Microporation of human skin for monitoring the concentration of an analyte

• US 5,885,211 A
• Filed: 09/05/1997
• Issued: 03/23/1999
• Est. Priority Date: 11/15/1993
• Status: Expired due to Term

• Current Assignee: Hyundai Motor Company (Hyundai Motor Group), MidCap Funding III, LLC, Nitto Denko Corporation
• Original Assignee: Altia Technology (Altia Group), Spectrix Incorporated
• Inventors: Eppstein, Jonathan A., Hatch, Michael R., Yang, Difei
• Primary Examiner(s): Smith, Ruth S.
• Application Number:
  US08/776,863
• Time in Patent Office: 564 Days
• Field of Search: 600/309, 600/310, 600/316, 600/365, 600/573, 600/476, 604/22, 604/20, 604/289, 604/290, 604/49, 606/9, 606/131, 607/96, 607/100, 607/104, 601/2
• US Class Current: 600/309
• CPC Class Codes: A61B 10/0045 Devices for taking samples of body liquids devices for taking blood samples A61B5/15
• CPC Class Codes: A61B 17/3203 Fluid jet cutting instruments
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 18/203 applying laser energy to the outside of the body
• CPC Class Codes: A61B 2017/00172 Pulse trains, bursts, intermittent continuous operation
• CPC Class Codes: A61B 2017/00761 Removing layer of skin tissue, e.g. wrinkles, scars or cancerous tissue
• CPC Class Codes: A61B 2017/00765 Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
• CPC Class Codes: A61B 2018/00452 Skin
• CPC Class Codes: A61B 2018/0047 Upper parts of the skin, e.g. skin peeling or treatment of wrinkles
• CPC Class Codes: A61B 2562/0295 Strip shaped analyte sensors for apparatus classified in A61B5/145 or A61B5/157 disposable multilayered or laminated electrodes G01N27/307; details of handling chemical test elements G01N33/4875
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61B 5/681 Wristwatch-type devices
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: A61M 2037/0007 having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Abstract

A method of enhancing the permeability of the skin to an analyte for diagnostic purposes or to a drug for therapeutic purposes is described utilizing microporation and optionally sonic energy and a chemical enhancer. If selected, the sonic energy may be modulated by means of frequency modulation, amplitude modulation, phase modulation, and/or combinations thereof. Microporation is accomplished by (a) ablating the stratum corneum by localized rapid heating of water such that such water is vaporized, thus eroding the cells; (b) puncturing the stratum corneum with a micro-lancet calibrated to form a micropore of up to about 1000 μm in diameter; (c) ablating the stratum corneum by focusing a tightly focused beam of sonic energy onto the stratum corneum; (d) hydraulically puncturing the stratum corneum with a high pressure jet of fluid to form a micropore of up to about 1000 μm in diameter, or (e) puncturing the stratum corneum with short pulses of electricity to form a micropore of up to about 1000 μm in diameter. A dye with an absorption maximum matched to the wavelength of a pulsed light source can be absorbed into the stratum corneum to concentrate the energy of the pulsed light source and aid in ablation of the stratum corneum. Alternatively, a hot wire can be caused to contact the stratum corneum.

Claims

1. A method for monitoring the concentration of an analyte in an individual'"'"'s body by enhancing the permeability of the stratum corneum of a selected area of the individual'"'"'s body surface to the analyte, comprising steps of:

(a) porating the stratum corneum of said selected area to form at least one micropore 1-1000 μ

m in diameter in said stratum corneum comprising the step of ablating the stratum corneum by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said stratum corneum such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances thereby removing the stratum corneum in said selected area;

(b) collecting a selected amount of the analyte through said micropore; and

(c) quantitating the analyte collected.

2. The method of claim 1, and further comprising the step of applying sonic energy to said selected area at a frequency in the range of 5 kHz to 100 MHz.

3. The method of claim 2, wherein said sonic energy is modulated by frequency modulation, amplitude modulation, phase modulation, or combinations thereof.

4. The method of claim 1, and further comprising the step of contacting the selected area of the individual'"'"'s body with a chemical enhancer to further enhance analyte withdrawal.

5. The method of claim 1, and further comprising the step of applying electroporation to enhance analyte withdrawal from capillary walls.

6. The method of claim 1, wherein the step of ablating comprises the steps of treating at least said selected area with an effective amount of a dye that exhibits absorption over the emission range of a pulsed light source and focusing the output of a series of pulses from said pulsed light source onto said dye such that said dye is heated sufficiently to conductively transfer heat to said stratum corneum to elevate the temperature of tissue-bound water and over vaporizable substances in said selected area above the vaporization point of said water and said other vaporizable substances.

7. The method of claim 6, wherein the step of treating comprises applying a film treated with said dye to said selected area.

8. The method of claim 6, wherein the step of treating comprises applying to said selected area an adhesive disposed on a solid support which is treated with said dye.

9. The method of claim 6, wherein the step of treating comprises applying said dye directly to said selected area.

10. The method of claim 6, wherein said dye is combined with a chemical enhancer.

11. The method of claim 6, wherein the step of ablating comprises controlling said pulsed light source to emit pulses at a wavelength that is not significantly absorbed by skin.

12. The method of claim 11, wherein the step of focusing said pulsed light source comprises focusing a laser diode emitting in the range of about 630 to 1550 nm.

13. The method of claim 11, wherein the step of focusing said pulsed light source comprises focusing a laser diode pumped optical parametric oscillator emitting in the range of about 700 to 3000 nm.

14. The method of claim 11, wherein the step of focusing said pulsed light source comprises focusing a pulsed light source selected from the group consisting of arc lamps, incandescent lamps, and light emitting diodes.

15. The method of claim 11, and further comprising the step of sensing to determine when the barrier properties of the stratum corneum have been surmounted.

16. The method of claim 15, wherein the step of sensing comprises receiving reflected light from said selected area and measuring a quality of said reflected light, and terminating application of the pulse light source based upon the quality of the reflected light.

17. The method of claim 6, wherein the step of ablating comprises controlling the duration of a pulse on-time and the duration of a pulse off-time of a cycle of the pulsed light source so as to reduce the sensation to the individual.

18. The method of claim 17, wherein the duration of the pulse on-time is less than 50 milliseconds and the duration of the pulse off-time is greater than 10 milliseconds.

19. The method of claim 6, and further comprising the step, prior to the step of porating said stratum corneum, of illuminating at least said selected area with unfocused light from said pulsed light source such that said selected area illuminated with said light is sterilized.

20. The method of claim 1, and further comprising the step of cooling said selected area of stratum corneum and adjacent skin tissues such that said selected area and adjacent skin tissues are in a selected cooled condition.

21. The method of claim 20, wherein the step of cooling comprises applying a Peltier device to said selected area.

22. The method of claim 1, wherein the step of ablating causes exudation of interstitial fluid and wherein the step of collecting said analyte comprises collecting a selected amount of said interstitial fluid.

23. The method of claim 22, and further comprising the step, after said selected amount of interstitial fluid is collected, of sealing said micropore by applying an effective amount of energy from said pulsed light source such that interstitial fluid remaining in said micropore is caused to coagulate.

24. The method of claim 22, and further comprising the step of applying a pressure gradient to said selected area of stratum corneum for enhancing exudation of interstitial fluid.

25. The method of claim 1, wherein the step of ablating comprises the step of contacting said selected area with a solid thermal probe, such that the temperature of said selected area is raised from ambient skin temperature to greater than 123°

C.

26. The method of claim 25, wherein the step of ablating further comprises the step of returning the temperature of said selected area to approximately ambient skin temperature by withdrawing said solid thermal probe from contact with the stratum corneum.

27. The method of claim 25, and further comprising the step of controlling the depth of said micropore by monitoring electrical impedance between said solid thermal probe and said individual'"'"'s body through said selected area of stratum corneum and adjacent skin tissues and withdrawing said solid thermal probe from contact with the stratum corneum when a change in impedance associated with contacting an epidermal layer underlying the stratum corneum is detected.

28. The method of claim 25, wherein the step of ablating comprises heating said solid thermal probe by an ohmic heating element.

29. The method of claim 25, wherein the step of ablating comprises the step of modulating the temperature of said solid thermal probe so as to reduce the sensation to the individual.

30. The method of claim 29, wherein the step of modulating comprises heating the solid thermal probe to greater than 123°

C. for less than 50 milliseconds for an on-time of a cycle, and returning the temperature of the solid thermal probe to approximately ambient temperature for greater than 10 milliseconds for an off-time of a cycle.

31. The method of claim 29, wherein the solid thermal probe is formed by a current loop having a high resistance point, and wherein the step of modulating the temperature of said solid thermal probe comprises passing a modulated electrical current through the current loop.

32. The method of claim 25, wherein the step of ablating comprises the step of heating said solid thermal probe by positioning it in a modulatable alternating magnetic field of an excitation coil such that energizing the excitation coil with alternating current produces eddy currents sufficient to heat the solid thermal probe by internal ohmic losses.

33. The method of claim 1, wherein the step of collecting an analyte comprises collecting glucose.

34. The method of claim 33, wherein the step of quantitating comprises quantitating glucose by means of a calorimetric glucose assay or an electro-chemical biosensor.

35. A method for forming micropores in a selected area of the stratum corneum for enhancing the permeability of skin, comprising the step of ablating the stratum corneum by placing a heat conducting element in substantial physical contact with the selected area of the stratum corneum to deliver sufficient energy by conduction to said selected area of said stratum corneum such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances thereby removing the stratum corneum and forming at least one micropore 1-1000 μ

m in diameter in said selected area of said stratum corneum.

36. The method of claim 35, and further comprising the step of applying sonic energy to said selected area at a frequency in the range of 5 KHz to 100 MHz to further enhance the permeability of the skin.

37. The method of claim 36, wherein said sonic energy is modulated by frequency modulation, amplitude modulation, phase modulation, or combinations thereof.

38. The method of claim 35, and further comprising the step of contacting the selected area of the individual'"'"'s body with a chemical enhancer to further enhance permeability of the skin.

39. The method of claim 35, and further comprising the step of applying electroporation to enhance permeability of capillary walls and cell membranes.

40. The method of claim 35, wherein the step of ablating comprises steps of treating at least said selected area with an effective amount of a dye that exhibits absorption over the emission range of a pulsed light source and focusing the output of a series of pulses from said pulsed light source onto said dye such that said dye is heated sufficiently to conductively transfer heat to said stratum corneum to elevate the temperature of tissue-bound water and other vaporizable substances in said selected area above the vaporization point of said water and other vaporizable substances.

41. The method of claim 40, wherein the step of treating comprises applying a film treated with said dye to said selected area.

42. The method of claim 40, wherein the step of treating comprises applying to said selected area an adhesive disposed on a solid support which is treated with said dye.

43. The method of claim 40, wherein the step of treating comprises applying said dye directly to said selected area.

44. The method of claim 40, wherein said dye is combined with a chemical enhancer.

45. The method of claim 40, wherein the step of ablating comprises controlling said pulsed light source to emit pulses at a wavelength that is not significantly absorbed by the skin.

46. The method of claim 45, wherein the step of focusing said pulsed light source comprises focusing a laser diode emitting in the range of about 630 to 1550 nm.

47. The method of claim 45, wherein the step of focusing said pulsed light source comprises focusing a laser diode pumped optical parametric oscillator emitting in the range of about 700 to 3000 nm.

48. The method of claim 45, wherein the step of focusing said pulsed light source comprises focusing a pulsed light source selected from the group consisting of arc lamps, incandescent lamps, and light emitting diodes.

49. The method of claim 40, wherein the step of ablating comprises controlling the duration of a pulse on-time and the duration of a pulse off-time of a cycle of the pulsed light source so as to reduce the sensation to the individual.

50. The method of claim 49, wherein the duration of the pulse on-time is less than 50 milliseconds and the duration of the pulse off-time is greater than 10 milliseconds.

51. The method of claim 40, and further comprising the step of sensing to determine when the barrier properties of the stratum corneum have been surmounted.

52. The method of claim 51, wherein the step of sensing comprises receiving reflected light from said selected area and measuring a quality of said reflected light, and terminating application of the pulse light source based upon the quality of the reflected light.

53. The method of claim 40, further comprising the step, prior to porating said stratum corneum, of illuminating at least said selected area with unfocused light from said pulsed light source such that said selected area illuminated with said light is sterilized.

54. The method of claim 35, and further comprising the step of cooling said selected area of stratum corneum and adjacent skin tissues such that said selected area and adjacent skin tissues are in a selected cooled condition.

55. The method of claim 54, wherein the step of cooling comprises applying a Peltier device to said selected area.

56. The method of claim 35, wherein the step of ablating causes exudation of interstitial fluid.

57. The method of claim 35, wherein the step of ablating comprises the step of contacting said selected area with a solid thermal probe which functions as a heat source, such that the temperature of said selected area is raised from ambient skin temperature to greater than 123°

C.

58. The method of claim 57, wherein the step of ablating further comprises the step of returning the temperature of said selected area to approximately ambient skin temperature by withdrawing said solid thermal probe from contact with the stratum corneum.

59. The method of claim 57, and further comprising the step of controlling the depth of said micropore by monitoring electrical impedance between said solid thermal probe and said individual'"'"'s body through said selected area of stratum corneum and adjacent skin tissues and withdrawing said solid thermal probe from contact with the stratum corneum when a change in impedance associated with contacting an epidermal layer underlying the stratum corneum is detected.

60. The method of claim 57, wherein the step of ablating comprises heating said solid thermal probe by an ohmic heating element.

61. The method of claim 57, wherein the step of ablating comprises the step of modulating the temperature of said solid thermal probe so as to reduce the sensation to the individual.

62. The method of claim 61, wherein the step of modulating comprises heating the solid thermal probe to greater than 123°

C. for less than 50 milliseconds for an on-time of a cycle and returning the temperature of the solid thermal probe to approximately ambient temperature for greater than 10 milliseconds for an off-time of a cycle.

63. The method of claim 61, wherein the solid thermal probe is formed by a current loop having a high resistance point, and wherein step of modulating the temperature of said solid thermal probe comprises passing a modulated electrical current through the current loop.

64. The method of claim 57, wherein the step of ablating comprises the step of heating said solid thermal probe by positioning it in a modulatable alternating magnetic field of an excitation coil such that energizing the excitation coil with alternating current produces eddy currents sufficient to heat the solid thermal probe by internal ohmic losses.

65. A method of applying a tattoo to said selected area on an individual'"'"'s body comprising the steps of claim 35, and further comprising the step of contacting said selected area with a composition comprising an effective amount of tattooing ink such that the flux of said tattooing ink into the body is enhanced.

66. A method of delivering a permeant into said selected area of an individual'"'"'s body comprising the steps of claim 35, and further comprising the step of contacting said selected area with a composition comprising an effective amount of said permeant such that the flux of said permeant into the body is enhanced.