Interstitial fluid monitoring

• US 6,056,738 A
• Filed: 10/22/1997
• Issued: 05/02/2000
• Est. Priority Date: 01/31/1997
• Status: Expired due to Fees

• Current Assignee: Transmedica International Incorporated
• Original Assignee: Transmedica International Incorporated
• Inventors: Marchitto, Kevin S., Flock, Stephen T.
• Primary Examiner(s): O'Connor, Cary
• Assistant Examiner(s): ASTORINO, MICHAEL C
• Application Number:
  US08/955,982
• Time in Patent Office: 923 Days
• Field of Search: 606/9, 606/2, 606/3, 600/573, 128/897, 128/898
• US Class Current: 606/2
• CPC Class Codes: A61B 17/3476 Powered trocars, e.g. electrosurgical cutting, lasers, powered knives
• 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 2010/008 Interstitial fluid
• CPC Class Codes: A61B 2017/00057 Light
• 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 2090/395 with marking agent for marking skin or other tissue
• CPC Class Codes: A61B 2218/008 for smoke evacuation
• CPC Class Codes: A61B 5/150022 for capillary blood or interstitial fluid
• CPC Class Codes: A61B 5/150076 by heating
• CPC Class Codes: A61B 5/150099 by negative pressure, other than vacuum extraction into a syringe by pulling on the piston rod or into pre-evacuated tubes
• CPC Class Codes: A61B 5/15138 provided with means to ensure the protection of the user, e.g. to avoid laser light entering the eyes of a user
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• 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 37/00 Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04
• CPC Class Codes: H04R 25/75 Electric tinnitus maskers providing an auditory perception

Abstract

The present invention provides an improved method of measuring analytes in bodily fluids without the use of a sharp. The method having the steps of irradiating the skin of a patient by focused pulses of electromagnetic energy emitted by a laser. By proper selection of wavelength, energy fluence, pulse temporal width and irradiation spot size, the pulses precisely irradiate the skin to a selectable depth, without causing clinically relevant damage to healthy portions of the skin. After irradiation, interstitial fluid is collected into a container or left on the skin. The interstitial fluid is then tested for a desired analyte to approximate the analyte concentration in other bodily fluids. Alternatively, after the forced formation of a microblister, the epidermis covering the microblister is lysed and the interstitial fluid is subsequently collected and tested.

Claims

1. A method of measuring analyte concentrations in bodily fluids, comprising the steps of:

a) focusing a laser beam with sufficient energy fluence to alter the skin at least as deep as the stratum corneum, but not as deep as the capillary layer; and

b) firing the laser to create a site of alteration, the site having a diameter of between 0.5 microns and 5.0 cm.

c) collecting a sample of interstitial fluid released by steps (a) and (b); and

d) testing the fluid for analyte concentration.

2. The method of claim 1, wherein the laser beam has a wavelength of 0.2-10 microns.

3. The method of claim 1, wherein the laser beam has a wavelength of between 1.5-3.0 microns.

4. The method of claim 1, wherein the laser beam has a wavelength of about 2.94 microns.

5. The method of claim 1, wherein a laser selected from the group consisting of Er:

YAG, pulsed CO₂, Ho;

YAG, Er;

YAP, Er/Cr;

YSGG, Ho;

YSGG, Er;

GGSG, Er;

YLF, Tm;

YAG, Ho;

YAG, Ho/Nd;

Yalo₃, cobalt;

MgF₂, HF chemical, DF chemical, carbon monoxide, deep UV lasers, and frequency tripled Nd;

YAG lasers emits the laser beam.

6. The method of claim 1, wherein an Er:

YAG laser emits the laser beam.

7. The method of claim 1, wherein a modulated laser selected from the group consisting of continuous-wave CO₂, Nd:

YAG, Thallium;

YAG and diode lasers emits the laser beam.

8. The method of claim 1, wherein the laser beam is focused to a diameter of 0.1 mm-5.0 mm at a site on the skin.

9. The method of claim 1, wherein the energy fluence of the laser beam at the skin is 0.03-100,000 J/cm².

10. The method of claim 1, wherein the energy fluence of the laser beam at the skin is 0.03-9.6 J/cm².

11. The method of claim 1, wherein multiple sites of alteration are created.

12. The method of claim 1, further comprising a beam splitter positioned to create, simultaneously from the laser, multiple sites of alteration.

13. The method of claim 12, wherein the beam splitter is selected from a series of partially silvered mirrors, a series of dichroic mirrors, and a series of beam-splitting prisms.

14. The method of claim 1, further comprising an acousto-optic modulator outside the laser cavity wherein the modulator consecutively deflects the beam at different angles to create different sites of alteration on the skin.

15. The method of claim 1, wherein the analyte to be measured is selected from the group consisting of Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, Cl^-, HCO₃^-, HHCO₃, phosphates, S₄^--, glucose, amino acid, cholesterol, phospholipids, neutral fat, PO₂^--, pH, organic acids or proteins.

16. The method of claim 1, further comprising a container positioned proximal to the site of alteration and through which the laser beam passes for collection of the interstitial fluid.

17. The method of claim 1, wherein the analyte concentration is tested while the container unit is attached to the laser device.

18. The method of claim 1, further comprising the step of applying a therapeutically effective amount of a pharmaceutical composition at the site of alteration.

19. The method of claim 18, wherein the anaylyte concentration is used to determine the amount of pharmaceutical substance administered.

20. The method of claim 1, further comprising the step of applying a pressure gradient to the skin after formation of the site of alteration to increase the diffusion rate of interstitial fluid.

21. The method of claim 1, further comprising the step of mechanically increasing the diffusion rate of interstitial fluid after formation of a site of alteration.

22. The method of claim 21, wherein sub-atmospheric pressure is applied at the site of alteration to increase diffusion.

23. The method of claim 22, wherein the container unit is under sub-atmospheric pressure.

24. The method of claim 1, wherein the removal of bodily fluids is increased by applying a pressure gradient at the site of alteration.

25. A method of measuring analyte concentration in bodily fluids, comprising the steps of:

a) applying sub-atmospheric pressure at the surface of the skin to induce the formation of a microblister;

b) focusing a laser beam with sufficient energy fluence to lyse a microblister;

c) firing the laser to lyse the blister;

d) collecting a sample of interstitial fluid released by steps (a), (b) and

(c); and

e) testing the fluid for analyte concentration.

26. The method of claim 25, wherein the laser beam has a wavelength of 0.2-10 microns.

27. The method of claim 25, wherein the laser beam has a wavelength of between 1.5-3.0 microns.

28. The method of claim 25, wherein the laser beam has a wavelength of about 2.94 microns.

29. The method of claim 25, wherein a laser selected from the group consisting of Er:

YAG, pulsed CO₂ Ho;

YAG, Er;

YAP, Er/Cr;

YSGG, Ho;

YSGG, Er;

GGSG, Er;

YLF, Tm;

YAG, Ho;

YAG, Ho/Nd;

Yalo₃, cobalt;

MgF₂, HF chemical, DF chemical, carbon monoxide, deep UV lasers, and frequency tripled Nd;

YAG lasers emits the laser beam.

30. The method of claim 25, wherein an Er:

YAG laser emits the laser beam.

31. The method of claim 25, wherein a modulated laser selected from the group consisting of continuous-wave CO₂, Nd:

YAG, Thallium;

YAG and diode lasers emits the laser beam.

32. The method of claim 25, wherein the laser beam is focused to a diameter 0.1 mm-5.0 mm at a site on the skin.

33. The method of claim 25, wherein the energy fluence of the laser beam at the skin is 0.03-100,000 J/cm².

34. The method of claim 25, wherein the energy fluence of the laser beam at the skin is 0.03-9.6 J/cm².

35. The method of claim 25, wherein multiple microblisters are created.

36. The method of claim 25, further comprising a beam splitter positioned to lyse, simultaneously from the laser, multiple microblisters.

37. The method of claim 36, wherein the beam splitter is selected from a series of partially silvered mirrors, a series of dichroic mirrors, and a series of beam-splitting prisms.

38. The method of claim 25, further comprising an acousto-optic modulator outside the laser cavity wherein the modulator consecutively deflects the beam at different angles to lyse different microblisters.

39. The method of claim 25, wherein the analyte to be measured is selected from the group consisting of Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, Cl^-, HCO₃^-, HHCO₃, phosphates, S₄^--, glucose, amino acid, cholesterol, phospholipids, neutral fat, PO₂^--, pH, organic acids or proteins.

40. The method of claim 25, further comprising a container positioned proximal to the microblister and through which the laser beam passes for collection of the interstitial fluid.

41. The method of claim 25, wherein the analyte concentration is tested while the container unit is attached to the laser device.

42. The method of claim 25, further comprising the step of applying a therapeutically effective amount of a pharmaceutical composition at the microblister site.

43. The method of claim 42, wherein the analyte concentration is used to determine the amount of pharmaceutical substance administered.