U.S. patent application number 10/831641 was filed with the patent office on 2005-01-13 for removable tip for laser device with transparent lens.
This patent application is currently assigned to Transmedica International, Inc.. Invention is credited to Flock, Stephen T., Marchitto, Kevin S..
Application Number | 20050010198 10/831641 |
Document ID | / |
Family ID | 25156545 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050010198 |
Kind Code |
A1 |
Marchitto, Kevin S. ; et
al. |
January 13, 2005 |
Removable tip for laser device with transparent lens
Abstract
The present invention provides an improved method of removing
fluids, gases or other biomolecules, or delivering a pharmaceutical
composition, through the skin of a patient without the use of a
sharp or needle. The method includes the step of irradiating the
stratum corneum, an applied pharmaceutical or an absorbing
material, using a laser. By selection of parameters, the laser
irradiates the selected material or tissue to create pressure
gradients, plasma, cavitation bubbles, or other forms of tissue
ablation or alteration. These methods increase the diffusion of
pharmaceuticals into, or fluids, gases or other biomolecules out
of, the body. For this invention, a pharmaceutical composition can
be applied to the skin before or after laser irradiation.
Inventors: |
Marchitto, Kevin S.; (Villa
Park, IL) ; Flock, Stephen T.; (Edmonton,
CA) |
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.: |
10/831641 |
Filed: |
April 23, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10831641 |
Apr 23, 2004 |
|
|
|
10098909 |
Mar 13, 2002 |
|
|
|
10098909 |
Mar 13, 2002 |
|
|
|
09457953 |
Dec 9, 1999 |
|
|
|
6443945 |
|
|
|
|
09457953 |
Dec 9, 1999 |
|
|
|
08955789 |
Oct 22, 1997 |
|
|
|
6315772 |
|
|
|
|
08955789 |
Oct 22, 1997 |
|
|
|
08792335 |
Jan 31, 1997 |
|
|
|
08792335 |
Jan 31, 1997 |
|
|
|
08126241 |
Sep 24, 1993 |
|
|
|
5643252 |
|
|
|
|
08126241 |
Sep 24, 1993 |
|
|
|
07968862 |
Oct 28, 1992 |
|
|
|
Current U.S.
Class: |
606/9 |
Current CPC
Class: |
A61B 5/411 20130101;
A61B 18/203 20130101; A61B 2090/395 20160201; A61M 37/00 20130101;
A61B 5/150099 20130101; A61B 2018/00452 20130101; A61B 5/150076
20130101; A61B 18/20 20130101; A61B 2218/008 20130101; A61B
2017/00765 20130101; A61B 17/3476 20130101; A61B 2017/00057
20130101; A61B 5/150022 20130101; A61M 2037/0007 20130101; A61B
5/15138 20130101; H04R 25/75 20130101; A61B 2010/008 20130101 |
Class at
Publication: |
606/009 |
International
Class: |
A61B 018/20 |
Claims
1-84. canceled
85. A container unit for use with a laser device housing,
comprising: a base mountable in the housing to actuate a mechanism
in the housing for operation of the laser device; and a receptacle
end affixed to the base for contacting the skin of a patient and
including a lens of at least partially transparent material to pass
a laser beam emitted by the laser device therethrough and onto the
skin.
86. The container unit of claim 85, wherein the base is formed to
actuate an interlock in the housing for operation of the laser
device.
87. The container unit of claim 85, wherein the base is formed to
actuate a spring-loaded interlock in the housing for operation of
the laser device.
88. The container unit of claim 85, wherein the base is formed to
actuate a switch in the housing for operation of the laser
device.
89. The container unit of claim 88, wherein the base is formed to
actuate a switch for charging capacitors in the laser device.
90. The container unit of claim 85, wherein the base is removable
from the housing.
91. The container unit of claim 85, wherein the lens is formed from
a substantially transparent material.
92. The container unit of claim 91, wherein the base is formed to
actuate an interlock in the housing for operation of the laser
device.
93. The container unit of claim 91, wherein the base is formed to
actuate a spring-loaded interlock in the housing for operation of
the laser device.
94. The container unit of claim 91, wherein the base is formed to
actuate a switch in the housing for operation of the laser
device.
95. The container unit of claim 94, wherein the base is formed to
actuate a switch for charging capacitors in the laser device.
96. The container unit of claim 91, wherein the base is removable
from the housing.
97. The container unit of claim 85, wherein the lens is formed from
a material selected from the group of materials comprising quartz,
rock salt, germanium, glass, crystalline sapphire, polyvinyl
chloride, and polyethylene.
98. The container unit of claim 97, wherein the base is formed to
actuate an interlock in the housing for operation of the laser
device.
99. The container unit of claim 97, wherein the base is formed to
actuate a spring-loaded interlock in the housing for operation of
the laser device.
100. The container unit of claim 97, wherein the base is formed to
actuate a switch in the housing for operation of the laser
device.
101. The container unit of claim 100, wherein the base is formed to
actuate a switch for charging capacitors in the laser device.
102. The container unit of claim 97, wherein the base is removable
from the housing.
103. The container unit of claim 85, wherein the receptacle end
comprises: a wall surrounding the lens and extending distally
therefrom to contact the skin of the patient.
104. The container unit of claim 103, wherein the base is formed to
actuate an interlock in the housing for operation of the laser
device.
105. The container unit of claim 103, wherein the base is formed to
actuate a spring-loaded interlock in the housing for operation of
the laser device.
106. The container unit of claim 103, wherein the base is formed to
actuate a switch in the housing for operation of the laser
device.
107. The container unit of claim 106, wherein the base is formed to
actuate a switch for charging capacitors in the laser device.
108. The container unit of claim 103, wherein the base is removable
from the housing.
109. The container unit of claim 103, wherein the lens is formed
from a substantially transparent material.
110. The container unit of claim 103, wherein the lens is formed
from a material selected from the group of materials comprising
quartz, rock salt, germanium, glass, crystalline sapphire,
polyvinyl chloride, and polyethylene.
111. A tip for use with a laser device housing, comprising: a tip
body mountable in the housing to actuate a mechanism in the housing
for operation of the laser device; and a tip distal end affixed to
the body for contacting the skin of a patient and including an
aperture covered by at least partially transparent material to pass
a laser beam emitted by the laser device therethrough and onto the
skin.
112. The tip of claim 111, wherein the body is formed to actuate an
interlock in the housing for operation of the laser device.
113. The tip of claim 111, wherein the body is formed to actuate a
spring-loaded interlock in the housing for operation of the laser
device.
114. The tip of claim 111, wherein the body is formed to actuate a
switch in the housing for operation of the laser device.
115. The tip of claim 114, wherein the body is formed to actuate a
switch for charging capacitors in the laser device.
116. The tip of claim 111, wherein the body is removable from the
housing.
117. The tip of claim 111, wherein the lens is formed from a
substantially transparent material.
118. The tip of claim 117, wherein the body is formed to actuate an
interlock in the housing for operation of the laser device.
119. The tip of claim 117, wherein the body is formed to actuate a
spring-loaded interlock in the housing for operation of the laser
device.
120. The tip of claim 117, wherein the body is formed to actuate a
switch in the housing for operation of the laser device.
121. The tip of claim 120, wherein the body is formed to actuate a
switch for charging capacitors in the laser device.
122. The tip of claim 117, wherein the body is removable from the
housing.
123. The tip of claim 111, wherein the lens is formed from a
material selected from the group of materials comprising quartz,
rock salt, germanium, glass, crystalline sapphire, polyvinyl
chloride, and polyethylene.
124. The tip of claim 123, wherein the body is formed to actuate an
interlock in the housing for operation of the laser device.
125. The tip of claim 123, wherein the body is formed to actuate a
spring-loaded interlock in the housing for operation of the laser
device.
126. The tip of claim 123, wherein the body is formed to actuate a
switch in the housing for operation of the laser device.
127. The tip of claim 126, wherein the body is formed to actuate a
switch for charging capacitors in the laser device.
128. The tip of claim 123, wherein the body is removable from the
housing.
129. The tip of claim 111, wherein the distal end comprises: a wall
surrounding the lens and extending distally therefrom to contact
the skin of the patient.
130. The tip of claim 129, wherein the body is formed to actuate an
interlock in the housing for operation of the laser device.
131. The tip of claim 129, wherein the body is formed to actuate a
spring-loaded interlock in the housing for operation of the laser
device.
132. The tip of claim 129, wherein the body is formed to actuate a
switch in the housing for operation of the laser device.
133. The tip of claim 132, wherein the body is formed to actuate a
switch for charging capacitors in the laser device.
134. The tip of claim 129, wherein the body is removable from the
housing.
135. The tip of claim 129, wherein the lens is formed from a
substantially transparent material.
136. The tip of claim 129, wherein the lens is formed from a
material selected from the group of materials comprising quartz,
rock salt, germanium, glass, crystalline sapphire, polyvinyl
chloride, and polyethylene.
137. The container unit of claim 85, wherein the lens is formed in
a predefined shape to selectively block a portion of the laser beam
emitted by the laser device before the laser beam reaches the
skin.
138. The container unit of claim 137, wherein the lens includes a
mask of substantially nontransparent material to block a portion of
the laser beam.
139. A method for forming a container unit for use with a laser
device housing, comprising: selecting a base for mounting in the
housing to actuate a mechanism in the housing for operation of the
laser device; and affixing a receptacle end to the base to contact
the skin of a patient, the receptacle end including a lens of at
least partially transparent material to pass a laser beam emitted
by the laser device therethrough and onto the skin.
140. The method of claim 139, wherein selecting the base comprises:
selecting a base formed to actuate an interlock in the housing for
operation of the laser device.
141. The method of claim 139, wherein selecting the base comprises:
selecting a base formed to actuate a spring-loaded interlock in the
housing for operation of the laser device.
142. The method of claim 139, wherein selecting the base comprises:
selecting a base formed to actuate a switch in the housing for
operation of the laser device.
143. The method of claim 142, wherein selecting the base comprises:
selecting a base formed to actuate a switch for charging capacitors
in the laser device.
144. The method of claim 139, wherein selecting the base comprises:
selecting a base formed to be removable from the housing.
145. The method of claim 139, wherein the lens is formed from a
substantially transparent material.
146. The method of claim 139, wherein the lens is formed from a
material selected from the group of materials comprising quartz,
rock salt, germanium, glass, crystalline sapphire, polyvinyl
chloride, and polyethylene.
147. The method of claim 139, wherein the receptacle end comprises:
a wall surrounding the lens and extending distally therefrom to
contact the skin of the patient.
148. The method of claim 139, wherein the lens is formed in a
predefined shape to selectively block a portion of the laser beam
emitted by the laser device before the laser beam reaches the
skin.
149. The method of claim 148, wherein the lens includes a mask of
substantially nontransparent material to block a portion of the
laser beam.
Description
[0001] This application is a continuation-in-part of pending U.S.
Ser. No. 08/792,335, filed Jan. 31, 1997, said application is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention is in the field of medical procedures, namely
laser medical equipment used in the delivery of anesthetics or
pharmaceuticals to, or the removal of fluids, gases or other
biomolecules from, a patient.
BACKGROUND
[0003] The traditional method for the collection of small
quantities of fluids, gases or other biomolecules from a patient
utilizes mechanical perforation of the skin with a sharp device
such as a metal lancet or needle. Additionally, the typical method
of administering anesthetics or other pharmaceuticals is through
the use of a needle.
[0004] These procedures have 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 administering anesthetics or
pharmaceuticals, as well as for drawing fluids, gases or other
biomolecules. 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, for drawing fluids, gases or other biomolecules the
stabbing procedure often must be repeated before sufficient fluid
is obtained.
[0008] The current technology for applying local anesthetic without
the use of needles typically involves either (a) topical lidocaine
mixtures, (b) iontophoresis, (c) carriers or vehicles which are
compounds that modify the chemical properties of either the stratum
corneum, or the pharmaceutical, and (d) sonophoresis which involves
modifying the barrier function of stratum corneum by ultrasound. A
cream containing lidocaine is commonly used, especially in
pediatric patients, but needs to be applied for up to 60 minutes,
and anesthesia is produced to a depth of only about 4 mm. The lack
of lidocaine penetration is a consequence of the barrier function
of the stratum corneum. Inherent problems with iontophoresis
include the complexity of the delivery system, cost, and unknown
toxicology of prolonged exposure to electrical current.
Additionally, the use of carriers or vehicles involves additional
compounds which might modify the pharmacokinetics of the
pharmaceutical of interest or are irritating.
[0009] Thus, a need exists for a technique to remove fluids, gases
or other biomolecules or to administer anesthetics or other
pharmaceuticals which does not require a sharp instrument. The
method and apparatus disclosed herein fulfill this need and obviate
the need for the disposal of contaminated instruments, thereby
reducing the risk of infection.
[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 the 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) which is
strongly absorbed by, among other things, 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. In addition, 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).
SUMMARY OF THE INVENTION
[0011] The present invention employs a laser to perforate or alter
the skin of a patient so as to remove fluids, gases or other
biomolecules or to administer anesthetics or other pharmaceuticals.
Perforation or alteration is produced by irradiating the surface of
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 so
as to precisely perforate or alter the target tissue to a select
depth and eliminate undesired damage to healthy proximal
tissue.
[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.
[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 in a diode
laser. 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. The term "modulated laser" is
used herein to indicate this duplication of a pulsed laser
beam.
[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 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 samples, fluids, gases
or other biomolecules, 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 to 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 the 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 pharmaceuticals, as well as fluids, gases or other
biomolecules, across the stratum corneum.
[0017] 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 the administration of
anesthetics or other pharmaceuticals, as well as the removal of
fluids, gases or other biomolecules, through the skin. Moreover,
this procedure allows 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.
[0018] 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. As
described herein, pressure waves, plasma, and cavitation bubbles
are 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 pressure waves, plasma, or
cavitation bubbles while limiting undesired damage to healthy
proximal tissue.
[0019] A further object of this invention is to provide an
alternative means for administering drugs that would otherwise be
required to be taken through other means, such as orally or
injected, thereby increasing patient compliance and decreasing
patient discomfort.
[0020] An additional object of this invention is to allow the
taking of measurements of various fluid constituents, such as
glucose, or to conduct measurements of gases.
[0021] 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 administering
anesthetics or other pharmaceuticals, as well as removing fluids,
gases or other biomolecules.
[0022] 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, gases or other
biomolecules; (2) reduce the noise created when the laser beam
perforates the patient's tissue; and (3) collect the ablated
tissue. The optional container unit is alternatively evacuated to
expedite the collection of the released materials such as the
fluids, gases or other biomolecules. 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, gas
or other biomolecule samples and/or ablated tissue as the
perforation or alteration occurs. The container unit may also be
modified for the purpose of containing materials, such as drugs,
which may be applied before, simultaneously or shortly after
irradiation.
[0023] A typical laser used for this invention requires no special
skills to use. It can be small, light-weight 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.
[0024] 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
[0025] The present invention may be better understood and its
advantages appreciated by those skilled in the art by referring to
the accompanying drawings wherein:
[0026] FIG. 1 shows a laser with its power source, high voltage
pulse-forming network, flashlamp, lasing rod, mirrors, housing and
focusing lens.
[0027] FIG. 2 shows an optional spring-loaded interlock and
optionally heated applicator.
[0028] FIG. 3 shows an alternative means of exciting a laser rod
using a diode laser.
[0029] FIG. 4 shows an alternative focusing mechanism.
[0030] FIGS. 5A & 5B show optional beam splatters for creating
multiple simultaneous perforations.
[0031] FIG. 6 shows a patch that can be used to sterilize the site
of irradiation.
[0032] FIGS. 7A & 7B show alternative patches for sterilization
and/or delivery of pharmaceuticals, and/or collection of fluids,
gases or other biomolecules.
[0033] FIG. 8 shows an optional container unit for collecting
fluids, gases or other biomolecules, 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.
[0034] FIG. 9 shows a plug and plug perforation center.
[0035] 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.
[0036] FIG. 11 shows a roll-on device for the delivery of
anesthetics or pharmaceuticals.
[0037] FIG. 12 shows an elastomeric mount for a solid state laser
crystal element with optional mirrored surfaces applied to each end
of the element.
[0038] FIG. 13 shows an example of a crystal rod with matte finish
around the full circumference of the entire rod.
[0039] FIG. 14 shows an example of a crystal rod with matte finish
around the full circumference of two-thirds of the rod.
[0040] FIG. 15 shows an example of a crystal rod with matte stripes
along its longitudinal axis.
[0041] 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.
[0042] FIGS. 17A-17G show various examples of a container unit.
[0043] FIG. 18 shows an atomizer for the delivery of anesthetics,
or pharmaceuticals.
[0044] FIG. 19 shows examples of a container unit in use with a
laser.
[0045] FIG. 20 shows an example of a lens with a mask.
[0046] FIG. 21 is a chart showing a study using corticosterone
which showed enhanced permeation (over controls) at an energies of
77 mJ and 117 mJ.
[0047] FIG. 22 shows the decrease in the impedance of skin in vivo
using various laser pulse energies.
[0048] FIGS. 23-24 show in a permeation study of tritiated
water(.sup.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).
[0049] FIG. 25 shows histological sections of human skin
irradiated-at energies 50 mJ and 80 mJ.
[0050] 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.
[0051] FIG. 27 shows laser pulse energy (J) versus water loss
through human skin in vivo.
[0052] 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.
[0053] 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 for stratum corneum treated different ways.
[0054] FIGS. 32-33 are charts of FTIR spectra of control and lased
stratum corneum.
[0055] FIG. 34 shows Amide I band position (cm.sup.-1) as a
function of stratum corneum treatment.
[0056] FIG. 35 shows CH.sub.2 vibration position (cm.sup.-1) as a
function of stratum corneum treatment.
[0057] FIG. 36 shows a histological section of rat skin that was
irradiated at 80 mJ.
[0058] FIG. 37 shows a histological section of human skin that was
irradiated at 80 mJ.
[0059] FIG. 38 shows in vivo blanching assay results.
[0060] FIGS. 39-41 shows permeation of .gamma.-interferon, insulin
and lidocaine, through human skin in vitro.
[0061] FIG. 42 shows an example of a beam splitter suitable for
making simultaneous irradiation sites.
[0062] FIG. 43 shows one possible pattern of perforation or
alteration sites using a beam splitter.
[0063] FIG. 44 shows a pressure gradient created in the stratum
corneum.
[0064] FIG. 45 is a schematic of modulating the pulse repetition
frequency of radiant energy from high (4 GHz) to low (4 MHz).
[0065] FIG. 46 shows a propagating pressure wave created in an
absorbing material located on the skin.
[0066] FIG. 47 shows a propagating pressure wave created at the
skin surface with a transparent, or partially transparent, optic
located on the skin.
[0067] FIG. 48 shows a propagating pressure wave created in an
absorbing material on the applied pharmaceutical.
[0068] FIG. 49 shows a propagating pressure wave created in the
applied pharmaceutical.
[0069] FIG. 50 shows the creation of pressure-waves in tissue
converging to a focal point.
DETAILED DESCRIPTION
[0070] This invention provides a method for perforating or altering
skin for either the sampling of fluids, gases or other biomolecules
or the administration of anesthetics or other pharmaceuticals. 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 about 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
irradiated spot on the skin with a size of approximately 0.5
microns-5.0 cm diameter. 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.
[0071] 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.
[0072] 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.
[0073] 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 a
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.
[0074] 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 0.5
microns-5.0 cm. The width can be of any size, being controlled by
the anatomy of the area irradiated and the desired permeation rate
of the pharmaceutical to be applied, or fluid, gas or other
biomolecule to be removed. The focal length of the focussing lens
can be of any length, but in one embodiment it is 30 mm.
[0075] 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 ablation
(alteration). Both ablation and non-ablative alternation of the
stratum corneum result in enhanced permeation of subsequently
applied pharmaceuticals, or removal of fluids, gases or other
biomolecules.
[0076] 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 ablation, while any
pulse energy below approximately 100 mJ causes non-ablative
alteration to the stratum corneum. Optionally, by using multiple
pulses, the threshold pulse energy required to enhance
pharmaceutical delivery is reduced by a factor approximately equal
to the number of pulses.
[0077] 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 with an absorbing filter, such as glass.
[0078] 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.
[0079] 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).
[0080] According to one embodiment of the present invention, the
anesthetic or pharmaceutical can be administered immediately after
laser irradiation. 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 irradiation,
the roll-on device is rolled over the irradiated site, thereby
administering the desired anesthetic or pharmaceutical. In the case
of an atomizer, the anesthetic is administered from a drug
reservoir 166 through the use of compressed gas. After irradiation,
a cylinder 168 containing compressed gas (such as, for example,
carbon dioxide) is triggered to spray a set amount of anesthetic or
pharmaceutical over the irradiated site.
[0081] Alternatively, it would be beneficial to apply positive
pressure to a drug reservoir thereby pushing the drug into the
skin, or negative pressure in a collection reservoir thus enhancing
the diffusion of analytes out of the skin. Ambient atmospheric
pressure is 760 mm Hg, or 1 atmosphere. Because of hydrostatic
pressure in a standing individual, the relative pressure difference
in the head may be 10 mm Hg below a reference value taken at the
level of the neck, and 90 mm Hg higher in the feet. The arms may be
between 8 and 35 mm Hg. Note also that because of the beating
heart, a dynamic pressure (in a normal, healthy individual) of
between 80-120 mm Hg is in the circulation. Thus, to permeate a
drug through the skin (say in the arm), a positive pressure of
greater than about 760 mm +35 mm Hg would be suitable. A pressure
just slightly over 1 atmosphere would be suitable to enhance drug
permeation, and yet would not enhance diffusion into the blood
stream because of the dynamic pressures in the blood stream. A
higher pressure might beneficially enhance diffusion into the blood
stream. However, extended pressures much greater than perhaps 5 or
so atmospheres for extended times might actually produce side
effects.
[0082] 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 apply the
anesthetic or pharmaceutical subsequent to laser irradiation. 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 ablation site, or a series of lines all pointing
inward to the ablation site can be used. Alternatively, the
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.
[0083] 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 can optionally be
added to the laser, or a rapidly pulsing laser, such as a diode or
related microchip lasers, 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 for use with a laser can be
found in FIG. 42. Any geometric pattern of spots can be produced on
the skin using this technique. Because the diffusion into skin of
topically applied drugs can be approximated as symmetric, a
beneficial pattern of irradiation spots for local drug delivery
(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).
[0084] 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.
[0085] For application of the laser device for anesthetic or
pharmaceutical delivery, as well as fluid, gas or other biomolecule
removal, 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 the
delivery of anesthetics and other pharmaceuticals, as well as
fluid, gas or other biomolecule removal, 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.
[0086] 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.
[0087] 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. However,
choosing a laser that emits a strongly absorbed wavelength is not
required. Altering the lipids in stratum corneum may allow enhanced
permeation while avoiding the higher energies that are necessary to
affect the proteins and water.
[0088] It would be beneficial to be able to use particular.lasers
other than the Er:YAG for stratum corneum ablation or alteration.
For example, laser diodes emitting radiant energy with a wavelength
of 810 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.
[0089] 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 nm
or 630 nm).
[0090] 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 delivery.
[0091] Additionally, the laser ablated 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 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.
[0092] Thus, in an additional embodiment of this invention, the
ablated or non-ablated site is kept open by keeping the area of
irradiation moist. This is accomplished by minimizing contact of
air with the ablated site and/or providing fluid to keep the
ablated site moist and/or biochemically similar to stratum corneum.
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, doxurubicin, and
methotrexate, for example, topically applied in low concentrations
would locally prevent cellular infiltration and wound repair.
Furthermore, application of 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.
[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 (e.g., pharmaceuticals) into 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 propogation 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. 50). 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] 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 pharmaceuticals.
[0106] Creation of Cavitation Bubbles to Increase Stratum Corneum
Permeability
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] Plasma Ablation to Increase Stratum Corneum Permeability
[0113] 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.
[0114] 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 a propagating pressure wave in
tissue. This is due to the fact that the 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.
[0115] 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 10.sup.8 W/cm.sup.2,
selection of a wavelength with radiant energy that is strongly
absorbed in tissue is not an important concern.
[0116] 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.).
[0117] To obtain a peak energy fluence rate greater than or
approximately equal to the lasma 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, 1J 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.
[0118] Continuous-Wave (CW) Laser Scanning
[0119] 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.
[0120] 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).
[0121] 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.
[0122] Delivery of Anesthesia
[0123] 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 localized anesthetics to be
topically administered. Topically applied anesthetics 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.
[0124] With the other parameters set, the magnitude 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
thicknesses of stratum corneum.
[0125] 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.
[0126] This method of delivering anesthetic 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 or as quick as
the healing after a skin puncture with a sharp implement. After
irradiation, anesthetic can then be applied directly to the skin or
in a pharmaceutically acceptable formulation such as a cream,
ointment, lotion or patch.
[0127] Alternatively, the delivery zone can be enlarged by
strategic location of the irradiation sites and by the use of
multiple sites. For example, a region of the 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. (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). Anesthetic (e.g., 10%
lidocaine) would then be applied over the treated area to achieve a
zone of anesthesia.
[0128] The present method can be used for transport of a variety of
anesthetics. These anesthetics are different in their system and
local toxicity, degree of anesthesia produced, time to onset of
anesthesia, length of time that anesthesia prevails,
biodistribution, and side effects. Examples of local anesthetic in
facial skin-resurfacing with a laser can be found in Fitzpatrick R.
E., Williams B. Goldman M. P., "Preoperative Anesthesia and
Postoperative Considerations in Laser Resurfacing," Semin. Cutan.
Med. Surg. 15(3):170-6, 1996. A partial list consists of: cocaine,
procaine, mepivacaine, etidocaine, ropivacaine, bupivacaine,
lidocaine, tetracain, dibucaine, prilocaine, chloroprocaine,
hexlcaine, fentanly, procainamide, piperocaine, MEGX (des-ethyl
lidocaine) and PPX (pipecolyl xylidine). A reference on local
anesthetic issues can be found in Rudolph de Jong, "Local
Anesthetics," Mosby-Year Book: St Louis, 1994.
[0129] Delivery of Pharmaceuticals
[0130] The present method can also be used to deliver
pharmaceuticals in a manner similar to the above described delivery
of anesthesia. By appropriate modification of the power level,
and/or the spot size of the laser beam, perforations or alterations
can be made which do not penetrate as deep as the capillary layer.
These perforations or alterations can be made through only the
outer surfaces, such as the stratum corneum layer or both the
stratum corneum layer and the epidermis. Optionally an optical
beam-splitter or multiply pulsed laser can be employed so that
either single or multiple perforations or alterations within a
desired area can be made. After perforation or alteration, the
pharmaceutical can be applied directly to the skin or in a
pharmaceutically acceptable formulation such as a cream, ointment,
lotion or patch.
[0131] The present method can be used for transport of a variety of
systemically acting pharmaceutical substances. For example
nitroglycerin and antinauseants such as scopolamine; antibiotics
such as tetracycline, streptomycin, sulfa drugs, kanamycin,
neomycin, penicillin, and chloramphenicol; various hormones, such
as parathyroid hormone, growth hormone, gonadotropins, insulin,
ACTH, somatostatin, prolactin, placental lactogen, melanocyte
stimulating hormone, thyrotropin, parathyroid hormone, calcitonin,
enkephalin, and angiotensin; steroid or non-steroid
anti-inflammatory agents, and systemic antibiotic, antiviral or
antifungal agents.
[0132] Delivery of Locally Acting Pharmaceuticals
[0133] Laser-assisted perforation or alteration provides a unique
site for local uptake of pharmaceutical substances to a desired
region. Thus, high local concentrations of a substance may be
achieved which are effective in a region proximal to the irradiated
site by virtue of limited dilution near the site of application.
This embodiment of the present invention provides a means for
treating local pain or infections, or for application of a
substance to a small specified area, directly, thus eliminating the
need to provide high, potentially toxic amounts systemically
through oral or i.v. administration. Locally acting pharmaceuticals
such as alprostadil (for example Caverject from Pharmacia &
Upjohn), various antibiotics, antiviral or antifungal agents, or
chemotherapy or anticancer agents, can be delivered using this
method to treat regions proximal to the delivery site. Protein or
DNA based biopharmaceutical agents can also be delivered using this
method.
[0134] Immunization
[0135] As for delivery of pharmaceuticals, antigens derived from a
virus, bacteria or other agent which stimulates an immune response
can be administered through the skin for immunization purposes. The
perforations or alterations are made through the outer layers of
the skin, either singly or multiply, and the immunogen is provided
in an appropriate formulation. For booster immunizations, where
delivery over a period of time increases the immune response, the
immunogen can be provided in a formulation which penetrates slowly
through the perforations or alterations, but at a rate faster than
possible through unperforated or unaltered skin.
[0136] This approach offers clinicians a new approach for
immunizations by solving some of the problems encountered with
other routes of administration (e.g. many vaccine preparations are
not efficacious through oral or intravenous routes). Further, the
skin is often the first line of defense for invading microbes and
the immune response in the skin is partially composed of
Immunoglobulin A (IgA) antibodies like that of the mucous
membranes. Scientists have long sought ways to induce mucosal
immunity using various vaccine preparations. Unfortunately they
have been met with limited success because in order to generate an
IgA response, vaccine preparations must be delivered to mucous
membranes in the gut or sinuses which are difficult to reach with
standard formulations. By immunizing intradermally, unique
populations of antibodies may be generated which include IgA, a
critical element of mucosal immunity. This laser-assisted
intradermal method of antigen presentation thereby may be used as a
means to generate IgA antibodies against invading organisms.
[0137] Delivery of Allergens
[0138] Traditional allergy testing requires the allergist to make
multiple pricks on the patient's skin and apply specific allergens
to make a determination regarding intradermal hypersensitivity. The
method of this invention can be used to deliver allergens
reproducibly for allergy testing. Multiple perforations or
alterations can be made through the outer layer of the skin without
penetrating to the capillary level. A variety of allergens can then
be applied to the skin, as in a skin patch test. One of the
benefits of this methodology is that the stratum corneum barrier
function compromise (i.e. laser irradiation) is more consistent
than pricks made with a sharp.
[0139] Delivers of Permeation Enhancers
[0140] Certain compounds may be used to enhance the permeation of
substances into the tissues below perforated or ablated stratum
corneum. Such enhancers include DMSO, alcohols and salts. Other
compounds specifically aid permeation based on specific effects
such as by increasing ablation or improving capillary flow by
limiting inflammation (i.e. salicylic acid). The method of this
invention can be used to deliver these permeation enhancers.
Multiple or single perforations or alterations can be made through
the outer layer of the skin without penetrating to the capillary
level. Subsequently, a variety of permeation enhancers can be
applied to the irradiated site, as in a skin patch.
[0141] Delivery of Anti-Inflammatory Drugs
[0142] Analgesics and other non-steroid anti-inflammatory agents,
as well as steroid anti-inflammatory agents may be caused to
permeate through perforated or altered stratum corneum to locally
affect tissue within proximity of the irradiated site. For example,
anti-inflammatory agents such as Indocin (Merck & Co.), a
non-steroidal drug, are effective agents for treatment of
rheumatoid arthritis when taken orally, yet sometimes debilitating
gastrointestinal effects can occur. By administering such agents
through laser-assisted perforation or alteration sites, these
potentially dangerous gastrointestinal complications may be
avoided. Further, high local concentrations of the agents may be
achieved more readily near the site of irradiation as opposed to
the systemic concentrations achieved when orally administered.
[0143] Drawing Fluids, Gases or Other Biomolecules
[0144] 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 the collection of fluids,
gases or other biomolecules. The fluid, gas or other biomolecule
can be used for a wide variety of tests. With the other parameters
set, the magnitude 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 penetration
of different thicknesses of skin.
[0145] 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 to be easily removed for situations when the
presence of the beam-dump would impede the placement of a body part
on the applicator.
[0146] This method of drawing fluids, gases or other biomolecule
creates a very small zone in which tissue is irradiated, and only
an extremely small zone of thermal necrosis. For example, a
practical round hole can range from about 0.1-1 mm in diameter,
while a slit shaped hole can range from about approximately
0.05-0.5 mm in width and up to approximately 2.5 mm in length. As a
result, healing is quicker or as quick as the healing after a skin
puncture with a sharp implement.
[0147] The fluid, gas or other biomolecule can be collected into a
suitable vessel, such as a small test tube or a capillary tube, or
in a container unit placed between the laser and the tissue as
described above. The process does not require contact. Therefore,
neither the patient, the fluid, gas or other biomolecule to be
drawn, or the instrument creating the perforation or alteration is
contaminated.
[0148] The technique of the present invention may be used to sample
extracellular fluid in order to quantify glucose or the like.
Glucose is present in the extracellular fluid in the same
concentration as (or in a known proportion to) the glucose level in
blood (e.g. Lonnroth P. Strindberg L. Validation of the "internal
reference technique" for calibrating micro dialysis catheters in
situ, Acta Physiological Scandinavica, 153(4):37580, 1995
April).
[0149] The perforation or alteration of the stratum corneum causes
a local increase in the water loss through the skin (referred to as
transepidermal water loss, or TEWL). As shown in FIG. 27, with
increasing laser energy fluence (J/cm.sup.2), there is a
corresponding increase in water loss. The tape strip data is a
positive control that proves that the measurement is indeed
sensitive to increased skin water evaporation.
[0150] Two of the energies used in FIG. 27, 40 mJ and 80 mJ (1.27
and 2.55 cm.sup.2) are non-ablative and therefore show that
non-ablative energies allow the alteration of the barrier function
of stratum corneum, thereby resulting in enhanced transepidermal
water loss which can provide a diagnostic sample of extracellular
fluid.
[0151] Besides glucose, other compounds and pathological agents
also can be assayed in extracellular fluid. For example, HIV is
present extracellularly and may be assayed according to the present
method. The benefit to obtaining samples for HIV analysis without
having to draw blood with a sharp that can subsequently contaminate
the health-care provider is obvious. Additionally, the present
invention can be used to employ lasers non-ablatively to reduce or
eliminate the barrier properties of non-skin barriers in the human
body, such as the blood-brain interface membranes, such as that
positioned between the brains third ventricle and the hypothalamus,
the sclera of the eye or any mucosal tissue, such as in the oral
cavity.
[0152] Alteration without Ablation
[0153] 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 allow 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.
[0154] Radiant Energy vs Laser Radiant Energy
[0155] 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
[0156] 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.
[0157] 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 continuous-wave radiant
energy.
[0158] Laser Device
[0159] 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 perforator, or the Schwartz
Electro-Optical Er:YAG laser. Preferably, 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 nonablative 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.
[0160] 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.
[0161] 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 keyswitch, 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.
[0162] 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.
[0163] 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 ate 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.
[0164] 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.
[0165] 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.1).sup.2 exp[(g.sub.21-.alpha.)2L]=1
[0166] where the R.sub.1 and R.sub.2 are the mirrors
reflectivities, a.sub.L 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, .alpha. 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).
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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: yttriuni,
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),
Tm:YAG (thulium: YAG; 2.01 microns), Ho:YAG (holmium: YAG; 2.127
microns); Ho/Nd:YA1O.sub.3 (holmium/neodymium: yttrium, alurninate;
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; 3.64 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).
[0171] 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.
[0172] 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 that
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.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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.
[0177] 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.
[0178] 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.
[0179] 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.
[0180] Portability
[0181] 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.
[0182] 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).
[0183] 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.
[0184] Container Unit
[0185] A container unit 68 is optionally fitted into the laser
housing and is positioned proximal to the perforation or alteration
site. The container unit reduces the intensity of the sound
produced when the laser beam perforates or alters the patient's
tissue, increases the efficiency of fluid, gas or other biomolecule
collection, and collects the ablated tissue and other matter
released by the perforation. The container unit can be shaped so as
to allow easy insertion into the laser housing and to provide a
friction fit within the laser housing. FIG. 8 shows a typical
container unit inserted into the laser housing and placed over the
perforation site.
[0186] The container unit 68 comprises a main receptacle 82,
including a lens 84. The main receptacle collects the fluid, gas or
other biomolecule sample, the ablated tissue, and/or other matter
released by the perforation. The lens is placed such that the laser
beam may pass through the lens to the perforation site but so that
the matter released by the perforation 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 as to be capable of being inserted into the applicator to
disengage a safety mechanism of the laser, thereby allowing the
laser beam to be emitted.
[0187] 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 fluid, gas or other
biomolecule samples, ablated tissue, and/or other matter released
by the perforation or alteration. 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 function
appropriately.
[0188] 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 material that transmits the laser wavelength
utilized and is positioned in the pathway of the laser beam, at the
end of the container unit proximal to the beam. The transmitting
material can be quartz, but other examples of suitable infrared
transmitting materials include rock salt, germanium, glass,
crystalline sapphire, polyvinyl chloride and polyethylene. However,
these materials should not contain impurities that absorb the laser
beam energy. 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 perforation
site.
[0189] 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 perforation or alteration site. The area defined by
the lens, wall of the main receptacle and perforation or alteration
site is thereby substantially enclosed during the operation of the
laser.
[0190] 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, allowing the
emission of the laser beam.
[0191] A typical container unit can comprise 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 that
shapes the beam that perforates the tissue. The interior of the
main receptacle is optionally coated with anticoagulating and/or
preservative chemicals. The container unit can be constructed of
glass or plastic. The container unit is optionally disposable.
[0192] FIG. 19 shows examples of the use of a container unit with a
laser for the purpose of drawing fluids, gases or other
biomolecules-or to administer pharmaceuticals. 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.
[0193] Additionally, the container unit can be evacuated. The
optional vacuum in the container unit exerts a less than
interstitial fluid or the pressure of gases in the blood over the
perforation or alteration site, thereby increasing the efficiency
in fluid, gas or other biomolecule collection. The container unit
is optionally coated with anticoagulating and/or preservative
chemicals. The container unit's end proximal to the perforation or
alteration site 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 perforation site (e.g., the finger). The
desired perforation or alteration site is firmly pressed against
the plug. The plug's material is preferably impermeable to gas
transfer. Furthermore, the plug's material is thin enough to permit
perforation of the material as well as perforation of the skin by
the laser. The plug can be constructed of rubber, for example.
[0194] 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 both the plug and the
tissue adjacent to the plug. For use with an Er:YAG laser, the plug
can be in the range of approximately about 100 to 500 microns
thick.
[0195] The plug perforation center 74 is large enough to cover the
perforation or alteration site. Optionally, the perforated site is
a round hole with an approximate diameter ranging from about 0.1-1
mm, or slit shaped with an approximate width of about 0.05-0.5 mm
and an approximate length up to about 2.5 mm. Thus, the plug
perforation center is sufficiently large to cover perforation sites
of these sizes.
[0196] As shown in FIG. 10, the container unit 68 can include a
hole 76 through which the laser passes. In this example, the
container unit optionally solely collects ablated tissue. As in the
other examples, the site of irradiation is firmly pressed against
the container unit. The container unit can optionally include a
plug proximal to the perforation site, however it is not essential
because there is no need to maintain a vacuum. The container unit
reduces the noise created from interaction between the laser beam
and the patient's tissue and thus alleviates 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 simultaneously, or shortly after irradiation
occurs. 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.
[0199] In order to sterilize the skin before perforation or
alteration, a sterile alcohol-impregnated patch of paper or other
thin material can optionally be placed over the site to be
perforated. This material can also prevent the blowing off of
potentially infected tissue in the plume released by the
perforation. The material must have low bulk absorption
characteristics for the wavelength of the laser beam. Examples of
such material include, but are not limited to, a thin layer of
glass, quartz, mica, or sapphire. Alternatively, a thin layer of
plastic, such as a film of polyvinyl chloride or polyethylene, can
be placed over the skin. Although the laser beam may perforate the
plastic, the plastic prevents most of the plume from flying out and
thus decreases any potential risk of contamination from infected
tissue. Additionally, a layer of a viscous sterile substance such
as vaseline can be added to the transparent material or plastic
film to increase adherence of the material or plastic to the skin
and further decrease plume contamination. Additionally, such a
patch can be used to deliver allergens, local anesthetics or other
pharmaceuticals as described below.
[0200] Examples of such a patch are provided in FIGS. 6 and 7. In
FIG. 6, alcohol inpregnated paper 54 is surrounded by a temporary
adhesive strip 58. Side views of two alternative patches are shown
in FIG. 7, where a sterilizing alcohol, antibiotic ointment,
allergen, or pharmaceutical is present in the central region of the
patch 60. This material is held in place by a paper or plastic
layer 62, optionally with a laser-transparent material 64. Examples
of such material include, but are not limited to, mica, quartz or
sapphire which is transparent to the laser beam at the center of
the patch. However, the material need not be totally transparent.
The patch can be placed on the skin using an adhesive 66.
[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, gases or other biomolecules. 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, Thullium: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 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, gases or other biomolecules, 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/m.sup.2/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 26G-0.5 needle
was subsequently inserted into the laser ablated site with no
observable pain. Additionally, after a 6-minute anesthetic
treatment, a 22G-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 (DSC): 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 delipidization. Permeation
with (.sup.3H.sub.20) 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 CH.sub.2, 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 subsequently examined 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 tissues.
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 (.sup.3H.sub.20) 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) than 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.
When the permeation of lidocaine was to be tested, a 254 mJ pulse
was used, and multiple samples were irradiated. In the case of
.gamma.-interferon, a 285 mJ pulse was used, and multiple samples
were irradiated. In the case of insulin, a 274 mJ pulse was used,
and multiple samples were irradiated. In the case of cortisone,
either 77 mJ or 117 mJ was used. 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.degree. C. The
radiolabelled lidocaine, gamma-interferon and insulin were 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. Graphs of the
resulting data are shown in FIGS. 39, 40 and 41. From this, and
similar data, the permeability constants were derived and are shown
as follows:
1 Drug Permeability Constant, k.sub.1 (.times.10.sup.-3 cm/hr)
Lidocaine 2.62 +/- 6.9 .gamma.-Interferon 9.74 +/- 2.05 Insulin
11.3 +/- 0.93
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 (.beta.-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 hydroccrtisone, 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.
EXAMPLE 14
[0225] An infrared laser radiation pulse was formed using a solid
state, pulsed, Er:YAC 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. The duration of the pulse was approximately
300 .mu.s. The spot size was approximately 2 mm, with an energy
fluence of 5 J/cm.sup.2. Single pulses were used.
[0226] Three 2 mm diameter spots were created on a flaccid penis.
Subsequent to ablation a pharmaceutical preparation of alprostadil
(Caverject from Pharmacia & Upjohn, Kalamazoo, Mich.) was
applied to a small patch consisting of tissue paper. The patch was
applied to the multiple perforated areas of the skin on the then
flaccid penis and held there with adhesive tape for 45 minutes.
After approximately 35 minutes, the patient obtained an erection
that was sustained for more than 1 hour.
[0227] The benefit of this route of administration is that it is
painless. The normal method of administration of alprostadil
involves injecting the compound deep into the corpus cavernosum of
the penis with a hypodermic needle. Not only is such a procedure
painful, but it also results in potentially infectious contaminated
sharp.
EXAMPLE 15
[0228] An infrared laser radiation pulse can be 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 is preferably 2.94 microns. The duration of the pulse is
preferably approximately 300 .mu.s. The spot size is preferably
approximately 2 mm, with an impulse energy of approximately 150 mJ
creating an energy fluence of approximately 5 J/cm.sup.2.
[0229] Single pulses of radiant energy from the TRANSMEDICA.TM.
Er:YAG laser, with the operating parameters described above, is
preferably used to irradiate 2 mm diameter spots on areas of the
scalp exhibiting hair loss. Multiple irradiation sites can be used.
Subsequent to irradiation, minoxidil (for example Rogaine from
Pharmacia & Upjohn, Kalamazoo, Mich.) may be applied to access
interstitial spaces in the scalp, allowing greater quantities of
the pharmaceutical to stimulate root follicles than is available by
transcutaneous absorption alone. Alternatively, subsequent to
ablation, androgen inhibitors may be applied through the laser
ablated sites. These inhibitors act to counter the effects of
androgens in hair loss.
EXAMPLE 16
[0230] Skin resurfacing is a widely used and commonly requested
cosmetic procedure whereby wrinkles are removed from (generally)
the face of a patient by ablating approximately the outermost 400
microns of skin with the radiant energy produced by a laser (Dover
J. S., Hruza G. J., "Laser Skin Resurfacing," Semin. Cutan. Med.
Surg., 15(3):177-88, 1996). After treatment, often a "mask" made
out of hydrogel (which is a gelatine-like material that consists
mostly of water) is applied to the irradiated area to provide both
a feeling of coolness and also to prevent undesirable desiccation
of the treated skin and "weeping" of bodily fluids.
[0231] The pain associated with this procedure would be intolerable
without the use of local or general anesthesia. Generally, multiple
(perhaps up to 30) local injections of lidocaine are completed
prior to the irradiation of the skin. These injections themselves
take a significant amount of time to perform and are themselves
relatively painful.
[0232] Single pulses of radiant energy from the TRANSMEDICA.TM.
Er:YAG laser is preferably used to irradiate 2 mm diameter spots on
areas of the face required for the multiple applications of
lidocaine prior to skin resurfacing. The energy used in each laser
pulse is preferably 150 mJ. Subsequent to irradiation, lidocaine is
applied for general anesthesia. Furthermore, by incorporating
lidocaine (preferably, the hydrophillic version which is
lidocaine-HCl) into the hydrogel, or other patch or gel means of
containment, and applying this complex (in the physical form of a
"face-mask") to the patient's face prior to the laser irradiation
but after ablating the stratum corneum with the Er:YAG laser from a
matrix of sites throughout the treatment area, sufficient
anesthesia will be induced for the procedure to be done painlessly.
It may also be beneficial to incorporate a sedative within the
hydrogel to further prepare the patient for what can be a
distressing medical procedure. Optionally, the "face-mask" can be
segmented into several aesthetic-units suitable for single
application to particular laser-treatment regions of the face.
Finally, another "face-mask" incorporating beneficial
pharmaceuticals, such as antibiotics (e.g. Bacitracin, Neosporin,
Polysporin, and Sulphadene) or long term topical or systemic
analgesics, such as fentanyl or demeral, can be applied to the
patient after skin resurfacing treatment.
EXAMPLE 17
[0233] The growth of hairs in the nose (primarily in men) is a
common cosmetic problem. The current therapy, which involves
pulling the hairs out with tweezers, is painful and nonpermanent.
An infrared laser radiation pulse can be 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 is preferably 2.94 microns. The duration of the pulse
approximately is preferably 300 .mu.s. The spot size is preferably
approximately 2 mm, with an impulse energy of approximately 150 mJ
creating an energy fluence of approximately 5 J/cm.sup.2.
[0234] Single pulses of radiant energy from the TRANSMEDICA.TM.
Er:YAG laser is preferably used, with the above described operating
parameters, to irradiate 2 mm diameter spots on the nasal mucosa
exhibiting cosmetically unappealing hair growth. Multiple
irradiation sites can be used. The irradiation by itself can be
sufficient to alter the tissue thereby inhibiting subsequent hair
growth thus irradiation may be itself sufficient to alter the
tissue, inhibiting subsequent hair growth. Alternatively,
subsequent to irradiation, a dye, for example indocyanine green,
which absorbs different wavelengths of radiation, can be applied.
After the dye has been absorbed into the nasal passage, 810 nm
radiant energy from a diode laser (GaAlAs laser) can be used to
raise the temperature of the surrounding tissue. This acts to
selectively damage the hair follicles in contact with the dye. As a
result the nasal tissue is modified so that hair growth does not
reoccur, or at least does not recur as quickly as it does after
manual hair removal.
[0235] 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.
* * * * *