Note: Descriptions are shown in the official language in which they were submitted.
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
INTERFACE MEDIUM FOR TISSUE SURFACE PROBE
Background of the Invention
1. Field of the Invention
This invention relates to compositions useful as interface media for
facilitating contact between a surface and a probe and to methods for using
these
compositions, and, in particular, to interface media for optically coupling,
standardizing,
and improving contact between a tissue surface, such as skin, and a probe
being used
to collect fluorescence or another desired spectra from the tissue.
2. Description of Background
Commercial spectrofluorometer products are available for taking skin
fluorescence spectra (e.g. the Instruments S.A. SkinSkan). These devices are
typically
used in the cosmetics industry and often involve a fiber optic probe, which is
simply
pressed against the skin. However, bringing the fiber optic probe into simple
direct
1 S contact with the skin has various disadvantages.
The surface of the skin is not perfectly smooth, but contains small hills
and valleys, due, for example, to pores, wrinkles, hair follicles, and other
surface
irregularities. These irregularities can lead to small air pockets between the
probe and
the skin surface. Although the fiber optic probe and skin often share similar
indices of
refraction, both are significantly higher than air. Thus, the presence of air
pockets may
lead to additional scattering due to index mismatch at the probe/air and
air/skin
interfaces. These effects can induce higher variation in the spectra than
would otherwise
be the case, causing unnecessary noise.
In addition, the wide variation between the skin of different individuals
causes the presence of air pockets and index mismatch to vary significantly
between
individuals. This leads to variation in the spectra and noise depending on the
state of
the individual's skin, making data interpretation more difficult. Finally, non-
repeatable
pressure and mechanical shear and torque forces are likely with the use of a
dry fiber
optic probe on skin, resulting in other non-repeatable effects.
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
2
Various oils and lubricants have been used to optimize optical properties
for microscopy, see U.S. Patent Nos. 3,929,667; 4,526,711; 5,354,825;
5,480,723; and
5,667,840. Glycerol has been used experimentally as an interface medium in
acquiring
spectra of mucous membranes, specifically for research programs aimed at early
detection of cancer of the cervix using fluorescence spectra, see, for example
PCT
Patent Application No. US99/07565; and U.S. Patent Nos. 5,601,079 and
5,341,805.
However, there is currently a need for an interface medium that optimizes
optical
coupling between a tissue surface, such as skin, and a probe. This optical
coupling
agent would enhance both the transfer of light from the probe to the tissue,
and the
collection of light, such as fluorescence spectra, from the tissue to the
probe.
Summary of the Invention
The present invention overcomes the problems and disadvantages
associated with current strategies and designs and provides compositions
useful as
interface media to optically couple and facilitate contact between a probe and
a tissue
surface, such as skin. Compositions of the invention may also be used for
calibration,
such as calibrating the application of pressure between a probe and a surface,
standardization such as standardizing the spectral output (e.g. fluorescence,
infrared,
thermal, or visible) of the instrument, or both, or to alter the metabolism,
physiology,
chemical, or other state of the tissue or surface.
Accordingly, one embodiment of the invention is directed to a
composition for optically coupling a surface to a probe, comprising a viscous
material
having an index of refraction which approximates both the index of refraction
of the
surface and the index of refraction of the probe. Preferably, the index of
refraction of
the material is approximately 1.4. The material may be a liquid or gel and is
preferably
clear in the spectral region of 270-500 run, water soluble, non-toxic, and pH
buffered.
Another embodiment is directed to an improved method for measuring
fluorescence emitted from a tissue surface comprising coupling a probe to the
tissue
surface using a composition according to the present invention and measuring
fluorescence collected by the probe.
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
3
Another embodiment is directed to a method for optically coupling a
surface to a probe comprising applying a composition according to the present
invention
to either the surface or probe or both, and bringing the surface, probe and
composition
into contact with each other.
Another embodiment is directed to a method for calibrating the pressure
applied by a probe to a tissue surface comprising disposing a composition
containing
a fluorescent or phosphorescent dye between the probe and the tissue surface,
applying
pressure to the tissue surface with the probe causing at least a portion of
the
composition between the probe and tissue surface to thin out or disperse,
exciting the
dye in the composition which remains between the probe and tissue surface, and
measuring excitation of the dye.
Other embodiments and advantages of the invention are set forth in part
in the description which follows, and in part, will be obvious from this
description, or
may be learned from the practice of the invention.
Description of the Invention
As embodied and broadly described herein, the present invention is
directed to the measurement of fluorescence spectra on the skin or other
tissue using a
novel composition which optimizes coupling of the tissue surface to the probe.
More
specifically, the present invention relates to compositions useful as an
interface media
between the fiber optic probe and skin, for the purpose of taking more
accurate and
repeatable spectra.
Compositions according to the present invention preferably comprise a
viscous material or medium, such as a liquid, paste or gel, having an index of
refraction
that matches or approximates the indices of both the tissue surface and the
probe which
may be, for example, a simply quartz fiber (i.e. fused silica) probe. "Probe"
or "optical
probe" denote the optical train used to bring light to, and collect light
from, the tissue
sample. The probe is made up of optical fibers, but it may contain other
refractive and
reflective optical elements. Tissue surfaces are preferably skin surfaces but
may also
include the surface of mucus membranes or other surfaces of the body that can
be easily
contacted with the probe and, preferably, non-invasively contacted.
Preferably, the
? .. _ H9RRISON GODDARD -
CA 02389450 2002-04-30
4
index of refraction is between 1-.1 and 2.0, more preferably between 12 and
1.8 send
even more preferably 1.4. The medium is preferably clear in the vis~'ble
spectral region
of 400 - 700 nee, mom p~oferably in the region of 270 - 500 rmn, and may be pH
buffazd; non-toxic, for example, not substantially toxic at the concentration
being used
to the orgaatism on which the composition is being administered; or both.
The modiuxa of the present invention aDows for improved
probe-to-tissue contact, even in the presage of dry clan, scaling sign, o~'
sir poclaets due
to skin texture, or other irregularities such as pits is the nail bed. The
medium
minimizes subject to-subject variability, or site-m-site variability on a
human subject,
based on skin diff~ces such as pigmentation, hair density, thicdmess, blood
flow, and
Like physiological variables. The medium is preferably slippery, allowing for
reduced
friction and mechanical stress betweau the skin and probe. Further, accu~rscy
and
reptadua'biiity are enhanced by providing improved t>eemoai contact between
the skin
and tl~e pmts. This thermal bu~'aing stabilizes and increases the thetxnal
stability of
the int~f~c. In ad3itio~ au inter6CO medium may contain ono or more
pharmacwttcal
agents that, upon applicadion to the tis~ introduce therapeutically effective
amotmts
of the pharmaceutical to the local envirvr~ment. An iaterfsce medium may
co~~tatn, for
example, an affective amount of a pharmaceutical agent that modifies err
stabilize local
fissus perfusion or metabolisar, or oth~x aspects of the dame rnvimnment.
Stabilization
or control of the local onvimnment au8an~ts and improves data acquisitio~a,
The medium is preferably water soluble for ease of application and
removal sad may be none but in some applications may be water insoluble. In
one prefar'ed embodiment, the medium compurises as the principal eomponout an
optically inactive ingredient, i.c., substantially inert and substanUially
transparent to
allow the transfer of light with no mare than negligible irnerferance, for
example,
glycerin, poly~lene glycol such as, for example, most nay PEG such as PEC3-
200,
PEG400 or PEG600, polypropylene glycol, phosphate or cvnabiaatioas of these
ingredients, and one or more burr: andlor wetting agents. Additional secondary
components include PEC3~-150 stearate or distearate, giyccrai steatite, cetyl
alcohol or
combinations tha~eof. Concentrations far the ~condary components ra~oge from
0.01%
g = AMENDED SHEET
Empfano~~r~ ~ ~~.~~~. ~~..~~-' _._ .y_
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
to 20%, preferably 0.1 % to 10%, and more preferably 1 % to 5%, and even more
preferably 2%.
The present invention may be used in a variety of applications,
including, but not limited to, human and veterinary medical and dental
applications,
5 forensic analysis, and other applications where spectral information is
collected with a
probe from a surface. An important feature of the present invention is its
ability to be
modified to serve as a calibrator of the amount of pressure used in
measurement.
Alternatively, the invention can be used as a standard which can serve as a
basis for
measuring the internal fluctuation in the components of the instrument, such
as the
wand. Ingredients that can be used include any optically responsive materials
such as,
for example, fluorescent, phosphorescent or bioluminescent ingredients, or
combinations of such ingredients. The calibration function may be achieved,
for
example, by the addition of a small amount of optically active material to the
medium
such as, for example, a fluorescent or phosphorescent dye. Examples of
optically active
ingredients include, for example, fluorescein, acridine orange,
6-diamidino-2-phenylindole (DAPI), Hoechst 33358, cascade yellow, rhodamine
and
rhodamine derivatives such as rhodamine 6G, tetramethylrhodamine, rhodamine
800,
5-carboxyrhodamine 6G hydrochloride, lissamine rhodamine B sulfonal chloride
and
Texas Red sulfonyl chloride, azure (e.g. azure B), ethidium bromide, thiazole
(e.g.
thiazole orange), nile blue, A1 phthalocyanine, Mag-Indo-1, oxazine, BIODIPY
and its
derivatives such as BIODIDY-FL, BIODIPY-R6G, BIODIPY-TMR,
BIODIPY-581/591, BIODIPY-Texas Red, fluorescine (e.g. fura-red fluorescein),
and
combinations thereof (many of these chemicals are commercially available from
Molecular Probes, Inc.). Preferably the optically active ingredient is soluble
in the
primary or secondary component of the medium which, in most cases, would
require
water solubility, but may require solubility in non-polar materials such as
methanol, is
insensitive to solvent polarity and pH variations, and is a dye with a useful
fluorescence
emission spectrum in the range of 450 nm to 750 nm, preferably between 500 and
700
nm, and more preferably between 550 nm and 650 nm.
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
6
The amount of the spectrally active component in the medium may vary
considerably depending on the analytical equipment and the activity of the
component
itself. Preferred concentrations range from less than 0.0001 % to more than
5%,
preferably between 0.001 % and 2%, and more preferably between 0.01 % and 1 %.
Using this medium, the dye is excited by the spectrofluorometer. The
spectrally active
component of the medium may be passive or active, and produce a colormetric
change
or other spectral change that can be easily detected. Preferably, the active
agent is a dye
that fluoresces or phosphoresces in a benign (i.e. not relevant) spectral
region.
Alternately, its spectral response may be built into the analysis algorithm.
Another
embodiment is directed to a thermo-regulated medium that can be actively or
passively
thermo-regulated such as a crystal that breaks down or crystallizes in
response to heat
or spectral energy. Accordingly, the medium may be used to monitor or
determine skin
temperature.
Another embodiment is directed to a medium of the invention that is
sterilized or sterilizable such that it can be used in a sterile environment
or when sterile
conditions are required. Alternatively, the interface medium may be packaged
in a
membrane or barner (which may be bacteria permeable or impermeable) such that
the
surface to which it is applied does not contact the medium, but the membrane
which
may itself be sterile. Membranes such as paper; glass; plastic; polymers, such
as nylon,
Tyvec~, Teflon; co-polymers of vinyliden chloride and vinyl chloride; and
combinations thereof may be used to package the medium for specific
applications such
as in a glove or sleeve, or for further processing such as conventional
sterilization.
Preferably such membranes or barriers are clear to allow easy visualization
and use of
the medium without allowing passage of the ingredients through the barner.
The invention may also serve as a standardization tool to standardize
instruments used in surface spectral analysis, for example, see PCT
Application No.
US99/07565. Similar to the calibration modification, a small amount of
fluorescent or
phosphorescent dye is added to the medium such that the dye is excited by the
spectrofluorometer or, alternatively, emits its own wavelength. In this
manner, the
instrument can be very precisely standardized. Of course, one modified medium
or a
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
7
mixture of mediums can perform both calibration and standardization functions
simultaneously.
In one application of the invention, a film of the medium is placed
between the probe and skin. Increased probe/skin pressure causes the film to
become
thinner and hence the dye output to be less. By monitoring the dye's response,
the
spectrofluorometer insures optimum skin contact. The film may be applied in a
number
of ways, for example, by being impregnated into a foam so that it is squeezed
out when
pressure is applied, or by being otherwise encapsulated near the probe. In one
embodiment, the intensity of returned light is indicative of the thickness of
the film and,
thus, the pressure being asserted against the skin. In addition to using the
intensity of
the returned light, the spectral location, i.e., wavelength, of the peak can
be used to
calibrate or otherwise standardize the instrument.
In addition to novel compositions, the present invention also is directed
to novel methods of using the compositions of the present invention. One such
embodiment is directed to a method for measuring fluorescence emitted from a
tissue
surface. This method comprises the steps of coupling a probe to the tissue
surface using
a composition according to the present invention and measuring fluorescence
collected
by the probe.
Another embodiment is directed to a method for optically coupling a
surface to a probe comprising applying a composition according to the present
invention
to the surface or probe or both, and bringing the surface, probe and
composition into
contact with each other.
Another embodiment is directed to a method for reducing variability in
the tissue, and particularly skin, by filling in and smoothing out surface
irregularities by
applying a composition according to the present invention to the surface.
Another embodiment is directed to a method for calibrating the pressure
applied by a probe to a tissue surface comprising disposing the composition of
the
present invention between the probe and the tissue surface, applying pressure
to the
tissue surface with the probe causing at least a portion of the composition
between the
probe and tissue surface to disperse or thin out, exciting the dye in the
composition
CA 02389450 2002-04-30
WO 01/33278 PCT/US00/30306
8
remaining between the probe and tissue surface, and measuring excitation of
the dye.
Excitation may be produced by the induced pressure or simply the increased
heat of the
living surface. In this manner, the composition may also be used as a
standardization
tool whereby the instrument or components of the instrument such as the
optical cable
of the wand are spectrally standardized.
Other embodiments and uses of the invention will be apparent to those
skilled in the art from consideration of the specification and practice of the
invention
disclosed herein. All references cited herein for any reason, including all
U.S. and
foreign patents and patent applications, are specifically and entirely
incorporated by
reference. It is intended that the specification and examples be considered
exemplary
only, with the true scope and spirit of the invention indicated by the
following claims.
