275618 Transdermal Delivery of Biopharmaceuticals Using Microsecond Thermal Ablation

Wednesday, October 31, 2012: 4:27 PM
Somerset West (Westin )
Jeong Woo Lee, Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, Priya Gadiraju, Georgia Institute of Technology, Jung-Hwan Park, Bionano Technology, Gachon University, Seongnam, South Korea, Mark G. Allen, Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA and Mark R. Prausnitz, School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA

 SEQ CHAPTER \h \r 1TRANSDERMAL DELIVERY OF BIOPHARMACEUTICALS USING MICROSECOND THERMAL ABLATION

Jeong Woo Lee1, Priya Gadiraju1, Jung-Hwan Park3, Mark G. Allen1,2, Mark R. Prausnitz1

1School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA

2School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA

3Department of BioNano Technology and Gachon BioNano Research Institute, Gachon University,

 Sungnam, Republic of Korea

Introduction

            The conventional transdermal patch has provided advantages of non-invasive and simple administration, but it is generally limited to only small molecular weight and lipophilic therapeutics due to the protective function of the skin, which mostly resides in the top superficial layer of epidermis, stratum corneum. Macromolecular biopharmaceuticals cannot be delivered through the skin at therapeutic rates due to the stratum corneum barrier, so that various technologies have been investigated to overcome the skin barrier property such as mechanical disruption, radio frequency-based heating, ohmic heating, and laser ablation. The key to success with skin ablation technology is to develop methods to remove the stratum corneum barrier selectively without causing deeper skin damage [1]. Here, we present transdermal delivery of biopharmaceuticals with microsecond thermal skin ablation technology assessed by modeling of heat penetration into the skin, fabrication and characterization of a novel thermal ablation device, and skin permeability measurement.

Methods and Materials

   Heat penetration into the skin was simulated using ANSYS software employing a one-dimensional transient semi-infinite model with the boundary condition [2] that the temperature of the skin surface was held constant at various temperatures up to 1100 during the thermal exposure of 1 µs to 100 ms. Simulations were carried out with and without a conductive mask used for guiding thermal energy only and with and without a "windows" mask used for localized ablation effect as shown in Fig. 1.

The thermal ablation device was designed by modifying a laminated gas generator actuator developed previously for aeronautical purposes [3]. A microchamber consisting of five patterned and integrated layers (two brass electrodes, two PMMA backing layers, and one microchamber layer) was fabricated using laser micromachining and lamination of each layer as shown in Fig. 2A. Two different mask designs were fabricated to facilitate mechanistic study and device optimization. A conductive mask was designed to efficiently conduct heat without allowing physical contact between the steam and the skin. A windows mask was designed to allow heat transfer to the skin through 100 µm-diameter holes in the mask and to insulate the skin everywhere else.

For the time characterization of thermal ablation, two voltage driver circuits were placed on either side of the microchamber to measure the voltage drop across the microchamber and the MOSFET switch. A ring-type piezoelectric force sensor was attached behind the microchamber to measure the force exerted by the actuation of the device. During device actuation, in some cases a high-speed video was taken at a rate of 100,000 frames per second (EKTAPRO 4540, Kodak).

To visualize the selective and localized removal of stratum corneum, a piece of full-thickness pig cadaver skin prepared with IACUC approval was ablated and then a hydrophilic sulforhodamine solution was applied to the skin surface. To measure the permeability of thermally abated skin, human cadaver skin was obtained with approval from the Georgia Tech Institutional Review Board and either left intact or exposed to thermal ablation. The skin permeability was measured for up to 48 h using a Franz diffusion cell, the donor compartment of which was filled with either 10-3 M sulforhodamine B or 10-4 M Texas Red-labeled bovine serum albumin (BSA) in PBS.

Results and Discussion

Our goal was to identify the longest thermal exposure that does not allow significant heat to reach the viable epidermis using finite element modeling. In Case I shown in Fig. 1A, when the skin is directly exposed to superheated steam at 1100 , the viable epidermis is predicted to have no significant temperature rise after exposures of 1 ms, 10 ms and 100 ms as shown in Fig. 1B. Because heat transfer is most delayed in the stratum corneum layer with the lowest thermal conductivity of all the skin layers, heat barely penetrates into the viable epidermis during these short exposures. After a 1 ms exposure, the viable epidermis is predicted to be heated to a temperature of 180 , which is expected to injure cells and cause pain as shown in Fig. 1E.

The mask design used in this study as in Case II and III shown in Fig. 1A permits sufficient heat transfer that the skin surface temperature is almost the same as the ejectate temperature after millisecond exposures, but is significantly lower after microsecond exposures as shown in Fig 1C and 1D. These data suggest that heating the skin for on the order of 100 ms may be optimal because that exposure time is long enough to allow the skin surface to be substantially heated, but still short enough to avoid heating below the stratum corneum.

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Figure 1. Simulation of heat penetration across skin heated on its surface to 1100oC for 1 ms to 100 ms. (A) Schematic showing skin heating with different schemes. Simulation predictions for heating (B) as direct exposure, (C) through a conductive mask and (D) through a conductive and a windows mask. (E) The time required to increase skin temperature by 10oC at the interface.

Guided by the heat transfer simulation, we designed a thermal ablation device to achieve thermal exposures on the order of 100 µs as shown in Fig. 2. After the microchamber is connected to a power supply circuit (Fig. 2B), the electrical energy stored in the capacitor (Fig. 2C) is discharged rapidly with the MOSFET switch on, generating an electrical discharge between the two electrodes in the microchamber. This nearly instantaneous event heats, vaporizes and ejects the saline from the microchamber through the nozzle, indicating the rapid transformation of electrical energy into thermal and mechanical energy that can be used for skin ablation.

We found that the thermal ablation device operates on a timescale on the order of 100 µs. The video image shown in Fig. 3A is the image of ejectate captured in a single frame, indicating that the steam jet was ejected within 10 µs at the most. As shown in Fig. 3B, the voltage across the microchamber rapidly rises and peaks at 7 µs, which is followed by a sudden voltage drop until 50 µs, which is the primary electrical discharge occurring in the microchamber. As shown in Fig. 3C, the force exerted during electrical discharge peaks at 100 µs, which corresponds to the timescale over which the primary steam ejection occurs. The force curve then oscillates due to resonance of the apparatus and dissipation of the reaction force energy, but is not believed to reflect forces generated directly by the steam jet ejection.

Figure 2. Microsecond thermal ablation system. (A) Schematic diagram of the disintegrated layers of the microchamber, (B) Image of a microchamber connected to a power supply circuit, (C) Diagram of the electrical circuit used to transform electrical energy into thermal and mechanical energy in the microchamber

Figure 3. (A) View of the ejectate from the device, (B) Voltage change across the microchamber, and (C) Force measured during electrical discharge.

Guided by the design, fabrication, and characterization of microsecond thermal ablation system, we ablated the skin to cause selective removal of the stratum corneum as shown in Fig 4A and 4B. The selective removal of stratum corneum led to a remarkable increase in the transdermal flux of both molecules studied, as shown in Fig 4C and 4D. After a lag time, skin permeability to sulforhodamine and BSA was 3.1 ( 0.9) • 10-2 cm/h and 3.6 ( 0.8) • 10-3 cm/h, respectively. This corresponds to a 104-fold increase in permeability to sulforhodamine and a 103-fold increase in permeability to BSA after thermal ablation in comparison with intact and untreated skin.

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Figure 4. (A) The surface of skin ablated with microsecond thermal ablation device using a windows mask, (B) Histological image of the skin sample in (B), Cumulative delivery of (C) sulforhodamine and (D) Texas Red-labeled BSA.

Conclusion

Through modeling, we determined that thermal ablation should occur on the 100 µs time scale in order to ablate the stratum corneum selectively. To generate the high temperatures needed for skin ablation on this time scale, we designed a microdevice that rapidly heats water by an electrical discharge, thereby ejecting a superheated steam jet at the skin surface. We found that this device was able to selectively ablate stratum corneum and, when combined with a windows mask, enabled three-dimensional control over tissue removal, resulting in the increase of skin permeability to sulforhodamine and BSA. This study was funded by NIH and by Tyco Healthcare (now Covidien).

Reference

[1]           J. W. Lee, P. Gadiraju, J. H. Park, M. G. Allen, M. R. Prausnitz, J Control Release 2011, 154, 58-68.

[2]       M. L. Cohen, Journal of Investigative Dermatology 1977, 69, 333-338.

[3]       B. English, in School of Mechanical Engineering, Vol. Doctor of Philosophy, Georgia Institute of Technology, Atlanta 2006.


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