Patent Description:
In a field of beauty care, various methods are proposed to introduce various molecules into a human skin. One example of such methods is an ionic introduction method. The ionic introduction method is a method for introducing various substances provided onto a human skin into the inside of the skin such as a stratum corneum by applying a voltage. Vitamin C derivatives such as an ascorbic acid generally have a negative charge. Therefore, when an aqueous solution including an ascorbic acid is provided onto skin and a negative voltage is applied to the portion where the solution is provided, the ascorbic acid is moved into the skin by the electrostatic repulsion force.

However, the ionic introduction method has a problem that the substances to be introduced into skin must be ionic molecule. Furthermore, the ionic introduction method has another problem in which molecules having a large molecular mass cannot be introduced because the mechanism of the delivery of substances into skin is infiltration between skin cells. Therefore, the ionic introduction method is not suitable to introduce substances having a large molecular mass such as a collagen and hyaluronic acid.

In order to solve the above problems, an electroporation method is proposed. The electroporation method comprises applying voltage pulses to skin after substances to be introduced into the skin are provided onto the skin. applying voltage pulses makes microscopic holes in the skin, the provided substances are introduced into the skin via the microscopic holes. The holes are cured and filled in a short time because the holes are extremely small. Therefore, electroporation has a capacity of introducing even electrically neutral molecules of substances into skin in contrast to the ionic introduction method. Since substances are introduced via holes made in skin instead of just infiltration, molecules having a larger molecule mass can be introduced compared with the ionic introduction method.

However, the electroporation method has a problem of discomfort for a user due to applying voltage pulses. The higher the voltage of the applied pulses is, the more holes are made on the skin and the larger the size of the holes is, and this results in more efficient introduction of substances into the skin. On the other hand, the higher the voltage of the applied pulses is, the more current is applied to the skin, and this results in discomfort for a user such as stimulation, irritation, or a pain sensation. Therefore, conventional methods have employed applying voltage pulses to skin of a user based on output pattern data which are the voltage heights of the pulses. The voltage heights are preliminarily determined based on data of measured electric resistance values of skin.

The electric resistance values of the skin are, however, not necessarily constant and are different with each person due to influences of moisture and fat included in skin. Even in the same person, the electric resistance value of the skin is variable due to the variation of moisture included in the skin affected by temperature and humidity of air and variations of other conditions of the surface of the skin. Since the voltage of pulses are generally set as high as possible in order to maximize the efficiency of the introduction of substances into the skin, the user may feel a pain sensation even applying the same voltage pulses if the electric resistance value of the skin varies. An exemplary electroporation device is disclosed in <CIT>.

The present invention provides an electroporation device according to claim <NUM>. For better understanding of the invention the present disclosure provides further examples of an electroporation device and methods of electroporation. In particular, the methods are not claimed and do not form part of the invention.

Further features and advantages of the present invention will be apparent by referring to the embodiments disclosed in the following detailed description of the invention and the accompanying drawings.

An electroporation method is a technology for introducing active substances inside of the skin; For example, with stratum corneum by applying voltage pulses to the skin to form microscopic holes in the skin. Thus, a higher voltage of the pulse is able to deliver the substrates more efficiently into the skin. However, the electroporation method provides a decrease of an electric resistance of the skin. The decrease of the electric resistance of the skin results from a decrease of a barrier function of the stratum corneum. Conventional electroporation devices apply a constant voltage to the skin regardless of the electric resistance of the skin. Therefore, when the electric resistance of the skin is high, an output current becomes lower and results in a decrease of an efficiency of introducing substances. On the other hand, when the electric resistance of the skin is low, the output current becomes higher and results in an increase of the efficiency of introducing substances but the user feels a stronger discomfort such as stimulation, irritation, or a pain sensation. Therefore, it is necessary to control the voltage of the pulses as much as possible within a range in which the user does not feel or can accept the discomfort but having maximum efficacy.

The present disclosure provides an electroporation device and a method for controlling an electroporation device for measuring an electric resistance of skin of a user in real time and determining parameters of an electroporation voltage pulse output to the skin. Based on the measured electric resistance of the skin, in order to improve an efficiency of an introduction of substances into the skin of the user within a range in which the user does not feel or can accept the discomfort such as stimulation, irritation, or a pain sensation.

<FIG> shows an illustrative configuration of an electroporation device <NUM>. The electroporation device <NUM> comprises a measurement unit <NUM> for measuring an electric resistance of skin and an output unit <NUM> for outputting electroporation voltage pulses. The electroporation device <NUM> may comprise a microprocessor <NUM> for controlling the measurement unit <NUM> and the output unit <NUM>, a timing unit <NUM>, a first electrode <NUM>, and a second electrode <NUM>. At least one of the measurement unit <NUM>, the output unit <NUM>, and the timing unit <NUM> may be incorporated in the microprocessor <NUM>. Although <FIG> shows the electroporation device <NUM> incorporating the measurement unit <NUM> in the microprocessor <NUM>, such a configuration does not limit embodiments of the present invention.

<FIG> shows a situation in which the first and second electrodes <NUM>, <NUM> of the electroporation device <NUM> shown in <FIG> are attached to a body of the user. The first electrode <NUM> is attached to a position for introducing an active substance by the electroporation method, for example, a cheek, and the second electrode <NUM> is attached to a position different from the position to which the first electrode <NUM> is attached, for example, a palm. Forming the first and second electrodes <NUM>, <NUM> in a shape of a tape or a patch helps to be easily attached to the skin of the user.

The measurement unit <NUM> outputs and applies one or more resistance measurement voltage pulses to the skin of the user via the first electrode <NUM>. After outputting the resistance measurement voltage pulses, the measurement unit <NUM> measures an electric resistance value of the skin by using various methods described below based on a potential difference between the first and second electrodes <NUM>, <NUM>.

<FIG> shows a schematic example of a circuit for measuring the electric resistance value of the skin by the resistance measurement voltage pulse. A first resistor R1 and a second resistor R2 are serially connected between an output voltage Vm of the resistance measurement voltage pulse of the measurement unit <NUM> and a ground potential and a third resistor R3 is connected to a point between the first and second resistors R1, R2. Further, the first electrode <NUM> is serially connected to the third resistor R3. The second electrode <NUM> is connected to the ground potential. When the first and second electrodes <NUM>, <NUM> are attached to the user as shown in <FIG>, the resistor Rskin of the skin of the user is connected between the first and second electrodes <NUM>, <NUM> of <FIG>. The output voltage Vm of the measurement unit <NUM> is divided by the first and second resistors R1, R2, and a potential between the first and second resistors R1, R2 is denoted by V0. The potential V0 is further divided by the third resistor R3 and the skin resistor Rskin, and a potential between the third resistor R3 and the first electrode <NUM> is denoted by V1. By measuring V1, an electric resistance value of the skin resistor Rskin is obtained. However, methods for measuring the electric resistance value of the skin by the measurement unit <NUM> are not limited to the circuit configuration shown in <FIG>, but bridge circuits such as a wheatstone bridge and other various methods for measuring an electric resistance can be employed.

After the measurement unit <NUM> measures the electric resistance value of the skin, the output unit <NUM> determines parameters of an electroporation voltage pulse for the electroporation method based on the measured electric resistance value of the skin. The parameters to-be determined may be at least one of a voltage, a pulse duration, an interval between pulses, a number of pulses, and a pulse duty ratio of the electroporation voltage pulse. As described above, a discomfort such as a pain sensation caused by applying the electroporation voltage pulses mainly results from a current applied to the skin. Therefore, it is advantageous to determine the voltage of the electroporation voltage pulse such that the current is maintained at a predetermined value lower than a value at which the user feels the discomfort. The voltage of the electroporation voltage pulse can be set to be, for example, <NUM> V or less, or for example, between <NUM> and <NUM> V. The voltage of the resistance measurement voltage pulse should be set to be sufficient to measure the electric resistance value of the skin but not to vary the electric resistance value of the skin. Therefore, while the electroporation voltage pulse is generally output at a voltage of <NUM> V or less, the voltage of the resistance measurement voltage pulse may be lower than that of the electroporation voltage pulse, for example, <NUM> V or less, or for example, <NUM> V or less.

<FIG> show a configuration in which the resistance measurement voltage pulse and the electroporation voltage pulse are output via the common electrode <NUM>. However, an electrode, to which the resistance measurement voltage pulses, may be different from an electrode to which the electroporation voltage pulses.

The voltage of the electroporation voltage pulse can be determined, for example, by using an analog multiplying circuit for multiplying the measured electric resistance value of the skin and the current value described above preliminarily set. Alternatively, the voltage of the electroporation voltage pulse can be determined by converting the measured electric resistance value to a digital value by using an analog-digital converter and processing the digital value by the microprocessor <NUM>. These methods can determine the voltage of the electroporation voltage device as a substantially continuous value.

Alternatively, a voltage corresponding to a comparator circuit matching with a comparing condition can be determined as the voltage of the electroporation voltage pulse by comparing the measured electric resistance value of the skin with a preliminarily set threshold value of each of a plurality of comparator circuits. <FIG> shows a schematic flow diagram for determining the voltage of the electroporation voltage pulse by using comparator circuits.

In <FIG>, the electric resistance value of the skin measured by the measurement unit <NUM> is converted to a digital value by an analog-digital converter (step <NUM>). Then, it is determined whether or not the measured electric resistance value is larger than a predetermined resistance value Rx (step <NUM>). If the measured electric resistance value is larger than Rx, it is determined that the electrodes are in an open state, i.e., at least one of the first and second electrodes <NUM>, <NUM> is not attached to the skin of the user (step <NUM>), then the process returns to a measurement of the electric resistance value of the skin by the measurement unit <NUM>. If the measured electric resistance value is smaller than Rx, a first comparator determines whether or not the measured electric resistance value is larger than a predetermined electric resistance value Ra (step <NUM>). If the measured electric resistance value is larger than Ra, the voltage of the electroporation voltage pulse is determined to be Va (step <NUM>). If the measured electric resistance is smaller than Ra, a second comparator circuit determines whether or not the measured electric resistance value is larger than a predetermined electric resistance value Rb (<NUM>). In the following steps, the measured resistance value is compared with a predetermined resistance value of a comparator circuit and it is determined whether the voltage of the electroporation voltage pulse is set or the process proceeds to the next comparator circuit similarly to the above steps. The example shown in <FIG> comprises the five comparator circuits and therefore a voltage can be determined among five voltage values as the electroporation voltage pulse in a stepwise manner. Although <FIG> shows the configuration in which the measured electric resistance value of the skin is converted to a digital value by the analog-digital converter and the voltage is selected, a configuration, in which a voltage is selected by analog circuits, can be used. Such circuits having the above configuration have an advantage in which the configuration of the circuits is simple and low-cost compared with the configuration of the circuits varying the voltage in a continuous manner as described above.

Then, the output unit <NUM> outputs and apply one or more electroporation voltage pulses having the determined parameters to the skin of the user via the second electrode <NUM>.

<FIG> shows an example of voltage pulses output by the measurement unit <NUM> and the output unit <NUM> over time. First, the measurement unit <NUM> outputs one resistance measurement voltage pulse <NUM> and measures the electric resistance of the skin as described above. Then, the output unit <NUM> determines, for example, a voltage of the electroporation voltage pulse based on the measured electric resistance value and outputs one electroporation voltage pulse <NUM> as described above. Then, the measurement unit <NUM> outputs a next resistance measurement voltage pulse <NUM>' with a predetermined interval after the output of the resistance measurement voltage pulse <NUM> and measures the electric resistance value of the skin. Then, the output unit <NUM> determines, for example, the voltage of the electroporation voltage pulse based on the measured electric resistance value and outputs a next electroporation voltage pulse <NUM>' with a predetermined interval after the output of the electroporation voltage pulse <NUM>. Until the output of the pulses is automatically or manually finished, the above cycle is repeated to perform the electroporation method to the skin of the user. Since, in general, an electric resistance value of skin decreases for each application of electroporation voltage pulse as described below, the voltage of the electroporation voltage pulse gradually decreases in order to maintain the current applied to the skin at a predetermined value.

As described above, in the case that the electroporation device is configured to alternatively output the resistance measurement voltage pulse <NUM> and the electroporation voltage pulse <NUM> one by one and measure the electric resistance value of the skin for one output of the electroporation voltage pulse, the voltage of the electroporation voltage pulse can be varied to follow the change of the electric resistance of the skin and precisely maintain the current applied to the skin to be a predetermined value. Therefore, discomfort such as a pain sensation to the user can be avoided.

<FIG> shows another example of voltage pulses output by the measurement unit <NUM> and the output unit <NUM> over time. First, the measurement unit <NUM> outputs one resistance measurement voltage pulse <NUM> and measures the electric resistance value of the skin as described above. Then, the output unit <NUM> determines, for example, the voltage of the electroporation voltage pulse based on the measured electric resistance value and outputs a bunch of electroporation voltage pulses <NUM> including a plurality of electroporation voltage pulses 704a, 704b, 704c as described above. Then, the measurement unit <NUM> outputs a next resistance measurement voltage pulse <NUM>' with a predetermined interval after outputting the resistance measurement voltage pulse <NUM> and measures the electric resistance value of the skin. Then, the output unit <NUM> determines, for example, the voltage of the electroporation voltage pulse based on the measured electric resistance value of the skin and outputs a bunch of electroporation voltage pulses <NUM>' including a plurality of electroporation voltage pulses 704a', 704b', 704c' with a predetermined interval after outputting the bunch of electroporation voltage pulses <NUM>. Until the output of the pulses is automatically or manually finished, the above cycle is repeated to perform the electroporation method to the skin of the user. Although <FIG> shows the example outputting three electroporation voltage pulses for one resistance measurement voltage pulse, the number of the electroporation voltage pulses in a bunch is not limited to the above example and any numbers of electroporation voltage pulses can be output in a bunch.

As described above, in the case that the electroporation device is configured to output a plurality of electroporation voltage pulses <NUM> after outputting one resistance measurement voltage pulse <NUM>, the power consumption associated with the output of the resistance measurement voltage pulse, measurement of the electric resistance value, and determination of the voltage of the electroporation voltage pulse can be reduced. Such a configuration is particularly suitable for a case that the change of the electric resistance value of the skin due to output of the electroporation voltage pulses is relatively small.

The output of the resistance measurement voltage pulses and the electroporation voltage pulses is not limited to the above examples but can employ various configurations. For example, the electroporation device can be configured such that output unit <NUM> outputs one or more electroporation voltage pulses after the measurement unit <NUM> outputs a plurality of resistance measurement voltage pulses and measures the electric resistance value of the skin. In this case, since the electric resistance value of the skin can be determined by averaging the measurement results obtained by the output of the plurality of resistance measurement voltage pulses, the electric resistance value can be stably determined even if the results of the measurement of the electric resistance value of the skin are unstable.

The output of the resistance measurement of the voltage pulses and the electroporation voltage pulses described above can be controlled by timing instructions output to the measurement unit <NUM> and the output unit <NUM> by the microprocessor <NUM> or the timing unit <NUM> such as a timer circuit.

The electroporation device and the method for controlling the electroporation device configured as described above can minimize discomfort of the user and facilitate delivering active substances to the skin such as the stratum corneum because the electric resistance value of the skin of the user is measured substantially in real time and the electroporation voltage pulses to be applied are modulated based on the measured electric resistance value.

<FIG> shows a side view of a schematic test system <NUM> for measuring a variation of an electric resistance value of skin and <FIG> shows a plan view of the test system <NUM>.

A piece of a porcine ear skin <NUM>, electric characteristics of which are similar to those of a human skin, was disposed on an aluminum heating plate <NUM> with interposing a sheet of paper <NUM> including <NUM> % NaCl solution. Then, two electrodes <NUM>, <NUM> were disposed on a surface of the porcine ear skin <NUM> with a predetermined gap. The electrodes <NUM>, <NUM> were wetted. Voltage pulses were repeatedly applied between the electrodes <NUM>, <NUM>. Table <NUM> shows electric resistance values of the porcine ear skin <NUM> after applying the electric pulses <NUM> times with a voltage between <NUM> to <NUM> V, a duration of <NUM> milliseconds, an interval of <NUM> milliseconds, and therefore a pulse duty ratio of <NUM> as relative values when an electric resistance value before applying the voltage pulses is <NUM> %.

As shown in Table <NUM>, it was found that the higher the voltage of the applied pulse is, the electric resistance value of the skin decreases.

Table <NUM> shows electric resistance values of the porcine ear skin <NUM> after applying the electric pulses <NUM> times with a voltage of <NUM> V, a duration between <NUM> to <NUM> milliseconds, and a pulse duty ratio of <NUM>, and electric resistance values of the porcine ear skin <NUM> after application of the voltage pulses with <NUM> cycles of <NUM> times as relative values when an electric resistance value before applying the voltage pulses is <NUM> %.

From the above experimental results, it was found that the electric resistance of the skin gradually decreased in response to the number of the application of the voltage pulses. Therefore, it was found that if voltage pulses based on a predetermined output pattern are applied, an electric resistance of skin of a user gradually decreases. This results in the increase of a current applied to the skin and causes a discomfort even if the user did not feel discomfort when the application of the pulses started. Conventional devices and methods using pulse heights predetermined based on data of preliminarily measured electric resistance of skins to apply voltage pulses to skin of a user based on the pattern data cannot vary parameters of the voltage pulse while applying the voltage pulses, and therefore cannot avoid an increase of discomfort due to an decrease of the electric resistance of the skin. However, since the present invention measures the electric resistance of the skin substantially in real time and varies the parameters of the voltage pluses substantially in real time based on the measurement during applying the electroporation voltage pulses, a current applied to the skin can be maintained at a predetermined value or less and avoid an increase of a discomfort due to a decrease of the electric resistance of the skin.

Claim 1:
An electroporation device (<NUM>) comprising:
a measurement unit (<NUM>) being configured to provide multiple outputs of one or more resistance measurement voltage pulses for measuring a resistance of skin of a user at a predetermined interval;
an output unit (<NUM>) being configured to provide an output of one or more electroporation voltage pulses to the skin of the user based on the resistance of the skin of the user per each output of the one or more resistance measurement voltage pulses,
a first electrode (<NUM>) having a shape of a tape or patch; and
a second electrode (<NUM>) having a shape of a tape or patch, wherein:
the measurement unit (<NUM>) is configured to output the resistance measurement voltage pulses having a voltage lower than a voltage of the electroporation voltage pulses
the measurement unit (<NUM>) and the output unit (<NUM>) are configured to output the resistance measurement voltage pulses and the electroporation voltage pulses on the skin of the user via the first electrode configured to be located on a position of the skin of the user where the active substance is introduced, and
the second electrode is configured to be located located on a position of the skin of the user different from the first electrode.