U.S. patent application number 10/734529 was filed with the patent office on 2004-07-01 for removable tip for laser device.
This patent application is currently assigned to Transmedica International, Inc.. Invention is credited to Flock, Stephen T., Marchitto, Kevin S..
Application Number | 20040127815 10/734529 |
Document ID | / |
Family ID | 25156545 |
Filed Date | 2004-07-01 |
United States Patent
Application |
20040127815 |
Kind Code |
A1 |
Marchitto, Kevin S. ; et
al. |
July 1, 2004 |
Removable tip for laser device
Abstract
The present invention provides an improved method of measuring
analytes in body 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 body 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.
Inventors: |
Marchitto, Kevin S.; (Little
Rock, AR) ; Flock, Stephen T.; (Little Rock,
AR) |
Correspondence
Address: |
IRELL & MANELLA LLP
1800 AVENUE OF THE STARS
SUITE 900
LOS ANGELES
CA
90067
US
|
Assignee: |
Transmedica International,
Inc.
|
Family ID: |
25156545 |
Appl. No.: |
10/734529 |
Filed: |
December 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10734529 |
Dec 11, 2003 |
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10083088 |
Feb 26, 2002 |
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10083088 |
Feb 26, 2002 |
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09443782 |
Nov 19, 1999 |
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6387059 |
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09443782 |
Nov 19, 1999 |
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08955982 |
Oct 22, 1997 |
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6056738 |
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09443782 |
Nov 19, 1999 |
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08792335 |
Jan 31, 1997 |
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08792335 |
Jan 31, 1997 |
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08126241 |
Sep 24, 1993 |
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5643252 |
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Current U.S.
Class: |
600/573 ;
128/898; 606/2; 606/9 |
Current CPC
Class: |
A61B 2018/00452
20130101; A61M 37/00 20130101; H04R 25/75 20130101; A61B 2017/00057
20130101; A61B 5/411 20130101; A61B 2017/00765 20130101; A61B 18/20
20130101; A61B 5/150099 20130101; A61B 5/150076 20130101; A61B
2218/008 20130101; A61M 2037/0007 20130101; A61B 2090/395 20160201;
A61B 17/3476 20130101; A61B 5/15138 20130101; A61B 2010/008
20130101; A61B 18/203 20130101; A61B 5/150022 20130101 |
Class at
Publication: |
600/573 ;
606/009; 606/002; 128/898 |
International
Class: |
A61B 010/00; A61B
018/18 |
Claims
We claim:
1. A method of measuring analyte concentrations in bodily fluids,
comprising the steps of: a) focusing a laser beam with sufficient
energy fluence to ablate the skin at least as deep as the stratum
corneum, but not as deep as the capillary layer; b) firing the
laser to create a site of ablation, 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 interstitial 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 the laser beam is emitted by a
laser selected from the group consisting of Er:YAG, pulsed
CO.sub.2, Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF,
Tm:YAG, Ho:YAG, Ho/Nd:Yalo.sub.3, cobalt:MgF2, HF chemical, DF
chemical, carbon monoxide, deep UV lasers, and frequency tripled
Nd:YAG lasers.
6. The method of claim 1 wherein the laser beam is emitted by an
Er:YAG laser.
7. The method of claim 1 wherein the laser beam is emitted by a
modulated laser selected from the group consisting of
continuous-wave CO.sub.2, Nd:YAG, Thallium:YAG and diode
lasers.
8. The method of claim 1 wherein the laser beam is focused at a
site on the skin with a diameter of 0.1-5.0 mm.
9. The method of claim 1 wherein the energy fluence of the laser
beam at the skin is 0.03-100,000 J/cm.sup.2.
10. The method of claim 1 wherein the energy fluence of the laser
beam at the skin is 0.03-9.6 J/cm.sup.2.
11. The method of claim 1 wherein multiple ablations are made to
prepare the skin for diffusion of interstitial fluid.
12. The method of claim 1 wherein multiple ablations are made to
prepare the skin for pharmaceutical delivery.
13. The method of claim 1 further comprising a beam splitter
positioned to create, simultaneously from the laser, multiple sites
of ablation.
14. The method of claim 13 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.
15. 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 ablation on the skin.
16. The method of claim 1 wherein the analyte to be measured is
selected from the group consisting of Na.sup.+, K.sup.+, Ca.sup.++,
Mg.sup.++, Cl.sup.-, HCO.sub.3.sup.-, HHCO3, phosphates, S4,
glucose, ammo acid, cholesterol, phospholipids, neutral fat,
PO.sub.2.sup.-, pH, organic acids or proteins.
17. The method of claim 1 wherein the analyte measurement is used
to represent the analyte concentration in blood.
18. The method of claim 1 wherein the interstitial fluid is
collected in a container positioned proximal to the ablation site
and through which the laser beam passes.
19. The method of claim 18 wherein the testing of analyte
concentration is conducted while the container unit is attached to
the laser device.
20. The method of claim 1 further comprising the step of applying a
therapeutically effective amount of a pharmaceutical composition at
the site of ablation.
21. The method of claim 20 wherein the pharmaceutical substance is
administered based on analyte concentration in the interstitial
fluid.
22. The method of claim 1 further comprising the step of applying a
pressure gradient to the skin after formation of the site of
ablation to increase the diffusion rate of interstitial fluid.
23. The method of claim 1 further comprising the step of
mechanically increasing the diffusion rate of interstitial fluid
after formation of a site of ablation.
24. The method of claim 23 wherein diffusion is increased by the
application of subatmospheric pressure at the ablation site.
25. The method of claim 24 wherein the container unit is under
subatmospheric pressure.
26. The method of claim 1 wherein a pressure gradient is created at
the site of ablation to increase the removal of bodily fluids.
27. 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.
28. The method of claim 27 wherein the laser beam has a wavelength
of 0.2-10 microns.
29. The method of claim 27 wherein the laser beam has a wavelength
of between 1.5-3.0 microns.
30. The method of claim 27 wherein the laser beam has a wavelength
of about 2.94 microns.
31. The method of claim 27 wherein the laser beam is emitted by a
laser selected from the group consisting of Er:YAG, pulsed
CO.sub.2, Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF,
Tm:YAG, Ho:YAG, Ho/Nd:Yalo.sub.3, cobalt:MgF2, HF chemical, DF
chemical, carbon monoxide, deep UV lasers, and frequency tripled
Nd:YAG lasers.
32. The method of claim 27 wherein the laser beam is emitted by an
Er:YAG laser.
33. The method of claim 27 wherein the laser beam is emitted by a
modulated laser selected from the group consisting of
continuous-wave CO.sub.2, Nd:YAG, Thallium:YAG and diode
lasers.
34. The method of claim 27 wherein the laser beam is focused at a
site on the skin with a diameter of 0.1-5.0 mm.
35. The method of claim 27 wherein the energy fluence of the laser
beam at the skin is 0.03-100,000 J/cm.sup.2.
36. The method of claim 27 wherein the energy fluence of the laser
beam at the skin is 0.03-9.6 J/cm.sup.2.
37. The method of claim 27 wherein multiple alterations are made to
prepare the skin for diffusion of interstitial fluid.
38. The method of claim 27 wherein multiple alterations are made to
prepare the skin for pharmaceutical delivery.
39. The method of claim 27 further comprising a beam splitter
positioned to create, simultaneously from the laser, multiple sites
of alteration.
40. The method of claim 39 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.
41. The method of claim 27 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.
42. The method of claim 27 wherein the analyte to be measured is
selected from the group consisting of Na.sup.+, K.sup.+, Ca.sup.++,
Mg.sup.++, Cl.sup.-, HCO3, HHCO3, phosphates, S4.sup.-, glucose,
amino acid, cholesterol, phospholipids, neutral fat, PO2.sup.-, pH,
organic acids or proteins.
43. The method of claim 27 wherein the analyte measurement is used
to represent the analyte concentration in blood.
44. The method of claim 27 wherein the interstitial fluid is
collected in a container positioned proximal to the ablation site
and through which the laser beam passes.
45. The method of claim 27 wherein the testing of analyte
concentration is conducted while the container unit is attached to
the laser device.
46. The method of claim 27 further comprising the step of applying
a therapeutically effective amount of a pharmaceutical composition
at the site of alteration.
47. The method of claim 46 wherein the pharmaceutical substance is
administered based on analyte concentration in the interstitial
fluid.
48. The method of claim 27 further comprising the step of applying
a pressure gradient to the skin after formation of the site of
ablation to increase the diffusion rate of interstitial fluid.
49. The method of claim 27 further comprising the step of
mechanically increasing the diffusion rate of interstitial fluid
after formation of a site of alteration.
50. The method of claim 49 wherein diffusion is increased by the
application of sub-atmospheric pressure at the alteration site.
51. The method of claim 50 wherein the container unit is under
subatmospheric pressure.
52. The method of claim 27 wherein a pressure gradient is created
at the site of alteration to increase the removal of bodily
fluids.
53. 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.
54. The method of claim 53 wherein the laser beam has a wavelength
of 0.2-10 microns.
55. The method of claim 53 wherein the laser beam has a wavelength
of between 1.5-3.0 microns.
56. The method of claim 53 wherein the laser beam has a wavelength
of about 2.94 microns.
57. The method of claim 53 wherein the laser beam is emitted by a
laser selected from the group consisting of Er:YAG, pulsed CO.sub.2
Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF, Tm:YAG,
Ho:YAG, Ho/Nd:Yalo.sub.3, cobalt:MgF2, HF chemical, DF chemical,
carbon monoxide, deep UV lasers, and frequency tripled Nd:YAG
lasers.
58. The method of claim 53 wherein the laser beam is emitted by an
Er:YAG laser.
59. The method of claim 53 wherein the laser beam is emitted by a
modulated laser selected from the group consisting of
continuous-wave CO.sub.2, Nd:YAG, Thallium:YAG and diode
lasers.
60. The method of claim 53 wherein the laser beam is focused at a
site on the skin with a diameter of 0.1-5.0 mm.
61. The method of claim 53 wherein the energy fluence of the laser
beam at the skin is 0.03-100,000 J/cm.sup.2.
62. The method of claim 53 wherein the energy fluence of the laser
beam at the skin is 0.03-9.6 J/cm.sup.2.
63. The method of claim 53 wherein multiple microblisters are made
for collection of interstitial fluid.
64. The method of claim 53 further comprising a beam splitter
positioned to lyse, simultaneously from the laser, multiple
microblisters.
65. The method of claim 64 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.
66. The method of claim 53 further comprising an acousto-optic
modulator outside the laser cavity wherein the modulator
consecutively deflects the beam at different angles to lyse
different microblisters.
67. The method of claim 53 wherein the analyte to be measured is
selected from the group consisting of Na.sup.+, K.sup.+, Ca.sup.++,
Mg.sup.++, Cl.sup.-, HCO.sub.3.sup.-, HHCO3, phosphates, S4.sup.-
glucose, ammo acid, cholesterol, phospholipids, neutral fat,
PO.sub.2.sup.-, pH, organic acids or proteins.
68. The method of claim 53 wherein the analyte measurement is used
to represent the analyte concentration in blood.
69. The method of claim 53 wherein the interstitial fluid is
collected in a container positioned proximal to the microblister
and through which the laser beam passes.
70. The method of claim 53 wherein the testing of analyte
concentration is conducted whue the container unit is attached to
the laser device.
71. The method of claim 53 further comprising the step of applying
a therapeutically effective amount of a pharmaceutical composition
at the site of the lysed microblister.
72. The method of claim 71 wherein the pharmaceutical substance is
administered based on analyte concentration in the interstitial
fluid.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/083,088, filed on Feb. 26, 2002, which is a
continuation of U.S. patent application Ser. No. 09/443,782, filed
on Nov. 19, 1999, now abandoned, which is a continuation of U.S.
patent application Ser. No. 08/955,982, filed Oct. 22, 1997, now
issued as U.S. Pat. No. 6,056,738, and which is a
continuation-in-part of U.S. patent application Ser. No. 08/792,335
filed Jan. 31, 1997, now abandoned, which is a continuation-in-part
of U.S. patent application Ser. No. 08/126,241, filed on Sep. 24,
1993, now issued as U.S. Pat. No. 5,643,252. All of said
applications are incorporated herein in their entirety by reference
thereto.
FIELD OF THE INVENTION
[0002] This invention is in the field of medical procedures, namely
laser medical equipment used to perforate or alter tissue for
monitoring analyte concentration in body fluids.
BACKGROUND
[0003] The traditional method of measuring blood glucose, or other
analytes, consists of taking a blood sample and then measuring the
analyte concentration in the blood or plasma. The blood is
typically collected from a patient utilizing mechanical perforation
of the skin with a sharp device such as a metal lancet or
needle.
[0004] This procedure has many drawbacks, including the possible
infection of health care workers and the public by the sharp device
used to perforate the skin, as well as the cost of handling and
disposal of biologically hazardous waste.
[0005] When skin is perforated with a sharp device such as a metal
lancet or needle, biological waste is created in the form of the
"sharp" contaminated by the patient's blood and/or tissue. If the
patient is infected with blood-born agents, such as human
immunodeficiency virus (HIV), hepatitis virus, or the etiological
agent of any other diseases, the contaminated sharp poses a serious
threat to others that might come in contact with it. For example,
many medical workers have contracted HIV as a result of accidental
contact with a contaminated sharp.
[0006] Post-use disposal of contaminated sharps imposes both
logistical and financial burdens on the end user. These costs are
imposed as a result of the social consequences of improper
disposal. For example, in the 1980's improperly disposed biological
wastes washed up on public beaches on numerous occasions. Improper
disposal also permits others, such as intravenous drug users, to
obtain contaminated needles and spread disease.
[0007] There exists an additional drawback of the traditional
method of using a needle for drawing fluids. The pain associated
with being stabbed by a the sharp instrument can be a traumatizing
procedure, especially in pediatric patients, causing significant
stress and anxiety in the patient. Moreover, the stabbing procedure
often must be repeated before sufficient fluid is obtained. For
analytes that need to be constantly monitored, patients may not
comply with the frequency of measurement due to the pain involved.
In the case of diabetics, failure to measure glucose levels can
result in a life-threatening situation.
[0008] In addition to blood withdrawal, concentrations of analytes
in interstitial fluid can be measured for accurate representation
of analyte concentration in the blood. Because of the strong
barrier properties of the stratum corneum, however, collecting
interstitial fluid through the stratum corneum poses problems. To
reduce the barrier function of the stratum corneum, a number of
different techniques are presently used, these include: (1) using a
metal lancet to cut the skin, (2) chemical enhancers, (3)
ultrasound, (4) tape stripping, and (5) iontophoresis. Chemical
enhancers pose the problem of potentially reacting with the analyte
to be measured. Moreover, the time lapse after application to
propagation of interstitial fluid is great. Tape stripping is
unsatisfactory because of the pain to the patient. Iontophoresis
and ultrasound, similarly have drawbacks in the collection time and
the quantity of fluid removed. As previously discussed, the use of
a metal lancet has the drawback of patient discomfort and the
possibility of contamination.
[0009] Thus, a need exists for a method to easily measure the
constituents in the blood or other body fluids, without: (I) the
use of a sharp object, (2) the slow speed of fluid collection, or
(3) the pain currently associated with the elimination or reduction
of the barrier function of the stratum corneum. The method would
further obviate the need for disposal of contaminated sharps and
eliminate the pain associated with sharp instruments. The desired
method would also, ideally, increase patient compliance for
monitoring the desired analyte. The method and apparatus disclosed
herein achieves these and other goals.
[0010] Lasers have been used in recent years as a very efficient
precise tool in a variety of surgical procedures. Among potentially
new sources of laser radiation, the rare-earth elements are of
major interest for medicine. One of most promising of these is a
YAG (yttrium, aluminum, garnet) crystal doped with erbium (Er)
ions. With the use of this crystal, it is possible to build an
erbium-YAG (Er:YAG) laser which can be configured to emit
electromagnetic energy at a wavelength (2.94 microns), among other
things, which is strongly absorbed by water. When tissue, which
consists mostly of water, is irradiated with radiation at or near
this wavelength, energy is transferred to the tissue. If the
intensity of the radiation is sufficient, rapid heating can result
followed by vaporization of tissue can result. In addition, or
alternatively, deposition of this energy can result in
photomechanical disruption of tissue. Some medical uses of Er:YAG
lasers have been described in the health-care disciplines of
dentistry, gynecology and ophthalmology. See, e.g., Bogdasarov, B.
V., et al., "The Effect of Er:YAG Laser Radiation on Solid and Soft
Tissues", Preprint 266, Institute of General Physics, Moscow, 1987;
Bol'shakov, E. N. et al., "Experimental Grounds for Er:YAG Laser
Application to Dentistry", SPIE 1353:160-169, Lasers and Medicine
(1989) (these and all other references cited herein are expressly
incorporated by reference as if fully set forth in their entirety
herein). Laser perforators of the type explained in U.S. Pat. No.
5,643,252, said patent being incorporated by reference herein, have
generally been designed to perforate or alter the tissue of a
patient to reduce the barrier function of the stratum corneum, thus
allowing for transport of fluid through the target tissue.
SUMMARY OF THE INVENTION
[0011] The present invention employs a laser to perforate or alter
the skin of a patient for removal and subsequent analysis of
interstitial fluid. These measurements can then be used to
approximate analyte concentrations in other body fluids, such as
blood. Prior to application, the care giver properly selects the
wavelength, energy fluence (energy of the pulse divided by the area
irradiated), pulse temporal width and irradiation spot size so as
to precisely perforate or alter the target tissue to a select depth
and eliminate undesired damage to healthy proximal tissue. After
perforation or alteration, interstitial fluid is allowed to
propagate to the surface of the skin for collection and
testing.
[0012] According to one embodiment of the present invention, a
laser emits a pulsed laser beam, focused to a small spot for the
purpose of perforating or altering the target tissue. By adjusting
the output of the laser, the laser operator can control the depth,
width and length of the perforation or alteration as needed, such
as to avoid drawing blood into the interstitial fluid sample.
[0013] In another embodiment, continuous-wave or diode lasers may
be used to duplicate the effect of a pulsed laser beam. These
lasers are modulated by gating their output, or, in the case of a
diode laser, by fluctuating the laser excitation current. The
overall effect is to achieve brief irradiation, or a series of
brief irradiations, that produce the same tissue permeating effect
as a pulsed laser.
[0014] The term "perforation" is used herein to indicate the
ablation of the stratum corneum to reduce or eliminate its barrier
function. The term "alteration" of the stratum corneum is used
herein to indicate a change in the stratum corneum which reduces or
eliminates the barrier function of the stratum corneum and
increases permeability without ablating, or by merely partially
ablating, the stratum corneum itself. A pulse or pulses of infrared
laser radiation at a subablative energy of, e.g., 60 mJ using a
TRANSMEDICA.TM. International, Inc. ("TRANSMEDICA.TM.") Er:YAG
laser (see U.S. Pat. No. 5,643,252, Waner et al., which is
incorporated herein by reference) with a beam of radiant energy
with a wavelength of 2.94 microns, a 200 .mu.s (microsecond) pulse,
and a 2 mm spot size) will alter the stratum corneum. The technique
may be used for transdermal drug delivery or for obtaining fluid
samples from the body. Different wavelengths of laser radiation and
energy levels less than or greater than 60 mJ may also produce the
enhanced permeability effects without ablating the skin.
[0015] The mechanism for this alteration of the stratum corneum is
not certain. It may involve changes in lipid or protein nature or
function or be due to desiccation of the skin or mechanical
alterations secondary for propagating pressure waves or cavitation
bubbles. The pathway that topically applied drugs take through the
stratum corneum is generally thought to be through cells and/or
around them, as well as through hair follicles. The impermeability
of skin to topically applied drugs is dependent on tight cell to
cell junctions, as well as the biomolecular makeup of the cell
membranes and the intercellular milieu. Any changes to either the
molecules that make up the cell membranes or intercellular milieu,
or changes to the mechanical structural integrity of the stratum
corneum and/or hair follicles can result in reduced barrier
function. It is believed that irradiation of the skin with radiant
energy produced by the Er:YAG laser causes measurable changes in
the thermal properties, as evidenced by changes in the Differential
Scanning Calorimeter (DSC spectra as well as the Fourier Transform
Infrared (FTIR) spectra of stratum corneum. Changes in DSC and FTIR
spectra occur as a consequence of changes in molecules or
macromolecular structure, or the environment around these molecules
or structures. Without wishing to be bound to any particular
theory, we can tentatively attribute these observations to changes
in lipids, water and protein molecules in the stratum corneum
caused by irradiation of molecules with electromagnetic radiation,
both by directly changing molecules as well as by the production of
heat and pressure waves which can also change molecules.
[0016] Both perforation and alteration change the permeability
parameters of the skin in a manner which allows for increased
passage of body fluids or pharmaceuticals across the stratum
corneum.
[0017] The term "lyse" is used herein to indicate the breaking up
of the epidermis layer covering a microblister. The energy pulse
used to accomplish this is between the energy required for ablation
and sub-ablation.
[0018] Accordingly, one object of the present invention is to
provide a means for perforating or altering the stratum corneum of
a patient in a manner that does not result in bleeding. For
example, the perforation or alteration created at the target tissue
is accomplished by applying a laser beam that penetrates through
the stratum corneum layer or both the stratum corneum layer and the
epidermis, thereby reducing or eliminating the barrier function of
the stratum corneum. This procedure allows for the subsequent
removal of fluids, specifically interstitial fluid, through the
skin.
[0019] Another object of this invention is to draw interstitial
fluid through the perforation or alteration site (or allowing the
interstitial to propagate on its own to the surface of the skin).
The interstitial fluid can then be collected.
[0020] In a preferred embodiment, by selection of appropriate
wavelength, energy fluence, pulse temporal width and irradiation
spot size, the skin tissue is perforated deep into the epidermis.
After perforation, interstitial fluid is collected into an awaiting
container.
[0021] In a further preferred embodiment, by selection of
appropriate wavelength, energy fluence, pulse temporal width and
irradiation spot size, just the stratum corneum is perforated or
altered and the interstitial fluid is then allowed to propagate to
surface. The fluid is then collected into a container unit for
testing, or the fluid is left on the skin surface for subsequent
testing.
[0022] In an additional preferred embodiment, before perforation or
alteration by the laser device, a blister, preferably a
microblister, is created at the surface of the skin by subjecting
the skin to sub-atmospheric pressure. This vacuum can be created by
a separate device, or the vacuum system can be part of the laser
perforator container unit. After the skin has been subjected to
sub-atmospheric pressure (a pressure of slightly less than 1
atmosphere), a microblister is formed, whereby the epidermis is
separated from the dermis. Interstitial fluid collects in this
pocket and the laser perforator is then used to lyse the blister.
After lysing, the interstitial fluid that formed inside the blister
is collected into a container.
[0023] To further the speed in the collection of interstitial
fluid, or to increase the delivery of pharmaceuticals into the
body, pressure gradients in the tissue can be created. In this
embodiment, pressure gradients are created using short rapid pulses
of radiant energy on the tissue. This pressure gradient can be used
to force substances, such as interstitial fluid, out of the body,
or to transfer a substance into the body, through a perforation or
alteration site. In another embodiment of this invention, pressure
waves, plasma, and cavitation bubbles are created in or above the
stratum corneum to increase the permeation of the compounds (e.g.,
pharmaceuticals) or fluid, gas or other biomolecule removal. This
method may simply overcome the barrier function of intact stratum
corneum without significant alteration or may be used to increase
permeation or collection in ablated or altered stratum corneum.
Additionally, to increase diffusion, plasma can be produced by
irradiating the surface of the target tissue, or material on the
target tissue, with a pulse or pulses of electromagnetic energy
from a laser. Prior to treatment, the care giver properly selects
the wavelength, energy fluence (energy of the pulse divided by the
area irradiated), pulse temporal width and irradiation spot size to
create the plasma while limiting undesired damage to healthy
proximal tissue. These technique for increasing the diffusion of
fluids through the skin is not meant to limit the scope of this
invention, but is merely an embodiment. Other techniques can be
used, such as manual compression of the skin surrounding the
perforation or alteration site, or the care giver can rely simply
on the reduced barrier function of the perforation or alteration
site for fluid to propagate to the skin surface.
[0024] In another embodiment, a typical laser is modified to
include a container unit. Such a container unit can be added to:
(1) increase the efficiency in the collection of fluids; (2)
further testing of the collected sample, (3) apply a vacuum to the
skin surface, (4) reduce the noise created when the laser beam
perforates the patient's tissue; and (5) collect the ablated
tissue. The optional container unit is alternatively evacuated to
expedite the collection of the released materials, such as the
fluids, or to expedite the blistering of the tissue. The container
can also be used to collect only ablated tissue. The noise created
from the laser beam's interaction with the patient's skin may cause
the patient anxiety. The optional container unit reduces the noise
intensity and therefore alleviates the patient's anxiety and
stress. The container unit also minimizes the risk of
cross-contamination and guarantees the sterility of the collected
sample. The placement of the container unit in the use of this
invention is unique in that it covers the tissue being irradiated,
at the time of irradiation by the laser beam, and is therefore able
to collect the fluid and/or ablated tissue as the perforation or
alteration occurs.
[0025] An additional object of this invention is to allow the
taking of measurements of various fluids constituents, such as
glucose, collected through the perforation or alteration site.
Typical testing techniques include infrared spectrometry, enzymatic
analysis, electro-chemical analysis and other means. The testing
can be incorporated into the laser perforator device or the testing
can be completed on the fluid after the container unit has been
removed from the device. Additionally, testing can be completed on
the surface of the skin, at the perforation or ablation site, after
the interstitial fluid has propagated through the target
tissue.
[0026] An additional object of this invention is to administer
pharmaceuticals after measurement of the interstitial fluid. The
appropriate drug dose can be delivered manually or automatically.
Drug delivery can be triggered in combination with the monitoring
of the desired analyte. For example, glucose measurements can be
used to trigger the administration of insulin in diabetics.
[0027] A further object of this invention is to allow drugs to be
administered continually on an outpatient basis over long periods
of time. The speed and/or efficiency of drug delivery is thereby
enhanced for drugs which were either slow or unable to penetrate
skin.
[0028] A further object of this invention is to avoid the use of
sharps. The absence of a contaminated sharp will eliminate the risk
of accidental injury and its attendant risks to health care
workers, patients, and others that may come into contact with the
sharp. The absence of a sharp in turn obviates the need for
disposal of biologically hazardous waste. Thus, the present
invention provides an ecologically sound method for removing body
fluids or administering pharmaceuticals.
[0029] A typical laser used for this invention requires no special
skills to use (for example, the TRANSMEDICA.TM. Er:YAG laser). It
can be small, lightweight and can be used with regular or
rechargeable batteries. The greater the laser's portability and
ease of use, the greater the utility of this invention in a variety
of settings, such as a hospital room, clinic, or home.
[0030] Safety features can be incorporated into the laser that
require that no special safety eyewear be worn by the operator of
the laser, the patient, or anyone else in the vicinity of the laser
when it is being used.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The present invention may be better understood and its
advantages appreciated by those skilled in the art by referring to
the accompanying drawings wherein:
[0032] FIG. 1 shows a laser with its power source, high voltage
pulse-forming network, flashlamp, lasing rod, mirrors, housing and
focusing lens.
[0033] FIG. 2 shows an optional spring-loaded interlock and
optionally heated applicator.
[0034] FIG. 3 shows an alternative means of exciting a laser rod
using a diode laser.
[0035] FIG. 4 shows an alternative focusing mechanism.
[0036] FIGS. 5A & 5B show optional beam splatters for creating
multiple simultaneous irradiation.
[0037] FIG. 8 shows an optional container unit for collecting
fluids, ablated tissue, and/or other matter released from the site
of irradiation, and for reducing noise resulting from the
interaction between the laser and the patient's tissue.
[0038] FIG. 9 shows a plug and plug perforation center.
[0039] FIG. 10 shows an optional container unit for collecting
ablated tissue and reducing noise resulting from the interaction
between the laser and the patient's tissue.
[0040] FIG. 11 shows a roll-on device for the delivery of
pharmaceuticals.
[0041] FIG. 12 shows an elastomeric mount for a solid state laser
crystal element with optional mirrored surfaces applied to each end
of the element.
[0042] FIG. 13 shows an example of a crystal rod with matte finish
around the full circumference of the entire rod.
[0043] FIG. 14 shows an example of a crystal rod with matte finish
around the full circumference of two-thirds of the rod.
[0044] FIG. 15 shows an example of a crystal rod with matte stripes
along its longitudinal axis.
[0045] FIG. 16 shows a cross-section of a crystal laser rod element
surrounded by a material having an index of refraction greater than
the index of refraction of the rod.
[0046] FIGS. 17A-17G show various examples of a container unit.
[0047] FIG. 18 shows an atomizer for the delivery of
pharmaceuticals.
[0048] FIG. 19 shows examples of a container unit in use with a
laser.
[0049] FIG. 20 shows an example of a lens with a mask.
[0050] FIG. 21 is a chart showing a study using corticosterone
which showed enhanced permeation through skin irradiated at an
energies of 77 mJ and 117 mJ.
[0051] FIG. 22 shows the decrease in the impedance of skin using
various laser pulse energies.
[0052] FIGS. 23-24 show in a permeation study of tritiated water
(3H.sub.2O) involving lased human skin at energies from 50 mJ (1.6
J/cm.sup.2) to 1250 mJ (40 J/cm.sup.2).
[0053] FIG. 25 shows histological sections of human skin irradiated
at energies of 50 mJ and 80 mJ.
[0054] FIG. 26 is a chart of a study using DNA showing enhanced
permeation through skin irradiated at an energy of 150 mJ and 300
mJ.
[0055] FIG. 27 shows laser pulse energy (J) versus water loss
through human skin in vivo.
[0056] FIG. 28 is a chart showing a DSC scan of normally hydrated
(66%) human stratum corneum, and a scan of Er:YAG laser irradiated
stratum corneum using a subablative pulse energy of 60 mJ.
[0057] FIGS. 29-31 are charts showing the heat of transition
(.mu.J), center of the transition (.degree. C.) and the full-width
at half-maximum of the transition (.degree. C.) of three peaks in
the DSC spectra of stratum corneum treated different ways.
[0058] FIGS. 32-33 are charts of FTIR spectra of control and lased
stratum corneum.
[0059] FIG. 34 shows Amide I band position (cm.sup.-1) as a
function of stratum corneum treatment.
[0060] FIG. 35 shows CH2 vibration position (cm.sup.-1) as a
function of stratum corneum treatment.
[0061] FIG. 36 shows a histological section of rat skin that was
irradiated at 80 mJ.
[0062] FIG. 37 shows a histological section of human skin that was
irradiated at 80 mJ.
[0063] FIG. 38 shows in vivo blanching assay results.
[0064] FIG. 39 shows an optional version of the collection
container unit that is especially useful when the container unit
includes a reagent for mixing with the sample.
[0065] FIG. 40 shows permeation of insulin through human skin in
vitro.
[0066] FIG. 41 shows the creation of pressure waves in tissue
converging to a focal point.
[0067] FIG. 42 shows an example of a beam splitter suitable for
making simultaneous irradiation sites.
[0068] FIG. 43 shows one possible pattern of perforation or
alteration sites using a beam splitter.
[0069] FIG. 44 shows a pressure gradient created in the stratum
corneum.
[0070] FIG. 45 is a schematic of modulating the pulse repetition
frequency of radiant energy from high (4 GHz) to low (4 MHz).
[0071] FIG. 46 shows a propagating pressure wave created in an
absorbing material located on the skin.
[0072] FIG. 47 shows a propagating pressure wave created at the
skin surface with a transparent, or partially transparent, optic
located on the skin.
[0073] FIG. 48 shows a propagating pressure wave created in an
absorbing material on the applied pharmaceutical.
[0074] FIG. 49 shows a propagating pressure wave created in the
applied pharmaceutical.
DETAILED DESCRIPTION
[0075] This invention provides a method for perforating or altering
skin for the sampling and measurement of body fluids. The invention
utilizes a laser beam, specifically focused, and lasing at an
appropriate wavelength, to create small perforations or alterations
in the skin of a patient. In a preferred embodiment, the laser beam
has a wavelength between 0.2 and 10 microns. More preferably, the
wavelength is between about 1.5 and 3.0 microns. Most preferably
the wavelength is about 2.94 microns. In one embodiment, the laser
beam is focused with a lens to produce an irradiation spot on the
skin through the epidermis of the skin. In an additional
embodiment, the laser beam is focused to create an irradiation spot
only through the stratum corneum of the skin.
[0076] The caregiver may consider several factors in defining the
laser beam, including wavelength, energy fluence, pulse temporal
width and irradiation spot-size. In a preferred embodiment, the
energy fluence is in the range of 0.03-100,000 J/cm.sup.2. More
preferably, the energy fluence is in the range of 0.03-9.6
J/cm.sup.2. The beam wavelength is dependent in part on the laser
material, such as Er:YAG. The pulse temporal width is a consequence
of the pulse width produced by, for example, a bank of capacitors,
the flashlamp, and the laser rod material. The pulse width is
optimally between 1 fs (femtosecond) and 1,000 .mu.s.
[0077] According to the method of the present invention the
perforation or alteration produced by the laser need not be
produced with a single pulse from the laser. In a preferred
embodiment the caregiver produces a perforation or alteration
through the stratum corneum by using multiple laser pulses, each of
which perforates or alters only a fraction of the target tissue
thickness.
[0078] To this end, one can roughly estimate the energy required to
perforate or alter the stratum corneum with multiple pulses by
taking the energy in a single pulse, and dividing by the number of
pulses desirable. For example, if a spot of a particular size
requires 1 J of energy to produce a perforation or alteration
through the entire stratum corneum, then one can produce
qualitatively similar perforation or alteration using ten pulses,
each having {fraction (1/10)}th the energy. Because it is desirable
that the patient not move the target tissue during the irradiation
(human reaction times are on the order of 100 ms or so), and that
the heat produced during each pulse not significantly diffuse, in a
preferred embodiment the pulse repetition rate from the laser
should be such that complete perforation is produced in a time of
less than 100 ms. Alternatively, the orientation of the target
tissue and the laser can be mechanically fixed so that changes in
the target location do not occur during the longer irradiation
time.
[0079] To penetrate the skin in a manner which does not induce much
if any blood flow, skin is perforated or altered through the outer
surface, such as the stratum corneum layer, but not as deep as the
capillary layer. The laser beam is focussed precisely on the skin,
creating a beam diameter at the skin in the range of approximately
0.5 microns-5.0 cm. Optionally, the spot can be slit-shaped, with a
width of about 0.05-0.5 mm and a length of up to 2.5 mm. The width
can be of any size, being controlled by the anatomy of the area
irradiated and the desired permeation rate of the fluid to be
removed or the pharmaceutical to be applied. The focal length of
the focusing lens can be of any length, but in one embodiment it is
30 mm.
[0080] By modifying wavelength, pulse length, energy fluence (which
is a function of the laser energy output (in Joules) and size of
the beam at the focal point (cm.sup.2)), and irradiation spot size,
it is possible to vary the effect on the stratum corneum between
ablation (perforation) and non-ablation or partial alteration
(alteration). Both ablation and non-ablative alteration of the
stratum corneum result in enhanced permeation of body fluids or
subsequently applied pharmaceuticals.
[0081] For example, by reducing the pulse energy while holding
other variables constant, it is possible to change between ablative
and non-ablative tissue-effect. Using the TRANSMEDICA.TM. Er:YAG
laser, which has a pulse length of about 300 .mu.s, with a single
pulse or radiant energy and irradiating a 2 mm spot on the skin, a
pulse energy above approximately 100 mJ causes partial or complete
ablation, while any pulse energy below approximately 100 mJ causes
partial ablation or non-ablative alteration to the stratum corneum.
Optionally, by using multiple pulses, the threshold pulse energy
required to enhance permeation of body fluids or for pharmaceutical
delivery is reduced by a factor approximately equal to the number
of pulses.
[0082] Alternatively, by reducing the spot size while holding other
variables constant, it is also possible to change between ablative
and non-ablative tissue-effect. For example, halving the spot area
will result in halving the energy required to produce the same
effect. Irradiations down to 0.5 microns can be obtained, for
example, by coupling the radiant output of the laser into the
objective lens of a microscope objective. (e.g., as available from
Nikon, Inc., Melville, N.Y.). In such a case, it is possible to
focus the beam down to spots on the order of the limit of
resolution of the microscope, which is perhaps on the order of
about 0.5 microns. In fact, if the beam profile is Gaussian, the
size of the affected irradiated area can be less than the measured
beam size and can exceed the imaging resolution of the microscope.
To non-ablatively alter tissue in this case, it would be suitable
to use a 3.2 J/cm.sup.2 energy fluence, which for a half-micron
spot size, would require a pulse energy of about 5 nJ. This low a
pulse energy is readily available from diode lasers, and can also
be obtained from, for example, the Er:YAG laser by attenuating the
beam by an absorbing filter, such as glass.
[0083] Optionally, by changing the wavelength of radiant energy
while holding the other variables constant, it is possible to
change between an ablative and non-ablative tissue-effect. For
example, using Ho:YAG (holmium:YAG; 2.127 microns) in place of the
Er:YAG (erbium:YAG; 2.94 microns) laser, would result in less
absorption of energy by the tissue, creating less of a perforation
or alteration.
[0084] Picosecond and femtosecond pulses produced by lasers can
also be used to produce alteration or ablation in skin. This can be
accomplished with modulated diode or related microchip lasers,
which deliver single pulses with temporal widths in the 1
femtosecond to 1 ms range. (See D. Stern et al., "Corneal Ablation
by Nanosecond, Picosecond, and Femtosecond Lasers at 532 and 625
nm," Corneal Laser Ablation, vol. 107, pp. 587-592 (1989),
incorporated herein by reference, which discloses the use of pulse
lengths down to 1 femtosecond).
[0085] According to another object of this invention, after
perforation or alteration of the target tissue, interstitial fluid
is collected for subsequent measurement. To further collection of
the fluid, different perforation or alteration depths can be
created. In a preferred embodiment, the laser device perforates
through the epidermis, allowing the interstitial fluid to propagate
to the surface of the skin. In an additional preferred embodiment,
perforation or alteration through the stratum corneum is completed,
allowing the interstitial fluid to propagate to the surface of the
skin, albeit more slowly.
[0086] Blistering to Enhance Collection of Interstitial Fluid
[0087] In a further embodiment, the laser perforator device is used
in combination with sub-atmospheric pressure to obtain samples of
interstitial fluid. By purposely applying a vacuum to the surface
of the skin, it is possible to gently and reversibly separate the
epidermis from the underlying dermis, thus creating a microblister
in which interstitial fluid can collect.
[0088] The epidermis and dermis are interlocked by ridges and root
like cytoplasmic microprocesses of basal cells that extend into the
corresponding indentations of the dermis. This junction is further
enforced by desmosomes which anchor the basal cells on the basal
lamina, which is itself attached to the dermis by anchoring
filaments and fibrils. In some cases, the hydrodynamic pressure of
the plasma released by the superficial dermal blood vessels can
lead to a lifting of the basal cells from the basal lamina thus
leading to a (junctional) blister. Such a blister can be induced by
suction, mild heat, certain compounds or liquid nitrogen. See
Dermatology in General Medicine, 3d ed., T B Fitzpatrick, A Z
Eisen, K. Wolff, I M Freedberg, and K F Austen, McGraw--Hill:NY
(1987), incorporated herein by reference.
[0089] Low and Van der Leun ("Suction Blister Device for Separation
of Viable Epidermis from Dermis", vol. 50, No. 2, pp. 308-314,
Journal of Investigative Dermatology, 1968) describe the use of
suction blisters, created in lower abdominal skin with reduced
vacuum, for the purpose of obtaining interstitial fluid. They
report that t=a/p, where a is a constant (9.times.10.sup.8
dyne/cm.sup.2/sec) and p is the suction pressure. Thus, for
example, a suction pressure of 200 mm Hg (760 mm Hg or
1.013.times.10.sup.6 dyne/cm.sup.2 is atmospheric pressure) will
produce a blister in about 60 minutes. Van der Leun et al., (vol.
62, pp. 42-46, Journal of Investigative Dermatology, 1974), make
the point that if skin temperature is raised (from 24.degree. C. to
34.degree. C., for example), the time to the onset of the blister
(for pressure of 410 mm Hg) is reduced from 30 to 7 minutes.
[0090] One embodiment of the present invention is to form a
microblister by using negative pressure (slightly less than 1
atmosphere) applied to a small area on the skin. Subsequent lysing
of the blister with the laser device produces a pathway through
which the interstitial fluid can be collected. The vacuum acts to
enhance the volume of interstitial fluid.
[0091] In another embodiment of the present invention, the vacuum
means for drawing a microblister is incorporated into the lasing
device. In an additional embodiment, the vacuum means is performed
by an alternative device and the laser is then used to lyse the
formed microblister.
[0092] In a further embodiment of the present invention, the vacuum
is applied after ablation or alteration of the tissue, thereby
propagating fluid through the lased site by negative pressure.
[0093] Pressure Wave to Enhance the Permeability of the Stratum
Corneum or Other Membranes
[0094] In another embodiment of the present invention, a pressure
gradient is created at the ablated or altered site to force
substances through the skin. This technique can be used for the
introduction of compounds including pharmaceuticals into the body
or to remove fluids, gases or biomolecules from the body.
[0095] When laser radiant energy is absorbed by tissue, expansion
(due to heating) and/or physical movement of tissue (due to heating
or non-thermal effects such as spallation) takes place. These
phenomena lead to production of propagating pressure waves, which
can have frequencies in the acoustic (20 Hz to 20,000 Hz) or
ultrasonic (>20,000 Hz) region of the pressure wave spectrum.
For example, Flock et al. (Proc SPIE Vol. 2395, pp. 170-176, 1995)
show that when a 20 ns pulse from a Q-switched frequency-doubled
Nd:YAG laser is impacted on blood, propagating transient high
pressure waves form. These pressure waves can be spectrally
decomposed to show that they consist of a spectrum of frequencies,
from about 0 to greater than 4 MHz. The high-pressure gradient
associated with these kinds of compressional-type pressure waves
can be transformed into tension-type or stress waves which can
"tear" tissue apart in a process referred to as "spallation".
[0096] The absorption of propagating pressure waves by tissue is a
function of the tissue type and frequency of wave. Furthermore, the
speed of these pressure waves in non-bone tissue is approximately
1400-1600 m/sec. Using these observations, a pressure gradient in
tissue can be created, directed either into the body or out of the
body, using pulsed laser radiant energy. To efficiently create
pressure waves with a pulsed laser, the pulse duration needs to be
less than the time it takes for the created heat to diffuse out of
the region of interest. The effect is qualitatively equivalent to
the effects of ultrasound on tissue. The attenuation coefficient
for sound propagation in tissue increases approximately linearly
with frequency (see, for example, J. Havlice and J. Taenzer,
"Medical Ultrasound Imaging: An Overview of Principles and
Instrumentation", Proc. IEEE 67, 620-641, 1979), and is
approximately 1 dB/cm/MHz (note that a 20 decibel (dB) intensity
difference is equivalent to a factor of 10 in relative intensity).
The thickness of the stratum corneum is about 25 microns and the
epidermis is about 200 microns. Thus, the frequency that is
attenuated by 10 dB when propagating through the stratum corneum is
10 dB/(1 dB/cm/MHz*0.0025 cm), or 4 GHz. Similarly, as strongly
absorbed radiant energy produced by a pulsed laser (say pulsed at 4
GHz) will produce propagating pressure waves of a similar frequency
as the pulse repetition rate, it is possible to selectively
increase the pressure in the stratum corneum or upper layers of
skin as compared to the lower layers, thus enhancing the diffusive
properties of topically applied drug (see, e.g., FIG. 44). A
transparent, or nearly transparent, optic 172, as shown in FIG. 47,
can be placed on the surface of the skin to contain the backward
inertia of the propagating pressure wave or ablated stratum
corneum.
[0097] In an additional embodiment, as shown in FIG. 45, by
modulating the pulse repetition frequency of the radiant energy
from high to low, it is possible to create transient pressure
fields that can be designed to be beneficial for enhancing the
diffusive properties of a topically applied pharmaceutical.
[0098] The high-frequency propagating pressure waves can also be
produced from a single laser pulse. When tissue absorbs a brief
pulse of laser irradiation, pressure waves with a spectrum of
frequencies result. Some of these frequencies will propagate into
lower layers in the skin, thus it may be possible to set up a
reverse pressure gradient (more pressure below and less
superficially) in order to enhance the diffusion of biomolecules
out of the body effectively "pumping" them through the skin.
[0099] Acoustic waves and/or spallation are believed to occur
during the use of the TRANSMEDICA.TM. Er:YAG laser in ablation of
stratum corneum for drug delivery or perforation, since the 2.94
micron radiant energy is absorbed in about 1 micron of tissue, yet
the tissue ablation can extend much deeper.
[0100] A continuous-wave laser can also be used to create pressure
waves. A continuous-wave laser beam modulated at 5-30 MHz can
produce 0.01-5 W/cm.sup.2 pressure intensities in tissue due to
expansion and compression of sequentially heated tissue (for
example, a Q-switched Er:YAG laser (40 ns pulse) at 10 mJ and
focussed to a spot size of 0.05 cm, with a pulse repetition rate of
5-30 MHz, would produce in stratum corneum a stress of about 3750
bars, or 0.025 W/cm.sup.2). It takes a few hundred bars to cause
transient permeability of cells. With this laser it requires about
0.01 W/cm.sup.2 of continuous pressure wave energy to provide
effective permeation of skin.
[0101] In an additional embodiment, pressure waves are induced on
the topically applied pharmaceutical. The propagation of the wave
towards the skin will carry some of the pharmaceutical with it
(see, e.g., FIG. 49).
[0102] In a further embodiment, pressure waves are induced on an
absorbing material 170 placed over the topically applied
pharmaceutical (see, e.g., FIG. 48). Preferably this material is a
thin film of water, however, it can be created in any liquid, solid
or gas located over the topically applied pharmaceutical. The
propagation of the wave towards the skin will carry some of the
pharmaceutical with it. Additionally, pressure waves can be induced
on an absorbing material 170 (preferably a thin film of water,
however, it can be created in any liquid, solid or gas) placed over
the target tissue. (see, e.g., FIG. 46). The propagation of the
wave towards the skin will increase the permeability of the stratum
corneum. Subsequent to the formation of these pressure waves, the
desired pharmaceutical can be applied.
[0103] In another embodiment, pressure gradients can be used to
remove fluids, gases or other biomolecules from the body. This can
be accomplished by focusing a beam of radiant energy down to a
small volume at some point within the tissue. The resulting heating
leads to pressure wave intensities (which are proportional to the
degree of heating) that will be greater near the focal point of the
radiant energy, and less near the surface. The consequence of this
is a pressure gradient directed outwards thus enhancing the removal
of fluids, gases or other biomolecules. Alternatively, propagating
pressure waves created at the surface of the skin can be focused to
a point within the tissue. This can be done, for example, by using
a pulsed laser to irradiate a solid object 174 above the skin,
which by virtue of its shape, induces pressure waves in the tissue
which converges to the focal point (see, e.g., FIG. 41). Again, the
consequence of this is a pressure gradient directed outwards thus
enhancing the removal of fluids, gases or other biomolecules.
[0104] The pressure waves described can be created after
perforation or alteration of the stratum corneum has taken place.
Alternatively, pressure waves can be used as the sole means to
increase the diffusive properties of compounds trough the skin or
the removal of fluids, gases or other biomolecules.
[0105] Creation of Cavitation Bubbles to Increase Stratum Corneum
Permeability
[0106] Cavitation bubbles, produced subsequent to the target
tissues perforation or alteration, can be used to enhance the
diffusive properties of a topically applied drug. While production
of cavitation bubbles within the tissue is known (See, for example,
R. Ensenaliev et al., "Effect of Tensile Amplitude and Temporal
Characteristics on Threshold of Cavitation-Driven Ablation," Proc.
SPIE vol. 2681, pp 326-333, (1996)), for the present invention,
cavitation bubbles are produced in a material on or over the
surface of the skin so that they propagate downwards (as they do
because of conservation of momentum) and impact on the stratum
corneum, thereby reducing the barrier function of the skin. The
cavitation bubbles can be created in an absorbing material 170
located on or over the skin.
[0107] Cavitation has been seen to occur in water at -8 to -100
bars, (Jacques et al. Proc. SPIE vol. 1546, p. 284 (1992)). Thus,
using a Q-switched Er:YAG laser (40 ns pulse) at 10 mJ and focussed
to a spot size of 0.05 cm in a thin film of water on the skin, with
a pulse repetition rate of 5-30 MHz, a stress of about 3750 bars,
or 0.025 W/cm.sup.2, is produced. This should generate the
production of cavitation bubbles, which, when they contact the skin
will cause mechanical and/or thermal damage thereby enhancing
stratum corneum permeability.
[0108] In a preferred embodiment, the cavitation bubbles are
produced in a thin film of water placed on or over the skin,
however, any liquid or solid material can be used. Subsequent to
production of the cavitation bubbles a pharmaceutical is applied to
the affected tissue.
[0109] In an additional embodiment, cavitation bubbles are produced
in the administered pharmaceutical subsequent to its application on
the skin. Cavitation bubbles can also be produced in the stratum
corneum itself before pharmaceutical application.
[0110] In a further embodiment, the target tissue is not perforated
or altered before the production of cavitation bubbles, the
cavitation bubbles' impact on the stratum corneum being the only
method used to increase stratum corneum permeability.
[0111] Plasma Ablation to Increase Stratum Corneum Permeability
[0112] Plasma is a collection of ionized atoms and free electrons.
It takes an extremely strong electric field or extremely high
temperature to ionize atoms, but at the focus of an intense pulsed
laser beam (>approx. 10.sup.8-10.sup.10 W/cm.sup.2), such
electric fields can result. Above this energy fluence rate, high
enough temperatures can result. What one sees when plasma is formed
is a transient bright white cloud (which results from electrons
recombining with atoms resulting in light emission at many
different wavelengths which combine to appear to the eye as white).
A loud cracking is usually heard when plasma is formed as a result
of supersonic shock waves propagating out of the heated (>1000K)
volume that has high pressures (perhaps >1000 atmospheres).
Since plasma is a collection of hot energetic atoms and electrons,
it can be used to transfer energy to other matter, such as skin.
See Walsh J T, "Optical-Thermal Response of Laser-Irradiated
Tissue," Chapter 25, pp. 865-902 (Plenum Press, NY 1995),
incorporated by reference herein as if fully set forth in its
entirety. For example, U.S. Pat. No. 5,586,981, issued to Hu,
discloses the use of plasma to treat cutaneous vascular or
pigmented lesions. The wavelength of the laser in Hu '981 is chosen
such that the laser beam passes through the epidermal and dermal
layers of skin and the plasma is created within the lesion,
localizing the disruption to the targeted lesion.
[0113] A plasma can also be used to facilitate diffusion through
the stratum corneum. In one embodiment of the present invention,
plasma is produced above the surface of the skin whereupon a
portion of the plasma cloud will propagate outwards (and downwards)
to the skin whereupon, ablation or tissue alteration will occur.
Plasma can be created in a liquid, solid or gas that is placed on
or over the skin, into which the laser beam is focussed. If the
plasma is created in a material with an acoustic impedance similar
to tissue (say, a fluid), then the resulting pressure waves would
tend to transfer most of their energy to the skin. The plasma
"pressure wave" behaves similarly to propagating pressure waves.
This is due to the fact that the acoustic impedance mismatch at the
upper surface between air and solid/liquid material is high, and,
furthermore, plasma, like ultrasonic energy propagates poorly in
low-density (i.e. air) media.
[0114] In another embodiment, plasma is produced within the stratum
corneum layer. Because the energy fluence rate needed to produce
the plasma is as high as approximately 108 W/cm2, selection of a
wavelength with radiant energy that is strongly absorbed in tissue
is not an important concern.
[0115] Important benefits in these embodiments are that (1) the
optical absorption of material to produce plasma is not an
important consideration, although the energy fluence rate required
to produce the plasma is less when the irradiated material strongly
absorbs the incident radiant energy, and (2) there are relatively
inexpensive diode-pumped Q-switched solid state lasers that can
produce the requisite radiant energy (such as are available from
Cutting Edge Optronics, Inc., St, Louis, Mo.).
[0116] To obtain a peak energy fluence rate greater than or
approximately equal to the plasma creation threshold of 10.sup.8
W/cm.sup.2, using a pulse length of 300 .mu.s (e.g. for the
TRANSMEDICA.TM. Er:YAG laser, 1 J for 300 .mu.s), the pulse power
is 3333 W, and the spot size needs to be 0.0065 mm. Alternatively,
a small diode-pumped Q-switched laser can be used. Such lasers have
pulse widths on the order of 10 ns, and, as such, the requisite
spot size for producing plasma could be much larger.
[0117] Continuous-Wave (CW) Laser Scanning
[0118] It is possible, under machine and microprocessor control, to
scan a laser beam (either continuous-wave or pulsed) over the
target tissue, and to minimize or eliminate thermal damage to the
epidermis or adjacent anatomical structures.
[0119] For example, a scanner (made up of electro-optical or
mechanical components) can be fashioned to continually move the
laser beam over a user-defined area. This area can be of arbitrary
size and shape. The path for the scan could be spiral or raster. If
the laser is pulsed, or modulated, then it would be possible to do
a discrete random pattern where the scanning optics/mechanics
directs the beam to a site on the skin, the laser lases, and then
the scanning optics/mechanics directs the beam to a different site
(preferable not adjacent to the first spot so that the skin has
time to cool before an adjacent spot is heated up).
[0120] This scanning technique has been used before with
copper-vapor lasers (in treating port-wine stains) and is in use
with CO.sub.2 lasers for the purpose of facial resurfacing. In the
case of the former, the subepidermal blood vessels are targeted,
while in the latter, about 100 microns of tissue is vaporized and
melted with each laser pass.
[0121] Interstitial Fluid Testing
[0122] Interstitial fluid contains concentrations of analytes that
correlate with the concentration of analytes in other body fluids,
such as blood. As such, the interstitial fluid analyte
concentration can be tested to give an accurate measurement of
analytes present in other body fluids.
[0123] One embodiment of the present invention is to perform
testing on a number of analytes in the collected interstitial fluid
sample to accurately measure levels of the analytes in other body
fluids. For example, Na.sup.+, K.sup.+, Ca.sup.++, Mg.sup.++,
Cl.sup.-, HCO.sub.3.sup.-, HHCO.sub.3, phosphates, S.sub.4.sup.--,
glucose, amino-acid, cholesterol, phospholipids, neutral fat,
PO.sub.2.sup.--, pH, organic acids and/or proteins are components
of interstitial fluid and can be monitored. See N. Tietz, Textbook
of Clinical Chemistry, W. B. Saunders Co., Philadelphia (1986),
incorporated herein by reference. Interstitial fluid is, in many
ways, filtered plasma, and has a similar constitution as plasma,
except that some of the large proteins are filtered out by walls of
the blood vessel. As such, components that can be assayed in serum
can be assayed in interstitial fluid and such interstitial fluid
components may be directly correlated to serum components. In one
embodiment of this invention glucose in interstitial fluid is
tested to monitor and treat blood sugar levels in diabetics.
[0124] Following the collection of interstitial fluid, as detailed
above, the sample is tested for the specific analyte of interest,
such as glucose. For glucose, testing can be done by infrared
measurements, enzymatic analysis, or other testing protocols.
Sodium and potassium are usually detected with ion-specific
electrodes which allow a particular ion to penetrate an electrode,
whereupon a current proportional to the ion concentration is
produced and detected (analogous to a pH meter). Proteins are
detected in various ways, for example, enzyme linked immunoassay
(ELISA), gel electrophoresis, ultracentrifugation,
radioimmunoassays, and fluorescence. These methodologies are
discussed in N. Tietz, Textbook of Clinical Chemistry, W. B.
Saunders Co., Philadelphia (1986).
[0125] There are a variety of substances that can be detected in
interstitial fluid that are not normally present in apparently
healthy individuals. Many of these substances are detected by
colorimetry (after reacting the analyte with a test chemical),
flame photometry, atomic absorption spectrometry, gas or mass
spectrometry, and high-pressure liquid chromatography. For example,
ethanol is detectable by reaction of the analyte with alcohol
dehydrogenase, followed by colorimetry. These testing examples are
not meant to limit the scope of the invention, but are merely
embodiments.
[0126] In one embodiment the testing is completed as part of the
laser perforation or alteration process. Using infrared radiation,
for example, testing can be conducted in the container unit
attached to the laser device. A section of the container unit, or
the entire unit, is optionally constructed of a material that
passes a predetermined light wavelength (e.g., for glucose, nylon,
polyethylene or polyamide, which are partially transparent to
infrared energy at 1040 nm, a wavelength absorbed by glucose, can
be used). By sending light of known intensity through the container
unit, as well as a reference beam sent through a portion of the
container with no interstitial fluid, the absorption of the sample
can be determined. A photosensitive diode, or other light detector
is placed on the opposite side of the container unit from the light
source. Absorption is determined by signals sent by the light
detector. Based on absorption, the concentration of the analyte can
then be determined. Specific techniques for conducting this type of
infrared, or other spectrum analysis, can be found in U.S. Pat. No.
5,582,184, issued to Erickson et al. and D. A. Christensen, in Vol.
1648 Proceedings of Fiber Optic, Medical and Fluorescent Sensors
and Applications, pp. 223-26 (1992), both incorporated herein by
reference.
[0127] In a further embodiment of the present invention, following
the collection of the interstitial fluid, the desired analyte is
subjected to enzymatic means. For example, to determine glucose
concentration, glucose can be oxidized using glucose oxidase. This
creates gluconolactone and hydrogen peroxide. In the presence of
colorless chromogen, the hydrogen peroxide is converted to water
and a colored product. Because the intensity of the colored product
is proportional to the amount of glucose, conventional absorbance
or reflectance methods can be used to determine concentration. By
calibrating the color to glucose concentration, the concentration
of glucose can thereafter be visually approximated. Specific
techniques for conducting this type of analysis can found in U.S.
Pat. No. 5,458,140, issued to Eppstein et al., incorporated herein
by reference.
[0128] In an additional embodiment of the present invention, the
testing analysis can be electronically processed and fed to a
digital readout, or other suitable means, on the lasing device.
[0129] In another embodiment of the present invention, the
interstitial fluid is removed from the container unit, or the fluid
is collected in a separate device. After collection, the above
described testing methods can be conducted using separate equipment
or by sending the sample to a testing laboratory.
[0130] In a further embodiment, after perforation or alteration,
testing is completed on the tissue using separate methods or
devices. For example, the 1994 monitoring technique described by N.
Ito et al. ("Development of a Transcutaneous Blood-Constituent
Monitoring Method Using a Suction Effusion Fluid Collection
Technique and an Ion-Sensitive Field-Effect Transistor Glucose
Sensor", vol. 32, No. 2, pp. 242-246, Medical & Biological
Engineering & Computing, 1994), incorporated herein by
reference, can be conducted at the site of perforation or
alteration.
[0131] Delivery of a Pharmaceutical
[0132] A laser can be used to perforate or alter the skin through
the outer surface, such as the stratum corneum layer, but not as
deep as the capillary layer, to allow pharmaceuticals to be
topically administered. Pharmaceuticals must penetrate the stratum
corneum layer in order to be effective. Presently, compounds acting
as drug carriers are used to facilitate the transdermal diffusion
of some drugs. These carriers sometimes change the behavior of the
drug, or are themselves toxic.
[0133] With the other parameters set, the intensity of the laser
pump source will determine the intensity of the laser pulse, which
will in turn determine the depth of the resultant perforation or
alteration. Therefore, various settings on the laser can be
adjusted to allow perforation or alteration of different thickness'
of stratum corneum.
[0134] Optionally, a beam-dump can be positioned in such a way as
not to impede the use of the laser for perforation or alteration of
extremities. The beam-dump will absorb any stray electromagnetic
radiation from the beam that is not absorbed by the tissue, thus,
preventing any scattered rays from causing damage. The beam-dump
can be designed so as to be easily removed for situations when the
presence of the beam-dump would impede the placement of a body part
on the applicator.
[0135] This method of delivering a pharmaceutical creates a very
small zone in which tissue is irradiated, and only an extremely
small zone of thermal necrosis. A practical round irradiation site
can range from 0.1-5.0 cm in diameter, while a slit shaped hole can
range from approximately 0.05-0.5 mm in width and up to
approximately 2.5 mm in length, although other slit sizes and
lengths can be used. As a result, healing is quicker than or as
quick as the healing after a skin puncture with a sharp implement.
After irradiation, pharmaceuticals can then be applied directly to
the skin or in a pharmaceutically acceptable formulation such as a
cream, ointment, lotion or patch.
[0136] Alternatively, the delivery zone can be enlarged by
strategic location of the irradiation sites and by the use of
multiple sites. The present method can be used for transport of a
variety of pharmaceuticals. For example, a region of skin may be
anesthetized by first scanning the desired area with a pulsing
laser such that each pulse is sufficient to cause perforation or
alteration. This can be accomplished with modulated diode or
related microchip lasers, which deliver single pulses with temporal
widths in the 1 femtosecond to 1 ms range. Anesthetic (e.g., 10%
lidocaine) would then be applied over the treated area to achieve a
zone of anesthesia.
[0137] According to one embodiment of the present invention, a
pharmaceutical is administered immediately after the analyte of
interest has been measured. For example, in the case of glucose,
after measurement, a signal can be sent to a drug reservoir to
deliver an appropriate amount of insulin. Two embodiments of this
invention incorporate an atomizer (FIG. 18) or a roll-on device
(FIG. 11). In the case of a roll-on device, the laser beam
propagates through hole 162 incorporated in ball 164 of the roll-on
device. In the alternative, the roll-on device can be positioned
adjacent to the path of the laser beam through the disposable
applicator. After measurement, if needed, the roll-on device is
rolled over the irradiated site, thereby administering the desired
pharmaceutical. In the case of an atomizer, the pharmaceutical is
administered from a drug reservoir 166 through the use of
compressed gas. After measurement of the desired analyte, a
cylinder 168 containing compressed gas (such as, for example,
carbon dioxide) can be triggered to spray a set amount of
pharmaceutical, such as insulin, over the irradiated site.
[0138] In another embodiment of the present invention, an ink jet
or mark is used for marking the site of irradiation. The irradiated
sites are often not easily visible to the eye, consequently the
health care provider may not know exactly where to collect the
fluid sample or to apply the pharmaceutical. This invention further
provides techniques to mark the skin so that the irradiation site
is apparent. For example, an ink-jet (analogous to those used in
ink-jet printers) can be engaged prior to, during or immediately
after laser irradiation. Additionally, a circle can be marked
around the irradiation site, or a series of lines all pointing
inward to the irradiation site can be used. Alternatively, a
disposable safety-tip/applicator can be marked on the end (the end
that touches up against the skin of the patient) with a pigment.
Engaging the skin against the applicator prior to, during, or
immediately after lasing results in a mark on the skin at the site
of irradiation.
[0139] For certain purposes, it is useful to create multiple
perforations or alterations of the skin simultaneously or in rapid
sequence. To accomplish this, a beam-splitter or multiply pulsed
laser can optionally be added to the laser or a rapidly pulsing
laser, such as a diode or related microchip laser, may be used.
Multiple irradiated sites, created simultaneously or sequentially,
would result in an increased uptake of drugs as compared to a
single irradiation site (i.e. an increase in uptake proportional to
the total number of ablated sites). An example of a beam splitter
48 suitable for making simultaneous irradiation sites can be found
in FIG. 42. Any geometric pattern of spots can be produced on the
skin using this technique. Because the diffusion of fluid out of
the skin or drugs into skin can be approximated as symmetric, a
beneficial pattern of irradiation spots (such that a uniform local
concentration would result over as wide an area as possible) would
be to position each spot equidistant from each other in a staggered
matrix pattern (FIG. 43).
[0140] Alternatively, multiple irradiation sites, or an irradiated
area of arbitrary size and shape, could be produced with use of a
scanner. For example, oscillating mirrors which reflect the beam of
laser radiant energy can operate as a scanner.
[0141] For application of the laser device in fluid removal or
pharmaceutical delivery, the laser is manipulated in such a way
that a portion of the patient's skin is positioned at the site of
the laser focus within the applicator. For perforations or
alterations for fluid, gas or other biomolecule removal or
pharmaceutical delivery, a region of the skin which has less
contact with hard objects or with sources of contamination is
preferred, but not required. Examples are skin on the arm, leg,
abdomen or back. Optionally, the skin heating element is activated
at this time in order to reduce the laser energy required for
altering or ablating the stratum corneum.
[0142] Preferably a holder is provided with a hole coincident with
the focal plane of the optical system. Optionally, as shown in FIG.
2, a spring-loaded interlock 36 can be attached to the holder, so
that when the patient applies a small amount of pressure to the
interlock, to recess it to the focal point, a switch is closed and
the laser will initiate a pulse of radiation. In this setup, the
focal point of the beam is not in line with the end of the holder
until that end is depressed. In the extremely unlikely event of an
accidental discharge of the laser before proper positioning of the
tissue at the end of the laser applicator, the optical arrangement
will result in an energy fluence rate that is significantly low,
thus causing a negligible effect on unintentional targets.
[0143] The method of this invention may be enhanced by using a
laser of a wavelength that is specifically absorbed by the skin
components of interest (e.g., water, lipids or protein) which
strongly affect the permeation of the skin tissues. Altering the
lipids in stratum corneum may allow enhanced permeation while
avoiding the higher energies that are necessary to affect the
proteins and water.
[0144] It would be beneficial to be able to use particular lasers
other than the Er:YAG for perforation or alteration of tissue. For
example, diode lasers emitting radiant energy with a wavelength of
910 nm (0.8 microns) are inexpensive, but such wavelength radiation
is only poorly absorbed by tissue. In a further embodiment of this
invention, a dye is administered to the skin surface, either by
application over intact stratum corneum, or by application over an
Er:YAG laser treated site (so the that deep dye penetration can
occur), that absorbs such a wavelength of radiation. For example,
indocyanine green (ICG), which is a harmless dye used in retina
angiography and liver clearance studies, absorbs maximally at 810
nm when in plasma (Stephen Flock and Steven Jacques, "Thermal
Damage of Blood Vessels in a Rat Skin-Flap Window Chamber Using
Indocyanine Green and a Pulsed Alexandrite Laser: A Feasibility
Study", Laser Med. Sci. 8, 185-196, (1993)). This dye, when in
stratum corneum, is expected to absorb the 810 nm radiant energy
from a diode laser (e.g. a GaAlAs laser) thereby raising the
temperature of the tissue, and subsequently leading to ablation or
molecular changes resulting in reduced barrier function.
[0145] Alternatively, it is possible to chemically alter the
optical properties of the skin to enhance subsequent laser radiant
energy absorption without chemicals actually being present at the
time of laser irradiation. For example, 5-aminolevulinic acid
(5-ALA) is a precursor to porphyrins, which are molecules involved
in hemoglobin production and behavior. Porphyrins are strong
absorbers of light. Administration of 5-ALA stimulates production
of porphyrins in cells, but is itself consumed in the process.
Subsequently, there will be enhanced absorption of radiant energy
in this tissue at wavelengths where porphyrins absorb (e.g., 400 mm
or 630 mm).
[0146] Another way to enhance the absorption of radiant energy in
stratum corneum without the addition of an exogenous absorbing
compound is to hydrate the stratum corneum by, for example,
applying an occlusive barrier to the skin prior to laser
irradiation. In this situation, the water produced within the body
itself continues to diffuse through the stratum corneum and
propagate out through pores in the skin, but is prevented from
evaporating by the occlusive barrier. Thus, the moisture is
available to further saturate the stratum corneum. As the radiant
energy emitted by the Er:YAG laser is strongly absorbed by water,
this process would increase the absorption coefficient of the
stratum corneum, and so less energy would be required to induce the
alterations or ablations in the stratum corneum necessary for
enhanced topical drug deliver.
[0147] Additionally, the laser irradiated site eventually heals as
a result of infiltration of keratinocytes and keratin (which takes
perhaps two weeks to complete), or by the diffusion of serum up
through the ablated sites which form a clot (or eschar) which
effectively seals the ablated site. For long term fluid collection
and measurement, topical delivery of drugs, or for multiple
sequential administrations of topical drugs, it would be beneficial
to keep the ablated site open for an extended length of time.
[0148] Thus, in an additional embodiment of this invention, the
ablated or non-ablated site is kept open by keeping the area of
irradiation moist and/or biochemically similar to stratum corneum.
This is accomplished by minimizing contact of air with the ablated
site and/or providing fluid to keep the ablated site moist. The
application of a patch (containing, for example, an ointment such
as petroleum jelly or an ointment containing hydrocortisone) over
the site would help to keep it open. A hydrogel patch would also
serve to provide the necessary moisture. Additionally, cytotoxic
drugs such as cisplatin, bleomycin, doxorubicin, and methotrexate,
for example, topically applied in low concentrations would locally
prevent cellular infiltration and wound repair. Furthermore,
application of a vitamin C (ascorbic acid) or other known
inhibitors of melanin production, following irradiation, would help
to prevent additional skin coloration in the area, following
treatment.
[0149] Alteration Without Ablation
[0150] There are advantages to the technique of altering and not
ablating the stratum corneum. In a preferred embodiment, the skin
is altered, not ablated, so that its structural and biochemical
makeup allows fluid to diffuse to the skin surface and allows drugs
to permeate. The consequence of this embodiment is: (1) the skin
after irradiation still presents a barrier, albeit reduced, to
external factors such as viruses and chemical toxins; (2) less
energy is required than is required to ablate the stratum corneum,
thus smaller and cheaper lasers can be used; and (3) less tissue
damage occurs, thus resulting in more rapid and efficient
healing.
[0151] Radiant Energy vs Laser Radiant Energy
[0152] The radiant energy emitted by lasers has the properties of
being coherent, monochromatic, collimated and (typically) intense.
Nevertheless, to enhance transdermal drug delivery or fluid, gas or
biomolecule collection, the radiant energy used need not have these
properties, or alternatively, can have one of all of these
properties, but can be produced by a non-laser source.
[0153] For example, the pulsed light output of a pulsed xenon
flashlamp can be filtered with an optical filter or other
wavelength selection device, and a particular range of wavelengths
can be selected out of the radiant energy output. While the
incoherent and quasi-monochromatic output of such a configuration
cannot be focussed down to a small spot as can coherent radiant
energy, for the aforementioned purpose that may not be important as
it could be focused down to a spot with a diameter on the order of
millimeters. Such light sources can be used in a continuous wave
mode if desirable.
[0154] The infrared output of incandescent lights is significantly
more than their output in the visible, and so such light sources,
if suitably filtered to eliminate undesirable energy that does not
reduce barrier function, could be used for this purpose. In another
embodiment of the invention, it would be possible to use an intense
incandescent light (such as a halogen lamp), filter it with an
optical filter or similar device, and used the continuous-wave
radiant energy output to decrease the barrier function of stratum
corneum without causing ablation. All of these sources of radiant
energy can be used to produce pulses, or continuos-wave radiant
energy.
[0155] Laser Device
[0156] The practice of the present invention has been found to be
effectively performed by various types of lasers; for example, the
TRANSMEDICA.TM. Er:YAG laser skin perforator, or the Schwartz
Electro-Optical Er:YAG laser. Any pulsed laser producing energy
that is strongly absorbed in tissue may be used in the practice of
the present invention to produce the same result at a non-ablative
wavelength, pulse length, pulse energy, pulse number, and pulse
rate. However, lasers which produce energy that is not strongly
absorbed by tissue may also be used, albeit less effectively, in
the practice of this invention. Additionally, as described herein,
continuous-wave lasers may also be used in the practice of this
invention.
[0157] FIGS. 1 and 2 are diagrammatic representations a typical
laser that can be used for this invention. As shown in FIGS. 1 and
2, a typical laser comprises a power connection which can be either
a standard electrical supply 10, or optionally a rechargeable
battery pack 12, optionally with a power interlock switch 14 for
safety purposes; a high voltage pulse-forming network 16; a laser
pump-cavity 18 containing a laser rod 20, preferably Er:YAG; a
means for exciting the laser rod, preferably a flashlamp 22
supported within the laser pump-cavity; an optical resonator
comprised of a high reflectance mirror 24 positioned posterior to
the laser rod and an output coupling mirror 26 positioned anterior
to the laser rod; a transmitting focusing lens 28 positioned beyond
the output coupling mirror; optionally a second focusing
cylindrical lens 27 positioned between the output coupling mirror
and the transmitting focusing lens; an applicator 30 for
positioning the subject skin at the focal point of the laser beam,
which is optionally heated for example with a thermoelectric heater
32, attached to the laser housing 34; an interlock 36 positioned
between the applicator and the power supply; and optionally a beam
dump 38 attached to the applicator with a fingertip access port
40.
[0158] The laser typically draws power from a standard 110 V or 220
V AC power supply 10 (single phase, 50 or 60 Hz) which is rectified
and used to charge up a bank of capacitors included in the high
voltage pulse-forming network 16. Optionally, a rechargeable
battery pack 12 can be used instead. The bank of capacitors
establishes a high DC voltage across a high-output flashlamp 22.
Optionally a power interlock 14, such as a key switch, can be
provided which will prevent accidental charging of the capacitors
and thus accidental laser excitation. A further interlock can be
added to the laser at the applicator, such as a spring-loaded
interlock 36, so that discharge of the capacitors requires both
interlocks to be enabled.
[0159] With the depression of a switch, a voltage pulse can be
superimposed on the already existing voltage across the flashlamp
in order to cause the flashlamp to conduct, and, as a consequence,
initiate the flash. The light energy from the flashlamp is located
in the laser cavity 18 that has a shape such that most of the light
energy is efficiently directed to the laser rod 20, which absorbs
the light energy, and, upon de-excitation, subsequently lases. The
laser cavity mirrors of low 26 and high 24 reflectivity, positioned
collinearly with the long-axis of the laser rod, serve to amplify
and align the laser beam.
[0160] Optionally, as shown in FIG. 12 the laser cavity mirrors
comprise coatings 124, 126, applied to ends of the crystal element
and which have the desired reflectivity characteristics. In a
preferred embodiment an Er:YAG crystal is grown in a boule two
inches in diameter and five inches long. The boule is core drilled
to produce a rod 5-6 millimeters in diameter and five inches long.
The ends of the crystal are ground and polished. The output end,
that is the end of the element from which the laser beam exits, is
perpendicular to the center axis of the rod within 5 arc minutes.
The flatness of the output end is {fraction (1/10)} a wavelength
(2.9 microns) over 90% of the aperture. The high reflectance end,
that is the end opposite the output end, comprises a two meter
convex spherical radius. The polished ends are polished so that
there are an average of ten scratches and five digs per Military
Specification Mil-0-13830A. Scratch and dig are subjective
measurements that measure the visibility of large surface defects
such as defined by U.S. military standards. Ratings consist of two
numbers, the first being the visibility of scratches and the latter
being the count of digs (small pits). A #10 scratch appears
identical to a 10 micron wide standard scratch while a #1 dig
appears identical to a 0.01 mm diameter standard pit. For
collimated laser beams, one normally would use optics with better
than a 40-20 scratch-dig rating.
[0161] Many coatings are available from Rocky Mountain Instruments,
Colorado Springs, Colo. The coating is then vacuum deposited on the
ends. For a 2.9 micron wavelength the coatings for the rear
mirrored surface 124 should have a reflectivity of greater than
99%. The coating for the output end surface, by contrast, should
have a reflectance of between 93% and 95%, but other mirrored
surfaces with reflectivity as low as 80% are useful. Other vacuum
deposited metallic coatings with known reflectance characteristics
are widely available for use with other laser wavelengths.
[0162] The general equation which defines the reflectivity of the
mirrors in a laser cavity necessary for the threshold for
population inversion is:
R.sub.1R.sub.2(1-a.sub.L).sub.2exp[(g.sub.21-I)2L]=1
[0163] where the R.sub.1 and R.sub.2 are the mirrors'
reflectivities, aL is the total scattering losses per pass through
the cavity, g.sub.21 is the gain coefficient which is the ratio of
the stimulated emission cross section and population inversion
density, I is the absorption of the radiation over one length of
the laser cavity, and L is the length of the laser cavity. Using
the above equation, one can select a coating with the appropriate
spectral reflectivity from the following references. W. Driscoll
and W. Vaughan, "Handbook of Optics," ch. 8, eds., McGraw-Hill: NY
(1978); M. Bass, et al., "Handbook of Optics," ch. 35, eds., McGraw
Hill: NY (1995).
[0164] Optionally, as also shown in FIG. 12, the crystal element
may be non-rigidly mounted. In FIG. 12 an elastomeric material
O-ring 128 is in a slot in the laser head assembly housing 120
located at the high reflectance end of the crystal element. A
second elastomeric material O-ring 130 is in a second slot in the
laser head assembly at the output end of the crystal element. The
O-rings contact the crystal element by concentrically receiving the
element as shown. However, elastomeric material of any shape may be
used so long as it provides elastomeric support for the element
(directly or indirectly) and thereby permits thermal expansion of
the element. Optionally, the flash lamp 22 may also be non-rigidly
mounted. FIG. 12 shows elastomeric O-rings 134, 136, each in its
own slot within the laser head assembly housing. In FIG. 12 the
O-rings 134 and 136 concentrically receive the flash lamp. However,
the flash lamp may be supported by elastomeric material of other
shapes, including shapes without openings.
[0165] Optionally, as shown in FIG. 3, a diode laser 42 that
produces a pump-beam collinear with the long-axis of the laser
crystal can be used instead of the flashlamp to excite the crystal.
The pump-beam of this laser is collimated with a collimating lens
44, and transmitted to the primary laser rod through the high
reflectance infrared mirror 45. This high reflectance mirror allows
the diode pump laser beam to be transmitted, while reflecting
infrared light from the primary laser.
[0166] The Er:YAG lasing material is the preferred material for the
laser rod because the wavelength of the electromagnetic energy
emitted by this laser, 2.94 microns, is very near one of the peak
absorption wavelengths (approximately 3 microns) of water. Thus,
this wavelength is strongly absorbed by water and tissue. The rapid
heating of water and tissue causes perforation or alteration of the
skin.
[0167] Other useful lasing material is any material which, when
induced to lase, emits a wavelength that is strongly absorbed by
tissue, such as through absorption by water, nucleic acids,
proteins or lipids and consequently causes the required perforation
or alteration of the skin (although strong absorption is not
required). A laser can effectively cut or alter tissue to create
the desired perforations or alterations where tissue exhibits an
absorption coefficient of 10-10,000 cm.sup.-1. Examples of useful
lasing elements are pulsed CO.sub.2 lasers, Ho:YAG (holmium:YAG),
Er:YAP, Er/Cr:YSGG (erbium/chromium:yttrium, scandium, gallium,
garnet; 2.796 microns), Ho:YSGG (holmium:YSGG; 2.088 microns),
Er:GGSG (erbium:gadolinium, gallium, scandium, garnet), Er:YLF
(erbium:yttrium, lithium, fluoride; 2.8 microns), Trn:YAG
(thulium:YAG; 2.01 microns), Ho:YAG (holmium:YAG; 2.127 microns);
Ho/Nd:YA103 (holmium/neodymium:yttrium, aluminate; 2.85-2.92
microns), cobalt:MgF.sub.2 (cobalt:magnesium fluoride; 1.75-2.5
microns), HF chemical (hydrogen fluoride; 2.6-3 microns), DF
chemical (deuterium fluoride; 3.6-4 microns), carbon monoxide (5-6
microns), deep UV lasers, and frequency tripled Nd:YAG
(neodymium:YAG, where the laser beam is passed through crystals
which cause the frequency to be tripled).
[0168] Utilizing current technology, some of these laser materials
provide the added benefit of small size, allowing the laser to be
small and portable. For example, in addition to Er:YAG, Ho:YAG
lasers also provide this advantage.
[0169] Solid state lasers, including but not limited to those
listed above, may employ a polished barrel crystal rod. The rod
surface may also contain a matte finish as shown in FIG. 13.
However, both of these configurations can result in halo rays which
surround the central output beam. Furthermore, an all-matte finish,
although capable of diminishing halo rays relative to a polished
rod, will cause a relatively large decrease in the overall laser
energy output. In order to reduce halo rays and otherwise affect
beam mode, the matte finish can be present on bands of various
lengths along the rod, each band extending around the entire
circumference of the rod. Alternatively, the matte finish may be
present in bands along only part of the rod's circumference. FIG.
14 shows a laser crystal element in which the matte finish is
present upon the full circumference of the element along two-thirds
of its length. Alternatively, as shown in FIG. 15, matte stripes
may be present longitudinally along the full length of the rod. The
longitudinal stripes may alternatively exist along only part of the
length of the rod, such as in stripes of various lengths. A
combination of the foregoing techniques may be used to affect beam
shape. Other variations of patterns may also be employed in light
of the beam shape desired. The specific pattern may be determined
based on the starting configuration of the beam from a 100%
polished element in light of the desired final beam shape and
energy level. A complete matte finish element may also be used as
the starting reference point.
[0170] For purposes of beam shape control, any surface finish of
greater than 30 microinches is considered matte. A microinch equals
one millionth (0.000001) inch, which is a common unit of
measurement employed in establishing standard roughness unit
values. The degree of roughness is calculated using the
root-mean-square average of the distances in microinches above or
below the mean reference line, by taking the square root of the
mean of the sum of the squares of these distances. Although matte
surfaces of greater than 500 microinches may be used to affect beam
shape, such a finish will seriously reduce the amount of light
energy that enters the crystal rod, thereby reducing the laser's
energy.
[0171] To remove the beam halo, a matte area of approximately 50
microinches is present around the full circumference of an Er:YAG
laser rod for two-thirds the length of the rod. The non-matte areas
of the rod are less than 10 microinches. A baseline test of the
non-matte rod can be first conducted to determine the baseline beam
shape and energy of the rod. The matte areas are then obtained by
roughing the polished crystal laser rod, such as with a diamond
hone or grit blaster. The specific pattern of matte can be
determined with respect to the desired beam shape and required beam
energy level. This results in a greatly reduced beam halo. The rod
may also be developed by core drilling a boule of crystal so that
it leaves an overall matte finish and then polishing the desired
areas, or by refining a partially matte, partially polished boule
to achieve the desired pattern.
[0172] The beam shape of a crystal laser rod element may
alternatively be modified as in FIG. 16 by surrounding the rod 20
in a material 160 which is transparent to the exciting light but
has an index of refraction greater than the rod. Such a
modification can reduce the halo of the beam by increasing the
escape probability of off-axis photons within the crystal. This
procedure may be used in place of or in addition to the foregoing
matte procedure.
[0173] The emitted laser beam is focused down to a millimeter or
submillimeter sized spot with the use of the focusing lens 28.
Consideration of laser safety issues suggests that a short focal
length focusing lens be used to ensure that the energy fluence rate
(W/cm.sup.2) is low except at the focus of the lens where the
tissue sample to be perforated or altered is positioned.
Consequently, the hazard of the laser beam is minimized.
[0174] The beam can be focused so that it is narrower along one
axis than the other in order to produce a slit-shaped perforation
or alteration through the use of a cylindrical focusing lens 27.
This lens, which focuses the beam along one axis, is placed in
series with the transmitting focusing lens 28. When perforations or
alterations are slit-shaped, the patient discomfort or pain
associated with the perforation or alteration is considerably
reduced.
[0175] Optionally, the beam can be broadened, for instance through
the use of a concave diverging lens 46 (FIG. 4) prior to focusing
through the focusing lens 28. This broadening of the beam results
in a laser beam with an even lower energy fluence rate a short
distance beyond the focal point, consequently reducing the hazard
level. Furthermore, this optical arrangement reduces the optical
aberrations in the laser spot at the treatment position,
consequently resulting in a more precise perforation or
alteration.
[0176] Also optionally, the beam can be split by means of a
beam-splitter to create multiple beams capable of perforating or
altering several sites simultaneously or near simultaneously. FIG.
5 provides two variations of useful beam splitters. In one version,
multiple beam splitters 48 such as partially silvered mirrors,
dichroic mirrors, or beam-splitting prisms can be provided after
the beam is focused. Alternatively, an acousto-optic modulator 52
can be supplied with modulated high voltage to drive the modulator
52 and bend the beam. This modulator is outside the laser cavity.
It functions by deflecting the laser beam sequentially and rapidly
at a variety of angles to simulate the production of multiple
beams.
[0177] Portability
[0178] Currently, using a portable TRANSMEDICA.TM. Er:YAG laser,
the unit discharges once per 20-30 seconds. This can be increased
by adding a battery and capacitor and cooling system to obtain a
quicker cycle. Multiple capacitors can be strung together to get
the discharge rate down to once every 5 or 10 seconds (sequentially
charging the capacitor banks). Thus, getting a higher repetition
rate than with a single capacitor.
[0179] The TRANSMEDICA.TM. Er:YAG laser incorporates a flashlamp,
the output of which is initiated by a high-voltage pulse of
electricity produced by a charged capacitor bank. Due to the high
voltages required to excite the flashlamp, and because the referred
to version of the laser incorporates dry cells to run (thus the
charging current is much less than a wall-plug could provide), then
the capacitors take about 20 seconds to sufficiently charge. Thus,
if a pulse repetition rate of 1 pulse/20 seconds is desirable, it
would be suitable to have multiple capacitor banks that charge
sequentially (i.e. as one bank fires the flashlamp, another bank,
which has been recharging, fires, and so on). Thus, the pulse
repetition rate is limited only be the number of capacitor banks
incorporated into the device (and is also limited by the efficiency
of waste-heat removal from the laser cavity).
[0180] A small heater, such as a thermoelectric heater 32, is
optionally positioned at the end of the laser applicator proximal
to the site of perforation. The heater raises the temperature of
the tissue to be perforated or altered prior to laser irradiation.
This increases the volume of fluid collected when the device is
used for that purpose. A suggested range for skin temperature is
between 36.degree. C. and 45.degree. C., although any temperature
which causes vasodilation and the resulting increase in blood flow
without altering the blood chemistry is appropriate.
[0181] Container Unit
[0182] A container unit 68 is optionally fitted into the laser
housing and is positioned proximal to the site of irradiation. The
container unit reduces the intensity of the sound produced when the
laser beam perforates the patient's tissue, increases the
efficiency of interstitial fluid collection, and collects the
ablated tissue and other matter released by irradiation. The
container unit is shaped so as to allow easy insertion into the
laser housing and to provide a friction fit within the laser
housing. FIG. 8 shows the container unit inserted into the laser
housing and placed over the site of irradiation.
[0183] The container unit 68 comprises a main receptacle 82,
including a lens 84. The main receptacle collects the interstitial
fluid sample, the ablated tissue, and/or other matter released by
irradiation. The lens is placed such that the laser beam may pass
through the lens to the site of irradiation but so that the matter
released by irradiation does not splatter back onto the applicator.
The container unit also optionally includes a base 86, attached to
the receptacle. The base can optionally be formed so at to be
capable of being inserted into the applicator to disengage a safety
mechanism of the device, thereby allowing the laser beam to be
emitted.
[0184] As shown in FIG. 17, the shape and size of the container
unit 68 are such as to allow placement next to or insertion into
the applicator, and to allow collection of the interstitial fluid
sample, ablated tissue, and/or other matter released by
irradiation. Examples of shapes that the main receptacle may take
include cylinders, bullet shapes, cones, polygons and free form
shapes. Preferably, the container unit has a main receptacle, with
a volume of around 1-2 milliliters. However, larger and smaller
receptacles will also work.
[0185] The lens 84, which allows the laser beam to pass through
while preventing biological and other matter from splattering back
onto the applicator, is at least partially transparent. The lens is
constructed of a laser light-transmitting material and is
positioned in the pathway of the laser beam, at the end of the
container unit proximal to the beam. In one embodiment, the
transmitting material is quartz, but other examples of suitable
infrared materials include rock salt, germanium, and polyethylene.
As shown in FIG. 20, the lens may optionally include a mask of
non-transmitting material 85 such that the lens may shape the
portion of the beam that is transmitted to the site of
irradiation.
[0186] The main receptacle 82 is formed by the lens and a wall 88,
preferably extending essentially away from the perimeter of the
lens. The open end of the main receptacle or rim 90 is placed
adjacent to the site of irradiation. The area defined by the lens,
wall of the main receptacle and the site of irradiation is thereby
substantially enclosed during the operation of the laser perforator
device.
[0187] The base 86 is the part of the container unit that can
optionally be inserted into the applicator. The base may comprise a
cylinder, a plurality of prongs or other structure. The base may
optionally have threading. Optionally, the base, when fully
inserted, disengages a safety mechanism of the laser perforator
device, allowing the emission of the laser beam.
[0188] As shown in FIG. 19, the container unit may also include an
additional vessel 92 which collects a portion of the matter
released as part of irradiation. For example, this vessel can
collect interstitial fluid and/or other liquid or particulate
matter, while the main receptacle 82 collects the ablated tissue.
The interstitial fluid and/or other liquid or particulate matter
may be channeled into the vessel through a capillary tube 94 or
other tubing which extends from the main receptacle into the
vessel. The vessel is optionally detachable. The main receptacle
may have a hole 95 in the wall through which the capillary tube or
other tubing may be securely inserted. The vessel may have a
removable stop 96 which sufficiently covers the open end of the
vessel to prevent contamination with undesired material, but has an
opening large enough for the capillary tube or other tubing to be
inserted. In the preferred embodiment, the capillary tube or other
tubing will extend outwardly from the main receptacle's wall and
into the vessel through the removable stop. Once the sample has
been collected, the stop may optionally be removed and discarded.
The vessel may then optionally be sealed with a cap 98 to prevent
spillage. The vessel is preferably bullet shaped.
[0189] In the first embodiment, the container unit comprises a
cylindrical main receptacle 82, a cylindrical base 86, and an at
least partially transparent circular lens 84 in the area between
the main receptacle and base. Optionally, the lens may include a
mask which shapes the beam that perforates the tissue. The
container unit is constructed of glass or plastic. The container
unit is optionally disposable.
[0190] In the second embodiment, the container unit comprises the
elements of the first embodiment and also includes an additional
vessel 92 and a capillary tube 94 extending outwardly from the main
receptacle's wall 88 and into the vessel through a removable stop
96. The vessel may optionally have a cap 98 to seal the opening so
as to prevent spillage. The container unit is constructed of glass
or plastic. The container unit, including the capillary tube and
the additional vessel, are optionally disposable.
[0191] FIG. 19 shows examples of the use of the container unit with
the laser perforator device. In this embodiment the applicator 30
is surrounded by the housing 34. The container unit is inserted in
the applicator 30 and aligned so as to be capable of defeating the
interlock 36. The base 86 of the container unit in this embodiment
is within the applicator 30, while the rim 90 of the receptacle 82
is located adjacent to the tissue to be perforated. The beam passes
through the lens 84.
[0192] In a third embodiment, the container unit is evacuated. The
optional vacuum in the container unit exerts a less than
interstitial fluid or pressure of gases in the blood over the site
of irradiation, thereby increasing the efficiency of interstitial
fluid collection. The container unit's end proximal to the site of
irradiation is optionally sealed air-tight with a plug 70. The plug
is constructed of material of suitable flexibility to conform to
the contours of the site of irradiation (e.g., the finger). The
desired site of irradiation is firmly pressed against the plug. The
plug's material is impermeable to gas transfer. Furthermore, the
plug's material is thin enough to permit perforation of the
material as well as irradiation of the skin by the laser. In the
preferred embodiment, the plug is constructed of rubber.
[0193] The plug perforation center 74, as shown in FIG. 9, is
preferably constructed of a thin rubber material. The thickness of
the plug is such that the plug can maintain the vacuum prior to
perforation, and the laser can perforate the plug and irradiate the
tissue adjacent to the plug. For use with an Er:YAG laser, the plug
should be in the range of approximately 100 to 500 microns thick,
but at the most 1 millimeter thick.
[0194] The plug perforation center 74 is large enough to cover the
site of irradiation. Optionally, the perforated site is a round
hole with an approximate diameter ranging from 0.1-1 mm, or slit
shaped with an approximate width of 0.05-0.5 mm and an approximate
length up to 2.5 mm. Thus, the plug perforation center is
sufficiently large to cover irradiation sites of these sizes.
[0195] The site of irradiation is firmly pressed against the rubber
material. Optionally, an annular ring of adhesive can be placed on
the rubber plug to provide an air-tight seal between the site of
irradiation and the container unit. Preferably the perforation site
on the plug is stretched when the tissue is pressed against the
plug. This stretching of the plug material causes the hole created
in the plug to expand beyond the size of the hole created in the
tissue. As a result, the interstitial fluid can flow unimpeded into
the container unit 68. The laser beam penetrates the container
unit, perforates the plug perforation center 74 and irradiates the
patient's tissue.
[0196] In a fourth embodiment of the container unit, as shown in
FIG. 10, the container unit 68 includes a hole 76 through which the
laser passes. In this fourth embodiment, the container unit
optionally solely collects ablated tissue. As in the other
embodiments, the site of irradiation is firmly pressed against the
container unit. The container unit can optionally include a plug
proximal to the site of irradiation, however it is not essential
because there is no need to maintain a vacuum in this embodiment.
All embodiments of the container unit reduce the noise created from
interaction between the laser beam and the patient's tissue and
thus alleviate the patient's anxiety and stress.
[0197] The container may also be modified to hold, or receive
through an opening, a pharmaceutical or other substance, which may
then be delivered shortly after testing of interstitial fluid. FIG.
11 shows an example of a container with a built-in drug reservoir
and roll-on apparatus for delivery. FIG. 18 shows a container with
an applicator which in turn comprises an atomizer with attached
high pressure gas cylinder.
[0198] Optionally, the container unit is disposable, so that the
container unit and plug can be discarded after use. Additionally,
the main receptacle of the container unit, capillary tube and/or
additional vessel can contain reagents for various tests to be
performed on the collected interstitial fluid, such as the glucose
oxidase test described above. The reagents are positioned so that
they will not be in the pathway of the laser light. The reagents
are preferably present in a dry form, coating the interior walls of
the collection part of the container unit, and thus readily
available for interaction with the interstitial fluid sample as it
is collected.
[0199] A preferable configuration for the container unit when it
contains a regent is shown in FIG. 39. In this configuration, the
container unit has an indentation 78 at the base such that any
fluid reagent present in the container unit will not fall into the
line of fire of the laser beam when the container unit is held
either vertically or horizontally. The apex 80 of the indented are
is made of an infrared-transparent substance, such as quartz, or a
near transparent substance.
[0200] When reagents are present in the container unit prior to
collection of the interstitial fluid sample, it is beneficial to
label the container unit in some manner as to the reagents
contained inside, or as to the test to be performed on the sample
using those reagents. A preferred method for such labelling is
through the use of color-coded plugs. For example, a blue plug
might indicate the presence of reagent A, while a red plug might
indicate the presence of reagents B plus C within the container
unit.
[0201] Modulated Laser
[0202] In addition to the pulsed lasers listed above, a modulated
laser can be used to duplicate a pulsed laser for the purpose of
enhancing topical drug delivery, as well as enhancing the removal
of fluids. This is accomplished by chopping the output of the
continuous-wave laser by either modulating the laser output
mechanically, optically or by other means such as a saturable
absorber. (See, e.g., Jeff Hecht, The Laser Guidebook,
McGraw-Hill:NY, 1992). Examples of continuous-wave lasers include
CO.sub.2, which lases over a range between 9-11 microns (e.g.
Edinburgh Instruments, Edinburgh, UK), Nd:YAG, Thallium:YAG
(Tm:YAG), which lases at 2.1 microns (e.g. CLR Photonics Inc.,
Boulder Colo.), semiconductor (diode) lasers which lase over a
range from 1.0-2.0 microns (SDL Inc., San Jose, Calif.).
[0203] The chopping of the laser output (for example, with a
mechanical chopper from Stanford Research Instruments Inc.,
Sunnyvale Calif.) will preferably result in discrete moments of
irradiation with temporal widths from a few tenths of milliseconds,
down to nanoseconds or picoseconds. Alternatively, in the case of
diode lasers, the lasing process can be modulated by modulating the
laser excitation current. A modulator for a laser diode power
supply can be purchased from SDL Inc., San Jose, Calif.
Alternatively, the continuous-wave beam can be optically modulated
using, for example, an electro-optic cell (e.g. from New Focus
Inc., Santa Clara, Calif.) or with a scanning mirror from General
Scanning, Inc., Watertown Mass.
[0204] The additive effect of multiple perforations or alterations
may be exploited with diode lasers. Laser diodes supplied by SDL
Corporation (San Jose, Calif.) transmit a continuous beam of from
1.8 to 1.96 micron wavelength radiant energy. These diodes operate
at up to 500 mW output power and may be coupled to cumulatively
produce higher energies useful for stratum corneum ablation. For
example, one diode bar may contain ten such diodes coupled to
produce pulsed energy of 5 mJ per millisecond. It has been shown
that an ablative effect may be seen with as little as 25 mJ of
energy delivered to a 1 mm diameter spot. Five (5) millisecond
pulses or (25) one millisecond pulses from a diode laser of this
type will thus have an ablative effect approximately equivalent to
one 25 mJ pulse in the same time period.
[0205] The following examples are descriptions of the use of a
laser to increase the permeability of the stratum corneum for the
purpose of drawing fluids, as well as for pharmaceutical delivery.
These examples are not meant to limit the scope of the invention,
but are merely embodiments.
EXAMPLE 1
[0206] The laser comprises a flashlamp (PSC Lamps, Webster, N.Y.),
an Er:YAG crystal (Union Carbide Crystal Products, Washagoul,
Wash.), optical-resonator mirrors (CVI Laser Corp., Albuquerque, N.
Mex.), an infrared transmitting lens (Esco Products Inc., Oak
Ridge, N.J.), as well as numerous standard electrical components
such as capacitors, resistors, inductors, transistors, diodes,
silicon-controlled rectifiers, fuses and switches, which can be
purchased from any electrical component supply firm, such as Newark
Electronics, Little Rock, Ark.
EXAMPLE 2
[0207] An infrared laser radiation pulse was formed using a solid
state, pulsed, Er:YAG laser consisting of two flat resonator
mirrors, an Er:YAG crystal as an active medium, a power supply, and
a means of focusing the laser beam. The wavelength of the laser
beam was 2.94 microns. Single pulses were used.
[0208] The operating parameters were as follows: The energy per
pulse was 40, 80 or 120 mJ, with the size of the beam at the focal
point being 2 mm, creating an energy fluence of 1.27, 2.55 or 3.82
J/cm.sup.2. The pulse temporal width was 300 .mu.s, creating an
energy fluence rate of 0.42, 0.85 or 1.27.times.10.sup.4
W/cm.sup.2.
[0209] Transepidermal water loss (TEWL) measurements were taken of
the volar aspect of the forearms of human volunteers. Subsequently
the forearms were positioned at the focal point of the laser, and
the laser was discharged. Subsequent TEWL measurements were
collected from the irradiation sites, and from these the
measurements of unirradiated controls were subtracted. The results
(shown in FIG. 27) show that at pulse energies of 40, 80 and 120
mJ, the barrier function of the stratum corneum was reduced and the
resulting water loss was measured to be 131, 892 and 1743
gm/m.sup.2/hr respectively. The tape stripe positive control (25
pieces of Scotch Transpore tape serially applied and quickly
removed from a patch of skin) was measured to be 9.0 gm/m2/hr,
greater than untouched controls; thus the laser is more efficient
at reducing the barrier function of the stratum corneum than
tape-stripping.
[0210] Clinical assessment was conducted 24 hours after
irradiation. Only a small eschar was apparent on the site lased at
high energy, and no edema was present. None of the volunteers
experienced irritation or required medical treatment.
EXAMPLE 3
[0211] An infrared laser radiation pulse was formed using a solid
state, pulsed, Er:YAG laser consisting of two flat resonator
mirrors, an Er:YAG crystal as an active medium, a power supply, and
a means of focusing the laser beam. The wavelength of the laser
beam was 2.94 microns. A single pulse was used.
[0212] The operating parameters were as follows: The energy per
pulse was 60 mJ, with the size of the beam at the focal point being
2 mm, creating an energy fluence of 1.91 J/cm.sup.2. The pulse
temporal width was 300 .mu.s, creating an energy fluence rate of
0.64.times.10.sup.4 W/cm.sup.2.
[0213] The volar aspect of the forearm of a volunteer was placed at
the focal point of the laser, and the laser was discharged. After
discharge of the laser, the ablated site was topically administered
a 30% liquid lidocaine solution for two minutes. A 26 G-0.5 needle
was subsequently inserted into the laser ablated site with no
observable pain. Additionally, after a 6 minute anesthetic
treatment, a 22 G-1 needle was fully inserted into the laser
ablated site with no observable pain. The volunteer experienced no
irritation and did not require medical treatment.
EXAMPLE 4
[0214] Ablation threshold energy: Normally hydrated (66%) stratum
corneum was sandwiched between two microscope cover slides, and
exposed to a single pulse of irradiation from the Er:YAG laser.
Evidence of ablation was determined by holding the sample up to a
light and seeing whether any stratum corneum was left at the
irradiated site. From this experiment, it was determined that the
irradiation threshold energy (for a 2 mm irradiation spot) was
approximately 90-120 mJ. The threshold will likely be higher when
the stratum corneum is still overlying epidermis, as in normal
skin, since it takes energy to remove the stratum corneum from the
epidermis, to which it is adherent.
EXAMPLE 5
[0215] Differential Scanning Calorimetry (DSQ: FIG. 28 shows a DSC
scan of normally hydrated (66%) human stratum corneum, and a scan
of stratum corneum irradiated with the Er:YAG laser using a
subablative pulse energy of 60 mJ. Defining the thermal transition
peaks at approximately 65, 80 and 92.degree. C., we determined the
heat of transition (.mu.J), center of the transition (.degree. C.)
and the full-width at half-maximum of the transition (.degree. C.)
(FIGS. 29-31). The results shown are on normal 66% hydrated stratum
corneum, dehydrated 33% stratum corneum, steam heated stratum
corneum, Er:YAG laser irradiated stratum corneum, or stratum
corneum that was immersed in chloroform-methanol (a lipid solvent),
or beta-mercaptoethanol (a protein denaturant). The effect of laser
irradiation on stratum corneum is consistent (depending on which
transition you look at, 1, 2 or 3) with changes seen due to thermal
damage (i.e. heated with steam), and de-lipidization. Permeation
with (3H.sub.2O) and transepidermal impedance experiments on skin
treated the same way showed that the result of these treatments
(heat, solvent or denaturant) resulted in increased permeation.
Thus, the changes induced in the stratum corneum with these
treatments, changes which are consistent with those seen in laser
irradiated stratum corneum, and changes which do not result in
stratum corneum ablation, result in increased permeation.
EXAMPLE 6
[0216] Fourier Transform Infrared (FTIR) Spectroscopy: FTIR
spectroscopy was used to study stratum corneum treated the same way
as in the above DSC experiments, except the energy used was between
53 and 76 mJ. The spectra (see, e.g., FIGS. 32-33) show that
absorption bands that are due to water, proteins and lipids change
when the stratum corneum is irradiated. Some of these changes are
consistent with changes seen during non-laser treatment of the
stratum corneum (e.g. desiccation, thermal damage, lipid
solubilization, or protein denaturation). For example, the Amide I
and II bands, which are due to the presence of proteins (most
likely keratin, which makes up the bulk of protein in stratum
corneum), shift to a larger wavenumber, consistent with the effect
of desiccation alone (in the case of Amide II) or desiccation and
beta-mercaptoethanol treatment (in the case of Amide I) (see, e.g.,
FIG. 34). The CH2 vibrations (due to bonds in lipids) always shift
to a smaller wavenumber indicating that either the intermolecular
association between adjacent lipid molecules has been disturbed
and/or the environment around the lipid molecules has changed in
such a way that the vibrational behavior of the molecules changes
(see, e.g., FIG. 35).
EXAMPLE 7
[0217] Histology: Numerous in vivo experiments have been done on
rats and humans. Usually, the skin is irradiated with the Er:YAG
laser and a 2 mm spot and with a particular pulse energy, and then
the irradiated site is biopsied immediately or 24 hours later. Two
examples of typical results are shown in FIGS. 36 and 37. FIG. 36
shows rat skin irradiated at 80 mJ, which is an energy sufficient
to make the skin permeable (to lidocaine, for instance) and yet
does not show any sign of stratum corneum ablation. FIG. 37 depicts
human skin 24 hours after being irradiated at 80 mJ. In this case,
some change in the appearance of the stratum corneum has taken
place (perhaps coagulation of some layers of stratum corneum into a
darkly staining single layer), and yet the stratum corneum is still
largely intact and is not ablated. Irradiation of human skin, in
vivo, and subsequent examination under a dissection microscope,
show that at subablative energies (less than about 90-120 mJ), the
stratum corneum is still present on the skin. The irradiated
stratum corneum appears slightly whitened in vivo, which might be
evidence of desiccation or separation of the stratum corneum from
the underlying tissue.
EXAMPLE 8
[0218] One way to quantify the reduction in the barrier function of
the stratum corneum is to measure the reduction in the electrical
impedance of the skin as a consequence of laser irradiation. In
this experiment, separate 2 mm spots on the volar aspect of the
forearm of a human volunteer were irradiated with a single pulse of
radiant energy from the Er:YAG laser using a range of energies. An
ECG electrode was then placed over the irradiated site and an
unirradiated site about 20 cm away on the same forearm. A 100 Hz
sine wave of magnitude 1 volt peak-to-peak was then used to measure
the impedance of the skin. The results of a series of measurements
are shown in FIG. 22, which shows that there is a decrease in skin
impedance in skin irradiated at energies as low as 10 mJ, using the
fitted curve to interpolate data.
EXAMPLE 9
[0219] Pieces of human skin were placed in diffusion cells and
irradiated with a single pulse of radiant energy produced by an
Er:YAG laser. The spot size was 2 mm and the energy of the pulse
was measured with a calibrated energy meter. After irradiation, the
diffusion cells were placed in a 37 degrees Celsius heating block.
Phosphate buffered saline was added to the receptor chamber below
the skin and a small stir bar was inserted in the receptor chamber
to keep the fluid continually mixed. Control skin was left
unirradiated. Small volumes of radiolabelled compounds (either
corticosterone or DNA) were then added to the donor chamber and
left for 15 minutes before being removed (in the case of
corticosterone) or were left for the entire duration of the
experiment (in the case of the DNA). Samples were then taken from
the receptor chamber at various times after application of the test
compound and measured in a scintillation or gamma counter. The
results of this experiment are shown in FIGS. 21 and 26. The
results illustrate that enhanced permeation can occur at
sub-ablative laser pulse energies (see the 77 mJ/pulse data for
corticosterone). Although, in the case of the DNA experiment the
energy used may have been ablative, enhanced permeation may still
occur when lower energies are used.
EXAMPLE 10
[0220] Histology studies on rat and human skin, irradiated either
in vivo or in vitro, show little or no evidence of ablation when
Er:YAG laser pulse energies less than about 100-200 mJ are used.
(See, e.g., FIG. 25). Repeating this study showed the same results
as the previous studies. An in vitro permeation study using
tritiated water (3H.sub.2O) involving human skin lased at energies
from 50 mJ (1.6 J/cm.sup.2) to 1250 mJ (40 J/cm.sup.2) determined
(FIGS. 23 and 24) that an increase in permeation was seen at low
energy fluences up to about 5 J/cm.sup.2, whereupon the permeation
is more-or-less constant. This shows that there has been a lased
induced enhancement of permeation (of tritiated water) at energies
that are sub-ablative.
EXAMPLE 11
[0221] The output of the Er:YAG laser was passed through an
aperture to define it's diameter as 2 mm. Human skin, purchased
from a skin bank, was positioned in Franz diffusion cells. The
receptor chamber of the cell was filled with 0.9% buffered saline.
A single pulse, of measured energy, was used to irradiate the skin
in separate diffusion cells. Control skin was left unirradiated. In
the case of insulin, a 274 mJ pulse was used, and multiple samples
were irradiated. After irradiation, a stirring magnet was place in
the receptor chamber of the diffusion cells and the cells were
placed in a heating block held at 37 .quadrature.C. The
radiolabelled insulin was diluted in buffered saline, and 100 .mu.L
of the resulting solutions was placed in the donor chamber of
separate diffusion cells. The donor was left on the skin for the
duration of the experiment. At various times post-drug-application,
samples were taken from the receptor chamber and the amount of drug
present was assayed with either a gamma-counter, or a liquid
scintillation counter. A graph of the resulting data is shown in
FIG. 40. From this, and similar data, the permeability constant
(K.sub.p) for insulin was derived to be 11.3 #.ident..about.0.93
(.times.10.sup.-3 cm/hr).
EXAMPLE 12
[0222] This data was collected during the same experiment as the
TEWL results (see Example 2 and FIG. 27). In the case of the
blanching assay, baseline skin color (redness) measurements were
then taken of each spot using a Minolta CR-300 Chromameter (Minolta
Inc., NJ). The Er:YAG laser was then used to ablate six 2 mm spots
on one forearm, at energies of 40, 80 and 120 mJ. A spot (negative
calorimeter control) directly adjacent to the laser irradiated
spots remained untouched. Subsequently, a thin film of 1%
hydrocortisone ointment was applied to six of the lased spots on
the treatment arm. One untouched spot on the contralateral arm was
administered a thin layer of Diprolene (.quadrature.-methasone),
which is a strong steroid that can permeate the intact stratum
corneum in an amount sufficient to cause measurable skin blanching.
An occlusive patch, consisting of simple plastic wrap, was fixed
with gauze and dermatological tape over all sites on both arms and
left in place for two hours, after which the administered steroids
were gently removed with cotton swabs. Colorimeter measurements
were then taken over every unirradiated and irradiated spot at 2,
4, 8, 10, 12 and 26 hours post-irradiation, these results are shown
in FIG. 38. Finally, the skin was clinically assessed for evidence
of irritation at the 26 hour evaluation.
[0223] The results of the chromameter measurements show that some
erythema (reddening) of the skin occurred, but because of the
opposite-acting blanching permeating hydrocortisone, the reddening
was less than that seen in the control spots which did not receive
hydrocortisone. The Diprolene control proved the validity of the
measurements and no problems were seen in the volunteers at the 26
hour evaluation, although in some of the cases the site of
irradiation was apparent as a small red spot.
EXAMPLE 13
[0224] The radiant output of the Er:YAG laser is focussed and
collimated with optics to produce a spot size at the surface of the
skin of, for example, 5 mm. The skin of the patient, being the site
of, or close to the site of, disease, is visually examined for
anything that might affect the pharmacokinetics of the soon to be
administered drug (e.g., significant erythema or a wide-spread loss
of the integrity of the stratum corneum). This site, which is to be
the site of irradiation, is gently cleansed to remove all debris
and any extraneous compounds such as perfume or a buildup of body
oils. A disposable tip attached to the laser pressed up to the skin
prior to irradiation is used to contain any ablated biological
debris, as well as to contain any errant radiant energy produced by
the laser. A single laser pulse (approximately 350 .mu.s long),
with an energy of 950 mJ, is used to irradiate the spot. The result
is a reduction or elimination of the barrier function of the
stratum corneum. Subsequently, an amount of pharmaceutical,
hydrocortisone for example, is spread over the irradiation site.
The pharmaceutical may be in the form of an ointment so that it
remains on the site of irradiation. Optionally, an occlusive patch
is placed over the drug in order to keep it in place over the
irradiation site.
[0225] While various applications of this invention have been shown
and described, it should be apparent to those skilled in the art
that many modifications of the described techniques are possible
without departing from the inventive concepts herein.
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