(184e) Microdermabrasion of Skin for Drug and Vaccine Delivery

INTRODUCTION Systemic delivery of drugs through the skin is an attractive mode of delivery. Skin provides a large surface area for drug delivery and is also easily accessible for drug application. This mode of drug delivery also eliminates some of the problems associated with oral drug delivery, like enzymatic degradation and liver's ?first pass effect'. However, extensive clinical application of this method to deliver a large number of drugs is severely limited by the presence of the top most layer of the skin called the stratum corneum. Stratum corneum is made up of dead cells and provides a major transport barrier to the inward diffusion of drugs applied topically onto the skin. Extensive research is being done in order to find methods that can eliminate or bypass this resistance layer, since presently it has restricted the range of drugs that can be systemically administered through the skin. Presently, only thirteen drugs are available as skin patches for systemic delivery. Expanding this range of drugs to include vaccines is especially appealing, since it may provide a needle-free, safe and painless method to administer vaccines.

In order to mechanically remove the transport barrier provided by stratum corneum, we investigated the use of microdermabrasion. Microdermabrasion is an FDA-approved cosmetic procedure. This procedure is currently used by physicians and aestheticians to rejuvenate facial skin for removing mild scars and treating photo-aging. This procedure utilizes a stream of microparticles under vacuum through a small hand-piece to ablate and aspirate away cells from the skin's surface, thereby causing micro-damage to the skin's surface and promoting remodeling of the skin, which is in turn believed to then treat the objective clinical condition. Our long-term goal is to use microdermabrasion to completely remove the stratum corneum layer to enable direct delivery of drugs into the skin. This method would be especially useful to target vaccines directly into the epidermis, which contains Langerhans cells that can help provide a stronger immune response.

Presently, the microdermabrasion procedure is more of an empirical art. The microdermabrasion device is itself classified as a type-I (non-life sustaining) device by the FDA, and it never went through any phase-III clinical trials to demonstrate safety and efficacy. The device-dependent variables of suction pressure and crystal flow rate, and operator variables of the speed of moving the hand-piece over the skin and number of passes, all affect the degree of microdermabrasion in a complex way that has not been quantified. It is not known what combination of these variables can precisely remove only the stratum corneum without damaging the underlying skin layers. This information is important to minimize trauma and pain during the procedure. Also, there does not exist a non-invasive method to determine stratum corneum removal during microdermabrasion. Presently, the only way to conclusively determine removal of stratum corneum is through histological analysis, which is impractical for clinical drug and vaccine delivery. Development of a non-invasive indicator of the presence or absence of the stratum corneum will help in automating the microdermabrasion procedure, eliminating operator dependence, and accommodating variability in stratum corneum thickness among individuals.

Given these needs, our goals in this study were to determine the mild conditions of microdermabrasion that would completely remove stratum corneum without damaging the underlying layers, and to develop a non-invasive method to determine complete removal of stratum corneum with real time feedback.

EXPERIMENTAL METHODS A commercially available microdermabrasion device was used to perform microdermabrasion on live humans or non-human primates, and in vitro pig/human cadaver skins. The protocols for human and primate experiments were respectively approved by the IRB and IACUC boards of Emory University. Skin electrical resistance before and after microdermabrasion was measured using an FDA-approved skin conductance meter. Biopsies were then taken from microdermabraded sites for histological examination to study the effect of device and operator parameters on the layers of the skin after microdermabrasion. A control biopsy from an untreated site was also collected as a negative control. The data on skin's electrical resistance was correlated with the amount of stratum corneum left after microdermabrasion.

RESULTS AND DISCUSSION To develop a non-invasive indicator of stratum corneum removal, we used skin's electrical resistance measurement. The electrical resistance of the skin has been found by other investigators to be mainly contributed by the stratum corneum. We therefore hypothesized that a drop in skin's electrical resistance could be used to determine if stratum corneum was removed upon microdermabrasion.

Both in humans and in non-human primates, skin electrical resistance was found to drop considerably from thousands of kohms to low hundreds and tens of kohms following microdermabrasion. Corresponding histological analysis of the stratum corneum showed decrease in its thickness. Upon using strong microdermabrasion conditions, complete denudation of stratum corneum and epidermis was observed, and the corresponding skin electrical resistance was 20-30 kohms. However, at mild microdermabrasion conditions, only partial stratum corneum was removed, and the skin's electrical resistance was found to be 70-80 kohms. This suggests that the final resistance of the skin may be a good indicator of stratum corneum removal and the end-point resistance value that corresponds to complete stratum corneum removal lies between 20-80 kohms. Experiments are in progress to determine the final end-point value.

To determine the mild conditions for microdermabrasion in humans, the hand-piece was evaluated in a stationary and mobile configuration, with the crystal flow rate kept at the maximum device setting, and vacuum pressure ranging from 25 to 45 kPa. It was found that the stationary configuration was more aggressive than the mobile configuration. An unexpected epidermal-dermal separation was also observed in the stationary hand-piece configuration, and even in some of the mobile microdermabrasion biopsies at 40 kPa. These results suggest that the mild condition will be in the mobile configuration at low pressures of around 25-30 kPa. Experiments are being conducted to determine this pressure. Once the mild condition is determined, it will be kept fixed across subjects while the number of passes will be varied until the final skin resistance is achieved. This will help in achieving our long term goal of automating the equipment for consistent stratum corneum removal without causing trauma and pain for subsequent drug and vaccine delivery.

CONCLUSION Skin electrical resistance was found to decrease following microdermabrasion in both humans and non-human primates. The deterministic end-point value of the skin electrical resistance corresponding to complete stratum corneum removal lies between 20-80 kohms. The mobile configuration of the hand-piece produced milder microdermabrasion results at 25-30 kPa.. These results suggest that skin's electrical resistance can be used as an indicator of complete stratum corneum removal, and mobile passes of the hand-piece at 25-30 kPa should help automate and standardize the procedure.

ACKNOWLEDGEMENTS This research was done at the Hope Clinic and the Yerkes Primate Research Center of Emory University, and at the Center for Drug Design, Development and Delivery at Georgia Tech,.and was funded by NIH.