U.S. patent application number 16/026348 was filed with the patent office on 2018-11-01 for methods for reducing noise in optical biological sensors.
The applicant listed for this patent is Verily Life Sciences LLC. Invention is credited to Victor Marcel Acosta, Vikram Singh Bajaj, Jason Donald Thompson, Tamara Lynn Troy.
Application Number | 20180310880 16/026348 |
Document ID | / |
Family ID | 54932049 |
Filed Date | 2018-11-01 |
United States Patent
Application |
20180310880 |
Kind Code |
A1 |
Thompson; Jason Donald ; et
al. |
November 1, 2018 |
Methods for Reducing Noise in Optical Biological Sensors
Abstract
Optical measurement of physiological parameters with wearable
devices often includes measuring signals in the presence of
significant noise sources. These noise sources include, but are not
limited to, noise associated with: variable optical coupling to
skin or tissue, variations in tissue optical properties with time
due to changes in humidity, temperature, hydration, variations in
tissue optical properties between individuals, variable coupling of
ambient light sources into detectors, and instrument and detector
noise, including electrical noise, radio frequency or magnetic
interference, or noise caused by mechanical movement of the
detector or its components. The present disclosure includes devices
and methods configured to produce representations of the raw data
in which noise, broadly defined, is separated from the data of
interest. The disclosed devices and methods may include subtracting
or calibrating out these noise sources and other spurious
fluctuations in wearable devices with optical sensors.
Inventors: |
Thompson; Jason Donald;
(Palo Alto, CA) ; Bajaj; Vikram Singh; (Mountain
View, CA) ; Acosta; Victor Marcel; (San Francisco,
CA) ; Troy; Tamara Lynn; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Verily Life Sciences LLC |
Mountain View |
CA |
US |
|
|
Family ID: |
54932049 |
Appl. No.: |
16/026348 |
Filed: |
July 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14319182 |
Jun 30, 2014 |
10039491 |
|
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16026348 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/1455 20130101;
A61B 5/681 20130101; A61B 5/6801 20130101; A61B 5/7475 20130101;
A61B 5/7203 20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 5/1455 20060101 A61B005/1455 |
Claims
1. A method comprising: providing, in a wearable medical diagnostic
device, a first and a second optical signal transmitted from within
a lumen of subsurface vasculature, wherein the first optical signal
comprises an unfiltered target signal and a first noise signal and
the second optical signal comprises a second noise signal, wherein
the first and second noise signals are correlated and wherein a
quotient of the unfiltered target signal and the first noise signal
comprises an unfiltered signal to noise ratio; and determining a
filtered signal, based at least on the unfiltered target signal,
the first noise signal, and the second noise signal, wherein the
filtered signal comprises a filtered target signal and a filtered
noise signal, and wherein a quotient of the filtered target signal
and the filtered noise signal comprises a filtered signal to noise
ratio wherein the filtered signal to noise ratio is higher than the
unfiltered signal to noise ratio.
2. The method of claim 1 wherein the wearable medical diagnostic
device comprises a detector and at least a first source and a
second source wherein the first and second sources are configured
to illuminate an analyte within the lumen substantially at a first
wavelength and a second wavelength, respectively, and the method
further comprising: periodically illuminating the analyte with the
first source at a given period and a given duty cycle wherein the
duty cycle is less than one; periodically illuminating the analyte
with the second source at the given period, wherein the second
source illuminates the analyte for at least a portion of the given
period while the first source is not illuminating the analyte;
detecting the first optical signal with the detector while the
analyte is illuminated by the first source; and detecting the
second optical signal with the detector while the analyte is
illuminated by the second source.
3. The method of claim 2 wherein the first source is configured to
substantially optically excite the analyte and the second source is
configured to substantially not optically excite the analyte.
4. The method of claim 1 wherein the wearable medical diagnostic
device comprises a detector and a source and wherein the lumen
comprises a primary contrast agent configured to fluoresce at a
first spectral maximum and a normalization contrast agent
configured to fluoresce at a second spectral maximum, the method
further comprising: illuminating the lumen with the source;
detecting the first optical signal substantially at the first
spectral maximum; and detecting the second optical signal
substantially at the second spectral maximum.
5. The method of claim 4 wherein the normalization contrast agent
is configured to provide a calibration reference for an optical
coupling factor between the detector and a skin surface.
6. The method of claim 1 wherein the lumen comprises at least a
first and a second portion and the wearable medical diagnostic
device comprises a source configured to illuminate at least the
first and second portions at a spectral illumination maximum, the
method further comprising: illuminating the first and second
portions of the lumen with the source so as to cause a first
portion emission and a second portion emission; detecting the first
optical signal from the first portion emission; and detecting the
second optical signal from the second portion emission.
7. The method of claim 6 wherein the wearable medical diagnostic
device further comprises a first and a second detector configured
to detect the first and the second optical signals,
respectively.
8. The method of claim 6 wherein the wearable medical diagnostic
device further comprises a detector, wherein illuminating the first
and second portions of the lumen comprises illuminating the first
and second portions of the lumen at a first time and a second time,
respectively, and wherein detecting the first optical signal
comprises the detector detecting the first optical signal during
the first time and wherein detecting the second optical signal
comprises the detector detecting the second optical signal during
the second time.
9. A wearable medical diagnostic device, comprising: at least one
detector configured to provide an unfiltered target signal, a first
noise signal, and a second noise signal, wherein the unfiltered
target signal is transmitted substantially from within a lumen of
subsurface vasculature, wherein the first and second noise signals
are correlated, and wherein a quotient of the unfiltered target
signal and the first noise signal comprises an unfiltered signal to
noise ratio; and a computing device configured to determine a
filtered signal, based at least on the unfiltered target signal,
the first noise signal, and the second noise signal, wherein the
filtered signal comprises a filtered target signal and a filtered
noise signal and wherein a quotient of the filtered target signal
and the filtered noise signal comprises a filtered signal to noise
ratio in which the filtered signal to noise ratio is higher than
the unfiltered signal to noise ratio.
10. The wearable medical diagnostic device of claim 9 further
comprising: a first source; and a second source, wherein the first
and second sources are configured to illuminate an analyte within
the lumen substantially at a first and a second wavelength,
respectively, and wherein the computing device is further
configured to: periodically illuminate the analyte with the first
source at a given period and a given duty cycle wherein the duty
cycle is less than one; periodically illuminate the analyte with
the second source at the given period, wherein the second source
illuminates the analyte for at least a portion of the given period
while the first source is not illuminating the analyte; detect the
unfiltered target signal and the first noise signal with the at
least one detector while the analyte is illuminated by the first
source; and detect the second noise signal with the at least one
detector while the analyte is illuminated by the second source.
11. The wearable medical diagnostic device of claim 9 further
comprising: a source, wherein the lumen comprises a primary
contrast agent configured to fluoresce at a first spectral maximum
and a normalization contrast agent configured to fluoresce at a
second spectral maximum, and wherein the computing device is
further configured to: illuminate the lumen with the source;
detect, with the at least one detector, the unfiltered target
signal and the first noise signal substantially at the first
spectral maximum; and detect, with the at least one detector, the
second noise signal substantially at the second spectral
maximum.
12. The wearable medical diagnostic device of claim 9, wherein the
lumen comprises at least a first and a second portion and the
wearable medical diagnostic device further comprises a source
configured to illuminate at least the first and second portions,
and wherein the computing device is further configured to:
illuminate the first and second portions of the lumen with the
source so as to cause a first portion emission and a second portion
emission; detect, with the at least one detector, the unfiltered
target signal and the first noise signal from the first portion
emission; and detect, with the at least one detector, the second
noise signal from the second portion emission.
13. A non-transitory computer readable medium having stored therein
instructions executable by a computing device to cause the
computing device to perform functions comprising: receiving, in a
wearable medical diagnostic device, a first and a second optical
signal transmitted from within a lumen of subsurface vasculature,
wherein the first optical signal comprises an unfiltered target
signal and a first noise signal and the second optical signal
comprises a second noise signal, wherein the first and second noise
signals are correlated and wherein a quotient of the unfiltered
target signal and the first noise signal comprises an unfiltered
signal to noise ratio; and determining a filtered signal, based at
least on the unfiltered target signal, the first noise signal, and
the second noise signal, wherein the filtered signal comprises a
filtered target signal and a filtered noise signal, and wherein a
quotient of the filtered target signal and the filtered noise
signal comprises a filtered signal to noise ratio in which the
filtered signal to noise ratio is higher than the unfiltered signal
to noise ratio.
14. The non-transitory computer readable medium of claim 13,
wherein the wearable medical diagnostic device comprises a detector
and at least a first source and a second source wherein the first
and second sources are configured to illuminate an analyte within
the lumen substantially at a first wavelength and a second
wavelength, respectively, and the non-transitory computer readable
medium further comprising: causing the first source to periodically
illuminate the analyte at a given period and a given duty cycle
wherein the duty cycle is less than one; causing the second source
to periodically illuminate the analyte at the given period, wherein
the second source illuminates the analyte for at least a portion of
the given period while the first source is not illuminating the
analyte; receiving the first optical signal from the detector while
the analyte is illuminated by the first source; and receiving the
second optical signal from the detector while the analyte is
illuminated by the second source.
15. The non-transitory computer readable medium of claim 13,
wherein the wearable medical diagnostic device comprises a detector
and a source and wherein the lumen comprises a primary contrast
agent configured to fluoresce at a first spectral maximum and a
normalization contrast agent configured to fluoresce at a second
spectral maximum, and the non-transitory computer readable medium
further comprising: causing the lumen to be illuminated by the
source; receiving the first optical signal substantially at the
first spectral maximum; and receiving the second optical signal
substantially at the second spectral maximum.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional patent application
claiming priority to U.S. application Ser. No. 14/319,182 filed
Jun. 30, 2014, the contents of which are hereby incorporated by
reference.
BACKGROUND
[0002] Unless otherwise indicated herein, the materials described
in this section are not prior art to the claims in this application
and are not admitted to be prior art by inclusion in this
section.
[0003] A number of scientific methods have been developed in the
medical field to evaluate physiological conditions of a person by
detecting and/or measuring one or more analytes in a person's blood
or other bodily fluids or tissues. The one or more analytes could
be any analytes that, when present in or absent from the blood, or
present at a particular concentration or range of concentrations,
may be indicative of a medical condition or health state of the
person. The one or more analytes could include enzymes, reagents,
hormones, proteins, cells or other molecules, such as
carbohydrates, e.g., glucose.
[0004] In a typical scenario, a person's blood is drawn and either
sent to a lab or input into a handheld testing device, such as a
glucose meter, where one or more tests are performed to measure
various analyte levels and parameters in the blood. For most
people, the blood tests are infrequent, and an abnormal analyte
level indicative of a medical condition may not be identified until
the next blood test is performed. Even in the case of relatively
frequent blood testing, such as may be found with those with
diabetes, who regularly draw blood to test for blood glucose
concentration, those blood tests are typically performed when the
user is awake, although the blood glucose levels (and potential
variations in such levels) occurring during the night could provide
important information to assist a physician in assessing that
person's medical condition. Further, most known methods of analyte
detection and analysis require the collection of blood or other
bodily fluid samples, which may be inconvenient, invasive and
require significant patient compliance.
[0005] Moreover, some blood analytes are particularly difficult to
identify and quantify with conventional sensing techniques. For
small or rarified analytes, such as circulating tumor cells, for
example, only 1 such cell may be present in 10 mL of blood.
Impractically large quantities of blood would have to be drawn or
otherwise sampled and analyzed in order to catch such cells with
statistical significance.
[0006] Methods for analyte detection and characterization often
suffer from a low signal-to-noise ratio (SNR), since the signal
obtained from the analyte (in general, a small object) is typically
weak in comparison to the background. This can make discerning
between target analytes present in the blood, versus other
analytes, particles, and tissues, etc. present in the blood and
elsewhere in the body can be very difficult, especially where the
measurements are taken non-invasively from outside the body. This
is particularly true with some methods of analyte characterization,
such as optical methods, or where the target analytes are rare in
the blood or are of a relatively small size. Accordingly, such
measurements can be much more time consuming (if a large volume of
blood must be analyzed), less sensitive, less specific and
generally less informative on the whole. For example, with
fluorescence detection techniques, it is often difficult to obtain
highly sensitive measurements of a target analyte because other
tissues, cells, and molecules in the body may have some inherent
fluorescent properties, creating a high level of background
noise.
SUMMARY
[0007] In a first aspect, a method is provided. The method includes
providing, in a wearable medical diagnostic device, a first and a
second optical signal transmitted from within a lumen of subsurface
vasculature. The first optical signal includes an unfiltered target
signal and a first noise signal. The second optical signal includes
a second noise signal. The first and second noise signals are
correlated and a quotient of the unfiltered target signal and the
first noise signal includes an unfiltered signal to noise ratio.
The method further includes determining a filtered signal, based at
least on the unfiltered target signal, the first noise signal, and
the second noise signal. The filtered signal includes a filtered
target signal and a filtered noise signal. A quotient of the
filtered target signal and the filtered noise signal includes a
filtered signal to noise ratio in which the filtered signal to
noise ratio is higher than the unfiltered signal to noise
ratio.
[0008] In a second aspect, a wearable medical diagnostic device is
provided. The wearable medical diagnostic device includes at least
one detector and a computing device. The at least one detector is
configured to provide an unfiltered target signal, a first noise
signal, and a second noise signal. The unfiltered target signal is
transmitted substantially from within a lumen of subsurface
vasculature. The first and second noise signals are correlated and
a quotient of the unfiltered target signal and the first noise
signal includes an unfiltered signal to noise ratio. The computing
device is configured to determine a filtered signal, based at least
on the unfiltered target signal, the first noise signal, and the
second noise signal. The filtered signal includes a filtered target
signal and a filtered noise signal. A quotient of the filtered
target signal and the filtered noise signal includes a filtered to
noise ratio in which the filtered signal to noise ratio is higher
than the unfiltered signal to noise ratio.
[0009] In a third aspect, a non-transitory computer readable medium
is provided. The non-transitory computer readable medium includes
instructions executable by a computing device to cause the
computing device to perform functions, the functions including
receiving, in a wearable medical diagnostic device, a first and a
second optical signal transmitted from within a lumen of subsurface
vasculature. The first optical signal includes an unfiltered target
signal and a first noise signal. The second optical signal includes
a second noise signal. The first and second noise signals are
correlated. The quotient of the unfiltered target signal and the
first noise signal includes an unfiltered signal to noise ratio.
The functions further include determining a filtered signal, based
at least on the unfiltered target signal, the first noise signal,
and the second noise signal. The filtered signal includes a
filtered target signal and a filtered noise signal. A quotient of
the filtered target signal and the filtered noise signal includes a
filtered signal to noise ratio in which the filtered signal to
noise ratio is higher than the unfiltered signal to noise
ratio.
[0010] These as well as other aspects, advantages, and
alternatives, will become apparent to those of ordinary skill in
the art by reading the following detailed description, with
reference where appropriate to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a perspective view of an example wearable device,
according to an illustrative embodiment.
[0012] FIG. 2A is a perspective top view of an example
wrist-mounted device, when mounted on a wearer's wrist, according
to an illustrative embodiment.
[0013] FIG. 2B is a perspective bottom view of an example
wrist-mounted device shown in FIG. 2A, when mounted on a wearer's
wrist, according to an illustrative embodiment.
[0014] FIG. 3A is a perspective bottom view of an example
wrist-mounted device, when mounted on a wearer's wrist, according
to an illustrative embodiment.
[0015] FIG. 3B is a perspective top view of an example
wrist-mounted device shown in FIG. 3A, when mounted on a wearer's
wrist, according to an illustrative embodiment.
[0016] FIG. 3C is a perspective view of an example wrist-mounted
device shown in FIGS. 3A and 3B, according to an illustrative
embodiment.
[0017] FIG. 4A is a perspective view of an example wrist-mounted
device, according to an illustrative embodiment.
[0018] FIG. 4B is a perspective bottom view of an example
wrist-mounted device shown in FIG. 4A, according to an illustrative
embodiment.
[0019] FIG. 5 is a perspective view of an example wrist-mounted
device, according to an illustrative embodiment.
[0020] FIG. 6 is a perspective view of an example wrist-mounted
device, according to an illustrative embodiment.
[0021] FIG. 7 is a block diagram of an example system that includes
a plurality of wearable devices in communication with a server,
according to an illustrative embodiment.
[0022] FIG. 8 is a functional block diagram of an example wearable
device, according to an illustrative embodiment.
[0023] FIG. 9 is a functional block diagram of an example wearable
device, according to an illustrative embodiment.
[0024] FIG. 10 is a flowchart of an example method for operating a
wearable device, according to an illustrative embodiment.
[0025] FIG. 11A is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0026] FIG. 11B is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0027] FIG. 12A is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0028] FIG. 12B is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0029] FIG. 13A is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0030] FIG. 13B is a side partial cross-sectional view of a
wrist-mounted device, while on a human wrist, according to an
illustrative embodiment.
[0031] FIG. 14 is a functional block diagram of a wearable medical
diagnostic system with noise reduction, according to an
illustrative embodiment.
[0032] FIG. 15 is a functional block diagram of a wearable medical
diagnostic system with noise reduction, according to an
illustrative embodiment.
DETAILED DESCRIPTION
[0033] In the following detailed description, reference is made to
the accompanying figures, which form a part hereof. In the figures,
similar symbols typically identify similar components, unless
context dictates otherwise. The illustrative embodiments described
in the detailed description, figures, and claims are not meant to
be limiting. Other embodiments may be utilized, and other changes
may be made, without departing from the scope of the subject matter
presented herein. It will be readily understood that the aspects of
the present disclosure, as generally described herein, and
illustrated in the figures, can be arranged, substituted, combined,
separated, and designed in a wide variety of different
configurations, all of which are explicitly contemplated
herein.
[0034] Further, while embodiments disclosed herein make reference
to use on or in conjunction with a living human body, it is
contemplated that the disclosed methods, systems and devices may be
used in any environment where non-invasive detection of an analyte
is desired. The environment may be any living or non-living body or
a portion thereof, a fluid conduit, a fluid reservoir, etc. For
example, one of skill in the art will recognize that the
embodiments disclosed herein may be used to sense analytes present
in a water system. Moreover, while the present disclosure describes
embodiments for use in vivo, one of skill in the art will also
recognize that in vitro applications are possible as well.
Accordingly, the environment may also include a test tube or other
vessel for holding a fluid.
I. OVERVIEW
[0035] A diagnostic system can non-invasively detect and measure a
plurality of physiological parameters of a person, which can
include any parameters that may relate to the person's health. For
example, the system could include sensors for measuring blood
pressure, pulse rate, skin temperature, etc. At least some of the
physiological parameters may be obtained by the system
non-invasively detecting and/or measuring one or more analytes in
blood circulating in subsurface vasculature. The one or more
analytes could be any analytes that, when present in or absent from
the blood, or present at a particular concentration or range of
concentrations, may be indicative of a medical condition or health
of the person. For example, the one or more analytes could include
enzymes, hormones, proteins, cells, or other molecules.
[0036] In an example embodiment, the system obtains at least some
of the health-related information by detecting the binding or
interaction of a clinically-relevant analyte to or with particles,
for example, microparticles or nanoparticles, introduced into a
lumen of the subsurface vasculature that have been functionalized
with a receptor that has a specific affinity to bind to or interact
with the specific analyte. The term "binding" is understood in its
broadest sense to also include a detectable interaction between the
clinically-relevant analyte and the functionalized particles. The
functionalized particles can be introduced into the person's blood
stream by injection, ingestion, inhalation, transdermally, or in
some other manner.
[0037] The particles can be functionalized by covalently or
otherwise attaching or associating a receptor that specifically
binds or otherwise interacts with a particular clinically-relevant
analyte. The functionalized receptor may be an antibody, peptide,
nucleic acid, phage, bacteria, virus, aptamer or any other molecule
with a defined affinity for a target analyte. Additionally or
alternatively, the receptor may be inherent to the particle itself.
For example, the particle itself may be a virus or a phage with an
inherent affinity for certain analytes. Other compounds or
molecules, such as fluorophores or autofluorescent or luminescent
markers or non-optical contrast agents (e.g. acoustic impedance
contrast, RF contrast and the like), which may assist in
interrogating the particles in vivo, may also be attached to the
particles.
[0038] The particles can have a diameter that is less than about 20
micrometers. In some embodiments, the particles have a diameter on
the order of about 10 nanometers to 1 micrometer. In further
embodiments, small particles on the order of 10-100 nanometers in
diameter may be assembled to form a larger "clusters" or
"assemblies on the order of 1-10 micrometers. Those of skill in the
art will understand a "particle" in its broadest sense and that it
may take the form of any fabricated material, a molecule,
cryptophan, a virus, a phage, etc. Further, a particle may be of
any shape, for example, spheres, rods, non-symmetrical shapes,
etc.
[0039] In some examples, the particles may also be magnetic and can
be formed from a paramagnetic, super-paramagnetic or ferromagnetic
material or any other material that responds to a magnetic field.
Alternatively, the particles may also be made of non-magnetic
materials such as polystyrene. Where magnetic particles are used,
the system may include a magnet that can direct into the portion of
subsurface vasculature a magnetic field that is sufficient to
manipulate functionalized magnetic particles in a lumen of that
portion of subsurface vasculature, for example, to collect or slow
down in a certain area. However, measurements may be taken without
localized "collection" of the functionalized particles. The system
may be configured to activate the magnetic field periodically, such
as at certain times of the day (e.g., every hour).
[0040] The system may further include one or more data collection
systems for interrogating, in a non-invasive manner, a target
analyte present in a lumen of the subsurface vasculature in a
particular local area. For example, the system may include a
detector configured to detect a response signal transmitted from a
portion of subsurface vasculature. The response signal may include
both an analyte response signal and a background noise signal.
[0041] In an example embodiment, the analyte response signal could
include light emitted from the target analyte. For example, the
target analyte may include a chemiluminescent marker, such as a
fluorophore, configured to produce a response signal in the form of
light. The analyte response signal may include light emitted in
response to a chemical reaction and/or biological interaction.
[0042] In some examples, the system may also include an
interrogating signal source for transmitting an interrogating
signal that can penetrate into a portion of subsurface vasculature,
or another body system, and a detector for detecting a response
signal that is transmitted from the portion of subsurface
vasculature, or other body system, in response to the interrogating
signal. The interrogating signal may be any kind of signal that is
benign to the patient, and may such as electromagnetic, magnetic,
optic, acoustic, thermal, mechanical, or electric. An interaction,
for example between the interrogating signal and the portion of
subsurface vasculature, may result in a response signal that may be
used to measure a physiological parameter or, more particularly,
that may detect and/or measure the presence of the
clinically-relevant analyte and/or the binding or interaction
between the analyte and other chemical or biological elements.
[0043] In an illustrative embodiment, the analyte response may be
related to an interaction between one or more target analytes and
the interrogating signal source. For example, the interrogating
signal source could include a light emitting diode or laser. The
interrogating signal source may be configured to emit within narrow
or wide bands throughout the electromagnetic spectrum. The target
analyte may include a fluorophore. The fluorophore may be
configured to emit light in response to excitation from the
interrogating signal source. The light emitted from the fluorophore
may represent the analyte response signal. The analyte response
signal may occur anywhere in the electromagnetic spectrum.
[0044] For example, the interrogating signal may include a radio
frequency (RF) signal and the response signal is a magnetic
resonance signal, such as nuclear magnetic resonance (NMR). In
another example, where the functionalized particles include a
fluorophore, the interrogating signal may be an optical signal with
a wavelength that can excite the fluorophore and penetrate the skin
or other tissue and subsurface vasculature (e.g., a wavelength in
the range of about 500 to about 1000 nanometers). The response
signal may include fluorescence radiation from the fluorophore that
can penetrate the subsurface vasculature and tissue to reach the
detector. In another example, where the functionalized particles
include an electrically conductive material or a magnetically lossy
material, the interrogation signal may be a time-varying magnetic
field or a radio frequency (RF) electromagnetic signal, with
sufficient signal power to rapidly heat the particles. The response
signal may be an acoustic emission from the particles, caused by
rapid thermal expansion of the particles, or caused by cavitation
of the liquid medium in contact with the particles.
[0045] Additionally, the system may further include a modulation
source configured to modulate the analyte response signal. The
modulation source can be configured to modulate the analyte
response signal differently than the background noise signal. To
this end, the modulation may help to discern between the target
analyte and, essentially, everything else in the body by, for
example, increasing the signal-to-noise ratio. Generally, the
modulation may include any spatial, temporal, spectral, thermal,
magnetic, mechanical, electrical, acoustic, chemical, or
electrochemical, etc. modulation technique or any combination
thereof.
[0046] In some scenarios, it may also be useful to detect and
distinguish both the analyte response signal--related to
functionalized particles bound to or interacting with target
analyte(s)--and an "unbound" particle signal--related to
functionalized particles not bound to or interacting with target
analyte(s). For example, in some measurement or characterization
schemes, it may be useful or necessary to determine the percentage
of functionalized particles introduced into the body that have
bound to the target analyte. In such cases, the modulation source
may be configured to modulate the analyte response signal
differently than the unbound particle signal.
[0047] The elements of the system, namely the type of modulation,
the type/shape/materials of particles, types of receptors and
target analytes may all be interrelated. Ultimately, the type of
particle and receptor used to detect a particular target analyte
may be dictated, to some extent, by the characteristics of the
target analyte (i.e., type, size, shape, affinities, etc.), the
chosen type of modulation (i.e., spatial, spectral, thermal,
magnetic, mechanical, chemical, etc.), and the mode of
interrogation (optical, acoustic, magnetic, RF, etc.).
[0048] Data collected by the detector may be sent to a processor
for analysis. The processor may be configured to non-invasively
detect the one or more target analytes by differentiating the
analyte response signal from the background noise signal based, at
least in part, on the modulation. In some cases where the analyte
includes a bound particle, the processor may further be configured
to differentiate the analyte response signal from the unbound
particle signal.
[0049] The processor may be configured to determine the
concentration of a particular target analyte in the blood from, at
least in part, the analyte response signal. The detection and
concentration data processed by the processor may be communicated
to the patient, transmitted to medical or clinical personnel,
locally stored or transmitted to a remote server, the cloud, and/or
any other system where the data may be stored or accessed at a
later time.
[0050] The processor may be located on an external reader, which
may be provided as an external body-mounted device, such as a
necklace, wristwatch, eyeglasses, a mobile phone, a handheld or
personal computing device or some combination thereof. Data
collected by the detector may be transmitted to the external reader
via a communication interface. Control electronics can wirelessly
communicate the data to the external reader by modifying the
impedance of an antenna in communication with the detector so as to
characteristically modify the backscatter from the antenna. In some
examples, the external reader can operate to intermittently
interrogate the detector to provide a reading by radiating
sufficient radiation to power the detector to obtain a measurement
and communicate the result. In this way, the external reader can
acquire a series of analyte identification and concentration
measurements over time without continuously powering the detector
and/or processor. The processor may also be provided at another
location distal to the detector, and the detector data is
communicated to the processor via a wired connection, a memory
card, a USB device or other known method. Alternatively, the
processor may be located proximal to the detector and may be
configured to locally analyze the data that it collects and then
transmit the results of the analysis to an external reader or
server.
[0051] The external reader may include a user interface, or may
further transmit the collected data to a device with a user
interface that can indicate the results of the data analysis. In
this way, the person wearing, holding or viewing the device can be
made aware of the nutritional analysis and/or potential medical
conditions. The external reader may also be configured to produce
an auditory or tactile (vibration) response to alert the patient of
a medical condition. Further, the external reader may also be
configured to receive information from the patient regarding
his/her health state, wellness state, activity state, nutrition
intake and the like, as additional input information to the
processor. For example, the user may input a health or wellness
state, such as, experiencing migraine symptoms, jittery, racing
heart, upset stomach, feeling tired, activity state including types
and duration of physical activity nutrition intake including meal
timing and composition, and other parameters including body weight,
medication intake, quality of sleep, stress level, personal care
products used, environmental conditions, social activity, etc.
Further, the reader may also receive signals from one or more other
detectors, such as a pedometer, heart rate sensor, blood pressure
sensor, blood oxygen saturation level, body temperature, GPS or
other location or positioning sensors, microphone, light sensor,
etc.
[0052] The system may be configured to obtain data during pre-set
measurement periods or in response to a prompt. For example, the
system may be configured to operate the detector and collect data
once an hour. In other examples, the system may be configured to
operate the detector in response to a prompt, such as a manual
input by the patient or a physician. The system may also be
configured to obtain data in response to an internal or external
event or combination of events, such as during or after physical
activity, at rest, at high pulse rates, high or low blood
pressures, cold or hot weather conditions, etc. In other examples,
the system could operate the detector more frequently or less
frequently, or the system could measure some analytes more
frequently than others.
[0053] Data collected by the system may be used to notify the
patient of, as described above, analyte levels or of an existing or
imminent medical emergency. In some examples, the data may be used
to develop an individual baseline profile for the patient. The
baseline profile may include patterns for how one or more of the
patient's analyte levels typically change over time, such as during
the course of a day, a week, or a month, or in response to
consumption of a particular type of food/drug. The baseline
profile, in essence, may establish "normal" levels of the measured
analytes for the patient. Additional data, collected over
additional measurement periods, may be compared to the baseline
profile. If the additional data is consistent with the patterns
embodied in the baseline profile, it may be determined that the
patient's condition has not changed. On the other hand, if the
additional data deviates from the patterns embodied in the baseline
profile, it may be determined that the patient's condition has
changed. The change in condition could, for example, indicate that
the patient has developed a disease, disorder, or other adverse
medical condition or may be at risk for a severe medical condition
in the near future. Further, the change in condition could further
indicate a change in the patient's eating habits, either positively
or negatively, which could be of interest to medical personnel.
Further, the patient's baseline and deviations from the baseline
can be compared to baseline and deviation data collected from a
population of wearers of the devices.
[0054] When a change in condition is detected, a clinical protocol
may be consulted to generate one or more recommendations that are
appropriate for the patient's change in condition. For example, it
may be recommended that the patient inject himself/herself with
insulin, change his/her diet, take a particular medication or
supplement, schedule an appointment with a medical professional,
get a specific medical test, go to the hospital to seek immediate
medical attention, abstain from certain activities, etc. The
clinical protocol may be developed based, at least in part, on
correlations between analyte concentration and health state derived
by the server, any known health information or medical history of
the patient, and/or on recognized standards of care in the medical
field. The one or more recommendations may then be transmitted to
the external reader for communication to the user via the user
interface.
[0055] Correlations may be derived between the analyte
concentration(s) measured by the system and the health state
reported by the patient. For example, analysis of the analyte data
and the health state data may reveal that the patient has
experienced certain adverse health conditions, such as a migraine
or a heart attack, when an analyte reaches a certain concentration.
This correlation data may be used to generate recommendations for
the patient, or to develop a clinical protocol. Blood analysis may
be complemented with other physiological measurements such as blood
pressure, heart rate, body temperature etc., in order to add to or
enhance these correlations.
[0056] Further, data collected from a plurality of patients,
including both the analyte measurements and the indications of
health state, may be used to develop one or more clinical protocols
used by the server to generate recommendations and/or used by
medical professionals to provide medical care and advice to their
patients. This data may further be used to recognize correlations
between blood analytes and health conditions among the population.
Health professionals may further use this data to diagnose and
prevent illness and disease, prevent serious clinical events in the
population, and to update clinical protocols, courses of treatment,
and the standard of care.
[0057] The above described system may be implemented as a wearable
device. The term "wearable device," as used in this disclosure,
refers to any device that is capable of being worn at, on or in
proximity to a body surface, such as a wrist, ankle, waist, chest,
ear, eye or other body part. In order to take in vivo measurements
in a non-invasive manner from outside of the body, the wearable
device may be positioned on a portion of the body where subsurface
vasculature is easily observable, the qualification of which will
depend on the type of detection system used. The device may be
placed in close proximity to the skin or tissue, but need not be
touching or in intimate contact therewith. A mount, such as a belt,
wristband, ankle band, headband, etc. can be provided to mount the
device at, on or in proximity to the body surface. The mount may
prevent the wearable device from moving relative to the body to
reduce measurement error and noise. Further, the mount may be an
adhesive substrate for adhering the wearable device to the body of
a wearer. The detector, modulation source, interrogation signal
source (if applicable) and, in some examples, the processor, may be
provided on the wearable device. In other embodiments, the above
described system may be implemented as a stationary measurement
device to which a user must be brought into contact or proximity
with or as a device that may be temporarily placed or held against
a body surface during one or more measurement periods.
[0058] In an illustrative embodiment, the processor and/or other
elements of the system may be configured in an effort to optimize
signal to noise ratio. For example, the system may be configured to
compare two or more signal channels whose noise is correlated. One
of the signal channels may substantially contain the signal of
interest, while each of the signal channels may contain
well-correlated noise signals. Through subtraction, division,
and/or other signal processing algorithms, a signal of interest may
be separated from the noise signals, which may result in a higher
signal to noise ratio.
[0059] It should be understood that the above embodiments, and
other embodiments described herein, are provided for explanatory
purposes, and are not intended to be limiting.
[0060] Further, the term "medical condition" as used herein should
be understood broadly to include any disease, illness, disorder,
injury, condition or impairment--e.g., physiologic, psychological,
cardiac, vascular, orthopedic, visual, speech, or hearing--or any
situation requiring medical attention.
II. ILLUSTRATIVE WEARABLE DEVICES
[0061] A wearable device 100 may automatically measure a plurality
of physiological parameters of a person wearing the device. The
term "wearable device," as used in this disclosure, refers to any
device that is capable of being worn at, on or in proximity to a
body surface, such as a wrist, ankle, waist, chest, or other body
part. In order to take in vivo measurements in a non-invasive
manner from outside of the body, the wearable device may be
positioned on a portion of the body where subsurface vasculature is
easily observable, the qualification of which will depend on the
type of detection system used. The device may be placed in close
proximity to the skin or tissue, but need not be touching or in
intimate contact therewith. A mount 110, such as a belt, wristband,
ankle band, etc. may be provided to mount the device at, on or in
proximity to the body surface. The mount 110 may prevent the
wearable device from moving relative to the body to reduce
measurement error and noise. In one example, shown in FIG. 1, the
mount 110, may take the form of a strap or band 120 that can be
worn around a part of the body. Further, the mount 110 may be an
adhesive substrate for adhering the wearable device 100 to the body
of a wearer.
[0062] A measurement platform 130 is disposed on the mount 110 such
that it can be positioned on the body where subsurface vasculature
is easily observable. An inner face 140 of the measurement platform
is intended to be mounted facing to the body surface. The
measurement platform 130 may house the data collection system 150,
which may include at least one detector 160 for detecting at least
one physiological parameter, which may include one or more
parameters that may relate to the health of the person wearing the
wearable device. For example, the detector 160 could be configured
to measure blood pressure, pulse rate, respiration rate, skin
temperature, etc. At least one of the detectors 160 may be
configured to non-invasively measure one or more analytes in blood
circulating in subsurface vasculature proximate to the wearable
device. In a non-exhaustive list, detector 160 may include any one
of an optical (e.g., CMOS, CCD, photodiode), acoustic (e.g.,
piezoelectric, piezoceramic), electrochemical (voltage, impedance),
thermal, mechanical (e.g., pressure, strain), magnetic, or
electromagnetic (e.g., magnetic resonance) sensor. The components
of the data collection system 150 may be miniaturized so that the
wearable device may be worn on the body without significantly
interfering with the wearer's usual activities.
[0063] In some examples, the data collection system 150 further
includes a signal source 170 for transmitting an interrogating
signal through the surface of the wearer's skin into the portion of
subsurface vasculature, for example, into a lumen of the subsurface
vasculature. The interrogating signal may be any kind of signal
that is benign to the wearer, such as electromagnetic, magnetic,
optic, acoustic, thermal, mechanical, and results in a response
signal that can be used to measure a physiological parameter or,
more particularly, that can detect the binding of the
clinically-relevant analyte to the functionalized particles. In one
example, the interrogating signal is an electromagnetic pulse
(e.g., a radio frequency (RF) pulse) and the response signal is a
magnetic resonance signal, such as nuclear magnetic resonance
(NMR). In another example, the interrogating signal is a
time-varying magnetic field, and the response signal is an
externally-detectable physical motion due to the time-varying
magnetic field. The time-varying magnetic field modulates the
particles by physical motion in a manner different from the
background, making them easier to detect. In a further example, the
interrogating signal is an electromagnetic radiation signal. In
particular, the interrogating signal may be electromagnetic
radiation having a wavelength between about 400 nanometers and
about 1600 nanometers. The interrogating signal may, more
particularly, comprise electromagnetic radiation having a
wavelength between about 500 nanometers and about 1000 nanometers.
In some examples, the functionalized particles include a
fluorophore. The interrogating signal may therefore be an
electromagnetic radiation signal with a wavelength that can excite
the fluorophore and penetrate the skin or other tissue and
subsurface vasculature (e.g., a wavelength in the range of about
500 to about 1000 nanometers), and the response signal is
fluorescence radiation from the fluorophore that can penetrate the
subsurface vasculature and tissue to reach the detector.
Alternatively, the interrogating signal may include electromagnetic
radiation with wavelengths outside the 400-1600 nm range.
[0064] In some cases, an interrogating signal is not necessary to
measure one or more of the physiological parameters and, therefore,
the wearable device 100 need not include a signal source 170. For
example, the functionalized particles may include an
autofluorescent or luminescent marker, such as a fluorophore, that
will automatically emit a response signal indicative of the binding
of the clinically-relevant analyte to the functionalized particles,
without the need for an interrogating signal or other external
stimulus. In some examples, the functionalized particles may
include a chemiluminescent marker configured to produce a response
signal in the form of luminescence radiation produced in response
to a chemical reaction initiated, at least in part, to the binding
of the target analyte to the particle.
[0065] A collection magnet 180 may also be included in the data
collection system 150. In such embodiments, the functionalized
particles may also be made of or be functionalized with magnetic
materials, such as ferromagnetic, paramagnetic, super-paramagnetic,
or any other material that responds to a magnetic field. The
collection magnet 180 may be configured to direct a magnetic field
into the portion of subsurface vasculature that is sufficient to
cause functionalized magnetic particles to collect in a lumen of
that portion of subsurface vasculature. The magnet may be an
electromagnet that may be turned on during measurement periods and
turned off when a measurement period is complete so as to allow the
magnetic particles to disperse through the vasculature.
[0066] The wearable device 100 may also include a user interface
190 via which the wearer of the device may receive one or more
recommendations or alerts generated either from a remote server or
other remote computing device, or from a processor within the
device. The alerts could be any indication that can be noticed by
the person wearing the wearable device. For example, the alert
could include a visual component (e.g., textual or graphical
information on a display), an auditory component (e.g., an alarm
sound), and/or tactile component (e.g., a vibration). Further, the
user interface 190 may include a display 192 where a visual
indication of the alert or recommendation may be displayed. The
display 192 may further be configured to provide an indication of
the measured physiological parameters, for instance, the
concentrations of certain blood analytes being measured.
[0067] In one example, the wearable device is provided as a
wrist-mounted device, as shown in FIGS. 2A, 2B, 3A-3C, 4A, 5, and
6. The wrist-mounted device may be mounted to the wrist of a living
subject with a wristband or cuff, similar to a watch or bracelet.
As shown in FIGS. 2A and 2B, the wrist mounted device 200 may
include a mount 210 in the form of a wristband 220, a measurement
platform 230 positioned on the anterior side 240 of the wearer's
wrist, and a user interface 250 positioned on the posterior side
260 of the wearer's wrist. The wearer of the device may receive,
via the user interface 250, one or more recommendations or alerts
generated either from a remote server or other remote computing
device, or alerts from the measurement platform. Such a
configuration may be perceived as natural for the wearer of the
device in that it is common for the posterior side 260 of the wrist
to be observed, such as the act of checking a wrist-watch.
Accordingly, the wearer may easily view a display 270 on the user
interface. Further, the measurement platform 230 may be located on
the anterior side 240 of the wearer's wrist where the subsurface
vasculature may be readily observable. However, other
configurations are contemplated.
[0068] The display 270 may be configured to display a visual
indication of the alert or recommendation and/or an indication of
the measured physiological parameters, for instance, the
concentrations of certain blood analytes being measured. Further,
the user interface 250 may include one or more buttons 280 for
accepting inputs from the wearer. For example, the buttons 280 may
be configured to change the text or other information visible on
the display 270. As shown in FIG. 2B, measurement platform 230 may
also include one or more buttons 290 for accepting inputs from the
wearer. The buttons 290 may be configured to accept inputs for
controlling aspects of the data collection system, such as
initiating a measurement period, or inputs indicating the wearer's
current health state (i.e., normal, migraine, shortness of breath,
heart attack, fever, "flu-like" symptoms, food poisoning,
etc.).
[0069] In another example wrist-mounted device 300, shown in FIGS.
3A-3C, the measurement platform 310 and user interface 320 are both
provided on the same side of the wearer's wrist, in particular, the
anterior side 330 of the wrist. On the posterior side 340, a watch
face 350 may be disposed on the strap 360. While an analog watch is
depicted in FIG. 3B, one of ordinary skill in the art will
recognize that any type of clock may be provided, such as a digital
clock.
[0070] As can be seen in FIG. 3C, the inner face 370 of the
measurement platform 310 is intended to be worn proximate to the
wearer's body. A data collection system 380 housed on the
measurement platform 310 may include a detector 382, a signal
source 384 and a collection magnet 386. As described above, the
signal source 384 and the collection magnet 386 may not be provided
in all embodiments of the wearable device.
[0071] In a further example shown in FIGS. 4A and 4B, a wrist
mounted device 400 includes a measurement platform 410, which
includes a data collection system 420, disposed on a strap 430.
Inner face 440 of measurement platform may be positioned proximate
to a body surface so that data collection system 420 may
interrogate the subsurface vasculature of the wearer's wrist. A
user interface 450 with a display 460 may be positioned facing
outward from the measurement platform 410. As described above in
connection with other embodiments, user interface 450 may be
configured to display data collected from the data collection
system 420, including the concentration of one or more measured
analytes, and one or more alerts generated by a remote server or
other remote computing device, or a processor located on the
measurement platform. The user interface 420 may also be configured
to display the time of day, date, or other information that may be
relevant to the wearer.
[0072] As shown in FIG. 5, in a further embodiment, wrist-mounted
device 500 may be provided on a cuff 510. Similar to the previously
discussed embodiments, device 500 includes a measurement platform
520 and a user interface 530, which may include a display 540 and
one or more buttons 550. The display 540 may further be a
touch-screen display configured to accept one or more input by the
wearer. For example, as shown in FIG. 6, display 610 may be a
touch-screen configured to display one or more virtual buttons 620
for accepting one or more inputs for controlling certain functions
or aspects of the device 600, or inputs of information by the user,
such as current health state.
[0073] FIG. 7 is a simplified schematic of a system including one
or more wearable devices 700. The one or more wearable devices 710
may be configured to transmit data via a communication interface
720 over one or more communication networks 730 to a remote server
740. In one embodiment, the communication interface 720 includes a
wireless transceiver for sending and receiving communications to
and from the server 740. In further embodiments, the communication
interface 720 may include any means for the transfer of data,
including both wired and wireless communications. For example, the
communication interface may include a universal serial bus (USB)
interface or a secure digital (SD) card interface. Communication
networks 730 may be any one of may be one of: a plain old telephone
service (POTS) network, a cellular network, a fiber network and a
data network. The server 740 may include any type of remote
computing device or remote cloud computing network. Further,
communication network 730 may include one or more intermediaries,
including, for example wherein the wearable device 710 transmits
data to a mobile phone or other personal computing device, which in
turn transmits the data to the server 740.
[0074] In addition to receiving communications from the wearable
device 710, such as collected physiological parameter data and data
regarding health state as input by the user, the server may also be
configured to gather and/or receive either from the wearable device
710 or from some other source, information regarding a wearer's
overall medical history, environmental factors and geographical
data. For example, a user account may be established on the server
for every wearer that contains the wearer's medical history.
Moreover, in some examples, the server 740 may be configured to
regularly receive information from sources of environmental data,
such as viral illness or food poisoning outbreak data from the
Centers for Disease Control (CDC) and weather, pollution and
allergen data from the National Weather Service. Further, the
server may be configured to receive data regarding a wearer's
health state from a hospital or physician. Such information may be
used in the server's decision-making process, such as recognizing
correlations and in generating clinical protocols.
[0075] Additionally, the server may be configured to gather and/or
receive the date, time of day and geographical location of each
wearer of the device during each measurement period. Such
information may be used to detect and monitor spatial and temporal
spreading of diseases. As such, the wearable device may be
configured to determine and/or provide an indication of its own
location. For example, a wearable device may include a GPS system
so that it can include GPS location information (e.g., GPS
coordinates) in a communication to the server. As another example,
a wearable device may use a technique that involves triangulation
(e.g., between base stations in a cellular network) to determine
its location. Other location-determination techniques are also
possible.
[0076] The server may also be configured to make determinations
regarding the efficacy of a drug or other treatment based on
information regarding the drugs or other treatments received by a
wearer of the device and, at least in part, the physiological
parameter data and the indicated health state of the user. From
this information, the server may be configured to derive an
indication of the effectiveness of the drug or treatment. For
example, if a drug is intended to treat nausea and the wearer of
the device does not indicate that he or she is experiencing nausea
after beginning a course of treatment with the drug, the server may
be configured to derive an indication that the drug is effective
for that wearer. In another example, a wearable device may be
configured to measure blood glucose. If a wearer is prescribed a
drug intended to treat diabetes, but the server receives data from
the wearable device indicating that the wearer's blood glucose has
been increasing over a certain number of measurement periods, the
server may be configured to derive an indication that the drug is
not effective for its intended purpose for this wearer.
[0077] Further, some embodiments of the system may include privacy
controls which may be automatically implemented or controlled by
the wearer of the device. For example, where a wearer's collected
physiological parameter data and health state data are uploaded to
a cloud computing network for trend analysis by a clinician, the
data may be treated in one or more ways before it is stored or
used, so that personally identifiable information is removed. For
example, a user's identity may be treated so that no personally
identifiable information can be determined for the user, or a
user's geographic location may be generalized where location
information is obtained (such as to a city, ZIP code, or state
level), so that a particular location of a user cannot be
determined.
[0078] Additionally or alternatively, wearers of a device may be
provided with an opportunity to control whether or how the device
collects information about the wearer (e.g., information about a
user's medical history, social actions or activities, profession, a
user's preferences, or a user's current location), or to control
how such information may be used. Thus, the wearer may have control
over how information is collected about him or her and used by a
clinician or physician or other user of the data. For example, a
wearer may elect that data, such as health state and physiological
parameters, collected from his or her device may only be used for
generating an individual baseline and recommendations in response
to collection and comparison of his or her own data and may not be
used in generating a population baseline or for use in population
correlation studies.
III. ILLUSTRATIVE ELECTRONICS PLATFORM FOR A WEARABLE DEVICE
[0079] FIG. 8 is a simplified block diagram illustrating the
components of a wearable device 800, according to an example
embodiment. Wearable device 800 may take the form of or be similar
to one of the wrist-mounted devices 200, 300, 400, 500, 600, shown
in FIGS. 2A, 2B, 3A-3C, 4A, 5, and 6. However, wearable device 800
may also take other forms, such as an ankle, waist, or
chest-mounted device. Alternatively, wearable device 800 may be
positioned on various parts of a wearer's body using, for instance,
an adhesive.
[0080] FIG. 8 shows an example of a wearable device 800 having a
data collection system 810, a user interface 820, communication
platform 830 for transmitting data to a server, and processor(s)
840. The components of the wearable device 800 may be disposed on a
mount 850 for mounting the device to an external body surface where
a portion of subsurface vasculature is readily observable.
[0081] Processor 840 may be a general-purpose processor or a
special purpose processor (e.g., digital signal processors,
application-specific integrated circuits, etc.). The one or more
processors 840 may be configured to execute computer-readable
program instructions 870 that are stored in the computer readable
medium 860 and are executable to provide the functionality of a
wearable device 800 described herein.
[0082] The computer readable medium 860 may include or take the
form of one or more non-transitory, computer-readable storage media
that may be read or accessed by at least one processor 840. The one
or more computer-readable storage media may include volatile and/or
non-volatile storage components, such as optical, magnetic, organic
or other memory or disc storage, which may be integrated in whole
or in part with at least one of the one or more processors 840. In
some embodiments, the computer readable medium 860 may be
implemented using a single physical device (e.g., one optical,
magnetic, organic or other memory or disc storage unit), while in
other embodiments, the computer readable medium 860 may be
implemented using two or more physical devices.
[0083] Data collection system 810 includes a detector 812 and, in
some embodiments, a signal source 814. As described above, detector
812 may include one or more detectors configured to detect at least
one physiological parameter, which may include parameters that may
relate to the health of the person wearing the wearable device 800.
For example, the detector 812 may be configured to measure blood
pressure, pulse rate, skin temperature, etc. Detector 812 may be
configured to non-invasively measure one or more analytes in blood
circulating in subsurface vasculature proximate to the wearable
device. In some examples, detector 812 may include one or more of
an optical (e.g., CMOS, CCD, photodiode), acoustic (e.g.,
piezoelectric, piezoceramic), electrochemical (voltage, impedance),
thermal, mechanical (e.g., pressure, strain), magnetic, or
electromagnetic (e.g., magnetic resonance) sensor.
[0084] In some examples, the data collection system 810 further
includes a signal source 814 for transmitting an interrogating
signal that can penetrate the wearer's skin into the portion of
subsurface vasculature. In general, signal source 814 may generate
an interrogation signal that may, in turn, for example through
interactions with a target analyte, produce a response signal that
may be detected by one or more of the detectors 812. The
interrogating signal can be any kind of signal that is benign to
the wearer, such as electromagnetic, magnetic, optic, acoustic,
thermal, mechanical, and results in a response signal that can be
used to measure a physiological parameter or, more particularly,
that can detect the binding of the clinically-relevant analyte to
the functionalized particles. In one example, the interrogating
signal is an electromagnetic pulse (e.g., a radio frequency (RF)
pulse) and the response signal is a magnetic resonance signal, such
as nuclear magnetic resonance (NMR). In another example, the
interrogating signal is a time-varying magnetic field, and the
response signal is an externally-detectable physical motion due to
the time-varying magnetic field. The time-varying magnetic field
modulates the particles by physical motion in a manner different
from the background, making them easier to detect. In a further
example, the interrogating signal is an electromagnetic radiation
signal. In particular, the interrogating signal may be
electromagnetic radiation having a wavelength between about 400
nanometers and about 1600 nanometers. The interrogating signal may,
more particularly, comprise electromagnetic radiation having a
wavelength between about 500 nanometers and about 1000 nanometers.
In examples where the functionalized particles include a
fluorophore, the interrogating signal may therefore be an
electromagnetic radiation signal with a wavelength that can excite
the fluorophore and penetrate the skin or other tissue and
subsurface vasculature (e.g., a wavelength in the range of about
500 to about 1000 nanometers), and the response signal is
fluorescence radiation from the fluorophore that can penetrate the
subsurface vasculature and tissue to reach the detector.
[0085] The program instructions 870 stored on the computer readable
medium 860 may include instructions to perform or facilitate some
or all of the device functionality described herein. For instance,
in the illustrated embodiment, program instructions 870 include a
controller module 872, calculation and decision module 874 and an
alert module 876.
[0086] The controller module 872 can include instructions for
operating the data collection system 810, for example, the detector
812 and signal source 814. For example, the controller 872 may
activate signal source 814 and/or detector 812 during one or more
pre-set measurement periods. In particular, the controller module
872 can include instructions for controlling the signal source 814
to transmit an interrogating signal at preset measurement times and
controlling the detector 812 to receive data representative of
response signals transmitted from the portion of subsurface
vasculature in response to the interrogating signals transmitted at
the preset measurement times.
[0087] The controller module 872 can also include instructions for
operating a user interface 820. For example, controller module 872
may include instructions for displaying data collected by the data
collection system 810 and analyzed by the calculation and decision
module 874, or for displaying one or more alerts generated by the
alert module 875. Further, controller module 872 may include
instructions to execute certain functions based on inputs accepted
by the user interface 820, such as inputs accepted by one or more
buttons disposed on the user interface.
[0088] Communication platform 830 may also be operated by
instructions within the controller module 872, such as instructions
for sending and/or receiving information via a wireless antenna,
which may be disposed on or in the wearable device 800. The
communication interface 830 can optionally include one or more
oscillators, mixers, frequency injectors, etc. to modulate and/or
demodulate information on a carrier frequency to be transmitted
and/or received by the antenna. In some examples, the wearable
device 800 is configured to indicate an output from the processor
by modulating an impedance of the antenna in a manner that is
perceivable by a remote server or other remote computing
device.
[0089] Calculation and decision module 872 may include instructions
for receiving data from the data collection system 810 in the form
of a responsive signal, analyzing the data to determine if the
target analyte is present or absent, quantify the measured
physiological parameter(s), such as concentration of a target
analyte, and analyzing the data to determine if a medical condition
is indicated. In particular, the calculation and decision module
872 may include instructions for determining, for each preset
measurement time, a concentration of a clinically-relevant analyte
based on the response signal detected by the detector at that
measurement time and determining, for each preset measurement time,
whether a medical condition is indicated based on at least the
corresponding concentration of the clinically-relevant analyte. The
preset measurement times may be set to any period and, in one
example, are about one hour apart.
[0090] The program instructions of the calculation and decision
module 872 may, in some examples, be stored in a computer-readable
medium and executed by a processor located external to the wearable
device. For example, the wearable device could be configured to
collect certain data regarding physiological parameters from the
wearer and then transmit the data to a remote server, which may
include a mobile device, a personal computer, the cloud, or any
other remote system, for further processing.
[0091] The computer readable medium 860 may further contain other
data or information, such as medical and health history of the
wearer of the device, that may be necessary in determining whether
a medical condition is indicated. Further, the computer readable
medium 860 may contain data corresponding to certain analyte
baselines, above or below which a medical condition is indicated.
The baselines may be pre-stored on the computer readable medium
860, may be transmitted from a remote source, such as a remote
server, or may be generated by the calculation and decision module
874 itself. The calculation and decision module 874 may include
instructions for generating individual baselines for the wearer of
the device based on data collected over a certain number of
measurement periods. For example, the calculation and decision
module 874 may generate a baseline concentration of a target blood
analyte for each of a plurality of measurement periods by averaging
the analyte concentration at each of the measurement periods
measured over the course of a few days, and store those baseline
concentrations in the computer readable medium 860 for later
comparison. Baselines may also be generated by a remote server and
transmitted to the wearable device 800 via communication interface
830. The calculation and decision module 874 may also, upon
determining that a medical condition is indicated, generate one or
more recommendations for the wearer of the device based, at least
in part, on consultation of a clinical protocol. Such
recommendations may alternatively be generated by the remote server
and transmitted to the wearable device.
[0092] In some examples, the collected physiological parameter
data, baseline profiles, health state information input by device
wearers and generated recommendations and clinical protocols may
additionally be input to a cloud network and be made available for
download by a wearer's physician. Trend and other analyses may also
be performed on the collected data, such as physiological parameter
data and health state information, in the cloud computing network
and be made available for download by physicians or clinicians.
[0093] Further, physiological parameter and health state data from
individuals or populations of device wearers may be used by
physicians or clinicians in monitoring efficacy of a drug or other
treatment. For example, high-density, real-time data may be
collected from a population of device wearers who are participating
in a clinical study to assess the safety and efficacy of a
developmental drug or therapy. Such data may also be used on an
individual level to assess a particular wearer's response to a drug
or therapy. Based on this data, a physician or clinician may be
able to tailor a drug treatment to suit an individual's needs.
[0094] In response to a determination by the calculation and
decision module 874 that a medical condition is indicated, the
alert module 876 may generate an alert via the user interface 820.
The alert may include a visual component, such as textual or
graphical information displayed on a display, an auditory component
(e.g., an alarm sound), and/or tactile component (e.g., a
vibration). The textual information may include one or more
recommendations, such as a recommendation that the wearer of the
device contact a medical professional, seek immediate medical
attention, or administer a medication.
[0095] Although wearable device 800 is shown in FIG. 8 with only
one signal source (signal source 814) and one detector (detector
812), it is to be understood that wearable device 800 could include
a plurality of signal sources and/or a plurality of detectors. For
example, wearable device 800 could include first and second signal
sources or first and second detectors, as described below in
relation to FIG. 10.
[0096] FIG. 9 is a simplified block diagram illustrating the
components of a wearable device 900, according to an example
embodiment. Wearable device 900 is the same as wearable device 800
in all respects, except that the data collection system 910 of
wearable device 900 further includes a collection magnet 916. In
this example, the collection magnet 916 may be used to locally
collect functionalized magnetic particles present in an area of
subsurface vasculature proximate to the collection magnet 916. As
described above, collection magnet 916 is configured to direct a
magnetic field into a portion of subsurface vasculature sufficient
to cause functionalized magnetic particles to collect in a lumen of
the portion of subsurface vasculature.
[0097] Wearable device 900 includes a data collection system 910,
which includes a detector 912, a signal source 914 (if provided)
and a collection magnet 916, a user interface 920, a communication
interface 930, a processor 940 and a computer readable medium 960
on which program instructions 970 are stored. All of the components
of wearable device 900 may be provided on a mount 950. In this
example, the program instructions 970 may include a controller
module 962, a calculation and decision module 964 and an alert
module 966 which, similar to the example set forth in FIG. 8,
include instructions to perform or facilitate some or all of the
device functionality described herein. Controller module 962
further includes instructions for operating collection magnet 916.
For example, controller module 962 may include instructions for
activating collection magnet during a measurement period, for a
certain amount of time.
[0098] Although wearable device 900 is shown in FIG. 9 with only
one signal source (signal source 914) and one detector (detector
912), it is to be understood that wearable device 900 could include
a plurality of signal sources and/or a plurality of detectors. For
example, wearable device 900 could include first and second signal
sources or first and second detectors, as described below in
relation to FIG. 10.
IV. ILLUSTRATIVE FUNCTIONALIZED PARTICLES
[0099] In some examples, the wearable devices described above
obtain at least some of the health-related information by detecting
the binding of a clinically-relevant analyte to functionalized
particles, for example, microparticles or nanoparticles. The
particles can be functionalized by covalently attaching a
bioreceptor designed to selectively bind or otherwise recognize a
particular clinically-relevant analyte. For example, particles may
be functionalized with a variety of bioreceptors, including
antibodies, nucleic acids (DNA, siRNA), low molecular weight
ligands (folic acid, thiamine, dimercaptosuccinic acid), peptides
(RGD, LHRD, antigenic peptides, internalization peptides), proteins
(BSA, transferrin, antibodies, lectins, cytokines, fibrinogen,
thrombin), polysaccharides (hyaluronic acid, chitosan, dextran,
oligosaccharides, heparin), polyunsaturated fatty acids (palmitic
acid, phospholipids), plasmids. The functionalized particles can be
introduced into the person's blood stream by injection, ingestion,
inhalation, transdermally, or in some other manner.
[0100] The clinically-relevant analyte could be any analyte that,
when present in or absent from the blood, or present at a
particular concentration or range of concentrations, may be
indicative of a medical condition or indicative that a medical
condition may be imminent. For example, the clinically-relevant
analyte could be an enzyme, hormone, protein, or other molecule. In
one relevant example, certain protein biomarkers are known to be
predictive of an impending arterial plaque rupture. Such protein
biomarkers are known to be present in the blood only directly
leading up to and at the onset of an arterial plaque rupture.
Plaques that rupture cause the formation of blood clots that can
block blood flow or break off and travel to another part of the
body. In either of these cases, if a clot blocks a blood vessel
that feeds the heart, it causes a heart attack. If it blocks a
blood vessel that feeds the brain, it causes a stroke. If blood
supply to the arms or legs is reduced or blocked, it can cause
difficulty walking and eventually gangrene. The presence of these
protein biomarkers in the vasculature may be detected, and the
medical condition (i.e., stroke, heart attack) prevented, by
providing particles functionalized with a bioreceptor that will
selectively bind to this target analyte.
[0101] The particles may be made of biodegradable or
non-biodegradable materials. For example, the particles may be made
of polystyrene. Non-biodegradable particles may be provided with a
removal means to prevent harmful buildup in the body. Generally,
the particles may be designed to have a long half-life so that they
remain in the vasculature or body fluids over several measurement
periods. Depending on the lifetime of the particles, however, the
user of the wearable device may periodically introduce new batches
of functionalized particles into the vasculature or body
fluids.
[0102] Bioreceptors can be used in diagnostic procedures, or even
in therapy to destroy a specific target, such as antitumor therapy
or targeted chemotherapy. The particles may be designed to remove
from the body or destroy the target analyte once bound to the
bioreceptor. Additional functional groups may be added to the
particles to signal that the particles can be removed from the body
through the kidneys, for example, once bound to the target
analyte.
[0103] Further, the particles may be designed to either releasably
or irreversibly bind to the target analyte. For example, if it is
desired for the particles to participate in destruction or removal
of the target analyte from the body, as described above, the
particles may be designed to irreversibly bind to the target
analyte. In other examples, the particles may be designed to
release the target analyte after measurement has been made, either
automatically or in response to an external or internal
stimulus.
[0104] Those of skill in the art will understand the term
"particle" in its broadest sense and that it may take the form of
any fabricated material, a molecule, cryptophan, a virus, a phage,
etc. Further, a particle may be of any shape, for example, spheres,
rods, non-symmetrical shapes, etc., and may be made of a solid,
liquid or gaseous material or combinations thereof. The particles
can have a diameter that is less than about 20 micrometers. In some
embodiments, the particles have a diameter on the order of about 10
nanometers to 1 micrometer. In further embodiments, small particles
on the order of 10-100 nanometers in diameter may be assembled to
form a larger "clusters" or "assemblies on the order of 1-10
micrometers. In this arrangement, the assemblies would provide the
signal strength of a larger particle, but would be deformable,
thereby preventing blockages in smaller vessels and
capillaries.
[0105] Binding of the functionalized particles to a target analyte
may be detected with or without a stimulating signal input. The
term "binding" is understood in its broadest sense to include any
detectable interaction between the receptor and the target analyte.
For example, some particles may be functionalized with compounds or
molecules, such as fluorophores or autofluorescent, luminescent or
chemiluminescent markers, which generate a responsive signal when
the particles bind to the target analyte without the input of a
stimulus. In other examples, the functionalized particles may
produce a different responsive signal in their bound versus unbound
state in response to an external stimulus, such as an
electromagnetic, acoustic, optical, or mechanical energy.
[0106] Further, the particles may be formed from a paramagnetic or
ferromagnetic material or be functionalized with a magnetic moiety.
The magnetic properties of the particles can be exploited in
magnetic resonance detection schemes to enhance detection
sensitivity. In another example, an external magnet may be used to
locally collect the particles in an area of subsurface vasculature
during a measurement period. Such collection may not only increase
the differential velocity between particles and analytes, hence
surveying a much larger volume per unit time, but may also enhance
the signal for subsequent detection.
V. ILLUSTRATIVE METHODS FOR REDUCING NOISE IN A WEARABLE DEVICE
[0107] FIG. 10 is a flowchart of a method 1000 for reducing the
influence of noise when taking non-invasive, in vivo, real-time
measurements of physiological parameters using a wearable device.
Block 1010 includes providing, in a wearable medical diagnostic
device, a first and a second optical signal transmitted from within
a lumen of subsurface vasculature. The first optical signal
includes an unfiltered target signal and a first noise signal and
the second optical signal includes a second noise signal. The first
and second noise signals are correlated and a quotient of the
unfiltered target signal and the first noise signal includes an
unfiltered signal to noise ratio. Block 1020 includes determining a
filtered signal, based at least on the unfiltered target signal,
the first noise signal, and the second noise signal. The filtered
signal includes a filtered target signal and a filtered noise
signal. A quotient of the filtered target signal and the filtered
noise signal includes a filtered signal to noise ratio wherein the
filtered signal to noise ratio is higher than the unfiltered signal
to noise ratio.
[0108] In an illustrative embodiment, the wearable device may be
mounted to a body surface of a human subject, wherein the body
surface is proximate to a portion of subsurface vasculature. The
wearable device, via a signal source, may transmit an interrogating
signal into the portion of subsurface vasculature. In some
examples, a response signal is generated in response to the
interrogating signal. For instance, functionalized particles may be
configured to bind to the clinically-relevant analyte and may
comprise a receptor, such as an antibody. The term "bind" may also
include any detectable interaction between the clinically-relevant
analyte and the functionalized particles.
[0109] The wearable device, via at least one detector, may detect
the response signal transmitted from the portion of subsurface
vasculature, wherein the response signal is related to binding of a
clinically-relevant analyte to functionalized particles present in
a lumen of the subsurface vasculature. Additionally or
alternatively, the response signal may include optical measurements
based on transmission, reflection, or absorbance of light. The
response signal may be considered as the first optical signal and
may include components based on the response signal as well as
noise. In other words, the response signal may be described as
including the unfiltered target signal and the first noise signal.
In some embodiments, the response signal may include the output of
the one or more detectors.
[0110] The second optical signal may be detected via at least one
detector. The second optical signal includes the second noise
signal, which is correlated to the first noise signal. Further, the
second optical signal may, but need not, include other components
related to the response signal. The first and second noise signals
may be correlated if the noise signal components include commonly
correlated noise types such as: external noise pick-up, capacitive
or inductive coupling, ground loops, scanning noise, or power
source noise (e.g. 60 Hz hum). Additionally or alternatively, the
first and second noise signals may be correlated based on their
variance, distribution, and spectral density. In other words, the
first and second noise signals may be correlated if the signals
resemble one another and/or one of the noise signals may be
predicted based on the other. The first and second noise signals
could be positively and/or negatively correlated in one or both of
time and state. Other types of correlated noise are possible and
contemplated herein.
[0111] Noise sources that may contribute to the first and second
noise signals may include, but are not limited to, those associated
with variable optical coupling to skin or tissue, variation in
optical properties of skin or tissue over time due to changes in
humidity, temperature, hydration, variations in optical properties
between individuals, variations in ambient light sources into
detectors, and instrument and detector noise, which may include
electrical noise, radio frequency or magnetic interference noise,
or noise caused by mechanical movement of the detector or its
components. Noise sources may be present both within the wearable
medical diagnostic device as well as external to the device.
[0112] Determining a filtered signal may include various signal
processing, or "denoising", algorithms. Generally, methods
contemplated herein include techniques that separate the target
signal from noise signals. In an illustrative embodiment,
subtraction of a "background" noise signal may be performed. In
other words, the second optical signal may be subtracted from the
first optical signal. In another embodiment, when a detector array
is utilized, demosaicing may be performed based on the correlation
between the first and second noise signals. Alternatively or
additionally, methods herein may include denoising algorithms known
in the art such as the Bayesian Least Squares GSM, Probshrink, or
Non Local Means (NLMS) methods. Other methods operable to separate
a target signal from a noise signal are contemplated within the
scope of this disclosure.
[0113] Upon determining a filtered signal, the wearable device may
then determine the presence, absence and/or a concentration of the
clinically-relevant analyte based on the response signal and
whether a medical condition is indicated based on at least the
presence, absence and/or concentration of the clinically-relevant
analyte. Further, in examples where the functionalized particles
are magnetic, the wearable device may further direct a magnetic
field into the portion of subsurface vasculature, the magnetic
field being sufficient to cause the functionalized magnetic
particles to collect in a lumen of the portion of subsurface
vasculature.
[0114] The wearable medical diagnostic device may carry out Block
1010 and Block 1020 of method 1000 in various ways. For example, in
an effort to separate out noise from the response signal, several
different noise-reduction measurement techniques may be
utilized.
[0115] In an illustrative embodiment, the medical diagnostic device
may include a first detector and a second detector and a source
configured to illuminate an analyte within the lumen. The analyte,
which may include a fluorophore, may be configured to emit emission
light at a known wavelength and/or set of wavelengths upon
illumination by the source. Thus, method 1000 may optionally
include spectrally separating at least a portion of the emission
light into at least a first spectral band and a second spectral
band. For example, the fluorophore may be configured to emit within
the first spectral band while the autofluorescence of the
illuminated tissue may occur within the second spectral band. In
such a scenario, the first optical signal (obtained by the first
detector) may include a portion of the first spectral band and the
second optical signal (obtained by the second detector) may include
a portion of the second spectral band. Spectral separation may be
performed using optical band pass filters or using a grating
spectrometer. Determining the filtered signal may include
subtracting the autofluorescence signal portion from the target
signal portion. Alternatively, a fluorophore need not be used. For
example, the autofluorescence of different tissues may occur within
different wavebands, which may then be spectrally separated using
the above method. As a further alternative, the second spectral
band may be chosen to coincide with the emission spectrum of the
autofluorescence. Other choices are possible for the first and the
second spectral bands.
[0116] In another illustrative embodiment, the wearable diagnostic
device may include a detector and a first and a second source. The
first and second sources may be configured to illuminate the
analyte within the lumen at a first and second wavelength (or
waveband), respectively. In such a scenario, the method 1000 may
optionally include periodically illuminating the analyte with the
first source at a given period and a given duty cycle. Generally,
the duty cycle may be configured to be less than one. The method
1000 may optionally include periodically illuminating the analyte
with the second source for at least a portion of the given period
while the first source is not illuminating the analyte. For
example, the first and second sources may alternate with a 50% duty
cycle. The frequency may range from mHz to tens of kHz. The method
1000 may optionally include detecting the first optical signal with
the detector while the analyte is illuminated by the first source
and detecting the second optical signal with the detector while the
analyte is illuminated by the second source. In some example
embodiments, the first source may be configured to substantially
optically excite the analyte of interest while the second source
may be configured to substantially not optically excite the
analyte. Alternatively, the first and second sources may be
configured to substantially optically excite the analyte to
different respective wavelengths. Further, while a simple
alternating illumination technique is disclosed above, more complex
pulse sequences, such as pulse code modulation schemes, may be used
to optimize duty cycle or to improve the separation of noise from
the signal of interest.
[0117] In yet another illustrative embodiment, the wearable
diagnostic device may include a detector and a source. In such a
scenario, a primary contrast agent and a normalization contrast
agent may be introduced into the lumen. The primary contrast agent
may be configured to fluoresce at a first spectral maximum and the
normalization contrast agent may be configured to fluoresce at a
second spectral maximum. In such an embodiment, the method 1000 may
optionally include illuminating the lumen with the source,
detecting the first optical signal substantially at the first
spectral maximum, and detecting the second optical signal
substantially at the second spectral maximum. A spectrometer may be
used to obtain the spectral information about the emission signal
in response to the source illumination. Additionally or
alternatively, the normalization contrast agent may be configured
to provide a calibration reference for an optical coupling factor
between the detector and the skin surface. For example, a "baseline
spectra" may be obtained after the normalization contrast agent is
introduced into the lumen, but before the primary contrast
introduced into same. The normalization contrast agent may be
introduced into circulation and/or may alternatively be introduced
into the skin as a "tattoo" such that it is substantially immobile
under the detection area. A further marker or probe utilizing the
normalization contrast agent may be introduced to serve as a
calibration guide for techniques that involve, for instance,
adaptive optics or spatially modulated light.
[0118] In a further illustrative embodiment, the lumen may include
a first and a second portion and the wearable medical diagnostic
device may include a source configured to illuminate at least the
first and second portions at a spectral illumination maximum. In
such a scenario, the method 1000 may optionally include
illuminating the first and second portions of the lumen with the
source so as to cause a first portion emission and a second portion
emission. The method 1000 may also include detecting the first
optical signal from the first portion emission (e.g., with a first
detector) and detecting the second optical signal from the second
portion emission (e.g., with a second detector). In other words,
two or more spatially separated detectors may obtain optical
signals from various locations along the lumen. The two or more
spatially separated detectors may include an array of photodiodes
or a multi-element detector. Accordingly, noise may be separated
from the response signal when the noise signal contributions from
the various locations are correlated. Optionally, such a scenario
need only include one detector configured to detect the first
portion emission as distinct from the second portion emission. That
is, the detector may be moved to be proximate to the first and
second portions of the lumen or light from the respective portions
of the lumen may otherwise be distinctly transmitted to the
detector.
[0119] In another illustrative embodiment, the wearable medical
diagnostic device may include a detector wherein illuminating the
first and second portions of the lumen includes illuminating the
first and second portions of the lumen at a first time and a second
time, respectively. In such a scenario, the method 1000 may include
the detector detecting the first optical signal during the first
time and may additionally include the detector detecting the second
optical signal during the second time. Put another way, various
elements of method 1000 may be carried out at different times so as
to determine a filtered signal.
[0120] In yet another illustrative embodiment, the wearable medical
diagnostic device may include a detector and a source. The method
1000 may also include illuminating the lumen with the source,
modulating the first and/or second noise signals, and then
detecting the first and second optical signals with the detector.
Modulating the first and second noise signals may include
modulating the source illumination in a way that need not
substantially change the emission of the analyte of interest. For
example, the source illumination may increase in intensity at a
wavelength or waveband different from a waveband that may induce
emission from an analyte such as a fluorophore. In so doing, the
emission of background tissues, for instance, may be modulated.
Signal processing may be used to subtract or otherwise separate the
noise signals from the signal of interest. Alternatively or
additionally, non-optical methods could be used to modulate the
background noise signal. For example, changing the temperature of
the surrounding tissues may affect emission, absorption, and/or
reflective properties of said tissues. In such a scenario, the
first and second noise signals may be affected or modulated
substantially independent of the signal of interest. In another
example, acoustic modulation of surrounding tissues may change the
emission, absorption, and/or reflective properties of the tissues.
Again, the acoustic modulation of surrounding tissues may affect
the first and second noise signals substantially independent of the
signal of interest. Other ways of modulating the background noise
signals will be evident to those with skill in the art and may
include other optical and non-optical means for changing the
background noise signal substantially independent from the signal
of interest.
[0121] The method 1000 may include other ways of performing
gradiometric measurements. For example, any combination of emission
unmixing or excitation unmixing may be included in the method 1000.
Furthermore, any combination of methods known in the art to provide
background normalization and/or background modulation may be
included in the method 1000.
VI. ILLUSTRATIVE WEARABLE MEDICAL DIAGNOSTIC SYSTEM WITH NOISE
REDUCTION
[0122] FIGS. 11A-11B, 12A-12B, and 13A-13B are partial
cross-sectional side views of a human wrist illustrating the
operation of various examples of a wrist-mounted device. In the
example shown in FIGS. 11A and 11B, the wrist-mounted device 1100
includes a measurement platform 1110 mounted on a strap or
wrist-band 1120 and oriented on the anterior side 1190 of the
wearer's wrist. Measurement platform 1110 is positioned over a
portion of the wrist where subsurface vasculature 1130 is easily
observable. Functionalized particles 1140 have been introduced into
a lumen of the subsurface vasculature by one of the means discussed
above. In this example, measurement platform 1110 includes a data
collection system having both a detector 1150 and a signal source
1160. FIG. 11A illustrates the state of the subsurface vasculature
when measurement device 1100 is inactive. The state of the
subsurface vasculature during a measurement period is illustrated
in FIG. 11B. At this time, signal source 1160 is transmitting an
interrogating signal 1162 into the portion of subsurface
vasculature and detector 1150 is receiving a response signal 1152
generated in response to the interrogating signal 1162. The
response signal 1152 is related to the binding of a
clinically-relevant analyte present in the subsurface vasculature
to the functionalized particles 1140. As described above, in some
embodiments, an interrogating signal may not be necessary to
generate a response signal related to the binding of an analyte to
the functionalized particles.
[0123] Similar to the system depicted in FIGS. 11A and 11B, FIGS.
12A and 12B illustrate a wrist-mounted device 1200 including a
measurement platform 1210 mounted on a strap or wristband 1220 and
oriented on the anterior side 1290 of the wearer's wrist. In this
example, measurement platform 1210 includes a data collection
system having a detector 1250, a signal source 1260 and a
collection magnet 1270. FIG. 12A illustrates the state of the
subsurface vasculature when measurement device 1200 is inactive.
The state of the subsurface vasculature when measurement device
1200 is active during a measurement period is illustrated in FIG.
12B. At this time, collection magnet 1270 generates a magnetic
field 1272 sufficient to cause functionalized magnetic particles
1240 present in a lumen of the subsurface vasculature 1230 to
collection in a region proximal to the magnet 1270. Signal source
1260 transmits an interrogating signal 1262 into the portion of
subsurface vasculature and detector 1250 is receiving a response
signal 1252 generated in response to the interrogating signal 1262.
The response signal 1252 is related to the binding of a clinically
relevant analyte present in the subsurface vasculature to the
functionalized magnetic particles 1240. As described above, in some
embodiments, an interrogating signal may not be necessary to
generate a response signal related to the binding of an analyte to
the functionalized magnetic particles.
[0124] FIGS. 13A and 13B illustrate a further embodiment of a
wrist-mounted device 1300 having a measurement platform 1310
disposed on a strap 1320, wherein the detector 1350 and signal
source 1360 are positioned on the posterior side 1390 of the
wearer's wrist and the collection magnet 1370 is disposed on the
anterior side 1380 of the wearer's wrist. Similar to the
embodiments discussed above, FIG. 13A illustrates the state of the
subsurface vasculature when measurement device 1300 is inactive.
The state of the subsurface vasculature when measurement device
1300 is active during a measurement period is illustrated in FIG.
13B. At this time, collection magnet 1370 generates a magnetic
field 1232 sufficient to cause functionalized magnetic particles
1340 present in a lumen of the subsurface vasculature 1330 to
collection in a region proximal to the magnet 1370. Signal source
1360 transmits an interrogating signal 1362 into the portion of
subsurface vasculature and detector 1350 is receiving a response
signal 1352 generated in response to the interrogating signal 1262.
The response signal 1352 is related to the binding of a clinically
relevant analyte present in the subsurface vasculature to the
functionalized magnetic particles 1340. As described above, in some
embodiments, an interrogating signal may not be necessary to
generate a response signal related to the binding of an analyte to
the functionalized magnetic particles.
[0125] Both FIGS. 12B and 13B illustrate the path of the
interrogating signal (1262, 1362) transmitted by the signal source
(1260, 1360) and the responsive signal (1252, 1352) detected by the
detector (1250, 1350) essentially overlapping over a portion of
subsurface vasculature. In some examples, the signal source (1260,
1360) and the detector (1250, 1350) may be angled towards each
other so that they are interrogating and detecting from essentially
the same area of subsurface vasculature. However, in some
instances, such as in the example shown in FIG. 11B, the paths of
the interrogating signal (1262, 1362) transmitted by the signal
source (1260, 1360) and the responsive signal (1252, 1352) detected
by the detector (1250, 1350) may not overlap.
[0126] The signal-to-noise ratio (SNR) in an analyte detection
system, such as any of those described above, may be increased by
modulating the analyte response signal transmitted from the
subsurface vasculature (or other body system) with respect to the
background signal and, in some cases, an unbound particle response
signal. Such modulation can increase the system's sensitivity and
ability to discern between target analytes present in the blood or
other bodily fluids, versus other analytes, particles, cells,
molecules, blood components, bone and tissues, etc. This can be
particularly valuable with some methods of analyte
characterization, such as optical methods, or where the target
analytes are rare in the blood or are of a relatively small size
and with fluorescence detection techniques, which can often suffer
from low resolution because other tissues, cells, and molecules in
the body may have some inherent fluorescent properties, creating a
high level of background noise.
[0127] FIG. 14 is a functional block diagram of a wearable medical
diagnostic system with noise reduction 1400, according to an
illustrative embodiment. The wearable medical diagnostic system
1400 may include a source 1402, filters 1410 and 1412, a dichroic
beamsplitter 1404, lenses 1406 and 1408, a target location 1420,
and a detector 1450. The source 1402 may be configured to transmit
an interrogating signal 1430 via the dichroic beamsplitter 1404,
and lens 1408 towards the target location 1420. The dichroic
beamsplitter 1404 may be configured to reflect and/or transmit
light based, at least in part, on the wavelength of such light. For
example, the dichroic beamsplitter 1404 may be configured to
reflect the interrogating signal 1430, which may include light at
first wavelength and/or a first waveband, from source 1402 towards
the target location 1420.
[0128] The source 1402 may include a laser, a light-emitting diode
(LED), or another device configured to produce light. The source
1402 may be configured to produce light at or around a particular
wavelength or within a particular waveband. For example, the source
1402 may be configured to emit light at a wavelength known to cause
a given fluorophore to emit light at a second wavelength or second
waveband. The light from source 1402 may be substantially
collimated, such as from a laser. Alternatively, the light from
source 1402 may be collected and collimated and/or focused so as to
illuminate target location 1420. The source 1402 may be configured
to provide continuous illumination. Alternatively, source 1402 may
provide pulsed or otherwise intermittent light. In an illustrative
embodiment source 1402 may include a LED that provides light
substantially in the infrared spectral band. Source 1402 may
additionally be configured to provide illumination at more than one
wavelength or over more than one waveband. Yet further, source 1402
may represent more than one light source. For example, source 1402
may be an array of light emitters or may include at least two light
sources at spatially-separated locations. In other words, although
FIG. 14 depicts one source 1402 and one associated optical path
(e.g. illustrated by interrogation signal 1430), multiple sources
and/or multiple optical paths could be utilized within the scope of
the present disclosure.
[0129] In one example, multiple sources 1402 may be configured to
spatially modulate the analyte response signal. For example, a
spatial modulation may exploit the speed, rotation, size,
thermodynamic properties, hydrodynamic properties, etc. of the
bound particles, versus unbound particles and other items that are
not of interest, travelling near the target location 1440 to
distinguish the analyte response signal. For example, an
analyte-bound particle is going to have a different size and shape
than an unbound particle and, therefore, may travel through the
subsurface vasculature a different speed, thereby modulating
between bound and unbound particles. In one example, analyte-bound
magnetic particles may travel through the subsurface vasculature at
a different speed when subject to a magnetic field than unbound
magnetic particles. The multiple sources 1402 may be used to
exploit this difference in speed to differentiate the analyte
response signal from other signals transmitted from the body.
[0130] In an illustrative embodiment, a first source and a second
source may be configured to illuminate the target location 1420,
which may include the location of a target analyte. The first
source may be configured to provide light substantially at a first
wavelength and the second source may be configured to provide light
substantially at a second wavelength. Furthermore, the first source
may periodically illuminate the target location 1420 at a given
period and a given duty cycle. The second source may periodically
illuminate the target location 1420 while the first source is not
illuminating the target location 1420. In such a scenario, the
detector 1450 may detect the unfiltered target signal and the first
noise signal while the target location 1420 is illuminated by the
first source. Additionally, the detector 1450 may detect the second
noise signal while the target location 1420 is illuminated by the
second source.
[0131] The target location 1420 may include a lumen of the
subsurface vasculature as described herein, for example with
reference to FIGS. 11A&B. The target location 1420 may
alternatively or additionally include other locations or
structures, such as a skin surface, a bone, a blood vessel, a
muscle, and/or another part of a body. The target location 1420 may
alternatively represent blood, another bodily fluid, or another
medium in which analytes of interest may be detected.
[0132] When light is emitted or reflected from the target location
1420, a response signal 1440 may be collected by the wearable
medical diagnostic system 1400. In an illustrative embodiment, the
response signal 1440 may be collected with lens 1408. The dichroic
beamsplitter 1404 may be configured to substantially transmit the
response signal 1440, which may include a second wavelength and/or
a second waveband. In such a scenario, the emitted light may pass
substantially through the dichroic beamsplitter 1404 towards the
detector 1450. Specifically, the response signal 1440 may pass
through emission filter 1410 and may be focused by lens 1406 onto
the detector 1450.
[0133] Detector 1450 may be configured to sense light at various
wavelengths or within various wavebands. For example, detector 1450
may be configured to sense infrared light, visible light,
ultraviolet light, and/or any other wavelength or waveband of
light.
[0134] Filters 1410 and 1412 may be spectral filters configured to
block, attenuate, and/or transmit various wavelengths and/or
wavebands of light. The filters could be, for example, gratings or
prisms. Other types of filters are possible as well.
[0135] Although lens 1408 is depicted as focusing the interrogating
signal 1430 onto the target location 1420, lens 1408 may affect the
interrogating signal 1430 in other ways. For example, lens 1408 may
represent a collimating lens. In such a scenario, the collimating
lens may be used so as to direct a collimated optical beam towards
the target location 1420. Alternatively or additionally, the lens
1408 may represent a spatial light modulator. In such a scenario,
the spatial light modulator may be utilized to direct light towards
various spatial locations near the target location 1420.
Alternatively, the spatial light modulator may be used to modulate
or block various portions of the interrogating signal 1430 and/or
modulate or block the entire interrogating signal 1430.
Furthermore, lens 1408 may represent more than one optical lens.
For example, instead of using lens 1408 as a focusing and
collection optic, two or more lenses could be utilized to achieve
one or more of focusing the interrogating signal 1430 and
collecting the response signal 1440. Other optical elements or
combinations thereof may be used in place of lens 1408.
[0136] Similarly, other optical elements or combinations thereof
may be used in place of lens 1406. For example, lens 1406 may
represent a spatial light modulator, a collimating lens, a focusing
mirror, a plane mirror, or another optical element.
[0137] Dichroic beamsplitter 1404 may represent various optical
components configured to reflect and/or transmit light based, in
part, on the wavelength of the incoming light. In an illustrative
embodiment, the dichroic beamsplitter may include a surface 1403
configured to reflect and/or transmit light based on its
wavelength. Alternatively, dichroic beamsplitter 1404 may represent
a prism or a grating, such as those used in a grating
spectrometer.
[0138] FIG. 15 is a functional block diagram of a wearable medical
diagnostic system with noise reduction 1500, according to an
illustrative embodiment. Wearable medical diagnostic system 1500
may include a source 1502, filters 1510, 1512, and 1514, lenses
1506, 1508, and 1516, detectors 1550 and 1552, as well as dichroic
beamsplitters 1504 and 1505. In an illustrative embodiment,
interrogating signal 1530 may be emitted from source 1502. The
interrogating signal 1530 may be directed towards a target location
1520 via dichroic beamsplitter 1504 and 1508. The interrogating
signal may interact with analytes near the target location 1520.
The analytes and/or bound particles may emit light that may be
collected as a response signal 1540. The response signal 1540 may
be directed towards dichroic beamsplitter 1505 via lens 1508 and
dichroic beamsplitter 1504. Dichroic beamsplitter 1505 may reflect
and/or transmit a portion of the response signal 1540 towards
detector 1550 or detector 1552. For example, dichroic beamsplitter
1505 may be configured to reflect a first portion of response
signal 1560 towards detector 1552 based, at least in part, on the
wavelength or waveband of the first portion of response signal
1560. Additionally or alternatively, dichroic beamsplitter 1552 may
be configured to transmit a second portion of response signal 1570
towards detector 1550 based, at least in part, on the wavelength or
waveband of the second portion of response signal 1570.
[0139] In another illustrative embodiment, dichroic beamsplitter
1552 may represent a flip mirror or another optical element
configured to steer or direct at least a portion of the response
signal 1540 towards detector 1550 and/or detector 1552. Similar to
system 1400, the optical components depicted in system 1500 may be
substituted with one or more other known optical components.
[0140] One with skill in the art will recognize that various
configurations of the wearable medical diagnostic systems 1400 and
1500 are contemplated within the scope of this disclosure. The
depicted configurations are not meant to limit the numerous
different optical configurations that may be used to carry out the
methods disclosed herein.
[0141] The wearable medical diagnostic devices 1400 and 1500 may
additionally include a computing device (not shown) configured to
determine a filtered signal, based at least on the response signal
1440 and 1540, which may include an unfiltered target signal, a
first noise signal, and a second noise signal. The first and second
noise signals may be correlated and a quotient of the unfiltered
target signal and the first noise signal may include an unfiltered
signal to noise ratio. The filtered signal may include a filtered
target signal and a filtered noise signal. The computing device may
be configured to provide a quotient of the filtered signal and the
filtered noise signal. The quotient of the filtered signal and the
filtered noise signal may represent a filtered signal to noise
ratio. The filtered signal to noise ratio may be higher than an
unfiltered signal to noise ratio. In reference to FIG. 10, the
wearable medical diagnostic devices 1400 and 1500 may be configured
so as to carry out method 1000 and each of the illustrative
embodiments disclosed herein.
[0142] The first and second signal may include any signal
transmitted from something other than what the systems 1400 and
1500 are monitoring, i.e., the target analyte(s). In some examples,
the background signal may be generated by other molecules, cells,
or particles in the blood or other bodily fluids; tissue, such as
skin, veins, muscle, etc.; bone; or other objects present in the
wearer's body. A background signal may be generated by excitation
of these objects from the interrogating signal, such as by
generating an autofluorescence signal, or due to some inherent
property of these objects, such as, chemiluminescence, etc.
[0143] In an illustrative embodiment, the computing device may be
configured to spectrally separate emission light (e.g. response
signal 1540) into a first spectral band and a second spectral band.
For example, a first detector (e.g. detector 1550) may be
configured to detect light within the first spectral band. In such
a scenario, a second detector (e.g. detector 1552) may be
configured to detect light within the second spectral band.
[0144] In another illustrative embodiment, a lumen may include a
primary contrast agent configured to fluoresce at a first spectral
maximum. The lumen may additionally include a normalization
contrast agent configured to fluoresce at a second spectral
maximum. In such a scenario, the computing device may be further
configured to receive, via the detector, the unfiltered target
signal and the first noise signal at the first spectral maximum.
Additionally, the computing device may be further configured to
receive, via the detector, the second noise signal at the second
spectral maximum.
[0145] In yet another illustrative embodiment, the system may be
configured to illuminate a first portion and a second portion of
the lumen (e.g. designating and illuminating multiple target
locations 1540). In such a scenario, illumination may produce first
portion emission and second portion emission. Thus, the detector
may detect the unfiltered target signal and the first noise signal
from the first portion emission. The detector may also detect the
second noise signal from the second portion emission.
VII. ILLUSTRATIVE NON-TRANSITIVE COMPUTER READABLE MEDIUM
[0146] Some or all of the functions described above and illustrated
in FIG. 10 may be performed by a computing device in response to
the execution of instructions stored in a non-transitory computer
readable medium. The non-transitory computer readable medium may
be, for example, a random access memory (RAM), a read-only memory
(ROM), a flash memory, a cache memory, one or more magnetically
encoded discs, one or more optically encoded discs, or any other
form of non-transitory data storage. The non-transitory computer
readable medium may also be distributed among multiple data storage
elements, which may be remotely located from each other. The
computing device that executes the stored instructions may include
the processor 940 as described and illustrated in FIG. 9.
Additionally or alternatively, the computing device may include
another computing device, such as a server in a server network.
[0147] The non-transitory computer readable medium may store
instructions executable by a computing device (e.g. processor 940
as described in reference to FIG. 9) to cause the computing device
to perform any of the functions described herein.
[0148] In one example, the functions include receiving, in a
wearable medical diagnostic device, a first and a second optical
signal transmitted from within a lumen of subsurface vasculature.
The first optical signal includes an unfiltered target signal and a
first noise signal. The second optical signal includes a second
noise signal. The first and second noise signals are correlated.
The quotient of the unfiltered target signal and the first noise
signal includes an unfiltered signal to noise ratio. The functions
further include determining a filtered signal, based at least on
the unfiltered target signal, the first noise signal, and the
second noise signal. The filtered signal includes a filtered target
signal and a filtered noise signal. A quotient of the filtered
target signal and the filtered noise signal includes a filtered
signal to noise ratio in which the filtered signal to noise ratio
is higher than the unfiltered signal to noise ratio.
VIII. CONCLUSION
[0149] Where example embodiments involve information related to a
person or a device of a person, some embodiments may include
privacy controls. Such privacy controls may include, at least,
anonymization of device identifiers, transparency and user
controls, including functionality that would enable users to modify
or delete information relating to the user's use of a product.
[0150] Further, in situations where embodiments discussed herein
collect personal information about users, or may make use of
personal information, the users may be provided with an opportunity
to control whether programs or features collect user information
(e.g., information about a user's medical history, social network,
social actions or activities, profession, a user's preferences, or
a user's current location), or to control whether and/or how to
receive content from the content server that may be more relevant
to the user. In addition, certain data may be treated in one or
more ways before it is stored or used, so that personally
identifiable information is removed. For example, a user's identity
may be treated so that no personally identifiable information can
be determined for the user, or a user's geographic location may be
generalized where location information is obtained (such as to a
city, ZIP code, or state level), so that a particular location of a
user cannot be determined. Thus, the user may have control over how
information is collected about the user and used by a content
server.
[0151] The particular arrangements shown in the Figures should not
be viewed as limiting. It should be understood that other
embodiments may include more or less of each element shown in a
given Figure. Further, some of the illustrated elements may be
combined or omitted. Yet further, an illustrative embodiment may
include elements that are not illustrated in the Figures.
[0152] While various aspects and embodiments have been disclosed
herein, other aspects and embodiments will be apparent to those
skilled in the art. The various aspects and embodiments disclosed
herein are for purposes of illustration and are not intended to be
limiting, with the true scope being indicated by the following
claims.
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