Novel 40 µm spot size 3050/3200 nm DFG laser versus CO2 laser for laser-assisted drug delivery.

BACKGROUND AND OBJECTIVES: The use of ablative fractional lasers to enhance the delivery of topical drugs through the skin is known as laser-assisted drug delivery. Here, we compare a novel 3050/3200 nm difference frequency generation (DFG) fiber laser (spot size: 40 µm) to a commercially used CO2 laser (spot size: 120 µm). The objective is to determine whether differences in spot size and coagulation zone (CZ) thickness influence drug uptake. MATERIALS AND METHODS: Fractional ablation was performed on ex-vivo human abdominal skin with the DFG (5 mJ) and CO2 (12 mJ) lasers to generate 680 µm deep lesions. To evaluate drug delivery, 30 kDa encapsulated fluorescent dye was topically applied to the skin and histologically analyzed at skin depths of 100, 140, 200, 400, and 600 µm. Additionally, transcutaneous permeation of encapsulated and 350 Da nonencapsulated dye was assessed using Franz Cells. RESULTS: The DFG laser generated smaller channels (diameter: 56.5 µm) with thinner CZs (thickness: 22.4 µm) than the CO2 laser (diameter: 75.9 µm, thickness: 66.8 µm). The DFG laser treated group exhibited significantly higher encapsulated dye total fluorescence intensities after 3 h compared to the CO2 laser treated group across all skin depths (p < 0.001). Permeation of nonencapsulated dye was also higher in the DFG laser treated group vs the CO2 laser treated group after 48 h (p < 0.0001), while encapsulated dye was not detected in any group. CONCLUSION: The DFG laser treated skin exhibited significantly higher total fluorescence uptake compared to the CO2 laser. Additionally, the smaller spot size and thinner CZ of the DFG laser could result in faster wound healing and reduced adverse effects while delivering similar or greater amount of topically applied drugs.

Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo.

BACKGROUND: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs. METHODS: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3). RESULTS: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure. CONCLUSION: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.

Intradermal Delivery of Calcium Hydroxylapatite With Fractionated Ablation.

OBJECTIVES: The absorption of biostimulatory particulate matter following its application to fractional skin defects remains poorly understood, and even less is known about its in vivo impact in terms of tissue integration. The objectives of this study are twofold: (1) to evaluate the potential of calcium hydroxylapatite (CaHA) to penetrate through skin treated with a fractional laser; and (2) to assess the effectiveness of clinical laser scanning microscopy technologies in monitoring the effects of such treatment over time. METHODS: One area on a volunteer's arm was treated with a fractional erbium laser (Sciton Inc., Palo Alto, CA), while a second area received the same laser treatment followed by CaHA topical application. We used reflectance confocal microscopy (RCM) and multiphoton microscopy (MPM) to noninvasively image beneath the surface of the treated skin to study and monitor the effects of these treatments within 1 h of treatment and at four additional time points over a 6-week period. RESULTS: One hour posttreatment, at different depths beneath the skin surface, MPM and RCM provided similar visualizations of laser-induced channels. In skin treated by both laser and CaHA, these two imaging methods provided complementary information. RCM captured the lateral and depth distribution of CaHA microspheres and were seen as bright spheres as they became incorporated into the healing tissue. MPM, meanwhile, visualized the CaHA microparticles as dark shadow spheres within the laser-induced channels and encroaching healing tissue. Furthermore, MPM provided critical information about collagen regeneration around the microspheres, with the collagen visually marked by its distinct second harmonic generation (SHG) signal. CONCLUSIONS: This observational pilot study demonstrates that CaHA, a collagen stimulator used as a dermal filler, can not only be inserted into the dermis after fractional laser treatment but remains in the healing skin for at least 6 weeks posttreatment. The noninvasive imaging techniques RCM and MPM successfully captured the presence of CaHA microspheres mid-dermis during the healing phase. They also demonstrated new collagen production around the microspheres, highlighting the effectiveness of these imaging approaches in monitoring such treatment over time.

A focused review on laser- and energy-assisted drug delivery for nail disorders.

The purpose of this review is to consolidate and summarize laser-assisted drug delivery (LADD) for nail diseases, particularly onychomycosis and psoriasis. A PubMed search was conducted in June 2023 using search terms (1) "laser assisted drug delivery" AND "nail," (2) "laser" AND "nail," and (3) "nail disorder" AND "laser treatment." References of papers were also reviewed, yielding 15 papers for this review. Fractional ablative CO2 laser (FACL) and Er:YAG laser can be used for LADD of topical medications such as amorolfine, terbinafine, and tioconazole to treat onychomycosis. A fungal culture should be performed to determine the type of dermatophyte, which will help determine which topical will be most effective. Laser settings varied between studies, but overall LADD tended to be more effective than topical treatments alone. Laser-assisted photodynamic therapy (PDT) was also found to be effective in treating onychomycosis. For psoriatic nails, LADD was used to deliver calcipotriol-betamethasone dipropionate foam, tazarotene, triamcinolone, or methotrexate into the nail. Again, LADD was found to be significantly more effective than topical treatment alone. FACL was the only laser noted for use for LADD in both diseases. Laser-assisted drug delivery for nail disease is a newer approach for onychomycosis and nail psoriasis with several benefits and drawbacks. Dermatologists should discuss the option of LADD with their patients who have recalcitrant onychomycosis or nail psoriasis.

Laser-mediated Solutions: Breaking Barriers in Transdermal Drug Delivery.

Skin diseases pose challenges in treatment due to the skin's complex structure and protective functions. Topical drug delivery has emerged as a preferred method for treating these conditions, offering localized therapy with minimal systemic side effects. However, the skin's barrier properties frequently limit topical treatments' efficacy by preventing drug penetration into deeper skin layers. In recent years, laser-assisted drug delivery (LADD) has gained attention as a promising strategy to overcome these limitations. LADD involves using lasers to create microchannels in the skin, facilitating the deposition of drugs and enhancing their penetration into the target tissue. Several lasers, such as fractional CO2, have been tested to see how well they work at delivering drugs. Despite the promising outcomes demonstrated in preclinical and clinical studies, several challenges persist in implementing LADD, including limited penetration depth, potential tissue damage, and the cost of LADD systems. Furthermore, selecting appropriate laser parameters and drug formulations is crucial to ensuring optimal therapeutic outcomes. Nevertheless, LADD holds significant potential for improving treatment efficacy for various skin conditions, including skin cancers, scars, and dermatological disorders. Future research efforts should focus on optimizing LADD techniques, addressing safety concerns, and exploring novel drug formulations to maximize the therapeutic benefits of this innovative approach. With continued advancements in laser technology and pharmaceutical science, LADD has the potential to revolutionize the field of dermatology and enhance patient care.

In vivo characterization of laser-assisted delivery of hyaluronic acid using multiphoton fluorescence lifetime imaging.

Laser-assisted drug delivery (LADD) is a treatment method to enhance the penetration of pharmaceuticals through the skin. The aim of the present study is to track hyaluronic acid (HA) and analyse its effect on human skin in vivo after ablative fractional laser (AFL) treatment. Healthy male and female subjects were recruited. Four areas were marked on their forearms of each volunteer, and each area was assigned to one of the following treatment options: AFL + HA, AFL only, HA only or untreated control. A carbon dioxide laser was used for the AFL treatment. Follow-up measurements were scheduled 30 min and 30 days after treatment using multiphoton tomography equipped with fluorescence lifetime imaging (MPT-FLIM). A total of 11 subjects completed the study. By detecting fluorescence lifetimes, the HA and the anaesthetic ointment were clearly distinguishable from surrounding tissue. After AFL treatment, HA could be visualized in all epidermal and upper dermal layers. In contrast, HA in intact skin was only detected in the superficial layers at distinctly lower levels. The applied HA gel seemed to have beneficial properties for the wound healing process after laser treatment. LADD has proven to be a fast and effective method to increase HA uptake into the skin, allowing for improved hydration and skin rejuvenation over time. Furthermore, LADD could be a beneficial treatment option in laser resurfacing. MPT-FLIM proved to be an appropriate diagnostic tool for drug delivery tracking and monitoring of treatment response for individualized therapy adjustment.

Laser-assisted drug delivery of synthetic alpha melanocyte stimulating hormone and L-tyrosine leads to increased pigmentation area and expression of melanogenesis genes in a porcine hypertrophic scar model.

OBJECTIVES: One symptom of hypertrophic scar (HTS) that can develop after burn injury is dyschromia with hyper- and hypopigmentation. There are limited treatments for these conditions. Previously, we showed there is no expression of alpha melanocyte stimulating hormone (α-MSH) in hypopigmented scars, and if these melanocytes are treated with synthetic α-MSH in vitro, they respond by repigmenting. The current study tested the same hypothesis in the in vivo environment using laser-assisted drug delivery (LADD). METHODS: HTSs were created in red Duroc pigs. At Day 77 (pre), they were treated with CO2 fractional ablative laser (FLSR). Synthetic α-MSH was delivered as a topical solution dissolved in  l-tyrosine (n = 6, treated). Control scars received LADD of  l-tyrosine only (n = 2, control). Scars were treated and examined weekly through Week 4. Digital images and punch biopsies of hyper, hypo-, and normally pigmented scar and skin were collected. Digital pictures were analyzed with ImageJ by tracing the area of hyperpigmentation. Epidermal sheets were obtained from punch biopsies through dispase separation and RNA was isolated. qRT-PCR was run for melanogenesis-related genes: tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Two-way ANOVA with multiple comparisons and Dunnett's correction compared the groups. RESULTS: The areas of hyperpigmentation were variable before treatment. Therefore, data is represented as fold-change where each scar was normalized to its own pre value. Within the LADD of NDP α-MSH + l-tyrosine group, hyperpigmented areas gradually increased each week, reaching 1.3-fold over pre by Week 4. At each timepoint, area of hyperpigmentation was greater in the treated versus the control (1.04 ± 0.05 vs. 0.89 ± 0.08, 1.21 ± 0.07 vs. 0.98 ± 0.24, 1.21 ± 0.08 vs. 1.04 ± 0.11, 1.28 ± 0.11 vs. 0.94 ± 0.25; fold-change from pre-). Within the treatment group, pretreatment, levels of TYR were decreased -17.76 ± 4.52 below the level of normal skin in hypopigmented scars. After 1 treatment, potentially due to laser fractionation, the levels decreased to -43.49 ± 5.52. After 2, 3, and 4 treatments, there was ever increasing levels of TYR to almost the level of normally pigmented skin (-35.74 ± 15.72, -23.25 ± 6.80, -5.52 ± 2.22 [p < 0.01, Week 4]). This pattern was also observed for TYRP1 (pre = -12.94 ± 1.82, Week 1 = -48.85 ± 13.25 [p < 0.01], Weeks 2, 3, and 4 = -34.45 ± 14.64, -28.19 ± 4.98, -6.93 ± 3.05 [p < 0.01, Week 4]) and DCT (pre = -214.95 ± 89.42, Week 1 = -487.93 ± 126.32 [p < 0.05], Weeks 2, 3, and 4 = -219.06 ± 79.33, -72.91 ± 20.45 [p < 0.001], -76.00 ± 24.26 [p < 0.001]). Similar patterns were observed for scars treated with LADD of  l-tyrosine alone without NDP α-MSH. For each gene, in hyperpigmented scar, levels increased at Week 4 of treatment compared to Week 1 (p < 0.01). CONCLUSIONS: A clinically-relevant FLSR treatment method can be combined with topical delivery of synthetic α-MSH and l-tyrosine to increase the area of pigmentation and expression of melanogenesis genes in hypopigmented HTS. LADD of  l-tyrosine alone leads to increased expression of melanogenesis genes. Future studies will aim to optimize drug delivery, timing, and dosing.

Fractional CO2 laser ablation leads to enhanced permeation of a fluorescent dye in healthy and mycotic nails-An imaging investigation of laser-tissue effects and their impact on ungual drug delivery.

PURPOSE: Conventional oral antifungal therapies for onychomycosis (OM) often do not achieve complete cure and may be associated with adverse effects, medical interactions, and compliance issues restricting their use in a large group of patients. Topical treatment can bypass the systemic side effects but is limited by the physical barrier of the nail plate. Ablative fractional laser (AFL) treatment can be used to improve the penetration of topical drugs into the nail. This study visualized the effects of laser ablation of nail tissue and assessed their impact on the biodistribution of a fluorescent dye in healthy and fungal nail tissue. METHODS: For the qualitative assessment of CO2 AFL effects on healthy nail tissue, scanning electron microscopy (SEM), coherent anti-Stokes Raman scattering microscopy (CARS-M), and widefield fluorescence microscopy (WFM) were used. To quantitate the effect of laser-pretreatment on the delivery of a fluorescent dye, ATTO-647N, into healthy and fungal nail tissue, ablation depth, nail plate thickness, and ATTO-647N fluorescence intensity in three nail plate layers were measured using WFM. A total of 30 nail clippings (healthy n = 18, fungal n = 12) were collected. An aqueous ATTO-647N solution was directly applied to the dorsal surface of 24 nail samples (healthy n = 12, fungal n = 12) and incubated for 4 hours, of which half (healthy n = 6, fungal n = 6) had been pretreated with AFL (30 mJ/mb, 15% density, 300 Hz, pulse duration <1 ms). RESULTS: Imaging revealed a three-layered nail structure, an AFL-induced porous ablation crater, and changes in autofluorescence. While intact fungal samples showed a 106% higher ATTO-647N signal intensity than healthy controls, microporation led to a significantly increased fluorophore permeation in all samples (p < 0.0001). AFL processing of nail tissue enhanced topical delivery of ATTO-647N in all layers, (average increase: healthy +108%, fungal +33%), most pronounced in the top nail layer (healthy +122%, fungal +68%). While proportionally deeper ablation craters correlated moderately with higher fluorescence intensities in healthy nail tissue, fungal samples showed no significant relationship. CONCLUSION: Fractional CO2 laser microporation is a simple way of enhancing the passive delivery of topically applied ATTO-647N. Although the impaired nail plate barrier in OM leads to greater diffusion of the aqueous solution, AFL can increase the permeability of both structurally deficient and intact nails.

Efficacy and safety of laser-assisted combination chemotherapy: A follow-up study of treatment with 5-fluorouracil and cisplatin for basal cell carcinoma.

BACKGROUND AND OBJECTIVES: There is a growing need for effective topical treatments for basal cell carcinoma (BCC). By altering the skin barrier, ablative fractional lasers (AFLs) enhance cutaneous uptake of the synergistic chemotherapeutic agents, cisplatin, and 5-fluorouracil (5-FU). In our recently reported clinical trial, AFL-assisted delivery of cisplatin and 5-FU showed favorable short-term clearance rates of 95% with good cosmetic results at 3 months. This follow-up study assessed sustained tumor clearance, safety, and cosmesis in the same patient cohort, observed 6- and 12-months posttreatment. MATERIALS AND METHODS: This follow-up study assessed AFL-assisted cisplatin and 5-FU in low-risk BCC. Among the 18/19 patients who achieved clinical tumor clearance in our 3-months primary trial, all were included for a 6-months follow-up. At 12 months, 17/19 were included due to one 6-month residual. During follow-up visits, treated areas were evaluated for signs of recurrent tumour by clinical inspection and optical coherence tomography (OCT). Residual tumors were confirmed histologically. Cosmetic outcome was evaluated at both follow-up visits by patients and physicians. RESULTS: Overall, complete tumor clearance was 89% (17/19) and 79% (15/19) at 6 and 12 months, respectively. Clearance rate for superficial BCCs (sBCCs) 1 year after treatment was 100% (6/6) and lower for nodular BCC (nBCC) at 69% (9/13). Among recurrent tumors, 67% (2/3) had received only a single treatment and all were of the nodular subtype, situated in the head and neck area. All histologically confirmed BCC recurrences were identified by OCT. Cosmetic outcomes were similarly rated "good" or "excellent" by patients and evaluators (p = 0.289 and p = 0.250). Treatment-related local skin reactions were mild and tolerable, consisting of persisting erythema in two patients at the end of the study. Dyspigmentation was commonly observed at both follow-up visits, while the appearance of scarring resolved in the majority of patients between 6 months (56%; 10/18) and 12 months (76%; 13/17). CONCLUSION: AFL-assisted cisplatin + 5-FU in double sessions represents an acceptable and safe treatment strategy for low-risk sBCC, while clearance rates following single treatment or for nBCC seem inferior. This intensified topical strategy may be best suited to cases of multiple lesions or in instances where surgical excision or extended courses of at-home therapy is challenging.

Local vasoregulative interventions impact drug concentrations in the skin after topical laser-assisted delivery.

INTRODUCTION: The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFL delivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL-assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL-assisted delivery, this study examined the impact of vasoregulative interventions on AFL-assisted 5-fluorouracil (5-FU) concentrations in in vivo skin. METHODS: 5-FU uptake was assessed in intact and AFL-exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5-FU cream application. At 0, 1, 4, 48, and 72 h, 5-FU concentrations were measured in 500 and 1500 µm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. RESULTS: Compared to intact skin, AFL facilitated a prompt peak in 5-FU delivery that remained elevated up to 4 hours (1500 µm: 1.5 vs. 31.8 ng/ml [1 hour, p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5-FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5-FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5-FU concentrations than AFL alone in both skin layers by 1 hour (e.g., 500 µm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone], p ≤ 0.024), and remained significantly elevated at 4 hours (p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5-FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hours in the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. CONCLUSION: Vasoregulative intervention in conjunction with AFL-assisted delivery enhances and prolongs 5-FU deposition in in vivo skin.

A systematic review of randomised controlled trials investigating laser assisted drug delivery for the treatment of keloid and hypertrophic scars.

The objective of this article is to study the clinical efficacy and adverse events of laser-assisted drug delivery in the treatment of hypertrophic and keloid scars. We searched the following databases up to 22 October 2020: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library, MEDLINE, EMBASE, and reference lists of articles for randomised clinical trials (RCTs) of laser-assisted drug delivery for the treatment of hypertrophic and keloid scars. We also searched online trials registries for ongoing trials and contacted trial authors where appropriate. Our outcomes of interest were objective clinical evaluation of scars, participant satisfaction, and adverse effects of the treatments. Two authors independently extracted data and assessed trial quality using Cochrane Risk of Bias 2. Two authors independently abstracted data. We included 10 RCTs involving a total of 329 participants: six trials utilised parallel-arm RCTs whilst four employed split-scar design. Three trials had high risk of bias with the remaining seven rated as having some concerns. The interventions and outcomes were too varied to be combined statistically. High-quality randomised controlled trials assessing laser-assisted delivery for drugs in the context of hypertrophic and/or keloid scarring are needed. Studies with a larger number of participants, with longer follow-up times, and standardised evaluation of outcome and adverse effects are warranted.

Efficacy and safety of 755-nm picosecond alexandrite laser with topical tranexamic acid versus laser monotherapy for melasma and facial rejuvenation: a multicenter, randomized, double-blinded, split-face study in Chinese patients.

To compare the efficacy and safety of 755-nm picosecond alexandrite laser and topical tranexamic acid (TTA) combination therapy with laser monotherapy, for the treatment of melasma and facial rejuvenation. This multicenter, randomized, double-blinded, split-face study enrolled 37 patients who presented with melasma and photoaging. Facial halves were randomized to receive either laser and TTA combination therapy or laser monotherapy. Three treatments were delivered at 4-5 weeks intervals. Patients were followed up for 1, 3, and 6 months post-final treatment and evaluated by blinded investigators for hemi-Melasma Area and Severity Index (hemi-MASI), facial dyschromia, skin texture, laxity, and rhytids. Daily diaries rating healing progress for 7 days posttreatment and satisfaction grading were performed by all patients. Adverse events were recorded. Thirty-six patients completed the follow-up. Compared with the baseline, hemi-MASI, dyschromia, and skin texture on both halves improved significantly through the follow-up (p = 0.000). A significant difference in hemi-MASI and dyschromia between combination therapy halves and monotherapy halves was noticed at 1- and 3-month follow-ups (p < 0.05). The laser monotherapy halves displayed significantly less redness and sensitivity during the 7-day posttreatment recovery period (p < 0.05). Patients' satisfaction ratings for the combination therapy halves were higher than the monotherapy halves at 1-month follow-up (p < 0.05). No severe adverse events were observed. The picosecond alexandrite laser and TTA combination therapy demonstrated synergistic efficacy for hemi-MASI and dyschromia improvements over laser monotherapy. The optimization of the picosecond laser and TTA combination regimen needs further investigation.

Hypertrophic Scar Outcomes in Fractional Laser Monotherapy Versus Fractional Laser-Assisted Topical Corticosteroid Delivery: A Randomized Clinical Trial.

Topical corticosteroid delivery following fractional laser treatment is an effective means of treating hypertrophic scars. However, the relative efficacy of adjuvant corticosteroid treatment vs fractional laser mono-therapy alone is unclear. The aim of this study was to compare the efficacy and safety of fractional laser-assisted topical corticosteroid delivery with fractional laser monotherapy in the treatment of hyper-trophic scars. In this randomized, comparative, split-scar trial of 19 subjects, a borderline significant reduction in scar thickness was observed at 3-month follow-up in the laser+steroid group compared with laser+petrolatum (p = 0.049). However, no significant long-term difference in scar flattening was observed between the 2 groups. Patient and Observer Scar Assessment Scale scores showed significant improvement in scar appearance from baseline without significant differences between treatment groups. In conclusion, fractional laser monotherapy is an effective treatment for hypertrophic scars, and the application of topical corticosteroid provides no long-term synergistic effect to fractional laser monotherapy.

A Comparison of Human and Porcine Skin in Laser-Assisted Drug Delivery of Chemotherapeutics.

BACKGROUND AND OBJECTIVES: Porcine skin is a widely used model in diffusion studies, but its usefulness for laser-assisted drug delivery (LADD) has not been evaluated in comparison with human skin. This study compared porcine and human skin in ex vivo LADD diffusion studies. STUDY DESIGN/MATERIALS AND METHODS: Ex vivo ablative fractional laser (AFL) treatments (5, 20, and 80 mJ/mb) were applied to skin samples from three sources: human, normal pig (Duroc × Landrace × Yorkshire breed), and a hyperkeratotic pig phenotype. Samples were stained using hematoxylin and eosin, photo-documented, and measured digitally. Samples (20 mJ/mb) were exposed to bleomycin or 5-fluorouracil (5-FU) for 19 hours in Franz diffusion cells. Drug uptake was quantified at three skin depths (100, 500, and 1,500 µm) by high-performance liquid chromatography-mass spectrometry. Drug biodistribution and endogenous lipids were visualized by matrix-assisted laser desorption/ionization-mass spectrometry imaging. RESULTS: Epidermal and dermal thicknesses of human and normal pig skin were similar (76-87 µm and 1,668-1,886 µm, respectively; P = 0.082-0.494). Endogenous lipids were investigated, and 116 compounds were identified. Of these compounds, 100 were found in all three skin types, while six were present exclusively in human skin. Laser channel depths (20 mJ/mb) in human and normal pig skin were similar (1,081 vs. 1,126 µm; P = 0.588). Bleomycin uptake was similar in all skin types at all depths (101.4-175.6 µg/cm3 ; P = 0.132-0.699). 5-FU uptake in human and normal pig skin was similar at 100 and 500 µm (80.5 vs. 140.3 µg/cm3 and 131.2 vs. 208.1 µg/cm3 , respectively; P = 0.065-0.093). At 1500 µm, 5-FU concentrations in the porcine skin types differed from those in human skin (104.7 vs. 196.7-344.8 µg/cm3 ; P = 0.002-0.026). Drug biodistribution was similar among skin types, but differences between bleomycin and 5-FU biodistribution were observed. CONCLUSIONS: Normal porcine and human skin showed similar morphology, the composition of endogenous lipids, and AFL-assisted cutaneous uptake, and biodistribution of chemotherapeutics. Therefore, normal porcine skin, but not hyperkeratotic pig phenotype skin, is a practical and reliable model for healthy human skin in ex vivo LADD diffusion studies. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Safety profile of laser-assisted drug delivery of vitamin C, E, and ferulic acid serum following ablative fractional resurfacing: A retrospective chart review.

OBJECTIVES: The topical application of a combination Vitamin C, Vitamin E, and Ferulic acid serum following ablative fractional resurfacing has been reported to shorten post-procedure downtime and improve wound healing. However, transcutaneous drug delivery of cosmeceuticals initially meant for topical application have also been shown to have unintended side effects. The objective of our study was to report safety data from our single academic center experience consisting of patients treated with topical application of a vitamin C-containing cosmeceutical immediately following fractional ablative CO2 laser treatment with a focus on reportable side effects. METHODS: A retrospective chart review of all patients at the University of Minnesota M Health Cosmetic Center who had fractional ablative CO2 (10,600 nm) laser procedure for any diagnosis followed by immediate one-time application of a combination serum containing 15% Vitamin C, 1% Vitamin E, and 0.5% Ferulic acid (C E Ferulic®, SkinCeuticals Inc., New York, NY) from Jan 1, 2015 to Dec 31, 2018 was performed. Pediatric and research opt-out patients were excluded. The medical records of these patients were manually reviewed for the following: age, sex, diagnosis, location, after-care instructions, antiviral and/or antibacterial prophylaxis use, and documentation of post-procedure side effects. RESULTS: Thirty-three patients, encompassing a total of 45 treatment encounters, met inclusion criteria. There were ten cases of expected side effects: erythema (6), erythema with tenderness (1), erythema with mild bumpiness (1), skin peeling with pattern marking (1), and pain with slight bleeding (1). These were attributed to the normal post-procedure course and resolved without complications. There were no reported side effects related to the topical application of Vitamin C, Vitamin E, and Ferulic acid serum. CONCLUSIONS: The topical application of a Vitamin C, Vitamin E, and Ferulic acid serum immediately following fractional ablative CO2 laser therapy did not result in associated complications. However, these results may not be generalizable to longer application courses beyond the immediate post-procedure time period, nor to other cosmeceutical formulations. More studies examining the safety profile of topical cosmeceutical serums in laser-assisted drug delivery are needed.

Fractional CO2 laser-assisted topical rifamycin drug delivery in the treatment of pediatric cutaneous leishmaniasis.

Cutaneous leishmaniasis is challenging to treat. Various drugs have been proposed to manage this condition, with variable results. In this case report, we describe laser-assisted delivery of rifamycin to treat this infection. Two sessions of fractional CO2 laser were performed one month apart. Each was followed by a topical application of rifamycin for three days. Resolution with minimal scarring was obtained, suggesting this technique might be safe and effective in treating cutaneous leishmaniasis.

Fractional CO2 laser-assisted Botulinum toxin type A delivery for the treatment of primary palmar hyperhidrosis.

Intradermal injections of botulinum toxin type A (BTX-A) have been used successfully to treat patients with primary palmoplantar hyperhidrosis (PPH). However, problems with local injections of BTX-A for palmar hyperhidrosis include injection pain and reduced palmar muscle strength. This case series describes three patients with PPH. Patients were followed up for 3 months and assessed using the minor iodine starch test and the visual analog scale (VAS). Over two sessions within a 2-week interval, all patients received treatment on one palm, while the other palm served as the untreated control. Treated palms received fractional CO2 laser therapy and immediate post-operative topical application of BTX-A solution for a total of 50 units. Sweat production was assessed based on the size of the sweat-producing area (measured by the minor iodine starch test) and subjective assessment of sweat production using the visual analog scale (VAS) at baseline, 2 weeks after the first treatment, and 1, 2, and 3 months after the second treatment. In the BTX-A-treated palm, the decrease in the mean sweat production was 51.6% at 2 weeks after the first treatment, and 88.5%, 67.8%, and 52.9%, at 1, 2, and 3 months after the final treatment when compared to the baseline. In the untreated palms, the decrease in the mean sweat production was 2% on all follow-ups when compared to the baseline. No adverse effect was observed in any patient. Fractional CO2 laser is a safe technique for BTX-A delivery on the palm area and is demonstrated to be safe and effective in decreasing sweat secretion of hyperhidrosis palm.

Efficacy of Er,Cr:YSGG laser-assisted delivery of topical anesthesia in the oral mucosa.

OBJECTIVE: Lasers which can reduce epithelium thickness will enhance the penetration of topical drugs. To date, no study has assessed the efficacy of this technique in the oral mucosa. The aim of this study was the evaluation of efficacy of this technique in increasing the effect of topical anesthesia in the oral mucosa. MATERIALS AND METHODS: On 20 volunteers, half of the lower lip mucosa was irradiated with Er,Cr:YSGG laser with 2780 nm wavelength and 1.3 J/cm2 energy for 1 min; then, topical lidocaine was applied on the entire lower lip mucosa. After 5 min, a 27-gauge needle was inserted to each half of the lip mucosa, and the length of the needle inserted into the mucosa without feeling pain was considered the depth of insertion. This measurement was repeated every 15 min for 1 h. RESULTS: The mean depth of anesthesia at the control side was 6.95 ± 2.43, 8.45 ± 4.05, 6.5 ± 3.00, and 3.85 ± 2.08 mm at 5, 20, 35, and 60 min, respectively. These values at the test side were 12.25 ± 5.42, 13.25 ± 5.02, 11.4 ± 5.03, and 9.10 ± 5.84 mm, respectively. According to repeated-measures ANOVA, the effect of the type of the treatment on the depth of insertion was significant (P < 0.001). CONCLUSIONS: The results showed that irradiation of Er,Cr:YSGG laser before the topical application of the anesthetic agents on the oral mucosa increases their efficacy. CLINICAL RELEVANCE: Topical anesthesia is used to enhance dental procedures painlessly, but there is controversy in their efficacy. Laser-assisted drug delivery to the oral mucosa can enhance their efficacy.

Treatment of Scars with Laser-Assisted Delivery of Growth Factors and Vitamin C: A Comparative, Randomised, Double-blind, Early Clinical Trial.

BACKGROUND: Scarring can jeopardize the final result of plastic surgeries. Deep dermal injuries activate dermal fibroblasts that produce excessive amount of collagen and inflammatory cytokines and growth factors, which contributes to increased fibrous tissue and scarring tissue formation. OBJECTIVES: The aim of this early study, double-blind, prospective, randomised clinical trial was to investigate the use of laser-assisted drug delivery (LADD) for scar improvement to support the establishment of LADD as standard therapy modality and to indicate suitable drugs for dermal administration. MATERIAL AND METHODS: In total, 132 patients seeking scar treatment were consented and randomised. The control group (64 patients) received laser resurfacing immediately followed by skin surface application of Vitamin C and 68 patients received laser treatment followed by skin surface application of a cosmeceutical containing growth factors (GFs) and Vitamin C. Photographs were obtained before and three months after the procedure and submitted to three-dimensional reconstruction by the software Dermapix®. Objective measurements provided by the software were statistically analysed and established the differences in the treatment result between the two groups. RESULTS: There was a significant reduction in scar roughness and volume in both groups (p < 0.01). Mann-Whitney test confirmed that the group treated vitamin C and GFs presented significantly better results than the group treated with vitamin C alone (p < 0.01). CONCLUSION: LADD has proven efficient as scars were reduced in both study groups. Furthermore, the addition of growth factors provided statistically significant better outcomes and resulted in more inconspicuous scars. No adverse reactions were observed. CLINICAL TRIAL REGISTRATION: Plataforma Brasil under the number CAAE: 63710716.2.0000.5664. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Comparative Study on the Outcome of Periorbital Wrinkles Treated with Laser-Assisted Delivery of Vitamin C or Vitamin C Plus Growth Factors: A Randomized, Double-blind, Clinical Trial.

BACKGROUND: Despite promising results, laser-assisted drug delivery (LADD) is not yet considered as standard therapies and published data rely mainly on laboratory tests, animal experiments or cadaver skin. OBJECTIVES: This double-blind, prospective, randomized clinical trial investigates the impact in topical application of vitamin C and a cosmeceutical containing growth factors (GFs) on periorbital wrinkles primarily treated with laser skin resurfacing. MATERIAL AND METHODS: In total, 149 female patients with periorbital wrinkles were consented and randomized into two study groups, R-C (receiving vitamin C only) and R-CGF (receiving vitamin C and a cosmeceutical containing growth factors). The statistical analysis evaluated the efficacy of each treatment regimen using software readouts provided by a three-dimensional stereophotogrammetry system prior to treatment and three months after the procedure. Results were compared to confirm if there was a significant change in the skin roughness and the average depth of the wrinkles between the two groups after treatment. RESULTS: There was a significant reduction in both skin roughness and average depth of the wrinkles in the group treated with vitamin C and growth factors (p <0.01) than those treated with LADD followed by topical application of vitamin C alone. There were no cutaneous reactions or adverse systemic reactions observed in this study related to LADD with vitamin C and GFs. CONCLUSION: Controlled laser application might have a great potential to facilitate the absorption of exogenous macromolecules by the skin. Periorbital wrinkles were reduced in both groups, but LADD using vitamin C and GFs provided significantly better results. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .