title: Fractional laser-assisted drug delivery: Laser channel depth influences biodistribution and skin deposition of methotrexate.
abstract: Ablative fractional laser (AFXL) facilitates delivery of topical methotrexate (MTX). This study investigates impact of laser-channel depth on topical MTX-delivery.
  
  
  
  MTX (1% [w/v]) diffused for 21 hours through AFXL-exposed porcine skin in in vitro Franz Cells (n = 120). A 2,940 nm AFXL generated microscopic ablation zones (MAZs) into epidermis (11 mJ/channel, MAZ-E), superficial-dermis (26 mJ/channel, MAZ-DS), and mid-dermis (256 mJ/channel, MAZ-DM). High performance liquid chromatography (HPLC) was used to quantify MTX deposition in full-thickness skin, biodistribution profiles at specific skin levels, and transdermal permeation. Fluorescence microscopy was used to visualize UVC-activated MTX-fluorescence (254 nm) and semi-quantify MTX distribution in skin.
  
  
  
  AFXL increased topical MTX-delivery (P < 0.001). Without laser exposure, MTX-concentration in full-thickness skin was 0.07 mg/cm(2) , increasing sixfold (MAZ-E), ninefold (MAZ-DS), and 11-fold (MAZ-DM) after AFXL (P < 0.001). Deeper MAZs increased MTX-concentrations in all skin layers (P < 0.038) and favored maximum accumulation in deeper skin layers (MAZ-E: 1.85 mg/cm(3) at 500 μm skin-level vs.
  
  
  
  3.75 mg/cm(3) at 800 μm, P = 0.002). Ratio of skin deposition versus transdermal permeation remained constant, regardless of MAZ depth (P = 0.172). Fluorescence intensities confirmed MTX biodistribution through coagulation zones and into surrounding skin, regardless of thickness of coagulation zones (6-47 μm, P ≥ 0.438).
  
  
  
  AFXL greatly increases topical MTX-delivery. Deeper MAZs deliver higher MTX-concentrations than superficial MAZs, which indicates that laser channel depth may be important for topical delivery of hydrophilic molecules. Lasers Surg. Med. 48:519-529, 2016. © 2016 Wiley Periodicals, Inc.
authors: Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Denmark.
authors: E H
authors: EH
authors: Taudorf
authors: Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Denmark.
authors: C M
authors: CM
authors: Lerche
authors: Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Denmark.
authors: A M
authors: AM
authors: Erlendsson
authors: Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Denmark.
authors: P A
authors: PA
authors: Philipsen
authors: Faculty of Health and Medical Sciences, Department of Pharmacy, University of Copenhagen, Denmark.
authors: S H
authors: SH
authors: Hansen
authors: Faculty of Health and Medical Sciences, Department of Pharmacy, University of Copenhagen, Denmark.
authors: C
authors: C
authors: Janfelt
authors: Division of Dermatopathology, Aesthetics and Laserdermatology, Departments of Dermatology, University of Leipzig, Germany.
authors: U
authors: U
authors: Paasch
authors: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: R R
authors: RR
authors: Anderson
authors: Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Denmark.|Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: M
authors: M
authors: Haedersdal
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D053844:Lasers, Solid-State; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008856:Microscopy, Fluorescence; D010539:Permeability; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013552:Swine
chemical_list: D003879:Dermatologic Agents; D008727:Methotrexate
keywords: Er:Yag laser; Franz skin permeability Cells; fluorescence microscopy; high performance liquid chromatography; laser-assisted drug delivery