare the efficacy of different skin pretreatment regimens in topical drug delivery. In six ex vivo human abdominal skin samples, test regions were pretreated with fractional CO2 and Er:YAG laser (both 70 and 300 µm ablation depth, density of 5%), microneedling (500 µm needle length), fractional radiofrequency (ablation depth of ± 80-90 µm), and no pretreatment. The fluorescent agent indocyanine green (ICG) was applied. After 3 h, fluorescence intensity was measured at several depths using fluorescence photography. Significantly higher surface fluorescence intensities were found for pretreatment with fractional Er:YAG and CO2 laser and for microneedling vs. no pretreatment (p < 0.05), but not for radiofrequency vs. no pretreatment (p = 0.173). Fluorescence intensity was highest for the Er:YAG laser with 300 µm ablation depth (mean 38.89 arbitrary units; AU), followed by microneedling (33.02 AU) and CO2 laser with 300 µm ablation depth (26.25 AU). Pretreatment with both lasers with 300 µm ablation depth gave higher fluorescence intensity than with 70 µm ablation depth (Er:YAG laser, 21.65; CO2 laser, 18.50 AU). Mean fluorescence intensity for radiofrequency was 15.27 AU. Results were comparable at 200 and 400 µm depth in the skin. Pretreatment of the skin with fractional CO2 laser, fractional Er:YAG laser, and microneedling is effective for topical ICG delivery, while fractional radiofrequency is not. Deeper laser ablation results in improved ICG delivery. These findings may be relevant for the delivery of other drugs with comparable molecular properties.

Drug penetration enhancement techniques in ablative fractional laser assisted cutaneous delivery of indocyanine green.

BACKGROUND AND OBJECTIVES: Topical drug delivery can be increased by pretreatment of the skin with ablative fractional laser (AFXL). Several physical penetration enhancement techniques have been investigated to further improve AFXL-assisted drug delivery. This study investigated the influence of three of these techniques, namely massage, acoustic pressure wave treatment, and pressure vacuum alterations (PVP) on the distribution of the fluorescent drug indocyanine green (ICG) at different depths in the skin after topical application on AFXL pretreated skin. MATERIALS AND METHODS: In ex vivo human skin, test regions were pretreated with AFXL (10,600 nm, channel depth 300 µm, channel width 120 µm, density 15%). Subsequently, ICG was applied, followed by massage, acoustic pressure wave treatment or PVP. ICG fluorescence intensity (FI) was assessed after 1, 3, and 24 hours at several depths using fluorescence photography. RESULTS: FI was higher when using enhancement techniques compared to control (AFXL-only) up to 3 hours application time (P < 0.05). After 3 hours, mean surface FI was highest after acoustic pressure wave treatment (61.5 arbitrary units; AU), followed by massage (57.5AU) and PVP (46.9AU), respectively (for comparison: AFXL-only 31.6AU, no pretreatment 14.9AU). Comparable or higher FI was achieved already after 1 hour with enhancement techniques compared to 3-24 hours application time without. After 24 hours, no significant differences between enhancement techniques and AFXL-only were observed (P = 0.31). CONCLUSION: Penetration enhancement techniques, especially acoustic pressure wave treatment and massage, result in improved drug accumulation in AFXL-pretreated skin and reduce the application time needed. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Parameters in fractional laser assisted delivery of topical anesthetics: Role of laser type and laser settings.

BACKGROUND AND OBJECTIVES: Efficacy of topical anesthetics can be enhanced by pretreatment of the skin with ablative fractional lasers. However, little is known about the role of parameters such as laser modality and laser density settings in this technique. Aims of this study were to compare the efficacy of pretreatment with two different ablative fractional laser modalities, a CO2 laser and an Er:YAG laser, and to assess the role of laser density in ablative fractional laser assisted topical anesthesia. STUDY DESIGN/MATERIALS AND METHODS: In each of 15 healthy subjects, four 10 × 10 mm test regions on the back were randomized to pretreatment (70-75 µm ablation depth) with CO2 laser at 5% density, CO2 laser at 15% density, Er:YAG laser at 5% density or Er:YAG laser at 15% density. Articaine hydrochloride 40 mg/ml + epinephrine 10 µg/ml solution was applied under occlusion to all four test regions. After 15 minutes, a pass with the CO2 laser (1,500 µm ablation depth) was administered as pain stimulus to each test region. A reference pain stimulus was given on unanesthetized skin. The main outcome parameter, pain, was scored on a 0-10 visual analogue scale (VAS) after each pain stimulus. RESULTS: Median VAS scores were 1.50 [CO2 5%], 0.50 [CO2 15%], 1.50 [Er:YAG 5%], 0.43 [Er:YAG 15%], and 4.50 [unanesthetized reference]. VAS scores for all pretreated test regions were significantly lower compared to the untreated reference region (P < 0.01). We found no significant difference in VAS scores between the CO2 and the Er:YAG laser pretreated regions. However, VAS scores were significantly lower at 15% density compared to 5% density for both for the CO2 laser (P < 0.05) and the Er:YAG laser (P < 0.01). Pretreatment with the CO2 laser was considered slightly more painful than pretreatment with Er:YAG laser by the subjects. CONCLUSION: Fractional laser assisted topical anesthesia is effective even with very low energy settings and an occlusion time of only 15 minutes. Both the CO2 laser and the Er:YAG laser can be used to assist topical anesthesia although the CO2 laser pretreatment is experienced as more painful. In our study settings, using articaine/epinephrine solution and an occlusion time of 15 minutes, a density of 15% was more effective than 5%. Lasers Surg. Med. 50:813-818, 2018. © 2018 Wiley Periodicals, Inc.

Fractional CO2 laser assisted delivery of topical anesthetics: A randomized controlled pilot study.

BACKGROUND AND OBJECTIVES: Many dermatological procedures are performed under local anesthesia. Topical anesthesia requires prolonged occlusion and is often insufficient. Infiltration anesthesia is associated with discomfort. Pretreatment with an ablative fractional laser (AFXL) may enhance penetration of topical drugs, including lidocaine. Primary aim of this study was to assess whether AFXL pretreatment enhances the efficacy of two regularly used anesthetics: (i) articain hydrochloride 40 mg/ml + epinephrine 10 µg/ml solution (AHES); (ii) lidocaine 25 mg/g + prilocaine 25 mg/g cream (EMLA cream). Secondary aim was to assess which anesthetic is superior on AFXL pretreated skin. MATERIALS AND METHODS: In 10 healthy subjects, four 1 cm(2) test regions on the back were randomized to [A] AFXL pretreatment (fractional CO2 laser, 5% density, 2.5 mJ/microbeam) + topical application of AHES, [B] AFXL pretreatment + EMLA cream, [C] sham AFXL + AHES, and [D] sham AFXL + EMLA cream. After ten minutes, an AFXL pass (35 mJ/microbeam) was given as pain stimulus at each test region. Pain was scored on a 0-10 visual analogue scale (VAS) after each stimulus. RESULTS: AFXL pretreatment was not considered painful. Median VAS scores for the pain stimulus were [A] 2.35, [B] 3.15, [C] 4.55, and [D] 4.35. VAS scores were significantly lower for region [A] (AFXL + AHES) versus region [B] (AFXL + EMLA; P < 0.01) and versus region [C] (sham AFXL + AHES; P < 0.01). VAS scores were not significantly different for region [B] (AFXL + EMLA) versus region [D] (sham AFXL + EMLA, P = 0.15). CONCLUSION: AFXL pretreatment at very low settings gives significant pain reduction already within ten minutes when AHES is used as topical anesthetic. AHES is clearly superior to EMLA cream on AFXL pretreated skin. Possibly, a liquid solution penetrates more easily into the AFXL channels than a cream. Further research should determine the clinical efficacy of laser assisted topical anesthesia and the exact role of the type of anesthetic, its vehicle and the laser settings.

Spatiotemporal closure of fractional laser-ablated channels imaged by optical coherence tomography and reflectance confocal microscopy.

BACKGROUND AND OBJECTIVE: Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) offer high-resolution optical imaging of the skin, which may provide benefit in the context of laser-assisted drug delivery. We aimed to characterize postoperative healing of ablative fractional laser (AFXL)-induced channels and dynamics in their spatiotemporal closure using in vivo OCT and RCM techniques. STUDY DESIGN/MATERIALS AND METHODS: The inner forearm of healthy subjects (n = 6) was exposed to 10,600 nm fractional CO2 laser using 5 and 25% densities, 120 µm beam diameter, 5, 15, and 25 mJ/microbeam. Treatment sites were scanned with OCT to evaluate closure of AFXL-channels and RCM to evaluate subsequent re-epithelialization. RESULTS: OCT and RCM identified laser channels in epidermis and upper dermis as black, ablated tissue defects surrounded by characteristic hyper-and hyporeflective zones. OCT imaged individual laser channels of the entire laser grid, and RCM imaged epidermal cellular and structural changes around a single laser channel to the depth of the dermoepidermal junction (DEJ) and upper papillary dermis. OCT images visualized a heterogeneous material in the lower part of open laser channels, indicating tissue fluid. By OCT the median percentage of open channels was evaluated at several time points within the first 24 hours and laser channels were found to gradually close, depending on the used energy level. Thus, at 5 mJ/microbeam, 87% (range 73-100%) of channels were open one hour after laser exposure, which declined to 27% (range 20-100%) and 20% (range 7-93%) at 12 and 24 hours after laser exposure, respectively. At 25 mJ/microbeam, 100% (range 100-100%) of channels were open 1 hour after laser exposure while 53% (range 33-100%) and 40% (range 0-100%) remained open at 12 and 24 hours after exposure. Median depth and width of open channels decreased over time depending of applied energy. RCM verified initial re-epithelialization from day 2 for all energy levels used. Morphology of ablation defects by OCT and RCM corresponded to histological assessments. CONCLUSIONS: OCT and RCM enabled imaging of AFXL-channels and their spatiotemporal closure. Laser channels remained open up to 24 hours post laser, which may be important for the time perspective to deliver topical substances through AFXL channels.

Generalized eczematous reaction after fractional carbon dioxide laser therapy for tattoo allergy.

Allergic tattoo reactions form a therapeutically difficult entity. Treatment with conventional quality-switched lasers does not completely remove the allergenic particles and may lead to generalized hypersensitivity reactions. Recently, ablative fractional laser therapy was introduced as a treatment for allergic tattoo removal. We present two cases of allergic reactions to red tattoo ink treated with 10,600-nm fractional CO2 laser. At the end of treatment, almost complete removal of red ink accompanied by a significant reduction of symptoms was observed in the first patient, whereas the second patient developed an acute generalized eczematous reaction after five treatments. These findings confirm that ablative fractional laser therapy is capable of significant removal of tattoo ink in an allergic tattoo reaction. However, it implies a risk of generalized hypersensitivity reactions. To our knowledge, this is the first case of a generalized hypersensitivity reaction following treatment of tattoo allergy with the fractional CO2 laser.

Fractionated carbon dioxide laser therapy as treatment of mild rhinophyma: report of three cases.

Rhinophyma is a bothersome condition of the nose that is regarded as a manifestation of rosacea (subtype 3). Whereas the efficacy of medical treatments, including antibiotics and retinoids, is often dissatisfying, conventional invasive procedures are limited by their unfavorable side effect profile. We present three patients who were treated by a minimally invasive approach using fractionated carbon dioxide (CO2) laser therapy, showing variable response. We observed that fractionated CO2 laser therapy may improve patient-reported outcome in some patients with mild rhinophyma and is associated with a relatively favorable side effect profile compared with conventional surgical techniques.

Transcutaneous laser treatment of leg veins.

Leg telangiectasias and reticular veins are a common complaint affecting more than 80% of the population to some extent. To date, the gold standard remains sclerotherapy for most patients. However, there may be some specific situations, where sclerotherapy is contraindicated such as needle phobia, allergy to certain sclerosing agents, and the presence of vessels smaller than the diameter of a 30-gauge needle (including telangiectatic matting). In these cases, transcutaneous laser therapy is a valuable alternative. Currently, different laser modalities have been proposed for the management of leg veins. The aim of this article is to present an overview of the basic principles of transcutaneous laser therapy of leg veins and to review the existing literature on this subject, including the most recent developments. The 532-nm potassium titanyl phosphate (KTP) laser, the 585-600-nm pulsed dye laser, the 755-nm alexandrite laser, various 800-983-nm diode lasers, and the 1,064-nm neodymium yttrium-aluminum-garnet (Nd:YAG) laser and various intense pulsed light sources have been investigated for this indication. The KTP and pulsed dye laser are an effective treatment option for small vessels (<1 mm). The side effect profile is usually favorable to that of longer wavelength modalities. For larger veins, the use of a longer wavelength is required. According to the scarce evidence available, the Nd:YAG laser produces better clinical results than the alexandrite and diode laser. Penetration depth is high, whereas absorption by melanin is low, making the Nd:YAG laser suitable for the treatment of larger and deeply located veins and for the treatment of patients with dark skin types. Clinical outcome of Nd:YAG laser therapy approximates that of sclerotherapy, although the latter is associated with less pain. New developments include (1) the use of a nonuniform pulse sequence or a dual-wavelength modality, inducing methemoglobin formation and enhancing the optical absorption properties of the target structure, (2) pulse stacking and multiple pass laser treatment, (3) combination of laser therapy with sclerotherapy or radiofrequency, and (4) indocyanin green enhanced laser therapy. Future studies will have to confirm the role of these developments in the treatment of leg veins. The literature still lacks double-blind controlled clinical trials comparing the different laser modalities with each other and with sclerotherapy. Such trials should be the focus of future research.

Formation of fibrosis after nonablative and ablative fractional laser therapy.

BACKGROUND: Fractional laser therapy (FLT) has become a widely accepted modality for skin rejuvenation and has also been used in various other skin diseases. OBJECTIVE: To observe long-term histologic effects of nonablative and ablative FLT in the treatment of pigment disorders. METHODS: A randomized controlled observer-blinded study was performed in 18 patients with pigment disorders. Two similar test regions were randomized to receive FLT with intermittent topical bleaching or topical bleaching alone. Patients with ashy dermatosis (AD) and postinflammatory hyperpigmentation (PIH) were treated using nonablative 1,550-nm FLT (15 mJ/microbeam, 14-20% coverage), whereas patients with Becker's nevus (BN) were treated with ablative 10,600-nm FLT (10 mJ/microbeam, 35-45% coverage) for three to five sessions. Biopsies were obtained 3 months after the last treatment. RESULTS: At follow-up, dermal fibrosis was observed in four of eight patients treated using ablative FLT and no patients treated using nonablative FLT (p < .05). CONCLUSIONS: Assuming that the dermal response is comparable in AD, PIH, and BN, at the given settings, ablative FLT may induce fibrosis, whereas treatment with nonablative FLT does not. Whether formation of fibrosis has to be regarded as dermal remodeling or a subtle subclinical form of scarring should be investigated in future research.

[Maternal lupus diagnosed through skin lesions of a newborn]. / Een pasgeborene met huidafwijkingen.

Directly after birth a newborn was found to have distinctive skin lesions on her face. The lesions were suspicious for neonatal lupus. Her asymptomatic mother tested positive for anti-SSA/Ro and anti-SSB/La antibodies. The newborn had no complications of neonatal lupus (e.g. atrioventricular block, anemia, neutropenia, or liver enzyme elevation) and the lesions faded within two weeks.

Ablative fractional laser therapy as treatment for Becker nevus: a randomized controlled pilot study.

BACKGROUND: Becker nevus (BN) is an uncommon pigment disorder characterized by hyperpigmentation and sometimes hypertrichosis. To date, no effective treatment has been available. OBJECTIVES: We sought to assess efficacy and safety of ablative 10,600-nm fractional laser therapy (FLT) in the treatment of BN. METHODS: Eleven patients with BN, older than 18 years, were included in a prospective randomized controlled, observer-blinded split-lesion trial. In each patient two similar square test regions were randomized to either ablative FLT at 10 mJ/microbeam, coverage 35% to 45%, and topical bleaching (to prevent laser-induced postinflammatory hyperpigmentation), or topical bleaching alone (to allow comparison of the regions). At 3- and 6-month follow-up, clearance of hyperpigmentation was assessed by physician global assessment, reflectance spectroscopy, melanin index, patient global assessment, patient satisfaction, and histology. RESULTS: At 6-month follow-up, physician global assessment improved in the FLT region (P < .05). Reflectance spectroscopy, melanin index, number of melanocytes, and amount of dermal melanin did not significantly differ between the regions. Patient global assessment and patient satisfaction were 5.0 and 5.9 (visual analog scale score, 0-10), respectively. Side effects were postinflammatory hyperpigmentation (n = 3), erythema (n = 3), burning sensation (n = 3), crusting (n = 3), edema (n = 2), and blistering (n = 2). LIMITATIONS: Limitations include the small number of patients, treatment in spring, possibly suboptimal laser settings, and the combined usage of FLT and a bleaching agent. CONCLUSION: Ablative FLT was moderately effective in some patients with BN. However, postinflammatory hyperpigmentation and relatively negative patient-reported outcomes still preclude ablative FLT from being a standard therapy. Larger studies with different laser settings will be required to optimize this treatment modality.

Non-ablative 1,550 nm fractional laser therapy versus triple topical therapy for the treatment of melasma: a randomized controlled split-face study.

BACKGROUND: Melasma is a uichronic, often relapsing skin disorder, with poor long-term results from all current therapies. OBJECTIVE: To assess efficacy and safety of non-ablative 1,550 nm fractional laser therapy (FLT) as compared to the gold standard, triple topical therapy (TTT). STUDY DESIGN: Twenty-nine patients with melasma were included in a randomized controlled observer-blinded study with split-face design. Each side of the face was randomly allocated to either 4-5 non-ablative FLT sessions (15 mJ/microbeam, 14-20% coverage) or TTT (hydroquinone 5%, tretinoin 0.05%, triamcinolone acetonide 0.1% cream). TTT was applied once daily for 15 weeks until the last FLT session. After this last treatment, patients were asked to apply TTT twice weekly on both sides of the face during follow-up. Improvement of melasma was assessed by patient's global assessment (PGA), patient's satisfaction, physician's global assessment (PhGA), melanin index, and lightness (L-value) at 3 weeks, and at 3 and 6 months after the last treatment. RESULTS: Mean PGA and satisfaction were significantly lower at the FLT side (P<0.001). PhGA, melanin index, and L-value showed a significant worsening of hyperpigmentation at the FLT side. At the TTT side, no significant change was observed. At 6 months follow-up, most patients preferred TTT. Side effects of FLT were erythema, burning sensation, edema, and pain. Nine patients (31%) developed PIH after two or more laser sessions. Side effects of TTT were erythema, burning sensation, and scaling. CONCLUSIONS: Given the high rate of postinflammatory hyperpigmentation, non-ablative 1,550 nm fractional laser at 15 mJ/microbeam is not recommendable in the treatment of melasma. TTT remains the gold standard treatment.

Long-term remission of folliculitis decalvans after treatment with the long-pulsed Nd:YAG laser.

Folliculitis decalvans (FD) is a rare inflammatory scalp disorder presenting with tufted folliculitis, follicular papules and pustules, progressing to cicatricial alopecia. Current treatments mainly consist of antibiotic and immunomodulatory therapies and are often disappointing. FD has previously shown to respond to treatment with neodymium:yttrium aluminium garnet (Nd:YAG) laser in one case. We present a case of recalcitrant FD, successfully treated with a long-pulsed Nd:YAG laser.

Non-ablative 1550 nm fractional laser therapy not effective for erythema dyschromicum perstans and postinflammatory hyperpigmentation: a pilot study.

BACKGROUND: Erythema dyschromicum perstans and postinflammatory hyperpigmentation (PIH) are characterized by papillary dermal pigmentation or pigment incontinence. To date, no standard treatment is available. Fractional laser therapy (FLT) was recently reported to improve different pigment disorders. OBJECTIVES: To assess the efficacy and safety of non-ablative FLT in the treatment of erythema dyschromicum perstans and PIH. METHODS: Eight patients with erythema dyschromicum perstans and six patients with PIH were included. In each patient, two similar test regions were randomized to receive either five fractional laser treatments in combination with intermittent daily topical bleaching or the same intermittent regimen of topical bleaching alone. Three months after the last treatment, improvement of hyperpigmentation was assessed by melanin index, reflectance spectroscopy, physician's assessment, patient's assessment and patient's satisfaction. In addition, a biopsy of both laser treated and control site was evaluated by an independent blinded pathologist. RESULTS: No clinical improvement of hyperpigmentation was observed. Reflectance spectroscopy, melanin index, number of melanocytes and amount of dermal melanin did not significantly differ. Patients considered FLT unsatisfactory. Moreover, three patients developed laser-induced PIH. CONCLUSIONS: With these specific laser settings, non-ablative FLT was not effective for the treatment of erythema dyschromicum perstans and PIH.