Fractional laser-assisted drug delivery: Active filling of laser channels with pressure and vacuum alteration.
OBJECTIVE
Ablative fractional laser (AFXL) is rapidly evolving as one of the foremost techniques for cutaneous drug delivery. While AFXL has effectively improved topical drug-induced clearance rates of actinic keratosis, treatment of basal cell carcinomas (BCCs) has been challenging, potentially due to insufficient drug uptake in deeper skin layers. This study sought to investigate a standardized method to actively fill laser-generated channels by altering pressure, vacuum, and pressure (PVP), enquiring its effect on (i) relative filling of individual laser channels; (ii) cutaneous deposition and delivery kinetics; (iii) biodistribution and diffusion pattern, estimated by mathematical simulation.


METHODS
Franz diffusion chambers (FCs) were used to evaluate the PVP-technique, comparing passive (AFXL) and active (AFXL + PVP) channel filling. A fractional CO2-laser generated superficial (225 µm;17.5 mJ/channel) and deep (1200 µm; 130.5 mJ/channel) channels, and PVP was delivered as a 3-minutes cycle of 1 minute pressure (+1.0 atm), 1 minute vacuum (-1.0 atm), and 1 minute pressure (+1.0 atm). Filling of laser channels was visualized with a colored biomarker liquid (n = 12 FCs, n = 588 channels). Nuclear magnetic resonance quantified intracutaneous deposition of topically applied polyethylene glycol (PEG400) over time (10 minutes, 1 hour, and 4 hours), investigated with (n = 36 FCs) and without (n = 30 FCs) PVP-filling. Two-dimensional mathematical simulation was used to simulate intradermal biodistribution and diffusion at a depth of 1,000 µm.


RESULTS
Active filling with application of PVP increased the number of filled laser channels. At a depth of 1,000 µm, filling increased from 44% (AFXL) to 94% with one PVP cycle (AFXL + PVP; P < 0.01). Active filling greatly enhanced intracutaneous deposition of PEG400, resulting in a rapid delivery six-folding uptake at 10 minutes (AFXL 54 µg/ml vs. AFXL + PVP 303 µg/ml, P < 0.01). AFXL alone generated an inhomogeneous uptake of PEG400, which greatly improved with active filling, resulting in a uniform uptake within the entire tissue.


CONCLUSIONS
Active filling with PVP secures filling of laser channels and induces a deeper, greater, more rapid delivery than conventional AFXL. This delivery technique has promise to improve treatment efficacy for medical treatments of dermally invasive lesions, such as BCCs.
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.|Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
Andrés M
AM
Erlendsson
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
Apostolos G
AG
Doukas
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
William A
WA
Farinelli
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
Brijesh
B
Bhayana
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
R Rox
RR
Anderson
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.|Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
Merete
M
Haedersdal
D000279:Administration, Cutaneous; D000818:Animals; D001696:Biomechanical Phenomena; D004058:Diffusion; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005260:Female; D007700:Kinetics; D054020:Lasers, Gas; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011312:Pressure; D012867:Skin / Q000737:chemistry*; D013552:Swine; D014618:Vacuum
D011092:Polyethylene Glycols; C000595213:polyethylene glycol 400
active filling; drug delivery; laser; laser-assisted drug delivery