Skin pre-ablation and laser assisted microjet injection for deep tissue penetration.

BACKGROUND AND AIMS: For conventional needless injection, there still remain many unresolved issues such as the potential for cross-contamination, poor reliability of targeted delivery dose, and significantly painstaking procedures. As an alternative, the use of microjets generated with Er:YAG laser for delivering small doses with controlled penetration depths has been reported. In this study, a new system with two stages is evaluated for effective transdermal drug delivery. First, the skin is pre-ablated to eliminate the hard outer layer and second, laser-driven microjet penetrates the relatively weaker and freshly exposed epidermis. Each stage of operation shares a single Er:YAG laser that is suitable for skin ablation as well as for the generation of a microjet. METHODS: In this study, pig skin is selected for quantification of the injection depth based on the two-stage procedure, namely pre-ablation and microjet injection. The three types of pre-ablation devised here consists of bulk ablation, fractional ablation, and fractional-rotational ablation. The number of laser pulses are 12, 18, and 24 for each ablation type. For fractional-rotational ablation, the fractional beams are rotated by 11.25° at each pulse. The drug permeation in the skin is evaluated using tissue marking dyes. The depth of penetration is quantified by a cross sectional view of the single spot injections. Multi-spot injections are also carried out to control the dose and spread of the drug. RESULTS: The benefits of a pre-ablation procedure prior to the actual microjet injection to the penetration is verified. The four possible combinations of injection are (a) microjet only; (b) bulk ablation and microjet injection; (c) fractional ablation and microjet injection; and (d) fractional-rotational ablation and microjet injection. Accordingly, the total depth increases with injection time for all cases. In particular, the total depth of penetration attained via fractional pre-ablation increased by 8 ∼ 11% and that of fractional-rotational pre-ablation increased by 13 ∼ 33%, when compared with the no pre-ablation or microjet only cases. A noticeable point is that the fraction-rotational pre-ablation and microjet result is comparable to the bulk ablation and microjet result of 11 ∼ 42%. The penetration depth underneath ablated stratum corneum (SC) is also measured in order to verify the pre-ablation effect. The penetration depths for each case are (a) 443 ± 104 µm; (b) 625 ± 98 µm; (c) 523 ± 95 µm; and (d) 595 ± 141 µm for microjet only, bulk ablation and microjet, fractional ablation and microjet, and fractional-rotational ablation and microjet, respectively. This is quite beneficial since any healing time associated with ablation is significantly reduced by avoiding hard-core bulk ablation. Thus the bulk pre-ablation and microjet may well be superseded by the less invasive fractiona-rotational ablation followed by the microjet injection. The density of micro-holes is 1.27 number/mm2 for fractional ablation and 4.84 number/mm2 for fractional-rotational ablation. The penetration depths measured underneath the ablated SC are 581 µm (fractional ablation and microjet) and 691 µm (fractional-rotational ablation and microjet). CONCLUSIONS: Fractional-rotational ablation increases number of micro-holes in a unit area, enabling fast reepithelialization and high drug delivery efficiency. Optimization of system parameters such as ablation time, number of ablations, and injection time will eventually ensure a macromolecule delivery technique with the potential to include vaccines, insulins, and growth hormones, all of which require deeper penetration into the skin. Lasers Surg. Med. 49:387-394, 2017. © 2016 Wiley Periodicals, Inc.

Laser-induced microjet injection into preablated skin for more effective transdermal drug delivery.

A breakthrough in the efficient transdermal delivery of drug via the laser-driven microjet is reported. A single source of laser beam is split into two: one beam ablates a targeted spot on a skin and another beam drives the injector for fast microjet ejection into a preablated spot. This combined ablation and microjet injection scheme using a beam splitter utilizes laser energy sharing between generation of the microhole via ablation and the microjet which is generated using the Er:YAG laser beam at a 2940-nm wavelength and pulse duration. A careful analysis of the injection mechanism is carried out by studying the response of the elastic membrane that separates a driving water unit for bubble expansion from a drug unit for a microjet ejection. The efficiency of the present delivery scheme is evaluated by the abdominal porcine skin test using the fluorescein isothiocyanate staining and the confocal microscopy for quantitative delivery confirmation. The depth of penetration and the injected volume of the drug are also confirmed by polyacrylamide gel tests.

Towards clinical use of a laser-induced microjet system aimed at reliable and safe drug delivery.

An Er:YAG laser with 2940-nm wavelength and 250-µs pulse duration is used to generate a microjet that is ejected at ∼50 m/s in air. The strength of the microjet depends on the bubble dynamics from the beam-water interaction within the driving chamber as well as the discharging of the drug solution underneath the elastic membrane that separates the drug from the driving liquid. The jet characteristics, such as velocity, volume, and level of atomization, are obtained by high-speed camera images taken at 42,000 fps. The enhancements in jet volume (dosage) and repeated jet generation, which are aimed at making the injector suitable for general clinical applications, are achieved. The generation of repeated microjets is achieved with the help of a stepping motor that provides a uniform pressure within the drug reservoir before an ejection occurs through a micro nozzle. Also, two types of human growth hormones are used for monitoring any potential thermal damage to the drug solution due to a repeated laser ablation when driving the microjet. We provide strong evidence to support that the drugs, as they are injected to porcine skins, are free of the damage associated with the present delivery method.

Er:YAG laser pulse for small-dose splashback-free microjet transdermal drug delivery.

The microjet injector system accelerates drugs and delivers them without a needle, which is shown to overcome the weaknesses of existing jet injectors. A significant increase in the delivered dose of drugs is reported with multiple pulses of laser beam at lower laser energy than was previously used in a Nd:YAG system. The new injection scheme uses the beam wavelength best absorbable by water at a longer pulse mode for elongated microjet penetration into a skin target. A 2.9 µm Er:YAG laser at 250 µs pulse duration is used for fluorescent staining of guinea pig skin and for injection controllability study. Hydrodynamic theory confirms the nozzle exit jet velocity obtained by the present microjet system.