U.S. patent application number 14/527923 was filed with the patent office on 2015-03-26 for techniques and devices associated with blood sampling.
This patent application is currently assigned to Seventh Sense Biosystems, Inc.. The applicant listed for this patent is Seventh Sense Biosystems, Inc.. Invention is credited to Howard Bernstein, Donald E. Chickering, III, Shawn Davis, Ramin Haghgooie, Douglas A. Levinson, Mark Michelman.
Application Number | 20150087944 14/527923 |
Document ID | / |
Family ID | 42145016 |
Filed Date | 2015-03-26 |
United States Patent
Application |
20150087944 |
Kind Code |
A1 |
Levinson; Douglas A. ; et
al. |
March 26, 2015 |
TECHNIQUES AND DEVICES ASSOCIATED WITH BLOOD SAMPLING
Abstract
The present invention generally relates to devices and
techniques associated with diagnostics, therapies, and other
applications, including skin-associated applications, for example,
devices for delivering and/or withdrawing fluid from subjects,
e.g., through the skin. In some embodiments, the device includes a
system for accessing an extractable medium from and/or through the
skin of the subject at an access site, and a pressure regulator
supported by a support structure, able to create a pressure
differential across the skin at at least a portion of the access
site. The device may also include, in some cases, a sensor
supported by the support structure for determining at least one
condition of the extractable medium from the subject, and
optionally a signal generator supported by the support structure
for generating a signal relating to the condition of the medium
determined by the sensor.
Inventors: |
Levinson; Douglas A.;
(Sherborn, MA) ; Bernstein; Howard; (Cambridge,
MA) ; Chickering, III; Donald E.; (Framingham,
MA) ; Davis; Shawn; (Boston, MA) ; Haghgooie;
Ramin; (Arlington, MA) ; Michelman; Mark;
(Reading, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Seventh Sense Biosystems, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Seventh Sense Biosystems,
Inc.
Cambridge
MA
|
Family ID: |
42145016 |
Appl. No.: |
14/527923 |
Filed: |
October 30, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12716226 |
Mar 2, 2010 |
|
|
|
14527923 |
|
|
|
|
61294543 |
Jan 13, 2010 |
|
|
|
61257731 |
Nov 3, 2009 |
|
|
|
61269436 |
Jun 24, 2009 |
|
|
|
61163710 |
Mar 26, 2009 |
|
|
|
61156632 |
Mar 2, 2009 |
|
|
|
Current U.S.
Class: |
600/365 ;
600/309; 600/578 |
Current CPC
Class: |
A61B 5/15125 20130101;
A61B 5/486 20130101; A61B 5/411 20130101; A61B 5/685 20130101; A61B
5/14865 20130101; A61B 5/150022 20130101; A61B 5/150503 20130101;
A61B 5/0013 20130101; A61B 5/4839 20130101; A61B 5/0022 20130101;
A61B 5/1438 20130101; A61B 5/150969 20130101; A61B 5/150389
20130101; A61B 5/150442 20130101; A61B 5/1459 20130101; A61B 5/0077
20130101; A61B 5/150099 20130101; A61B 5/14532 20130101; A61B
5/150221 20130101; A61B 5/150984 20130101; A61B 5/150358 20130101;
A61B 5/6898 20130101; A61B 5/4845 20130101; A61B 5/150412 20130101;
A61B 5/157 20130101; A61B 5/743 20130101; A61B 5/151 20130101; A61B
5/14546 20130101; A61B 5/14539 20130101 |
Class at
Publication: |
600/365 ;
600/578; 600/309 |
International
Class: |
A61B 5/15 20060101
A61B005/15; A61B 5/00 20060101 A61B005/00; A61B 5/145 20060101
A61B005/145; A61B 5/157 20060101 A61B005/157 |
Claims
1-26. (canceled)
27. A method, comprising: receiving fluid from a subject in a
device applied to the skin of the subject, the device comprising a
microneedle and a vacuum chamber having an internal pressure less
than atmospheric pressure before the device is applied to the skin
of the subject, wherein the device is configured to produce a
display based on the fluid received into the device; and acquiring
an image of the display using a cell phone.
28. The method of claim 27, further comprising determining an
analyte within the fluid received into the device, wherein the
display is based on the analyte.
29. The method of claim 28, wherein the display is a color
display.
30. The method of claim 29, wherein the color of the display is
based on the analyte.
31. The method of claim 28, wherein the analyte comprises
glucose.
32. The method of claim 27, wherein the display can be analyzed
quantitatively.
33. The method of claim 27, comprising acquiring the image of the
display using a camera in the cell phone.
34. The method of claim 27, further comprising transmitting the
image of the display to an external entity.
35. The method of claim 34, wherein the external entity sends a
message regarding the analyte to the cell phone.
36-46. (canceled)
47. The method of claim 35, wherein the message comprises a
prescription.
48. The method of claim 35, wherein the message causes the device
to dispense a pharmaceutical to the subject.
49. A device, comprising: one or more microneedles; a vacuum
chamber having an internal pressure less than atmospheric pressure
before the device is applied to the skin of the subject, wherein
the vacuum chamber is configured to withdraw fluid from the subject
into the device after application of the one or more microneedles
to the subject; a sensor configured to sense the fluid withdrawn
into the device; a display configured to display a signal based on
sensing of the withdrawn fluid by the sensor; and a cell phone
configured to image the display.
50. The device of claim 49, wherein the sensor is configured to
sense an analyte within the fluid withdrawn from the subject.
51. The device of claim 50, wherein the display displays a signal
based on the analyte.
52. The device of claim 51, wherein the signal is quantitatively
related to the analyte.
53. The device of claim 50, wherein the analyte comprises
glucose.
54. The device of claim 49, wherein the display is a color
display.
55. The device of claim 49, wherein the cell phone is configured to
acquire an image of the display via a camera.
56. The device of claim 49, wherein the cell phone is configured to
transmit the image of the display to an external entity.
57. The device of claim 49, wherein the device further comprises a
storage chamber, separate from the vacuum chamber, for receiving
the fluid from the subject.
58. The device of claim 49, wherein the fluid comprises blood.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/163,710, filed Mar. 26, 2009,
entitled "Systems and Methods for Creating and Using Suction
Blisters or Other Pooled Regions of Fluid within the Skin," by
Levinson, et al.; U.S. Provisional Patent Application Ser. No.
61/156,632, filed Mar. 2, 2009, entitled "Oxygen Sensor," by
Levinson, et al.; U.S. Provisional Patent Application Ser. No.
61/269,436, filed Jun. 24, 2009, entitled "Devices and Techniques
associated with Diagnostics, Therapies, and Other Applications,
Including Skin-Associated Applications," by Levinson, et al.; U.S.
Provisional Patent Application Ser. No. 61/257,731, filed Nov. 3,
2009, entitled "Devices and Techniques associated with Diagnostics,
Therapies, and Other Applications, Including Skin-Associated
Applications," by Bernstein, et al.; and U.S. Provisional Patent
Application Ser. No. 61/294,543, filed Jan. 13, 2010, entitled
"Blood Sampling Device and Method," by Levinson, et al. Each of the
above is incorporated herein by reference.
FIELD OF INVENTION
[0002] The present invention generally relates to interstitial and
other bodily fluids for use in analyzing a condition of a subject
or treating a subject. The present invention also relates to
systems and methods for delivering and/or withdrawing fluid from
subjects, e.g., through the skin.
BACKGROUND
[0003] A variety of techniques and methods exist for sensing and
responding to conditions to which a subject is exposed, including
sensing of physiological conditions of a mammal and/or a
surrounding environment. Other techniques exist for delivering
and/or withdrawing a fluid from a mammal, such as blood. While many
such techniques are suitable for various purposes, techniques that
have one or more features such as added simplicity and flexibility
of use would be advantageous.
SUMMARY OF THE INVENTION
[0004] The present invention, in some aspects, generally relates to
interstitial and other bodily fluids (e.g., blood) for use in
analyzing a condition of a subject or treating a subject. In some
cases, the present invention also relates to systems and methods
for delivering and/or withdrawing fluid from subjects, e.g.,
through the skin. The subject matter of the present invention
involves, in some cases, interrelated products, alternative
solutions to a particular problem, and/or a plurality of different
uses of one or more systems and/or articles.
[0005] The present invention is directed to a device for analysis
of an extractable medium from a subject in one aspect. In one set
of embodiments, the device includes a support structure, means
associated with the support structure for accessing the extractable
medium from and/or through the skin of the subject at an access
site, and a pressure regulator supported by the support structure,
able to create a pressure differential across the skin at at least
a portion of the access site. In some cases, the device may also
include a sensor supported by the support structure, for
determining at least one condition of the extractable medium from
the subject, and optionally a signal generator supported by the
support structure, for generating a signal relating to the
condition of the medium determined by the sensor. In some
embodiments, the support structure is constructed and arranged to
be positioned proximate the skin of the subject.
[0006] In another set of embodiments, the device includes a support
structure constructed and arranged to be positioned proximate the
skin of the subject, a fluid transporter for accessing the
extractable medium from and/or through the skin of the subject at
an access site, a pressure regulator supported by the support
structure, able to create a pressure differential across the skin
at at least a portion of the access site, a sensor supported by the
support structure for determining at least one condition of the
extractable medium from the subject, and a signal generator
supported by the support structure for generating a signal relating
to the condition of the medium determined by the sensor.
[0007] The device, according to yet another set of embodiments,
includes means for accessing the extractable medium from and/or
through the skin of the subject at an access site, a pressure
regulator able to create a pressure differential across the skin at
at least a portion of the access site, a sensor for determining at
least one condition of the extractable medium from the subject, and
a signal generator for generating a signal relating to the
condition of the medium determined by the sensor.
[0008] In another set of embodiments, the device includes means for
accessing the extractable medium from skin and/or from beneath the
skin of the subject at an access site, a pressure differential
chamber able to create a pressure differential across the skin in
at least a portion of the access site in the absence of a piston
pump associated with the chamber, a sensor for determining at least
one condition of the extractable medium from the subject, and a
signal generator for generating a signal relating to the condition
of the medium determined by the sensor.
[0009] The invention, in another aspect, is generally directed to a
device. According to one set of embodiments, the device can be
applied or is applicable to the skin for determining an analyte in
a subject. The device, in one embodiment, includes a first portion
able to create a pooled region of fluid within the skin of a
subject, and a second portion able to determine fluid of the pooled
region of fluid. In another set of embodiments, the device includes
a first portion able to create a pooled region of fluid within the
skin of a subject, and a microfluidic channel in fluidic
communication with the first portion.
[0010] The device, in yet another set of embodiments, is applicable
to a site proximate the skin of a subject. In some cases, the
device is able to determine a physical condition of a subject and
produces a signal related to the condition. In one embodiment, the
signal is not readily understandable by the subject.
[0011] The device, in yet another set of embodiments, is a device
applicable to a site proximate the skin of a subject. In some
embodiments, the device is able to determine a physical condition
of the subject. In one embodiment, the device comprises an agent
that reacts or interacts with an analyte to be detected and
generates a signal that can be detected visually, by feel, by
smell, or by taste. In some cases, the agent that reacts with or
interacts with an analyte and the signaling agent can be the same
or different. In certain cases, the signal can vary as a function
of an attribute of the analyte, producing a signal that can be
analyzed qualitatively. In some instances, the device acquires
fluid from the subject and transports the fluid from a site of
acquisition to a site of analysis for reaction.
[0012] In some cases, the device includes a first component and a
second component connected to the first component for application
to the site and separable from the first component after
application to the site. In some instances, the first component can
be activated to acquire a bodily fluid of the subject, and the
second component comprises an agent that reacts or interacts with
an analyte to be detected and generates a signal that can be
detected visually, by feel, by smell, or by taste.
[0013] The device, in accordance with another set of embodiments,
includes an agent that reacts or interacts with an analyte in
saliva of the subject to generate a signal.
[0014] In still another set of embodiments, the device comprises an
agent that reacts or interacts with an analyte to be detected to
generate a signal that can be detected visually, by feel, by smell,
or by taste. In some cases, the device comprises a membrane
comprising the agent that participates in generation of the signal.
The membrane, in some embodiments, may be selective to one or more
of passage of an analyte and/or an analyte indicator, and reaction
with an analyte and/or an analyte indicator.
[0015] According to still another set of embodiments, the device is
a device for withdrawing blood from the skin and/or from beneath
the skin of a subject. In some embodiments, the device comprises a
fluid transporter, a vacuum chamber having an internal pressure
less than atmospheric pressure before blood is withdrawn into the
device, and a storage chamber, separate from the vacuum chamber,
for receiving blood withdrawn from the subject through the fluid
transporter when a negative pressure is applied to the skin of the
subject. The device, in certain embodiments, includes at least 6
microneedles, and a storage chamber for receiving blood withdrawn
from the subject, the storage chamber having an internal pressure
less than atmospheric pressure prior to receiving blood.
[0016] The device, in some embodiments, includes a fluid
transporter, a first storage chamber for receiving blood withdrawn
from the subject through the fluid transporter, the storage chamber
having an internal pressure less than atmospheric pressure prior to
receiving blood, and a reaction entity contained within the first
storage chamber able to react with an analyte contained within the
blood. In some instances, a product of the reaction entity with the
analyte is determinable. According to still other embodiments, the
device includes a fluid transporter, a storage chamber for
receiving blood withdrawn from the subject through the fluid
transporter, and a potassium sensor able to determine potassium
ions within blood contained within the device. In some cases, the
storage chamber has an internal pressure less than atmospheric
pressure prior to receiving blood.
[0017] In yet another set of embodiments, the device includes a
fluid transporter, a storage chamber for receiving blood withdrawn
from the subject through the fluid transporter, and a flow
controller able to control blood flow into the storage chamber. In
some cases, the storage chamber has an internal pressure less than
atmospheric pressure prior to receiving blood.
[0018] In another aspect, the present invention is directed to a
method. The method, in one set of embodiments, includes acts of
causing formation of a pooled region of fluid between the dermis
and epidermis of the skin of a subject, and delivering an agent
into the pooled region of fluid for indication of a past, present
and/or future condition of the subject. The method, according to
another set of embodiments, includes acts of causing formation of a
pooled region of fluid between the dermis and epidermis of the skin
of a subject, removing at least a portion of the fluid from the
pooled region, and analyzing at least a portion of the removed
fluid thereby determining a past, present and/or future condition
of the subject by exposing the fluid to an agent.
[0019] The method, according to another set of embodiments,
includes acts of providing a device at a site proximate the skin of
a subject, acquiring a representation of the signal, and
transporting the representation of the signal to an entity that
analyzes the representation. In some cases, the device can
determine a physical condition of a subject and produces a signal
related to the condition. In yet another set of embodiments, the
method includes an act of applying, proximate the skin of a subject
in need of emergency care, a device comprising a reactive agent
that reacts or interacts with an analyte to generate a signal
indicative of a condition of the subject. The method, in still
another set of embodiments, includes an act of applying, to a
solution containing a plurality of first particles of a first color
and a plurality of second particles of a second color, an electric
field and/or a magnetic field sufficient to cause a change in color
of the solution. According to yet another set of embodiments, the
method includes an act of determining a characteristic of a sample
by visualizing a color change effected by a change in population of
particles of different color upon preferential binding of particles
of one color to a component of the sample via a binding
partner.
[0020] The method, in one set of embodiments, includes acts of
exposing, to a sample, a population of particles including at least
a first sub-population having a first determinable characteristic
and a second sub-population having a second determinable
characteristic, allowing at least some particles of the first
sub-population of particles to bind a component of the sample via a
binding partner, separating the particles bound to the component
from those not bound, and determining a characteristic of the
sample by determining the separation. In some embodiments, the
second sub-population of particles remains essentially unbound to
the component, such that the ratio of the number of particles from
the first sub-population bound to the component, to the number of
particles from the second sub-population bound to the component, is
at least 5:1.
[0021] In another set of embodiments, the method includes an act of
providing a plurality of analysis sites proximate the skin of a
subject, including at least a first analysis site that generates a
first signal related to a first physical condition of the subject
and a second analysis site that generates a second signal related
to a second physical condition of the subject. The method, in
accordance with still another set of embodiments, includes an act
of providing a reaction site proximate the skin of a subject
comprising a reactive agent that reacts or interacts with an
analyte to generate an signal in the form of an icon.
[0022] In yet another set of embodiments, the method is a method
for analyzing an extractable medium from a subject. In some
embodiments, the method includes acts of positioning an analysis
device comprising a pathway adjacent the skin of the subject and,
while the device is adjacent the skin, activating an access
component of the device to connect the extractable medium with the
pathway of the device, activating a pressure controller of the
device to urge the extractable medium into the device via the
pathway, exposing the medium to a sensor of the device and
determining at least one condition of the extractable medium from
the subject, and generating a signal relating to the condition of
the medium determined by the sensor.
[0023] In another aspect, the present invention is directed to a
method of making one or more of the embodiments described herein.
In another aspect, the present invention is directed to a method of
using one or more of the embodiments described herein.
[0024] Other advantages and novel features of the present invention
will become apparent from the following detailed description of
various non-limiting embodiments of the invention when considered
in conjunction with the accompanying figures. In cases where the
present specification and a document incorporated by reference
include conflicting and/or inconsistent disclosure, the present
specification shall control. If two or more documents incorporated
by reference include conflicting and/or inconsistent disclosure
with respect to each other, then the document having the later
effective date shall control.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Non-limiting embodiments of the present invention will be
described by way of example with reference to the accompanying
figures, which are schematic and are not intended to be drawn to
scale. In the figures, each identical or nearly identical component
illustrated is typically represented by a single numeral. For
purposes of clarity, not every component is labeled in every
figure, nor is every component of each embodiment of the invention
shown where illustration is not necessary to allow those of
ordinary skill in the art to understand the invention. In the
figures:
[0026] FIGS. 1A-1E schematically illustrate various systems and
methods for creating pooled regions of fluid in the skin, according
to certain embodiments of the invention;
[0027] FIGS. 2A-2C illustrate various devices useful for creating
pooled regions of fluid in the skin, in some embodiments;
[0028] FIGS. 3A-3C illustrate an example of one embodiment of the
invention useful for puncturing and creating a pooled region of the
skin;
[0029] FIGS. 4A-4B illustrate additional examples of various
devices of the invention;
[0030] FIG. 5 illustrates a check valve according to one embodiment
of the invention;
[0031] FIG. 6 illustrates certain non-circular interfaces, in
accordance with another embodiment of the invention;
[0032] FIG. 7 illustrates another embodiment of the invention
useful for creating a pooled region of the skin;
[0033] FIGS. 8A-8B illustrates top and side views, respectively, of
a pre-loaded vacuum chamber, in another embodiment of the
invention;
[0034] FIGS. 8C-8E illustrate a device containing a compressed
foam, in yet another embodiment of the invention;
[0035] FIG. 9A-9B illustrate devices according to certain
embodiments of the invention;
[0036] FIGS. 10A-10B illustrate devices according to various
embodiments of the invention;
[0037] FIG. 11A illustrates a device according to still another
embodiment of the invention;
[0038] FIG. 11B illustrates a kit containing more than one device,
in yet another embodiment of the invention; and
[0039] FIG. 11C illustrates a device according to still another
embodiment of the invention.
DETAILED DESCRIPTION
[0040] The present invention generally relates to devices and
techniques associated with diagnostics, therapies, and other
applications, including skin-associated applications, for example,
devices for delivering and/or withdrawing fluid from subjects,
e.g., through the skin. In some embodiments, the device includes a
system for accessing an extractable medium from and/or through the
skin of the subject at an access site, and a pressure regulator
supported by a support structure, able to create a pressure
differential across the skin at at least a portion of the access
site. The device may also include, in some cases, a sensor
supported by the support structure for determining at least one
condition of the extractable medium from the subject, and
optionally a signal generator supported by the support structure
for generating a signal relating to the condition of the medium
determined by the sensor.
[0041] Non-limiting examples of various devices of the invention
are shown in FIG. 9. In FIG. 9A, device 290 is used for withdrawing
a fluid from a subject when the device is placed on the skin of a
subject. Device 290 includes sensor 295 and fluid transporter 292,
e.g., a needle, a microneedle, etc., as discussed herein. In
fluidic communication with fluid transporter 292 via fluidic
channel 299 is sensing chamber 297. In one embodiment, sensing
chamber 297 may contain agents such as particles, enzymes, dyes,
etc., for analyzing bodily fluids, such as interstitial fluid or
blood. In some cases, fluid may be withdrawn using fluid
transporter 292 by a vacuum, for example, a self-contained vacuum
contained within device 290. Optionally, device 290 also contains a
display 294 and associated electronics 293, batteries or other
power supplies, etc., which may be used to display sensor readings
obtained via sensor 295. In addition, device 290 may also
optionally contain memory 298, transmitters for transmitting a
signal indicative of sensor 295 to a receiver, etc.
[0042] As used herein, "fluid transporter" is any component or
combination of components that facilitates movement of a fluid from
one portion of the device to another. For example, at or near the
skin, a fluid transporter can be a hollow needle when a hollow
needle is used or, if a solid needle is used, then if fluid
migrates along the needle due to surface forces (e.g., capillary
action), then the solid needle can be a fluid transporter. If fluid
(e.g. blood or interstitial fluid) partially or fully fills an
enclosure surrounding a needle after puncture of skin (whether the
needle is or is not withdrawn from the skin after puncture), then
the enclosure can define a fluid transporter. Other components
including partially or fully enclosed channels, microfluidic
channels, tubes, wicking members, vacuum containers, etc. can be
fluid transporters
[0043] In the example shown in FIG. 9A, device 290 may contain a
vacuum source (not shown) that is self-contained within device 290,
although in other embodiments, the vacuum source may be external to
device 290. (In still other instances, other systems may be used to
deliver and/or withdraw fluid from the skin, as is discussed
herein.) In one embodiment, after being placed on the skin of a
subject, the skin may be drawn upward into a recess containing
fluid transporter 292, for example, upon exposure to the vacuum
source. Access to the vacuum source may be controlled by any
suitable method, e.g., by piercing a seal or a septum; by opening a
valve or moving a gate, etc. For instance, upon activation of
device 290, e.g., by the subject, remotely, automatically, etc.,
the vacuum source may be put into fluidic communication with the
recess such that skin is drawn into the recess containing fluid
transporter 292 due to the vacuum. Skin drawn into the recess may
come into contact with fluid transporter 292 (e.g., solid or hollow
needles), which may, in some cases, pierce the skin and allow a
fluid to be delivered and/or withdrawn from the skin. In another
embodiment, fluid transporter 292 may be actuated and moved
downward to come into contact with the skin, and optionally
retracted after use.
[0044] Another non-limiting example of a device is shown in FIG.
9B. This figure illustrates a device useful for delivering a fluid
to the subject. Device 290 in this figure includes fluid
transporter 292, e.g., a needle, a microneedle, etc., as discussed
herein. In fluidic communication with fluid transporter 292 via
fluidic channel 299 is chamber 297, which may contain a drug or
other agent to be delivered to the subject. In some cases, fluid
may be delivered with a pressure controller, and/or withdrawn using
fluid transporter 292 by a vacuum, for example, a self-contained
vacuum contained within device 290. For instance, upon creating a
vacuum, skin may be drawn up towards fluid transporter 292, and
fluid transporter 292 may pierce the skin. Fluid from chamber 297
can then be delivered into the skin through fluid channel 299 and
fluid transporter 292. Optionally, device 290 also contains a
display 294 and associated electronics 293, batteries or other
power supplies, etc., which may be used control delivery of fluid
to the skin. In addition, device 290 may also optionally contain
memory 298, transmitters for transmitting a signal indicative of
device 290 or fluid delivery to a receiver, etc.
[0045] Yet another non-limiting example of a device of the
invention is shown in FIG. 10. FIG. 10A illustrates a view of the
device (with the cover removed), while FIG. 10B schematically
illustrates the device in cross-section. In FIG. 10B, device 250
includes a needle 252 contained within a recess 255. Needle 252 may
be solid or hollow, depending on the embodiment. Device 250 also
includes a self-contained vacuum chamber 260, which wraps around
the central portion of the device where needle 252 and recess 255
are located. A channel 262 connects vacuum chamber 260 with recess
255, separated by foil or a membrane 267. Also shown in device 250
is button 258. When pushed, button 258 breaks foil 267, thereby
connecting vacuum chamber 250 with recess 255, creating a vacuum in
recess 255. The vacuum may be used, for example, to draw skin into
recess 255, preferably such that it contacts needle 252 and pierces
the surface, thereby gaining access to an internal fluid. The fluid
may be controlled, for example, by controlling the size of needle
252, and thereby the depth of penetration. For example, the
penetration may be limited to the epidermis, e.g., to collect
interstitial fluid, or to the dermis, e.g., to collect blood. In
some cases, the vacuum may also be used to at least partially
secure device 250 on the surface of the skin, and/or to assist in
the withdrawal of fluid from the skin. For instance, fluid may flow
into channel 262 under action of the vacuum, and optionally to
sensor 261, e.g., for detection of an analyte contained within the
fluid. For instance, sensor 261 may produce a color change if an
analyte is present, or otherwise produce a detectable signal.
[0046] Other components may be added to the example of the device
illustrated in FIG. 10, in some embodiments of the invention. For
example, device 250 may contain a cover, displays, ports,
transmitters, sensors, microfluidic channels, chambers, fluid
channels, and/or various electronics, e.g., to control or monitor
fluid transport into or out of device 250, to determine an analyte
present within a fluid delivered and/or withdrawn from the skin, to
determine the status of the device, to report or transmit
information regarding the device and/or analytes, or the like, as
is discussed in more detail herein. As another example, device 250
may contain an adhesive, e.g., on surface 254, for adhesion of the
device to the skin.
[0047] Yet another non-limiting example is illustrated with
reference to FIG. 11A. In this example, device 500 includes a
support structure 501, and an associated fluid transporter system
503. Fluid transporter system 503 includes a plurality of needles
or microneedles 505, although other fluid transporters as discussed
herein may also be used. Also shown in FIG. 11A is sensor 510,
connected via channels 511 to recess 508 containing needles or
microneedles 505. Chamber 513 may be a self-contained vacuum
chamber, and chamber 513 may be in fluidic communication with
recess 508 via channel 511, for example, as controlled by a
controller or an actuator (not shown). In this figure, device 500
also contains display 525, which is connected to sensor 510 via
electrical connection 522. As an example of use of device 500, when
fluid is drawn from the skin (e.g., blood, interstitial fluid,
etc.), the fluid may flow through channel 511 to be determined by
sensor 510, e.g., due to action of the vacuum from vacuum chamber
513. In some cases, the vacuum is used, for example, to draw skin
into recess 508, e.g., such that it contacts needles or
microneedles 505 and pierces the surface of the skin to gain access
to a fluid internal of the subject, such as blood or interstitial
fluid, etc. The fluid may be controlled, for example, by
controlling the size of needle 505, and thereby the depth of
penetration. For instance, the penetration may be limited to the
epidermis, e.g., to collect interstitial fluid, or to the dermis,
e.g., to collect blood. Upon determination of the fluid and/or an
analyte present or suspected to be present within the fluid, a
microprocessor or other controller may display a suitable signal on
display 525. As is discussed below, a display is shown in this
figure by way of example only; in other embodiments, no display may
be present, or other signals may be used, for example, lights,
smell, sound, feel, taste, or the like. In some cases, more than
one fluid transporter system may be present within the device. For
instance, the device may be able to be used repeatedly, and/or the
device may be able to deliver and/or withdraw fluid at more than
one location on a subject, e.g., sequentially and/or
simultaneously. In some cases, the device may be able to
simultaneously deliver and withdraw fluid to and from a subject. A
non-limiting example of a device having more than one fluid
transporter system is illustrated with reference to FIG. 11C. In
this example, device 500 contains a plurality of structures such as
those described herein for delivering to and/or withdrawing fluid
from a subject. For example, device 500 in this example contains 3
such units, although any number of units are possible in other
embodiments. In this example, device 500 contains three such fluid
transporter systems 575. Each of these fluid transporter systems
may independently have the same or different structures, depending
on the particular application, and they may have structures such as
those described herein.
[0048] As noted, the invention in one set of embodiments involves
determination of a condition of a subject. In such a case, bodily
fluid and/or material associated with the skin may be analyzed, for
instance, as an indication of a past, present and/or future
condition of the subject, or to determine conditions that are
external to the subject. Determination may occur, for instance,
visually, tactilely, by odor, via instrumentation, etc. Other
aspects of the invention are directed to devices able to create
pooled regions within the skin, and are optionally able to remove
fluid from the pooled region and/or add material to the pooled
region. Still other aspects of the invention are generally directed
to making or using such devices, methods of promoting the making or
use of such devices, and the like.
[0049] Agents such as particles can be used to analyze bodily
fluids, such as interstitial fluid or blood. Other suitable agents
include enzymes, dyes, nucleic acids, antibodies, oligonucleotides,
reaction entities, or the like, e.g., as discussed herein. The
interstitial fluids may be accessed or collected using a suction
blister device in certain embodiments, or using other techniques
such as those described below. The agent may be any agent able to
determine an analyte. For example, the agent may be an antibody
which is labeled with a colorimetric, gold, or fluorescent label,
which binds analyte, producing a color change which is proportional
to the amount of analyte. In some cases, more than one agent may be
used. For example, a first agent may react with an analyte and the
second agent may be used to create a determinable signal, for
instance, visual, tactile, smell, taste, shape change, or the like.
Combinations of these can also be utilized in some cases. For
example, an antibody to a carcinoembryonic antigen ("CEA") and an
antibody to a prostate specific antigen ("PSA") may be used to
monitor for cancer of either origin; the antibodies may be used to
produce various colors upon detection of their corresponding
analytes, for instance, the colors may be yellow for CEA and blue
for PSA, resulting in green if both are elevated.
[0050] In one set of embodiments, one or more of the agents may be
particles, such as anisotropic particles or colloids. Accordingly,
in the descriptions that follow, it should be understood that
"particles" are described by way of example only, and in other
embodiments, other agents, such as antibodies, may also be used, in
addition and/or instead of particles.
[0051] In other embodiments, fluid may be delivered to the subject,
and such fluids may contain materials useful for delivery, e.g.,
forming at least a portion of the fluid, dissolved within the
fluid, carried by the fluid (e.g., suspended or dispersed), or the
like. Examples of suitable materials include, but are not limited
to, particles such as microparticles or nanoparticles, a chemical,
a drug or a therapeutic agent, a diagnostic agent, a carrier, or
the like.
[0052] As used herein, the term "fluid" generally refers to a
substance that tends to flow and to conform to the outline of its
container. Typically, fluids are materials that are unable to
withstand a static shear stress, and when a shear stress is
applied, the fluid experiences a continuing and permanent
distortion. The fluid may have any suitable viscosity that permits
at least some flow of the fluid. Non-limiting examples of fluids
include liquids and gases, but may also include free-flowing solid
particles, viscoelastic fluids, and the like. For example, the
fluid may include a flowable matrix or a gel, e.g., formed from
biodegradable and/or biocompatible material such as polylactic
acid, polyglycolic acid, poly(lactic-co-glycolic acid), etc., or
other similar materials.
[0053] One set of embodiments generally relates to interstitial and
other bodily fluids for use in analyzing a condition of a subject
or treating a subject. For instance, certain aspects of the
invention are directed to causing the formation of a pooled region
of fluid between the dermis and epidermis, such as in a suction
blister. Fluid may be removed from the pooled region and analyzed
in some fashion, or material may be delivered to the pooled region
of fluid, in either case for diagnosis and/or treatment of a
condition of a subject. In one set of embodiments, various
particles may be delivered to the fluid, whether pooled between the
dermis or epidermis, or in fluid removed from the subject, and the
particles can assist in diagnosis or treatment as described herein.
Optionally, fluid within a pooled region may be drained, e.g.,
externally, or the fluid may be resorbed, which may leave particles
or other material embedded within the skin between the epidermis
and dermis.
[0054] In some cases, as discussed herein, pooled regions of fluid
may be created in the skin for facilitating delivery and/or
withdraw of fluid from the skin. For instance, fluid may be pooled
within the skin that is drawn from the surrounding dermal and/or
epidermal layers within the skin. The fluid may include
interstitial fluid, or even blood in some cases. In other cases,
however, no pooling is necessary for the delivery and/or withdraw
of fluid from the skin. For example, fluid may be withdrawn from
the skin of a subject into a device, for example, using vacuum or
other techniques such as discussed below, and/or fluid may be
delivered into the skin of a subject without necessarily needing to
create a suction blister or a pooled region of fluid in which to
deliver fluid. Accordingly, it should be understood that in the
descriptions herein, references to a "suction blister" or "pooled
region of fluid" are by way of example only, and in other
embodiments, fluid may be delivered to the skin without using a
suction blister and/or without creating a pooled region of fluid
within the skin.
[0055] It should also be understood that, in some cases, fluid may
be created beneath the skin, e.g., in the fatty or muscle layers
below the skin. Accordingly, descriptions herein of delivering
and/or withdrawing fluid "in the skin" should also be understood to
include, in other embodiments, the deliver and/or withdraw of fluid
into layers directly beneath the skin.
[0056] One embodiment of the invention is illustrated in FIG. 1. In
FIG. 1A, the skin 10 of a subject is shown, having two layers: an
upper epidermis layer 15, and a lower dermis layer 17. Of course,
other structures are typically present within the skin, for
example, blood vessels, nerve endings, sweat glands, hair
follicles, or the like, but these are not illustrated here for
clarity. In FIG. 1B, epidermis 15 has been partially separated from
dermis 17, creating a region 20 within the skin between the
epidermis and the dermis. This region typically fills with fluid,
such as interstitial fluid from the body, forming a pooled region
of fluid. As shown in the example of FIG. 1B, the separation of the
dermis and epidermis is created using interface 25 that is able to
apply vacuum to the surface of the skin, thereby creating a suction
blister within the skin formed by the pooled region of fluid. For
example, vacuum may be created via conduit 27, which may be in
fluidic communication with a vacuum source, such as a vacuum pump
or an external (line) vacuum source. However, as discussed below,
other methods may be used to create a pooled region of fluid within
the skin besides, or in addition to, the use of vacuum. In
addition, as previously discussed, certain embodiments of the
invention do not require the creation of a pooled region of fluid
within the skin.
[0057] FIG. 1C shows an embodiment in which fluid is removed from
pooled region 20. In this figure, needle 35, such as a hypodermic
needle, may be used to remove at least a portion of the fluid from
pooled region 20. The fluid may be stored, and/or analyzed to
determine one or more analytes, e.g., a marker for a disease state,
or the like. In some cases, the fluid may be actively removed, for
example, upon the application of vacuum to the surface of skin 10,
or upon the application of hygroscopic material to facilitate the
removal of fluid from pooled region 20. In other cases, the fluid
may be extracted, for example, via vacuum applied to the surface of
skin 10 or to needle 35. In other cases, the fluid may be allowed
to leave pooled region 20 passively. For example, in one
embodiment, a cutter may be used to create a conduit by which fluid
from pooled region 20 can escape. The cutter may be, for example, a
needle or other piercing instrument, a cutting blade, or the
like.
[0058] In FIG. 1D, material 29 is shown being delivered into the
pooled region of fluid 20. Material 29 may be, for example,
particles, such as microparticles or nanoparticles, a chemical, a
drug or a therapeutic agent, a diagnostic agent, a reaction entity,
or the like. In some cases, material 29 may comprise a carrier,
such as a fluid carrier, that comprises the particles, chemicals,
drugs, therapeutic agents, diagnostic agents, reaction entities,
etc. As shown in this figure, needle 32 is used to deliver material
29 into pooled region 20. However, in other embodiments, other
systems, such as a jet injector, may be used to deliver material 29
into the pooled region 20.
[0059] Once needle 32 has been removed from skin 10, material 29
may become embedded within pooled region 20, or may be dispersed
within the subject, depending on the nature of material 29. For
example, if fluid within the pooled region of fluid 20 is drained
in some fashion, e.g., externally or is resorbed, etc., material 29
may remain embedded between epidermis 15 and dermis 17, as is shown
in FIG. 1E. The material may become temporarily or permanently
embedded between the dermis and the epidermis, or in some cases,
the material may disperse within the subject, for example,
dissolving or biodegrading within the subject, or the material may
be one that can be transported within the subject, such as within
the bloodstream. For example, in some cases, material 29 may
contain a drug or other therapeutic agent that can be released from
material 29, e.g., upon degradation of material 29. In one
embodiment, for instance, material 29 may comprise particles able
to controllably release a drug, a diagnostic agent, a therapeutic
agent, etc.
[0060] Thus, certain aspects of the present invention are generally
directed to the creation of suction blisters or other pooled
regions of fluid within the skin. In one set of embodiments, a
pooled region of fluid can be created between the dermis and
epidermis of the skin. Suction blisters or other pooled regions may
form in a manner such that the suction blister or other pooled
region is not significantly pigmented in some cases, since the
basal layer of the epidermis contains melanocytes, which are
responsible for producing pigments. Such regions can be created by
causing the dermis and the epidermis to at least partially
separate, and as will be discussed below, a number of techniques
can be used to at least partially separate the dermis from the
epidermis. As mentioned, however, some embodiments of the invention
do not necessarily require the creation of a pooled region of fluid
within the skin.
[0061] The subject is usually human, although non-human subjects
may be used in certain instances, for instance, other mammals such
as a dog, a cat, a horse, a rabbit, a cow, a pig, a sheep, a goat,
a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a
guinea pig, a hamster, a primate (e.g., a monkey, a chimpanzee, a
baboon, an ape, a gorilla, etc.), or the like.
[0062] In one technique, a pool of interstitial fluid is formed
between layers of skin of a subject and, after forming the pool,
fluid is drawn from the pool by accessing the fluid through a layer
of skin, for example, puncturing the outer layer of skin with a
needle, e.g., with a microneedle. Specifically, for example, a
suction blister can be formed and then the suction blister can be
punctured and fluid can be drawn from the blister. In another
technique, an interstitial region can be accessed and fluid drawn
from that region without first forming a pool of fluid via a
suction blister or the like. For example, a needle or a microneedle
can be applied to the interstitial region and fluid can be drawn
there from. In some cases, however, fluid may be withdrawn from the
skin even without creating a suction blister or a pooled region of
fluid within the skin.
[0063] Where needles are used, it can be advantageous to select
needles of length such that interstitial fluid is preferentially
obtained and, where not desirable, blood is not accessed. Those of
ordinary skill in the art can arrange needles relative to the skin
for these purposes including, in one embodiment, introducing
needles into the skin at an angle, relative to the skin's surface,
other than 90.degree., i.e., to introduce a needle or needles into
the skin in a slanting fashion so as to limit the depth of
penetration. In another embodiment, however, the needles may enter
the skin at approximately 90.degree..
[0064] Pooled regions of fluids, if present, may be formed on any
suitable location within the skin of a subject. Factors such as
safety or convenience may be used to select a suitable location, as
(in humans) the skin is relatively uniform through the body, with
the exception of the hands and feet. As non-limiting examples, the
pooled region may be formed on an arm or a leg, on the hands (e.g.,
on the back of the hand), on the feet, on the chest, abdomen, or
the back of the subject, or the like. The size of the pooled region
of fluid that is formed in the skin and/or the duration that the
pooled region lasts within the skin depends on a variety of
factors, such as the technique of creating the pooled region, the
size of the pooled region, the size of the region of skin to which
the technique is applied, the amount of fluid removed from the
pooled region (if any), any materials that are delivered into the
pooled region, or the like. For example, if vacuum is applied to
the skin to create a suction blister, the vacuum applied to the
skin, the duration of the vacuum, and/or the area of the skin
affected may be controlled to control the size and/or duration of
the suction blister. In some embodiments, it may be desirable to
keep the pooled regions relatively small, for instance, to prevent
an unsightly visual appearance, to allow for greater sampling
accuracy (due to a smaller volume of material), or to allow for
more controlled placement of particles within the skin. For
example, the volume of the pooled region may be kept to less than
about 2 ml, less than about 1 ml, less than about 500 microliters,
less than about 300 microliters, less than about 100 microliters,
less than about 50 microliters, less than about 30 microliters,
less than about 10 microliters, etc., in certain cases, or the
average diameter of the pooled region (i.e., the diameter of a
circle having the same area as the pooled region) may be kept to
less than about 5 cm, less than about 4 cm, less than about 3 cm,
less than about 2 cm, less than about 1 cm, less than about 5 mm,
less than about 4 mm, less than about 3 mm, less than about 2 mm,
or less than about 1 mm.
[0065] A variety of techniques may be used to cause pooled regions
of fluid to form within the skin and/or to withdraw a bodily fluid
from the skin of a subject such as interstitial fluid or blood. In
one set of embodiments, vacuum is applied to create a suction
blister, or otherwise used to collect interstitial fluid or blood
from a subject. In one set of embodiments, for example, a device
containing a vacuum source, for instance, a self-contained vacuum
source such as a pre-packaged vacuum chamber, may be used to
withdraw blood or interstitial fluid from the subject. The fluid
may be analyzed and/or stored for later use.
[0066] In other embodiments, other methods may be used to create as
a pooled region of fluid within the skin and/or withdraw fluid from
the skin besides, or in addition to, the use of vacuum. When vacuum
(i.e., the amount of pressure below atmospheric pressure, such that
atmospheric pressure has a vacuum of 0 mmHg, i.e., the pressure is
gauge pressure rather than absolute pressure) is used to at least
partially separate the dermis from the epidermis to cause the
pooled region to form, the pooled region of fluid thus formed can
be referred to as a suction blister. For example, pressures of at
least about 50 mmHg, at least about 100 mmHg, at least about 150
mmHg, at least about 200 mmHg, at least about 250 mmHg, at least
about 300 mmHg, at least about 350 mmHg, at least about 400 mmHg,
at least about 450 mmHg, at least about 500 mmHg, at least about
550 mmHg, at least about 600 mmHg, at least about 650 mmHg, at
least about 700 mmHg, or at least about 750 mmHg may be applied to
the skin, e.g., to cause a suction blister and/or to collect
interstitial fluid from a subject (as discussed, these measurements
are negative relative to atmospheric pressure). For instance, a
vacuum pressure of 100 mmHg corresponds to an absolute pressure of
about 660 mmHg (i.e., 100 mmHg below 1 atm). Different amounts of
vacuum may be applied to different subjects in some cases, for
example, due to differences in the physical characteristics of the
skin of the subjects.
[0067] The vacuum may be applied to any suitable region of the
skin, and the area of the skin to which the vacuum may be
controlled in some cases. For instance, the average diameter of the
region to which vacuum is applied may be kept to less than about 5
cm, less than about 4 cm, less than about 3 cm, less than about 2
cm, less than about 1 cm, less than about 5 mm, less than about 4
mm, less than about 3 mm, less than about 2 mm, or less than about
1 mm. In addition, such vacuums may be applied for any suitable
length of time at least sufficient to cause at least some
separation of the dermis from the epidermis to occur. For instance,
vacuum may be applied to the skin for at least about 1 min, at
least about 3 min, at least about 5 min, at least about 10 min, at
least about 15 min, at least about 30 min, at least about 45 min,
at least about 1 hour, at least about 2 hours, at least about 3
hours, at least about 4 hours, etc. Examples of devices suitable
for creating such suction blisters are discussed in more detail
below. In other cases, however, bodily fluids such as blood or
interstitial fluid may be removed from the skin using vacuum
without the creation of a suction blister. Other non-limiting
fluids include saliva, sweat, tears, mucus, plasma, lymph, or the
like.
[0068] Other methods besides vacuum may be used to cause such
separation to occur. For example, in another set of embodiments,
heat may be used. For instance, a portion of the skin may be heated
to at least about 40.degree. C., at least about 50.degree. C., or
at least about 55.degree. C., using any suitable technique, to
cause such separation to occur. In some (but not all) cases, the
temperature may be limited to no more than about 60.degree. C. or
no more than about 55.degree. C. The skin may be heated, for
instance, using an external heat source (e.g., radiant heat or a
heated water bath), a chemical reaction, electromagnetic radiation
(e.g., microwave radiation, infrared radiation, etc.), or the like.
In some cases, the radiation may be focused on a relatively small
region of the skin, e.g., to at least partially spatially contain
the amount of heating within the skin that occurs.
[0069] In yet another set of embodiments, a separation chemical may
be applied to the skin to at least partially cause separation of
the dermis and the epidermis to occur. Non-limiting examples of
such separation chemicals include proteases such as trypsin,
purified human skin tryptase, or compound 48/80. Separation
compounds such as these are commercially available from various
sources. The separation chemical may be applied directly to the
skin, e.g., rubbed into the surface of the skin, or in some cases,
the separation chemical can be delivered into the subject, for
example, between the epidermis and dermis of the skin. The
separation chemical can, for example, be injected in between the
dermis and the epidermis.
[0070] Another example of a separation chemical is a blistering
agent, such as pit viper venom or blister beetle venom.
Non-limiting examples of blistering agents include phosgene oxime,
Lewisite, sulfur mustards (e.g., mustard gas or
1,5-dichloro-3-thiapentane, 1,2-bis(2-chloroethylthio)ethane,
1,3-bis(2-chloroethylthio)-n-propane,
1,4-bis(2-chloroethylthio)-n-butane,
1,5-bis(2-chloroethylthio)-n-pentane,
2-chloroethylchloromethylsulfide, bis(2-chloroethyl)sulfide,
bis(2-chloroethylthio)methane, bis(2-chloroethylthiomethyl)ether,
or bis(2-chloroethylthioethyl)ether), or nitrogen mustards (e.g.,
bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, or
tris(2-chloroethyl)amine).
[0071] In still another set of embodiments, a device may be
inserted into the skin and used to mechanically separate the
epidermis and the dermis, for example, a wedge or a spike. Fluids
may also be used to separate the epidermis and the dermis, in yet
another set of embodiments. For example, saline or another
relatively inert fluid may be injected into the skin between the
epidermis and the dermis to cause them to at least partially
separate.
[0072] These and/or other techniques may also be combined, in still
other embodiments. For example, in one embodiment, vacuum and heat
may be applied to the skin of a subject, sequentially and/or
simultaneously, to cause such separation to occur. As a specific
example, in one embodiment, vacuum is applied while the skin is
heated to a temperature of between about 40.degree. C. and about
50.degree. C.
[0073] The fluid contained within the skin, e.g., within the pooled
region of fluid is typically drawn from the surrounding dermal
and/or epidermal layers within the skin, and includes interstitial
fluid, or even blood in some cases. In some cases, such fluids may
be collected even without creating a suction blister within the
skin. For instance, a vacuum may be applied to the skin, e.g.,
through a needle as described herein, to withdraw interstitial
fluid from the skin.
[0074] Often, such fluids will contain various analytes within the
body that are important for diagnostic purposes, for example,
markers for various disease states, such as glucose (e.g., for
diabetics); other example analytes include ions such as sodium,
potassium, chloride, calcium, magnesium, and/or bicarbonate (e.g.,
to determine dehydration); gases such as carbon dioxide or oxygen;
H.sup.+ (i.e., pH); metabolites such as urea, blood urea nitrogen
or creatinine; hormones such as estradiol, estrone, progesterone,
progestin, testosterone, androstenedione, etc. (e.g., to determine
pregnancy, illicit drug use, or the like); or cholesterol. Other
examples include insulin, or hormone levels.
[0075] As previously discussed, agents such as particles can be
used to analyze bodily fluids, such as interstitial fluids. In some
cases, the particles may be used to determine pH or metal ions,
proteins, enzymes, antibodies, nucleic acids (e.g. DNA, RNA, etc.),
drugs, sugars (e.g., glucose), hormones (e.g., estradiol, estrone,
progesterone, progestin, testosterone, androstenedione, etc.),
carbohydrates, or other analytes of interest. Other conditions that
can be detected can include pH changes, which may indicate disease,
yeast infection, periodontal disease at a mucosal surface, oxygen
or carbon monoxide levels which indicate lung dysfunction, and drug
levels, both legal prescription levels of drugs such as coumadin
and illegal such as cocaine or nicotine. Further examples of
analytes include those indicative of disease, such as cancer
specific markers such as CEA and PSA, viral and bacterial antigens,
and autoimmune indicators such as antibodies to double stranded
DNA, indicative of Lupus. Still other conditions include exposure
to elevated carbon monoxide, which could be from an external source
or due to sleep apnea, too much heat (important in the case of
babies whose internal temperature controls are not fully
self-regulating) or from fever.
[0076] Still other potentially suitable analytes include various
pathogens such as bacteria or viruses, and/or markers produced by
such pathogens. Thus, in certain embodiments of the invention, as
discussed below, one or more analytes within the skin, e.g., within
a pooled region of fluid, may be determined in some fashion, which
may be useful in determining a past, present and/or future
condition of the subject.
[0077] In one embodiment as discussed below, an analyte may be
determined as an "on/off" or "normal/abnormal" situation. In some
cases, the particles (or other agents) indicate a change. Detection
of the analyte, for example, may be indicative that insulin is
needed; a trip to the doctor to check cholesterol; ovulation is
occurring; kidney dialysis is needed; drug levels are present
(e.g., especially in the case of illegal drugs) or too high/too low
(e.g., important in care of geriatrics in particular in nursing
homes). As another embodiment, however, an analyte may be
determined quantitatively.
[0078] In some embodiments of the invention, one or more materials
may be delivered to the skin. Examples of suitable materials
include, but are not limited to, particles such as microparticles
or nanoparticles, a chemical, a drug or a therapeutic agent, a
diagnostic agent, a carrier, or the like. The materials may be
delivered into the skin using any suitable technique; various
techniques for delivery into the skin are well-known to those of
ordinary skill in the art. Examples of suitable delivery techniques
include, but are not limited to, injection (e.g., using needles
such as hypodermic needles) or a jet injector, such as those
discussed below.
[0079] In one set of embodiments, particles are delivered to the
skin. The particles may be, for example, nanoparticles or
microparticles, and in some cases, the particles may be anisotropic
particles. Examples of such particles are discussed in more detail
herein. In some cases, a plurality of particles may be used, and in
some cases, some, or substantially all, of the particles may be the
same. For example, at least about 10%, at least about 30%, at least
about 40%, at least about 50%, at least about 60%, at least about
70%, at least about 80%, at least about 90%, at least about 95%, or
at least about 99% of the particles may have the same shape, and/or
may have the same composition. For example, in one embodiment, at
least about 50% of the particles delivered to the skin may have the
same shape, and/or may have the same composition. For instance, at
least about 50% of the particles may be anisotropic particles.
[0080] The particles may be used for a variety of purposes. For
instance, the particles may contain a diagnostic agent or a
reaction entity able to interact with and/or associate with an
analyte, or another reaction entity, or other particles. Such
particles may be useful, for example, to determine one or more
analytes, such as a marker of a disease state, as discussed below.
As another example, the particles may contain a drug or a
therapeutic agent, positioned on the surface and/or internally of
the particles, which may be released by the particles and delivered
to the subject. Specific examples of these and other embodiments
are discussed in detail below.
[0081] In some cases, materials such as particles may become
embedded within the skin, e.g., within a pooled region of fluid,
for example, due to physical properties of the materials (e.g.,
size, hydrophobicity, etc.), and/or by draining at least a portion
of the fluid within the pooled region such that the material is
unable to escape, thereby remaining contained between the dermis
and epidermis layers of the skin. Thus, in some cases, a depot of
material may be formed within the skin, and the depot may be
temporary or permanent. For instance, materials within the depot
may eventually degrade (e.g., if the material biodegradable), enter
the bloodstream, or be sloughed off to the environment, e.g., as
the cells of the dermis differentiate to form new epidermis and
accordingly push the material towards the surface of the skin.
Thus, the depot of material may be present within the subject on a
temporary basis (e.g., on a time scale of days or weeks), in
certain instances.
[0082] Fluid may be drained from the pooled region using any
suitable technique, for example, by externally removing the fluid
from the pooled region (e.g., using techniques such as those
discussed below), and/or by removing the vacuum or other stimulus
used to cause the pooled region to occur, thereby allowing the
fluid to become resorbed within the subject. Such resorption may
occur, for example on a time scale of minutes to hours, depending
on factors such as the size or volume of the pooled region of
fluid. For example, in one embodiment, fluid is withdrawn using a
needle such as a hypodermic needle. In some cases, this needle may
also be used to deliver particles or other materials to the
skin.
[0083] Fluids may also be externally removed from skin, e.g., from
a pooled region of fluid, for example, to at least partially drain
the pooled region of fluid, and/or for analysis. For instance, at
least a portion of the fluid may be stored, and/or analyzed to
determine one or more analytes, e.g., a marker for a disease state,
or the like. The fluid withdrawn from the skin may be subjected to
such uses, and/or one or more materials previously delivered to the
skin (e.g., particles) may be subject to such uses. The fluid may
be removed using any suitable technique. For example, in one
embodiment, fluid is withdrawn using a needle such as a hypodermic
needle. In some cases, this needle may also be used to deliver
particles or other materials to the skin. The fluid may also be
withdrawn using vacuums such as those discussed herein in another
embodiment of the invention. For example, vacuum may be applied to
a conduit, such as a needle, in fluidic communication with
interstitial fluid, e.g., within a pooled region of fluid, in order
to draw up at least a portion of the fluid from the pooled region.
In yet another embodiment, fluid is withdrawn using capillary
action (e.g., using a hypodermic needle having a suitably narrow
inner diameter). In still another embodiment, pressure may be
applied to force fluid out of the needle.
[0084] In still another embodiment, fluid may be withdrawn using a
hygroscopic agent applied to the surface of the skin, or proximate
the skin. In some cases, pressure may be applied to drive the
hygroscopic agent into the skin. Hygroscopic agents typically are
able to attract water from the surrounding environment, for
instance, through absorption or adsorption. Non-limiting examples
of hygroscopic agents include sugar, honey, glycerol, ethanol,
methanol, sulfuric acid, methamphetamine, iodine, many chloride and
hydroxide salts, and a variety of other substances. Other examples
include, but are not limited to, zinc chloride, calcium chloride,
potassium hydroxide or sodium hydroxide. In some cases, a suitable
hygroscopic agent may be chosen based on its physical or reactive
properties, e.g., inertness or biocompatibility towards the skin of
the subject, depending on the application.
[0085] In some cases, fluids or other materials delivered to the
subject may be used for indication of a past, present and/or future
condition of the subject. Thus, the condition of the subject to be
determined may be one that is currently existing in the subject,
and/or one that is not currently existing, but the subject is
susceptible or otherwise is at an increased risk to that condition.
The condition may be a medical condition, e.g., diabetes or cancer,
or other physiological conditions, such as dehydration, pregnancy,
illicit drug use, or the like. Additional non-limiting examples are
discussed below. In one set of embodiments, the materials may
include a diagnostic agent, for example, one which can determine an
analyte within the subject, e.g., one that is a marker for a
disease state. Examples of such markers have been discussed above.
As a specific non-limiting example, material delivered to the skin,
e.g., to the dermis or epidermis, to a pooled region of fluid,
etc., of a subject may include a particle including an antibody
directed at a marker produced by bacteria.
[0086] In other cases, however, the materials delivered to the
subject may be used to determine conditions that are external to
the subject. For example, the materials may contain reaction
entities able to recognize pathogens or other environmental
conditions surrounding the subject, for example, an antibody able
to recognize an external pathogen (or pathogen marker). As a
specific example, the pathogen may be anthrax and the antibody may
be an antibody to anthrax spores. As another example, the pathogen
may be a Plasmodia (some species of which causes malaria) and the
antibody may be an antibody that recognizes the Plasmodia.
[0087] Another aspect of the present invention is generally
directed to devices able to cause the formation of the pooled
region of fluids within the skin of a subject, and in some cases,
to devices able to deliver and/or remove fluids or other materials
from the pooled region of fluids. It should be understood, however,
that other devices in other aspects do not require the formation of
pooled regions of fluids within the skin. In some cases, the device
may be able to collect bodily fluids such as interstitial fluid or
blood from the skin, including fluid from a pooled region of fluid,
or from other locations. For example, the device may take the form
of a skin "patch," according to one embodiment. Typically, a skin
patch includes one or more layers of material that are adhered to
the surface of the skin, and can be applied by the subject or
another person. In certain embodiments, layers or portions of the
skin patch may be removed, leaving other layers or portions behind
on the skin. Often, the skin patch lacks an external power source,
although the various layers of the patch may contain various
chemicals, such as drugs, therapeutic agents, diagnostic agents,
reaction entities, etc. In some cases, the skin patch may also
include mechanical elements as well, for example, a cutter such as
is discussed herein.
[0088] As a specific, non-limiting example, in one embodiment, a
skin patch or other device may be used to create a suction blister
without an external power and/or a vacuum source. Examples of such
devices include, besides skin patches, strips, tapes, bandages, or
the like. For instance, a skin patch may be contacted with the skin
of a subject, and a vacuum created through a change in shape of a
portion of the skin patch or other device (e.g., using a shape
memory polymer), which may be used to create a suction blister
and/or withdraw fluid from the skin. As a specific example, a shape
memory polymer may be shaped to be flat at a first temperature
(e.g., room temperature) but curved at a second temperature (e.g.,
body temperature), and when applied to the skin, the shape memory
polymer may alter from a flat shape to a curved shape, thereby
creating a vacuum. As another example, a mechanical device may be
used to create the vacuum, For example, springs, coils, expanding
foam (e.g., from a compressed state), a shape memory polymer, shape
memory metal, or the like may be stored in a compressed or wound
released upon application to a subject, then released (e.g.,
unwinding, uncompressing, etc.), to mechanically create the vacuum.
Thus, in some cases, the device is "pre-packaged" with a suitable
vacuum source (e.g., a pre-evacuated vacuum chamber); for instance,
in one embodiment, the device may be applied to the skin and
activated in some fashion to create and/or access the vacuum
source. One example is described below with respect to FIG. 8. In
yet another example, a chemical reaction may be used to create a
vacuum, e.g., a reaction in which a gas is produced, which can be
harnessed to provide the mechanical force to create a vacuum. In
still another example, a component of the device may be able to
create a vacuum in the absence of mechanical force. In another
example, the device may include a self-contained vacuum actuator,
for example, chemical reactants, a deformable structure, a spring,
a piston, etc.
[0089] FIGS. 8C-8E illustrates an embodiment where a compressed
foam is used to create a suction blister. In FIG. 8C, device 80 is
placed on skin 57, and includes compressed foam 95. Device 80
includes a cutter 54 able to cut a portion of the skin, e.g., when
pressed down onto the skin as is shown in FIG. 8D, e.g., creating a
hole 97. In addition, the foam may be allowed to expand in some
fashion after the device has been placed on the skin. For example,
a housing portion of device 80 may be removed to allow expansion of
the foam to occur. Expansion of the foam, as is shown in FIG. 8E,
may create a suction and thereby cause the formation of a suction
blister 99, and/or may allow fluids to be withdrawn from the
skin.
[0090] Accordingly, in one set of embodiments, the skin patch or
other device may be used to create a suction blister automatically,
once activated, without any external control by a user. In other
embodiments, however, the device may be larger. For instance, the
device may be a handheld device that is applied to the surface of
the skin of a subject. In some cases, however, the device may be
sufficiently small or portable that the subject can self-administer
the device. In certain embodiments, the device may also be powered.
In some instances, the device may be applied to the surface of the
skin, and is not inserted into the skin.
[0091] In other embodiments, however, at least a portion of the
device may be inserted into the skin, for example, mechanically.
For example, in one embodiment, the device may include a cutter,
such as a hypodermic needle, a knife blade, a piercing element
(e.g., a solid or hollow needle), or the like, as discussed herein.
In some cases, the device may comprise a cutter able to cut or
pierce the surface of the skin. The cutter may comprise any
mechanism able to create a path to a fluid within the skin, e.g.,
through which fluids may be delivered and/or removed from the skin.
For example, the cutter may comprise a hypodermic needle, a knife
blade, a piercing element (e.g., a solid or a hollow needle), or
the like, which can be applied to the skin to create a suitable
conduit for the withdrawal of fluid from the skin. In one
embodiment, a cutter is used to create such a pathway and removed,
then fluid is removed via this pathway using any suitable
technique. In another embodiment, the cutter remains in place
within the skin, and fluid may be drawn through a conduit within
the cutter.
[0092] As an example, the device may be constructed such that a
cutter or a needle is inserted into the skin after a suction
blister is formed. In some cases, the device may be designed such
that portions of the device are separable. For example, a first
portion of the device may be removed from the surface of the skin,
leaving other portions of the device behind on the skin. In one
embodiment, a stop may also be included to prevent or control the
depth to which the cutter or other device inserts into the skin,
e.g., to control penetration to the epidermis, dermis, etc.
[0093] Various non-limiting examples of such devices are
illustrated in FIG. 2. In FIG. 2A, device 50 includes an interface
25 that can be used to apply vacuum to the surface of the skin 10,
thereby creating a pooled region of fluid 20 within the skin
between the epidermis 15 and the dermis 17. In the embodiment
illustrated, device 50 includes conduit 27, which can be connected
in fluidic communication with a vacuum source, such as a vacuum
pump or an external (line) vacuum source. In this figure, device 50
also includes a cutter, in this case a hypodermic needle, that can
be extended into the pooled region of fluid, and used to deliver
and/or remove fluids or other materials from the pooled region of
fluid. In this figure, the hypodermic needle is used both to create
a conduit within the skin and to delivery and/or remove fluids from
the skin; in other embodiments, however, the needle (or other
device) may be removed from the skin, leaving behind a "hole"
within the skin through which fluids can be delivered and/or
removed. In this figure, fluid withdrawn from the pooled region of
fluid may be delivered to a sensor 52, which can be used to
determine an analyte, such as a marker for a disease state, that is
present within skin 10. The cutter may be an integral part of
device 50, or a separate device. In some cases, device 50 may
comprise separably removable portions. For instance, after creating
the suction blister, interface 25 may be removable from device 50,
leaving hypodermic needle 40 within skin 10.
[0094] Another example of a device is shown in FIG. 2B. In this
figure, device 10 includes conduit 27, in which fluids can be
delivered and/or removed. In one embodiment, a fluid, such as
saline, is delivered through conduit 27, thereby creating a pooled
region of fluid between the epidermis 15 and the dermis 17.
Optionally, materials such as particles may be delivered into the
pooled region of fluid using conduit 27, e.g., for therapeutic or
diagnostic purposes. In some cases, after creation of the pooled
region of fluid within skin 10, at least a portion of the fluid may
be removed through conduit 27 (or a separate conduit, in some
cases) for analysis, e.g., as previously discussed.
[0095] In FIG. 2C, a similar device is shown, including a cutter
54, such as a hypodermic needle or a knife blade, that can be
inserted into the skin and used to at least partially separate the
epidermis from the dermis to allow for the creation of a pooled
region of fluid 20. For example, cutter 54 may separate the
epidermis from the dermis by delivering a separation chemical to
this region, and/or by conducting heat to this region. Also shown
in this example is conduit 27, which may be used to deliver and/or
remove fluid from the pooled region of fluid. In some cases, cutter
54 and conduit 27 may be separately administered to the subject,
e.g., sequentially or simultaneously. In another embodiment, both
may be part of the same device that is administered to skin 10, and
in some cases, cutter 54 may be separated from conduit 27, e.g.,
such that cutter 54 can be removed from the skin while conduit 27
remains within the skin.
[0096] FIG. 3A illustrates a device according to another embodiment
of the invention. In this example, a device 60 is applied to skin
63. Device 60 may be, for instance, a patch, an applique, a
mechanical device, or the like. A vacuum is created between device
60 and the skin in region 65. The vacuum may be contained by the
device itself, and/or through connection with a vacuum source, such
as a vacuum pump or an external (line) vacuum source. Other
examples of vacuum sources include, but are not limited to,
syringes, bulbs, vacuum pumps, Venturi tubes, or even manual
(mouth) suction. Also shown in FIG. 3B is cutter 70. Cutter 70 may
be, for example, a needle or a microneedle, a knife blade, or the
like.
[0097] As the suction blister forms within the skin, portions of
the skin may be uplifted due to the pooled region of fluid, shown
in FIG. 3B as portion 64 extending upwardly into region 65 of
device 60. As portion 64 extends upward into region 65, it comes
into contact with cutter 70. Under certain conditions, the skin may
extend upward sufficiently into region 65 that cutter 70 cuts into
skin 65, as is shown in FIG. 3C. For instance, if cutter 70 is a
hypodermic needle, upon piercing of the needle into the skin, the
needle may be used to access interstitial fluid within the skin,
e.g., within a pooled region of fluid within the skin forming the
suction blister. Accordingly, fluid may be withdrawn and/or
materials such as particles may be delivered into the pooled region
using the hypodermic needle.
[0098] As additional examples, the device may comprise a first
portion able to create a pooled region of fluid within the skin of
a subject and a second portion able to determine fluid removed from
the pooled region, or a first portion able to create a pooled
region of fluid within the skin of a subject and a second portion
able to deliver fluid to the pooled region of fluid, where the
various portions may be separated from each other. For instance,
the fluid itself may be determined (for example, the presence
and/or absence of the fluid, the concentration of fluid, the volume
of fluid, etc.), or an analyte within the fluid may be determined,
e.g., qualitatively or quantitatively, whether the analyte is
present and/or absent, etc. As yet another example, the device may
comprise a first portion able to create a pooled region of fluid
within the skin of a subject, a second portion able to determine
fluid removed from the pooled region, and a third portion able to
deliver fluid to the pooled region of fluid, where some or all of
the portions may be separated from each other.
[0099] In certain embodiments, the device is able to create a
pooled region of fluid within the skin of a subject. In one
embodiment, the device is able to create vacuum on the surface of
the skin, e.g., to form a suction blister within the skin. In other
embodiments, however, the device may create a vacuum to withdraw
fluid from the skin without necessarily creating a pooled region of
fluid or forming a suction blister within the skin. In one set of
embodiments, fluids may be delivered to or withdrawn from the skin
using vacuum. The vacuum may be an external vacuum source, and/or
the vacuum source may be self-contained within the device. For
example, vacuums of at least about 50 mmHg, at least about 100
mmHg, at least about 150 mmHg, at least about 200 mmHg, at least
about 250 mmHg, at least about 300 mmHg, at least about 350 mmHg,
at least about 400 mmHg, at least about 450 mmHg, at least about
500 mmHg, at least 550 mmHg, at least 600 mmHg, at least 650 mmHg,
at least about 700 mmHg, or at least about 750 mmHg may be applied
to the skin to cause a suction blister. Any source of vacuum may be
used. For example, the device may comprise a vacuum source, and/or
be connectable to a vacuum source is external to the device, such
as a vacuum pump or an external (line) vacuum source. In some
cases, vacuum may be created manually, e.g., by manipulating a
syringe pump or the like, or the low pressure may be created
mechanically or automatically, e.g., using a piston pump, a
syringe, a bulb, a Venturi tube, manual (mouth) suction, etc. or
the like.
[0100] As mentioned, any source of vacuum may be used. For example,
the device may comprise an internal vacuum source, and/or be
connectable to a vacuum source is external to the device, such as a
vacuum pump or an external (line) vacuum source.
[0101] In one set of embodiments, a device of the present invention
may not have an external power and/or a vacuum source. In some
cases, the device is "pre-loaded" with a suitable vacuum source;
for instance, in one embodiment, the device may be applied to the
skin and activated in some fashion to create and/or access the
vacuum source. As one example, a device of the present invention
may be contacted with the skin of a subject, and a vacuum created
through a change in shape of a portion of the device (e.g., using a
shape memory polymer), or the device may contain one or more
sealed, self-contained vacuum compartments, where a seal is
punctured in some manner to create a vacuum. For instance, upon
puncturing the seal, a vacuum compartment may be in fluidic
communication with a needle, which can be used to move the skin
towards the device, withdraw fluid from the skin, or the like.
[0102] As another example, a shape memory polymer may be shaped to
be flat at a first temperature (e.g., room temperature) but curved
at a second temperature (e.g., body temperature), and when applied
to the skin, the shape memory polymer may alter from a flat shape
to a curved shape, thereby creating a vacuum. As yet another
example, a mechanical device may be used to create the vacuum. For
example, springs, coils, expanding foam (e.g., from a compressed
state), a shape memory polymer, shape memory metal, or the like may
be stored in a compressed or wound released upon application to a
subject, then released (e.g., unwinding, uncompressing, etc.), to
mechanically create the vacuum. Non-limiting examples of
shape-memory polymers and metals include Nitinol, compositions of
oligo(epsilon-caprolactone)diol and crystallizable
oligo(rho-dioxanone)diol, or compositions of
oligo(epsilon-caprolactone)dimethacrylate and n-butyl acrylate.
[0103] In some cases, the device includes an interface that is able
to apply vacuum to the skin. The interface may be, for example, a
suction cup or a circular bowl that is placed on the surface of the
skin, and vacuum applied to the interface to create a vacuum. In
one set of embodiments, the interface is part of a support
structure, as discussed herein. The interface may be formed from
any suitable material, e.g., glass, rubber, polymers such as
silicone, polyurethane, nitrile rubber, EPDM rubber, neoprene, or
the like. In some cases, the seal between the interface and the
skin may be enhanced (e.g., reducing leakage), for instance, using
vacuum grease, petroleum jelly, a gel, a hydrogel, or the like. In
some cases, the interface may be relatively small, for example,
having a diameter of less than about 5 cm, less than about 4 cm,
less than about 3 cm, less than about 2 cm, less than about 1 cm,
less than about 5 mm, less than about 4 mm, less than about 3 mm,
less than about 2 mm, or less than about 1 mm. The interface may be
circular, although other shapes are also possible, for example,
square, star-shaped (having 5, 6, 7, 8, 9, 10, 11, etc. points),
tear-drop, oval, rectangular, or the like. In some cases,
non-circular shapes may be used since high-energy points, e.g., the
points or corners of the shape may enhance or accelerate blister
formation. Non-limiting examples of such shapes are shown in FIG.
6. Other non-circular shapes besides these may also be used in
other embodiments.
[0104] The interface may also be selected, in some cases, to keep
the size of the pooled region below a certain area, e.g., to
minimize pain or discomfort to the subject, for aesthetic reasons,
or the like. The interface may be constructed out of any suitable
material, e.g., glass, plastic, or the like.
[0105] The device may also comprise, in some cases, a portion able
to deliver materials such as particles into the skin, for example,
into the dermis or epidermis, into a pooled region within the skin,
etc. For example, the device may include a needle such as a
hypodermic needle or microneedles, or jet injectors such as those
discussed below. As an example, in one embodiment, a needle such as
a hypodermic needle can be used to deliver and/or withdraw fluid to
or from the skin. In some cases, for example, fluid may be
delivered and/or withdrawn from a pooled region of fluid in the
skin, if present. Hypodermic needles are well-known to those of
ordinary skill in the art, and can be obtained commercially with a
range of needle gauges. For example, the needle may be in the 20-30
gauge range, or the needle may be 32 gauge, 33 gauge, 34 gauge,
etc.
[0106] Accordingly, in one set of embodiments, many techniques for
delivering and/or withdrawing fluid are described in the
applications incorporated herein. It is to be understood that,
generally, fluids may be delivered and/or withdrawn in a variety of
ways, and various systems and methods for delivering and/or
withdrawing fluid from the skin are discussed herein. It should
also be understood that techniques for delivering materials into a
pooled region of the skin are by way of example only, and that in
other aspects, the invention is directed to techniques for
delivering and/or withdrawing fluid from the skin of a subject
(with or without the presence of a pooled region of the skin). Some
additional non-limiting examples of such techniques are discussed
below. In one set of embodiments, for example, techniques for
piercing or altering the surface of the skin to transport a fluid
are discussed, for example, a needle such as a hypodermic needle or
microneedles, chemicals applied to the skin (e.g., penetration
enhancers), or jet injectors or other techniques such as those
discussed below.
[0107] If needles are present, the needles may be of any suitable
size and length, and may be solid or hollow. The needles may have
any suitable cross-section (e.g., perpendicular to the direction of
penetration), for example, circular, square, oval, elliptical,
rectangular, rounded rectangle, triangular, polygonal, hexagonal,
irregular, etc. For example, the needle may have a length of less
than about 5 mm, less than about 4 mm, less than about 3 mm, less
than about 2 mm, less than about 1 mm, less than about 800
micrometers, less than 600 micrometers, less than 500 micrometers,
less than 400 micrometers, less than about 300 micrometers, less
than about 200 micrometers, less than about 175 micrometers, less
than about 150 micrometers, less than about 125 micrometers, less
than about 100 micrometers, less than about 75 micrometers, less
than about 50 micrometers, etc. The needle may also have a largest
cross-sectional dimension of less than about 5 mm, less than about
4 mm, less than about 3 mm, less than about 2 mm, less than about 1
mm, less than about 800 micrometers, less than 600 micrometers,
less than 500 micrometers, less than 400 micrometers, less than
about 300 micrometers, less than about 200 micrometers, less than
about 175 micrometers, less than about 150 micrometers, less than
about 125 micrometers, less than about 100 micrometers, less than
about 75 micrometers, less than about 50 micrometers, etc. For
example, in one embodiment, the needle may have a rectangular cross
section having dimensions of 175 micrometers by 50 micrometers. In
one set of embodiments, the needle may have an aspect ratio of
length to largest cross-sectional dimension of at least about 2:1,
at least about 3:1, at least about 4:1, at least 5:1, at least
about 7:1, at least about 10:1, at least about 15:1, at least about
20:1, at least about 25:1, at least about 30:1, etc. In one
embodiment, the needle is a microneedle.
[0108] For example, the needle may be a microneedle such as those
disclosed in U.S. Pat. No. 6,334,856, issued Jan. 1, 2002, entitled
"Microneedle Devices and Methods of Manufacture and Use Thereof,"
by Allen, et al., and the microneedle may be used to deliver and/or
withdraw fluids or other materials to or from the skin of a
subject. The microneedles may be hollow or solid, and may be formed
from any suitable material, e.g., metals, ceramics, semiconductors,
organics, polymers, and/or composites. Examples include, but are
not limited to, pharmaceutical grade stainless steel, titanium,
nickel, iron, gold, tin, chromium, copper, alloys of these or other
metals, silicon, silicon dioxide, and polymers, including polymers
of hydroxy acids such as lactic acid and glycolic acid polylactide,
polyglycolide, polylactide-co-glycolide, and copolymers with
polyethylene glycol, polyanhydrides, polyorthoesters,
polyurethanes, polybutyric acid, polyvaleric acid,
polylactide-co-caprolactone, polycarbonate, polymethacrylic acid,
polyethylenevinyl acetate, polytetrafluorethylene, polymethyl
methacrylate, polyacrylic acid, or polyesters. In some cases, more
than one microneedle may be used. For example, arrays of
microneedles may be used, and the microneedles may be arranged in
the array in any suitable configuration, e.g., periodic, random,
etc. In some cases, the array may have 3 or more, 4 or more, 5 or
more, 6 or more, 10 or more, 15 or more, 20 or more, 35 or more, 50
or more, 100 or more, or any other suitable number of microneedles.
It should be understood that references to "needle" or
"microneedle" as discussed herein are by way of example and ease of
presentation only, and that in other embodiments, more than one
needle and/or microneedle may be present in any of the descriptions
herein.
[0109] As still another example, pressurized fluids may be used to
deliver fluids or other materials into the skin, for instance,
using a jet injector or a "hypospray." Typically, such devices
produce a high-pressure "jet" of liquid or powder (e.g., a
biocompatible liquid, such as saline) that drives material into the
skin, and the depth of penetration may be controlled, for instance,
by controlling the pressure of the jet. The pressure may come from
any suitable source, e.g., a standard gas cylinder or a gas
cartridge. A non-limiting example of such a device can be seen in
U.S. Pat. No. 4,103,684, issued Aug. 1, 1978, entitled
"Hydraulically Powered Hypodermic Injector with Adapters for
Reducing and Increasing Fluid Injection Force," by Ismach.
Pressurization of the liquid may be achieved, for example, using
compressed air or gas, for instance, from a gas cylinder or a gas
cartridge.
[0110] In addition, in certain embodiments, the device may comprise
a portion able to remove at least a portion of the fluid from the
skin. For instance, the device may comprise a hypodermic needle, a
vacuum source, a hygroscopic agent, or the like. In certain cases,
the portion of the device able to remove fluid may also be used to
deliver fluids to the skin. Fluid may be removed from the skin
using any suitable technique. For instance, in one embodiment, the
fluid is removed manually, e.g., by manipulating a plunger on a
syringe. In another embodiment, the fluid can be removed from the
skin mechanically or automatically, e.g., using a piston pump or
the like.
[0111] In some aspects, the device may include channels such as
microfluidic channels, which may be used to deliver and/or withdraw
fluids and/or other materials such as particles into or out of the
skin, e.g., within the pooled region of fluid. In some cases, the
microfluidic channels are in fluid communication with a fluid
transporter that is used to deliver and/or withdraw fluids to or
from the skin. For example, in one set of embodiments, the device
may include a hypodermic needle that can be inserted into the skin,
and fluid may be delivered into the skin via the needle and/or
withdrawn from the skin via the needle. The device may also include
one or more microfluidic channels to contain fluid for delivery to
the needle, e.g., from a source of fluid, and/or to withdraw fluid
from the skin, e.g., for delivery to an analytical compartment
within the device, to a reservoir for later analysis, or the
like.
[0112] One embodiment of a device including microfluidic channels
is now disclosed with reference to FIG. 4A. In this figure, device
80, applicable to skin 87, includes a first compartment 81 and a
second compartment 82. It should be noted that, in some
embodiments, the compartments are not necessarily discrete chambers
as are shown in FIG. 4A, and various compartments may be separated
from each other through the use of controllers such as valves,
membranes, or the like, e.g., as is shown in FIG. 7 with
compartments 81, 82 and 83 and valves 91 and 92. Referring again to
FIG. 4A, device 80 may be, for instance, a patch, an applique, a
mechanical device, etc. First compartment 81 and second compartment
82 may be fluidic communication, e.g., using a microfluidic channel
85. Optionally, a check valve 88 may be used to prevent backflow of
fluid from second compartment 82 into first compartment 81 (or vice
versa, depending on the embodiment). Check valve 88, if present,
may be any valve that preferentially allows fluid flow in one
direction, relative to the opposite direction. For instance, as is
shown in FIG. 5, check valve may comprise one or more hinged
portions that are able to swing in one direction (e.g.,
downstream), but are not able to swing in the opposite direction
(e.g., upstream).
[0113] In one example, vacuum is applied to the device from a
vacuum source attached to channel 89, and the vacuum can be used to
create a suction blister in the skin, as discussed above. For
example, first compartment 81 may include a needle 86 that is used
to access the fluid within the skin, e.g., within a pooled region
of fluid created by the suction blister. Second compartment 82 may
be used, for example, to analyze a component of a fluid withdrawn
from the skin. In another example, channel 89 may be connected to a
source of pressure, and second compartment 82 may contain a fluid
to be delivered to the skin.
[0114] In some cases, more than one compartment may be present
within the device, and in some cases, some or all of the
compartments may be in fluidic communication, e.g., via channels
such as microfluidic channels. In various embodiments, a variety of
compartments and/or channels may be present within the device,
depending on the application. For example, the device may contain
compartments for sensing an analyte, compartments for holding
reagents, compartments for controlling temperature, compartments
for controlling pH or other conditions, compartments for creating
or buffering pressure or vacuum, compartments for controlling or
dampening fluid flow, mixing compartments, or the like.
[0115] As a specific non-limiting example, in FIG. 4B, third
compartment 83 is used to facilitate the creation of pressure or
vacuum within first compartment 81. The compartments may be
arranged in any suitable arrangement, e.g., as shown in FIG. 4B
with first compartment 81 in fluid communication via a first
channel to second compartment 82, which is in fluid communication
via a third channel to third compartment 83. As discussed above,
first compartment 81 may be used to create a vacuum on the skin
and/or access fluid within the skin, facilitated by vacuum created
using third compartment 83, and fluid drawn from the skin may pass
through microfluidic channel 85 (and optional check valve 88) to
enter second compartment 82 for analysis. The analysis of the fluid
may be performed using any suitable technique such as those
described herein. For example, second compartment 82 may contain an
agent able to determine an analyte, e.g., particles producing a
color change which is proportional to the amount of analyte.
[0116] Yet another example is described with reference to FIG. 8,
showing top (FIG. 8A) and side (FIG. 8B) views of an example device
80. In this figure, first compartment 81 and second compartment 82
are in fluidic communication, e.g., using a microfluidic channel
85. A valve 88 separates these compartments. The device may be
"pre-loaded" with a vacuum within second compartment 82, which is
not in fluidic communication with first compartment due to closure
of valve 88. After device 80 is applied to the skin 87 of a
subject, e.g., in an air-tight fashion such that first compartment
81 is not exposed to the external environment, valve 88 may be
opened, thereby allowing first compartment 81 to become fluidically
exposed to the vacuum within second compartment 82. In this way,
vacuum may be applied to the skin via first compartment 81 once
valve 88 has been opened. Thus, certain embodiments of the present
invention are directed to devices able to withdraw a fluid from the
skin, e.g., blood or interstitial fluid, for analysis and/or
storage for later use.
[0117] Thus, in one set of embodiments, the device may include a
microfluidic channel. As used herein, "microfluidic,"
"microscopic," "microscale," the "micro-" prefix (for example, as
in "microchannel"), and the like generally refers to elements or
articles having widths or diameters of less than about 1 mm, and
less than about 100 microns (micrometers) in some cases. In some
embodiments, larger channels may be used instead of, or in
conjunction with, microfluidic channels for any of the embodiments
discussed herein. For examples, channels having widths or diameters
of less than about 10 mm, less than about 9 mm, less than about 8
mm, less than about 7 mm, less than about 6 mm, less than about 5
mm, less than about 4 mm, less than about 3 mm, or less than about
2 mm may be used in certain instances. In some cases, the element
or article includes a channel through which a fluid can flow. In
all embodiments, specified widths can be a smallest width (i.e. a
width as specified where, at that location, the article can have a
larger width in a different dimension), or a largest width (i.e.
where, at that location, the article has a width that is no wider
than as specified, but can have a length that is greater). Thus,
for instance, the microfluidic channel may have an average
cross-sectional dimension (e.g., perpendicular to the direction of
flow of fluid in the microfluidic channel) of less than about 1 mm,
less than about 500 microns, less than about 300 microns, or less
than about 100 microns. In some cases, the microfluidic channel may
have an average diameter of less than about 60 microns, less than
about 50 microns, less than about 40 microns, less than about 30
microns, less than about 25 microns, less than about 10 microns,
less than about 5 microns, less than about 3 microns, or less than
about 1 micron.
[0118] A "channel," as used herein, means a feature on or in an
article (e.g., a substrate) that at least partially directs the
flow of a fluid. In some cases, the channel may be formed, at least
in part, by a single component, e.g. an etched substrate or molded
unit. The channel can have any cross-sectional shape, for example,
circular, oval, triangular, irregular, square or rectangular
(having any aspect ratio), or the like, and can be covered or
uncovered (i.e., open to the external environment surrounding the
channel). In embodiments where the channel is completely covered,
at least one portion of the channel can have a cross-section that
is completely enclosed, and/or the entire channel may be completely
enclosed along its entire length with the exception of its inlet
and outlet.
[0119] A channel may have any aspect ratio, e.g., an aspect ratio
(length to average cross-sectional dimension) of at least about
1:1, at least about 2:1, more typically at least about 3:1, at
least about 5:1, at least about 10:1, etc. As used herein, a
"cross-sectional dimension," in reference to a fluidic or
microfluidic channel, is measured in a direction generally
perpendicular to fluid flow within the channel. A channel generally
will include characteristics that facilitate control over fluid
transport, e.g., structural characteristics and/or physical or
chemical characteristics (hydrophobicity vs. hydrophilicity) and/or
other characteristics that can exert a force (e.g., a containing
force) on a fluid. The fluid within the channel may partially or
completely fill the channel. In some cases the fluid may be held or
confined within the channel or a portion of the channel in some
fashion, for example, using surface tension (e.g., such that the
fluid is held within the channel within a meniscus, such as a
concave or convex meniscus). In an article or substrate, some (or
all) of the channels may be of a particular size or less, for
example, having a largest dimension perpendicular to fluid flow of
less than about 5 mm, less than about 2 mm, less than about 1 mm,
less than about 500 microns, less than about 200 microns, less than
about 100 microns, less than about 60 microns, less than about 50
microns, less than about 40 microns, less than about 30 microns,
less than about 25 microns, less than about 10 microns, less than
about 3 microns, less than about 1 micron, less than about 300 nm,
less than about 100 nm, less than about 30 nm, or less than about
10 nm or less in some cases. In one embodiment, the channel is a
capillary.
[0120] In some cases, the device may contain one or more chambers
or reservoirs for holding fluid. In some cases, the chambers may be
in fluidic communication with one or more fluid transporters and/or
one or more microfluidic channels. For instance, the device may
contain a chamber for collecting fluid withdrawn from a subject
(e.g., for storage and/or later analysis), a chamber for containing
a fluid for delivery to the subject (e.g., blood, saline,
optionally containing drugs, hormones, vitamins, pharmaceutical
agents, or the like), etc.
[0121] A variety of materials and methods, according to certain
aspects of the invention, can be used to form the device, e.g.,
microfluidic channels. For example, various components of the
invention can be formed from solid materials, in which the channels
can be formed via micromachining, film deposition processes such as
spin coating and chemical vapor deposition, laser fabrication,
photolithographic techniques, etching methods including wet
chemical or plasma processes, and the like. See, for example,
Scientific American, 248:44-55, 1983 (Angell, et al).
[0122] In one set of embodiments, various components of the systems
and devices of the invention can be formed of a polymer, for
example, an elastomeric polymer such as polydimethylsiloxane
("PDMS"), polytetrafluoroethylene ("PTFE" or Teflon.RTM.), or the
like. For instance, according to one embodiment, a microfluidic
channel may be implemented by fabricating the fluidic system
separately using PDMS or other soft lithography techniques (details
of soft lithography techniques suitable for this embodiment are
discussed in the references entitled "Soft Lithography," by Younan
Xia and George M. Whitesides, published in the Annual Review of
Material Science, 1998, Vol. 28, pages 153-184, and "Soft
Lithography in Biology and Biochemistry," by George M. Whitesides,
Emanuele Ostuni, Shuichi Takayama, Xingyu Jiang and Donald E.
Ingber, published in the Annual Review of Biomedical Engineering,
2001, Vol. 3, pages 335-373; each of these references is
incorporated herein by reference).
[0123] Other examples of potentially suitable polymers include, but
are not limited to, polyethylene terephthalate (PET), polyacrylate,
polymethacrylate, polycarbonate, polystyrene, polyethylene,
polypropylene, polyvinylchloride, polytetrafluoroethylene, a
fluorinated polymer, a silicone such as polydimethylsiloxane,
polyvinylidene chloride, bis-benzocyclobutene ("BCB"), a polyimide,
a fluorinated derivative of a polyimide, or the like. Combinations,
copolymers, or blends involving polymers including those described
above are also envisioned. The device may also be formed from
composite materials, for example, a composite of a polymer and a
semiconductor material.
[0124] In some embodiments, various components of the invention are
fabricated from polymeric and/or flexible and/or elastomeric
materials, and can be conveniently formed of a hardenable fluid,
facilitating fabrication via molding (e.g. replica molding,
injection molding, cast molding, etc.). The hardenable fluid can be
essentially any fluid that can be induced to solidify, or that
spontaneously solidifies, into a solid capable of containing and/or
transporting fluids contemplated for use in and with the fluidic
network. In one embodiment, the hardenable fluid comprises a
polymeric liquid or a liquid polymeric precursor (i.e. a
"prepolymer"). Suitable polymeric liquids can include, for example,
thermoplastic polymers, thermoset polymers, waxes, metals, or
mixtures or composites thereof heated above their melting point. As
another example, a suitable polymeric liquid may include a solution
of one or more polymers in a suitable solvent, which solution forms
a solid polymeric material upon removal of the solvent, for
example, by evaporation. Such polymeric materials, which can be
solidified from, for example, a melt state or by solvent
evaporation, are well known to those of ordinary skill in the art.
A variety of polymeric materials, many of which are elastomeric,
are suitable, and are also suitable for forming molds or mold
masters, for embodiments where one or both of the mold masters is
composed of an elastomeric material. A non-limiting list of
examples of such polymers includes polymers of the general classes
of silicone polymers, epoxy polymers, and acrylate polymers. Epoxy
polymers are characterized by the presence of a three-membered
cyclic ether group commonly referred to as an epoxy group,
1,2-epoxide, or oxirane. For example, diglycidyl ethers of
bisphenol A can be used, in addition to compounds based on aromatic
amine, triazine, and cycloaliphatic backbones. Another example
includes the well-known Novolac polymers. Non-limiting examples of
silicone elastomers suitable for use according to the invention
include those formed from precursors including the chlorosilanes
such as methylchlorosilanes, ethylchlorosilanes,
phenylchlorosilanes, etc.
[0125] Silicone polymers are used in certain embodiments, for
example, the silicone elastomer polydimethylsiloxane. Non-limiting
examples of PDMS polymers include those sold under the trademark
Sylgard by Dow Chemical Co., Midland, Mich., and particularly
Sylgard 182, Sylgard 184, and Sylgard 186. Silicone polymers
including PDMS have several beneficial properties simplifying
fabrication of the microfluidic structures of the invention. For
instance, such materials are inexpensive, readily available, and
can be solidified from a prepolymeric liquid via curing with heat.
For example, PDMSs are typically curable by exposure of the
prepolymeric liquid to temperatures of about, for example, about
65.degree. C. to about 75.degree. C. for exposure times of, for
example, about an hour. Also, silicone polymers, such as PDMS, can
be elastomeric and thus may be useful for forming very small
features with relatively high aspect ratios, necessary in certain
embodiments of the invention. Flexible (e.g., elastomeric) molds or
masters can be advantageous in this regard.
[0126] One advantage of forming structures such as microfluidic
structures of the invention from silicone polymers, such as PDMS,
is the ability of such polymers to be oxidized, for example by
exposure to an oxygen-containing plasma such as an air plasma, so
that the oxidized structures contain, at their surface, chemical
groups capable of cross-linking to other oxidized silicone polymer
surfaces or to the oxidized surfaces of a variety of other
polymeric and non-polymeric materials. Thus, components can be
fabricated and then oxidized and essentially irreversibly sealed to
other silicone polymer surfaces, or to the surfaces of other
substrates reactive with the oxidized silicone polymer surfaces,
without the need for separate adhesives or other sealing means. In
most cases, sealing can be completed simply by contacting an
oxidized silicone surface to another surface without the need to
apply auxiliary pressure to form the seal. That is, the
pre-oxidized silicone surface acts as a contact adhesive against
suitable mating surfaces. Specifically, in addition to being
irreversibly sealable to itself, oxidized silicone such as oxidized
PDMS can also be sealed irreversibly to a range of oxidized
materials other than itself including, for example, glass, silicon,
silicon oxide, quartz, silicon nitride, polyethylene, polystyrene,
glassy carbon, and epoxy polymers, which have been oxidized in a
similar fashion to the PDMS surface (for example, via exposure to
an oxygen-containing plasma). Oxidation and sealing methods useful
in the context of the present invention, as well as overall molding
techniques, are described in the art, for example, in an article
entitled "Rapid Prototyping of Microfluidic Systems and
Polydimethylsiloxane," Anal. Chem., 70:474-480, 1998 (Duffy et
al.), incorporated herein by reference.
[0127] Another advantage to forming microfluidic structures of the
invention (or interior, fluid-contacting surfaces) from oxidized
silicone polymers is that these surfaces can be much more
hydrophilic than the surfaces of typical elastomeric polymers
(where a hydrophilic interior surface is desired). Such hydrophilic
channel surfaces can thus be more easily filled and wetted with
aqueous solutions than can structures comprised of typical,
unoxidized elastomeric polymers or other hydrophobic materials.
[0128] In some embodiments, the device may be an electrical and/or
a mechanical device applicable or affixable to the surface of the
skin, e.g., using adhesive, or other techniques such as those
described herein. As another example, the device may be a handheld
device that is applied to the surface of the skin of a subject. In
some cases, however, the device may be sufficiently small or
portable that the subject can self-administer the device. In
certain embodiments, the device may also be powered. In some
instances, the device may be applied to the surface of the skin,
and is not inserted into the skin. In other embodiments, however,
at least a portion of the device may be inserted into the skin, for
example, mechanically. For example, in one embodiment, the device
may include a cutter, such as a hypodermic needle, a knife blade, a
piercing element (e.g., a solid or hollow needle), or the like, as
discussed herein.
[0129] In some cases, the device may be designed such that portions
of the device are separable. For example, a first portion of the
device may be removed from the surface of the skin, leaving other
portions of the device behind on the skin. In one embodiment, a
stop may also be included to prevent or control the depth to which
the cutter or other device inserts into the skin, e.g., to control
penetration to the epidermis, dermis, etc.
[0130] Accordingly, as described herein, devices of the invention
can be single-stage or multi-stage in some cases. That is, the
device can define a single unit that includes one or more
components integrally connected to each other which cannot readily
be removed from each other by a user, or can include one or more
components which are designed to be and can readily be removed from
each other. As a non-limiting example of the later, a two-stage
patch can be provided for application to the skin of a subject. The
patch can include a first stage designed to reside proximate the
skin of the subject for the duration of the analysis, which might
include an analysis region, a reservoir or other material for
creating vacuum or otherwise promoting the flow of fluid or other
materials relative to the analysis region, a needle or a
microneedle to access interstitial fluid via suction blister or
without a suction blister or the like. A second stage or portion of
the device can be provided that can initiate operation of the
device. For example, the two stage device can be applied to the
skin of the user. A button or other component or switch associated
with the second portion of the device can be activated by the
subject to cause insertion of a needle or a microneedle to the skin
of the subject, or the like. Then, the second stage can be removed,
e.g., by the subject, and the first stage can remain on the skin to
facilitate analysis. In another arrangement, a two-stage device can
be provided where the first stage includes visualization or other
signal-producing components and the second stage includes
components necessary to facilitate the analysis, e.g., the second
stage can include all components necessary to access bodily fluid,
transport the fluid (if necessary) to a site of analysis, and the
like, and that stage can be removed, leaving only a visualization
stage for the subject or another entity to view or otherwise
analyze as described herein.
[0131] Any or all of the arrangements described herein can be
provided proximate a subject, for example on or proximate a
subject's skin. Activation of the devices can be carried out as
described herein. For example, an on-skin device can be in the form
of a patch or the like, optionally including multiple layers for
activation, sensing, fluid flow, etc. Activation of the devices can
be carried out in a variety of ways. In one manner, a patch can be
applied to a subject and a region of the patch activated (e.g.,
tapped by a user) to inject a needle or a microneedle so as to
access interstitial fluid. The same or a different tapping or
pushing action can activate a vacuum source, open and/or close one
or more of a variety of valves, or the like. The device can be a
simple one in which it is applied to the skin and operates
automatically (where e.g., application to the skin access
interstitial fluid and draws interstitial fluid into an analysis
region) or the patch or other device can be applied to the skin and
one tapping or other activation can cause fluid to flow through
administration of a needle or a microneedle, opening of a valve,
activation of vacuum, or any combination. Any number of activation
protocols can be carried out by a user repeatedly pushing or
tapping a location or selectively, sequentially, and/or
periodically activating a variety of switches (e.g., tapping
regions of a patch). In another arrangement, activation of needles
or microneedles, creation of suction blisters, opening and/or
closing of valves, and other techniques to facilitate one or more
analysis can be carried out electronically or in other manners
facilitated by the subject or by an outside controlling entity. For
example, a device or patch can be provided proximate a subject's
skin and a radio frequency, electromagnetic, or other signal can be
provided by a nearby controller or a distant source to activate any
of the needles, blister devices, valves or other components of the
devices described so that any assay or assays can be carried out as
desired.
[0132] As discussed, various devices of the invention include
various systems and methods for delivering and/or withdrawing fluid
from the subject, according to certain embodiments. For instance,
the device may comprise a hypodermic needle, a vacuum source, a
hygroscopic agent, or the like. Non-limiting examples of suitable
delivery techniques include, but are not limited to, injection
(e.g., using needles such as hypodermic needles) or a jet injector,
such as those discussed below. For instance, in one embodiment, the
fluid is delivered and/or withdrawn manually, e.g., by manipulating
a plunger on a syringe. In another embodiment, the fluid can be
delivered and/or withdrawn from the skin mechanically or
automatically, e.g., using a piston pump or the like. Fluid may
also be withdrawn using vacuums such as those discussed herein. For
example, vacuum may be applied to a conduit, such as a needle, in
fluidic communication with interstitial fluid, e.g., within a
pooled region of fluid, in order to draw up at least a portion of
the fluid from the pooled region. In yet another embodiment, fluid
is withdrawn using capillary action (e.g., using a hypodermic
needle having a suitably narrow inner diameter). In still another
embodiment, pressure may be applied to force fluid out of the
needle.
[0133] In some embodiments, fluids may be delivered to or withdrawn
from the skin using vacuum. The vacuum may be an external vacuum
source, and/or the vacuum source may be self-contained within the
device. For example, vacuums of at least about 50 mmHg, at least
about 100 mmHg, at least about 150 mmHg, at least about 200 mmHg,
at least about 250 mmHg, at least about 300 mmHg, at least about
350 mmHg, at least about 400 mmHg, at least about 450 mmHg, at
least about 500 mmHg, at least 550 mmHg, at least 600 mmHg, at
least 650 mmHg, at least about 700 mmHg, or at least about 750 mmHg
may be applied to the skin. As used herein, "vacuum" refers to
pressures that are below atmospheric pressure.
[0134] In one set of embodiments, a pressure differential (e.g. a
vacuum) may be created by a pressure regulator. As used here,
"pressure regulator" is a pressure controller component or system
able to create a pressure differential between two or more
locations. The pressure differential should be at least sufficient
to urge the movement of fluid or other material in accordance with
various embodiments of the invention as discussed herein, and the
absolute pressures at the two or more locations are not important
so long as their differential is appropriate, and their absolute
values are reasonable for the purposes discussed herein. For
example, the pressure regulator may produce a pressure higher than
atmospheric pressure in one location, relative to a lower pressure
at another location (atmospheric pressure or some other pressure),
where the differential between the pressures is sufficient to urge
fluid in accordance with the invention. In another example, the
regulator or controller will involve a pressure lower than
atmospheric pressure (a vacuum) in one location, and a higher
pressure at another location(s) (atmospheric pressure or a
different pressure) where the differential between the pressures is
sufficient to urge fluid in accordance with the invention. Wherever
"vacuum" or "pressure" is used herein, in association with a
pressure regulator or pressure differential of the invention, it
should be understood that the opposite can be implemented as well,
as would be understood by those of ordinary skill in the art, i.e.,
a vacuum chamber can be replaced in many instances with a pressure
chamber, for creating a pressure differential suitable for urging
the movement of fluid or other material.
[0135] The pressure regulator may be an external source of vacuum
(e.g. a lab, clinic, hospital, etc., house vacuum line or external
vacuum pump), a mechanical device, a vacuum chamber, pre-packaged
vacuum chamber, or the like. Vacuum chambers can be used in some
embodiments, where the device contains, e.g., regions in which a
vacuum exits or can be created (e.g. a variable volume chamber, a
change in volume of which will affect vacuum or pressure). A vacuum
chamber can include pre-evacuated (i.e., pre-packaged) chambers or
regions, and/or self-contained actuators.
[0136] A "self-contained" vacuum (or pressure) regulator means one
that is associated with (e.g., on or within) the device, e.g. one
that defines an integral part of the device, or is a separate
component constructed and arranged to be specifically connectable
to the particular device to form a pressure differential (i.e., not
a connection to an external source of vacuum such as a hospital's,
clinic's, or lab's house vacuum line, or a vacuum pump suitable for
very general use). In some embodiments, the self-contained vacuum
source may be actuated in some fashion to create a vacuum within
the device. For instance, the self-contained vacuum source may
include a piston, a syringe, a mechanical device such as a vacuum
pump able to create a vacuum within the device, and/or chemicals or
other reactants that can react to increase or decrease pressure
which, with the assistance of mechanical or other means driven by
the reaction, can form a pressure differential associated with a
pressure regulator. Chemical reaction can also drive mechanical
actuation with or without a change in pressure based on the
chemical reaction itself. A self-contained vacuum source can also
include an expandable foam, a shape memory material, or the
like.
[0137] One category of self-contained vacuum or pressure regulators
of the invention includes self-contained assisted regulators. These
are regulators that, upon actuation (e.g., the push of a button, or
automatic actuation upon, e.g., removal from a package or urging a
device against the skin), a vacuum or pressure associated with the
device is formed where the force that pressurizes or evacuates a
chamber is not the same as the actuation force. Examples of
self-contained assisted regulators include chambers evacuated by
expansion driven by a spring triggered by actuation, release of a
shape-memory material or expandable material upon actuation,
initiation of a chemical reaction upon actuation, or the like.
[0138] Another category of self-contained vacuum or pressure
regulators of the invention are devices that are not necessarily
pre-packaged with pressure or vacuum, but which can be pressurized
or evacuated, e.g. by a subject, health care professional at a
hospital or clinic prior to use, e.g. by connecting a chamber of
the device to a source of vacuum or pressure. For example, the
subject, or another person, may actuate the device to create a
pressure or vacuum within the device, for example, immediately
prior to use of the device.
[0139] The vacuum or pressure regulator may be a "pre-packaged"
pressure or vacuum chamber in the device when used (i.e., the
device can be provided ready for use by a subject or practitioner
with an evacuated region on or in the device, without the need for
any actuation to form the initial vacuum). A pre-packaged pressure
or vacuum chamber regulator can, e.g., be a region evacuated
(relative to atmospheric pressure) upon manufacture and/or at some
point prior to the point at which it is used by a subject or
practitioner. For example, a chamber is evacuated upon manufacture,
or after manufacture but before delivery of the device to the user,
e.g. the clinician or subject. For instance, in some embodiments,
the device contains a vacuum chamber having a vacuum of at least
about 50 mmHg, at least about 100 mmHg, at least about 150 mmHg, at
least about 200 mmHg, at least about 250 mmHg, at least about 300
mmHg, at least about 350 mmHg, at least about 400 mmHg, at least
about 450 mmHg, at least about 500 mmHg, at least about 550 mmHg,
at least about 600 mmHg, at least about 650 mmHg, at least about
700 mmHg, or at least about 750 mmHg below atmospheric
pressure.
[0140] In some cases, the device may be applicable or affixable to
the surface of the skin. For example, in one set of embodiments,
the device may include a support structure that contains an
adhesive that can be used to immobilize the device to the skin. The
adhesive may be permanent or temporary, and may be used to affix
the device to the surface of the skin. The adhesive may be any
suitable adhesive, for example, a pressure sensitive adhesive, a
contact adhesive, a permanent adhesive, a hydrogel adhesive, a
cyanoacrylate, glue, gum, hot melts, epoxy, or the like. In most
cases, the adhesive is chosen to be biocompatible or
hypoallergenic.
[0141] In another set of embodiments, the device may be
mechanically held to the skin, for example, the device may include
mechanical elements such as straps, belts, buckles, strings, ties,
elastic bands, or the like. For example, a strap may be worn around
the device to hold the device in place against the skin of the
subject. In yet another set of embodiments, a combination of these
and/or other techniques may be used. As one non-limiting example,
the device may be affixed to a subject's arm or leg using adhesive
and a strap.
[0142] In some embodiments, the device may include a support
structure for application to the skin of the subject. The support
structure may be used, as discussed herein, for applying the fluid
transporter to the surface of the skin of the subject, e.g., so
that fluid may be delivered and/or withdrawn from the skin of the
subject. In some cases, the support structure may immobilize the
fluid transporter such that the fluid transporter cannot move
relative to the support structure; in other cases, however, the
fluid transporter may be able to move relative to the support
structure. In one embodiment, as a non-limiting example, the fluid
transporter is immobilized relative to the support structure, and
the support structure is positioned within the device such that
application of the device to the skin causes at least a portion of
the fluid transporter to pierce the skin of the subject.
[0143] For instance, in one set of embodiments, the support
structure, or a portion of the support structure, may move from a
first position to a second position. For example, the first
position may be one where the support structure has been
immobilized relative thereto a fluid transporter does not contact
the skin (e.g., the fluid transporter may be contained within a
recess), while the second position may be one where the fluid
transporter does contact the skin, and in some cases, the fluid
transporter may pierce the skin. The support structure may be moved
using any suitable technique, e.g., manually, mechanically,
electromagnetically, using a servo mechanism, or the like. In one
set of embodiments, for example, the support structure may be moved
from a first position to a second position by pushing a button on
the device, which causes the support structure to move (either
directly, or through a mechanism linking the button with the
support structure). Other mechanisms (e.g., dials, etc., as
discussed herein) may be used in conjunction of or instead of a
button. In another set of embodiments, the support structure may be
moved from a first position to a second position automatically, for
example, upon activation by a computer, upon remote activation,
after a period of time has elapsed, or the like. For example, in
one embodiment, a servo connected to the support structure is
activated electronically, moving the support structure from the
first position to the second position.
[0144] In some cases, the support structure may also be moved from
the second position to the first position. For example, after fluid
has been delivered and/or withdrawn from the skin, e.g., using a
fluid transporter the support structure may be moved, which may
move the fluid transporter away from contact with the skin. The
support structure may be moved from the second position to the
first position using any suitable technique, including those
described above, and the technique for moving the support structure
from the second position to the first position may be the same or
different as that moving the support structure from the first
position to the second position.
[0145] In some cases, the support structure may be able to draw
skin towards the fluid transporter. For example, in one set of
embodiments, the support structure may include a vacuum interface,
such as is described herein. The interface may be connected with a
vacuum source (external and/or internal to the device), and when a
vacuum is applied, skin may be drawn towards the support structure,
e.g., for contact with a fluid transporter, such as one or more
needles and/or microneedles.
[0146] In certain embodiments, the device may also contain an
activator. The activator may be constructed and arranged to cause
exposure of the fluid transporter to the skin upon activation of
the activator. For example, the activator may cause a chemical to
be released to contact the skin, a needle to be driven into the
skin, a vacuum to be applied to the skin, a jet of fluid to be
directed to the skin, or the like. The activator may be activated
by the subject, and/or by another person (e.g., a health care
provider), or the device itself may be self-activating, e.g., upon
application to the skin of a subject. The activator may be
activated once, or multiple times in some cases.
[0147] The device may be activated, for example, by pushing a
button, pressing a switch, moving a slider, turning a dial, or the
like. The subject, and/or another person, may activate the
activator. In some cases, the device may be remotely activated. For
example, a health care provider may send an electromagnetic signal
which is received by the device in order to activate the device,
e.g., a wireless signal, a Bluetooth signal, an Internet signal, a
radio signal, etc.
[0148] In one set of embodiments, the device may also include a
sensor, for example embedded within or integrally connected to the
device, or positioned remotely but with physical, electrical,
and/or optical connection with the device so as to be able to sense
a compartment within the device. For example, the sensor may be in
fluidic communication with fluid withdrawn from a subject,
directly, via a microfluidic channel, an analytical chamber, etc.
The sensor may be able to sense an analyte, e.g., one that is
suspected of being in a fluid withdrawn from a subject. For
example, a sensor may be free of any physical connection with the
device, but may be positioned so as to detect the results of
interaction of electromagnetic radiation, such as infrared,
ultraviolet, or visible light, which has been directed toward a
portion of the device, e.g., a compartment within the device. As
another example, a sensor may be positioned on or within the
device, and may sense activity in a compartment by being connected
optically to the compartment. Sensing communication can also be
provided where the compartment is in communication with a sensor
fluidly, optically or visually, thermally, pneumatically,
electronically, or the like, so as to be able to sense a condition
of the compartment. As one example, the sensor may be positioned
downstream of a compartment, within a channel such a microfluidic
channel, or the like.
[0149] The sensor may be, for example, a pH sensor, an optical
sensor, an oxygen sensor, a sensor able to detect the concentration
of a substance, or the like. Other examples of analytes that the
sensor may be used to determine include, but are not limited to,
metal ions, proteins, nucleic acids (e.g. DNA, RNA, etc.), drugs,
sugars (e.g., glucose), hormones (e.g., estradiol, estrone,
progesterone, progestin, testosterone, androstenedione, etc.),
carbohydrates, or other analytes of interest. Non-limiting examples
of sensors useful in the invention include dye-based detection
systems, affinity-based detection systems, microfabricated
gravimetric analyzers, CCD cameras, optical detectors, optical
microscopy systems, electrical systems, thermocouples and
thermistors, pressure sensors, etc. Those of ordinary skill in the
art will be able to identify other sensors for use in the
invention. The sensor can include a colorimetric detection system
in some cases, which may be external to the device, or
microfabricated into the device in certain cases. As an example of
a colorimetric detection system, if a dye or a fluorescent entity
is used (e.g. in a particle), the colorimetric detection system may
be able to detect a change or shift in the frequency and/or
intensity of the dye or fluorescent entity.
[0150] As described herein, any of a variety of signaling or
display methods, associated with analyses, can be provided
including signaling visually, by smell, sound, feel, taste, or the
like, in one set of embodiments. Signal structures and generators
include, but are not limited to, displays (visual, LED, light,
etc.), speakers, chemical-releasing compartments (e.g., containing
a volatile chemical), mechanical devices, heaters, coolers, or the
like. In some cases, the signal structure or generator may be
integral with the device (e.g., integrally connected with a support
structure for application to the skin of the subject, e.g.,
containing a fluid transporter such as a needle or a microneedle),
or the signal structure or generator may not be integrally
connected with the support structure. As used herein, a "signal
structure" or a "signal generator" is any apparatus able to
generate a signal that is related to a condition of a medium. For
example, the medium may be a bodily fluid, such as blood or
interstitial fluid.
[0151] In some embodiments, signaling methods such as these may be
used to indicate the presence and/or concentration of an analyte
determined by the sensor, e.g., to the subject, and/or to another
entity, such as those described below. Where a visual signal is
provided, it can be provided in the form of change in opaqueness, a
change in intensity of color and/or opaqueness, or can be in the
form of a message (e.g., numerical signal, or the like), an icon
(e.g., signaling by shape or otherwise a particular medical
condition), a brand, logo, or the like. For instance, in one
embodiment, the device may include a display. A written message
such as "take next dose," or "glucose level is high" or a numerical
value might be provided, or a message such as "toxin is present."
These messages, icons, logos, or the like can be provided as an
electronic read-out by a component of a device and/or can be
displayed as in inherent arrangement of one or more components of
the device.
[0152] In some embodiments, a device is provided where the device
determines a physical condition of a subject and produces a signal
related to the condition that can be readily understood by the
subject (e.g., by provision of a visual "OK" signal as described
above) or can be designed so as not to be readily understandable by
a subject. Where not readily understandable, the signal can take a
variety of forms. In one form, the signal might be a series of
letters or numbers that mean nothing to the subject (e.g.,
A1278CDQ) which would have meaning to a medical professional or the
like (and/or be decodable by the same, e.g., with reference to a
suitable decoder) and can be associated with a particular
physiological condition. Alternatively, a signal in the form of bar
code can be provided by a device such that, under a particular
condition or set of conditions the bar code appears and/or
disappears, or changes, and can be read by a bar code reader to
communicate information about the subject or analyte. In another
embodiment, the device can be designed such that an ultraviolet
signal is produced, or a signal that can be read only under
ultraviolet light (e.g., a simple spot or patch, or any other
signal such as a series of number, letters, bar code, message, or
the like that can be readily understandable or not readily
understandable by a subject) can be provided. The signal may be
invisible to the human eye but, upon application UV light or other
excitation energy, may be readable. The signal can be easily
readable or understandable by a user via visual observation, or
with other sensory activity such as smell, feel, etc. In another
set of embodiments equipment as described above may be needed to
determine a signal provided by the device, such as equipment in a
clinical setting, etc. In some cases, the device is able to
transmit a signal indicative of the analyte to a receiver, e.g., as
a wireless signal, a Bluetooth signal, an Internet signal, a radio
signal, etc.
[0153] In some embodiments, quantitative and/or qualitative
analyses can be provided by a device. That is, the device in some
cases may provide analyses that allow "yes/no" tests or the like,
or tests that provide information on the quantity, concentration,
or level of a particular analyte or analytes. Display
configurations can be provided by the invention that reflect the
amount of a particular analyte present in a subject at a particular
point in time, or any other variable (presence of analysis over
time, type of analyte, etc.) display configurations can take a
variety of forms. In one example, a dial can be provided, similar
to that of a speedometer with a series of level indications (e.g.,
numbers around the dial) and a "needle" or other device that
indicates a particular level. In other configurations, a particular
area of the device (e.g., on a display) can exist that is filled in
to a greater or lesser extent depending upon the presence and/or
quantity of a particular analyte present, e.g., in the form of a
bar graph. In another arrangement a "color wheel" can be provided
where the amount of a particular analyte present can control which
colors of the wheel are visible. Or, different analytes can cause
different colors of a wheel or different bars of a graph to become
visible or invisible in a multiple analyte analysis.
Multiple-analyte quantitative analyses can be reflected in multiple
color wheels, a single color wheel with different colors per
analyte where the intensity of each color reflects the amount of
the analyte, or, for example, a plurality of bar graphs where each
bar graph is reflective of a particular analyte and the level of
the bar (and/or degree to which an area is filled in with visible
color or other visible feature) is reflective of the amount of the
analyte. As with all embodiments here, whatever signal is displayed
can be understandable or not understandable to any number of
participants. For example, it can be understandable to a subject or
not understandable to a subject. Where not understandable it might
need to be decoded, read electronically, or the like. Where read
electronically, for example, a device may provide a signal that is
not understandable to a subject or not even visible or otherwise
able to be sensed by a subject, and a reader can be provided
adjacent or approximate to the device that can provide a visible
signal that is understandable or not understandable to the subject,
or can transmit a signal to another entity for analysis.
[0154] In connection with any signals associated with any analyses
described herein, another, potentially related signal or other
display (or smell, taste, or the like) can be provided which can
assist in interpreting and/or evaluating the signal. In one
arrangement, a calibration or control is provided proximate to (or
otherwise easily comparable with) a signal, e.g., a visual
calibration/control or comparator next to or close to a visual
signal provided by a device and/or implanted agents, particles, or
the like.
[0155] A visual control or reference can be used with another
sensory signal, such as that of smell, taste, temperature, itch,
etc. A reference/control and/or experimental confirmation component
can be provided, to be used in connection with an in-skin test or
vice versa. References/indicators can also be used to indicate the
state of life of a device, changing color or intensity and/or
changing in another signaling aspect as the device changes relative
to its useful life, so that a user can determine when the device
should no longer be relied upon and/or removed. For certain
devices, an indicator or control can be effected by adding analyte
to the control (e.g., from a source outside of the source to be
determine) to confirm operability of the device and/or to provide a
reference against which to measure a signal of the device. For
example, a device can include a button to be tapped by a user which
will allow an analyte from a reservoir to transfer to an indicator
region to provide a signal, to demonstrate operability of the
device and/or provide a comparator for analysis.
[0156] Many of the embodiments described herein involve a
quantitative analysis and related signal, i.e., the ability to
determine the relative amount or concentration of an analyte in a
medium. This can be accomplished in a variety of ways. For example,
where an agent (e.g. a binding partner attached to a nanoparticle)
is used to capture and analyze an analyte, the agent can be
provided in a gradient in concentration across a sensing region of
the device. Or a sensing region can include a membrane or other
apparatus through which analyte is required to flow or pass prior
to capture and identification, and the pathway for analyte travel
can vary as a function of position of display region. For example,
a membrane can be provided across a sensing region, through which
analyte must pass prior to interacting with a layer of binding
and/or signaling agent, and the membrane may vary in thickness
laterally in a direction related to "bar graph" readout. Where a
small amount of analyte is present, it may pass through the thinner
portion but not the thicker portion of the membrane, but where a
larger amount is present, it may pass across a thicker portion. The
boundary (where one exists) between a region through which analyte
passes, and one through which it does not completely pass, can
define the "line" of the bar graph. Other ways of achieving the
same or a similar result can include varying the concentration of a
scavenger or transporter of the analyte, or an intermediate
reactive species (between analyte and signaling event), across a
membrane or other article, gradient in porosity or selectivity of
the membrane, ability to absorb or transport sample fluid, or the
like. These principles, in combination with other disclosure
herein, can be used to facilitate any or all of the quantitative
analyses described herein.
[0157] In one set of embodiments, a subject having a condition such
as a physiological condition to be analyzed (or other user, such as
medical personnel) reads and/or otherwise determines a signal from
a device. For example, the device may transmit a signal indicative
of a condition of the subject and/or the device. Alternatively, or
in addition, a signal produced by a device can be acquired in the
form of a representation (e.g. a digitized signal, or the like) and
transmitted to another entity for analysis and/or action. For
example, a signal can be produced by a device, e.g., based on a
sensor reading of an analyte, based on fluid delivered and/or
withdrawn from the skin, based on a condition of the device, or the
like. The signal may represent any suitable data or image. For
example, the signal may represent the presence and/or concentration
of an analyte in fluid withdrawn from a subject, the amount of
fluid withdrawn from a subject and/or delivered to the subject, the
number of times the device has been used, the battery life of the
device, the amount of vacuum left in the device, the cleanliness or
sterility of the device, the identity of the device (e.g., where
multiple devices are given unique identification numbers, to
prevent counterfeiting, accidental exchange of equipment to
incorrect users, etc.), or the like. For instance, in one set of
embodiments, an image of the signal (e.g., a visual image or
photograph) can be obtained and transmitted to a different entity
(for example, a user can take a cell phone picture of a signal
generated by the device and send it, via cell phone, the other
entity).
[0158] The other entity that the signal is transmitted to can be a
human (e.g., a clinician) or a machine. In some cases, the other
entity may be able to analyze the signal and take appropriate
action. In one arrangement, the other entity is a machine or
processor that analyzes the signal and optionally sends a signal
back to the device to give direction as to activity (e.g., a cell
phone can be used to transmit an image of a signal to a processor
which, under one set of conditions, transmits a signal back to the
same cell phone giving direction to the user, or takes other
action). Other actions can include automatic stimulation of the
device or a related device to dispense a medicament or
pharmaceutical, or the like. The signal to direct dispensing of a
pharmaceutical can take place via the same used to transmit the
signal to the entity (e.g., cell phone) or a different vehicle or
pathway. Telephone transmission lines, wireless networks, Internet
communication, and the like can also facilitate communication of
this type.
[0159] As one specific example, a device may be a glucose monitor.
As signal may be generated by the device and an image of the signal
captured by a cell phone camera and then transmitted via cell phone
to a clinician. The clinician may then determine that the glucose
(or e.g., insulin) level is appropriate or inappropriate and send a
message indicating this back to the subject via cell phone.
[0160] Information regarding the analysis can also be transmitted
to the same or a different entity, or a different location simply
by removing the device or a portion of the device from the subject
and transferring it to a different location. For example, a device
can be used in connection with a subject to analyze presence and/or
amount of a particular analyte. At some point after the onset of
use, the device, or a portion of the device carrying a signal or
signals indicative of the analysis or analyses, can be removed and,
e.g., attached to a record associated with the subject. As a
specific example, a patch or other device can be worn by a subject
to determine presence and/or amount of one or more analytes
qualitatively, quantitatively, and/or over time. The subject can
visit a clinician who can remove the patch (or other device) or a
portion of the patch and in some cases, attach it to a medical
record associated with the subject.
[0161] According to various sets of embodiments, the device may be
used one, or multiple times, depending on the application. For
instance, obtaining samples for sensing, according to certain
embodiments of the invention, can be done such that sensing can be
carried out continuously, discretely, or a combination of these.
For example, where a bodily fluid such as blood or interstitial
fluid is accessed for determination of an analyte, fluid can be
accessed discretely (i.e., as a single dose, once or multiple
times), or continuously by creating a continuous flow of fluid
which can be analyzed once or any number of times. Additionally,
testing can be carried out once, at a single point in time, or at
multiple points in time, and/or from multiple samples (e.g., at
multiple locations relative to the subject).
[0162] Alternatively or in addition, testing can be carried out
continuously over any number of points in time involving one or any
number of locations relative to the subject or other multiple
samples. As an example, one bolus or isolated sample, of fluid such
as interstitial fluid can be obtained. From that fluid a test can
be carried out to determine whether a particular analyte or other
agent exists in the fluid. Alternatively, two or more tests can be
carried out involving that quantity of fluid to determine the
presence and/or quantity of two or more analytes, and any number of
such tests can be carried out. Tests involving that quantity of
fluid can be carried out simultaneously or over a period of time.
For example, a test for a particular analyte can be carried out at
various points in time to determine whether the result changes over
time, or different analytes can be determined at different points
in time. As another example, a pool of fluid can be formed between
layers of skin via, e.g., a suction blister and either within the
suction blister or from fluid drawn from the suction blister and
placed elsewhere, any of the above and other analysis can be
carried out at one or more points in time. Where a suction blister
is formed in such a way that interstitial fluid within the blister
changes over time (where an equilibrium exists between interstitial
fluid within the subject and interstitial fluid in the suction
blister itself, i.e., the fluid within the blister is ever changing
to reflect the content of the interstitial fluid of the subject in
the region of the blister over time). Testing of fluid within or
from the suction blister at various points in time can provide
useful information.
[0163] In another example, a needle or a microneedle, or other
device(s) can be used to access a fluid of a subject such as
interstitial fluid (with or without use of a suction blister).
Fluid can be drawn to a point of analysis and analyzed in any
manner described herein. For example, an analysis can be carried
out once, to determine the presence and/or quantity of a single
analyte, or a number of tests can be carried out. From a single
sample of fluid, a particular test or number of tests can be
carried out essentially simultaneously, or analyses can be carried
out over time. Moreover, fluid can be drawn continuously from the
subject and one or more tests can be carried out of any number of
points in time. A variety of reasons for carrying out one or more
tests over the course of time exists, as would be understood by
those of ordinary skill in the art. One such reason is to determine
whether the quantity or another characteristic of an analyte is
constant in a subject, or changes over time. A variety of specific
techniques for continuous and/or discrete testing will be described
herein.
[0164] In some cases, the device may comprise a cutter able to cut
or pierce the surface of the skin. The cutter may comprise any
mechanism able to create a path to a fluid within the skin, e.g.,
through which fluids may be delivered and/or removed from the skin.
For example, the cutter may comprise a hypodermic needle, a knife
blade, a piercing element (e.g., a solid or a hollow needle), or
the like, which can be applied to the skin to create a suitable
conduit for the withdrawal of fluid from the skin. In one
embodiment, a cutter is used to create such a pathway and removed,
then fluid is removed via this pathway using any suitable
technique. In another embodiment, the cutter remains in place
within the skin, and fluid may be drawn through a conduit within
the cutter.
[0165] In some embodiments, fluid may be withdrawn using an
electric charge. For example, reverse iontophoresis may be used.
Without wishing to be bound by any theory, reverse iontophoresis
uses a small electric current to drive charged and highly polar
compounds across the skin. Since the skin is negatively charged at
physiologic pH, it acts as a permselective membrane to cations, and
the passage of counterions across the skin induces an
electroosmotic solvent flow that may carry neutral molecules in the
anode-to-cathode direction. Components in the solvent flow may be
analyzed as described elsewhere herein. In some instances, a
reverse iontophoresis apparatus may comprise an anode cell and a
cathode cell, each in contact with the skin. The anode cell may be
filled, for example, with an aqueous buffer solution (i.e., aqueous
Tris buffer) having a pH greater than 4 and an electrolyte (i.e.
sodium chloride). The cathode cell can be filled with aqueous
buffer. As one example, a first electrode (e.g., an anode) can be
inserted into the anode cell and a second electrode (e.g., a
cathode) can be inserted in the cathode cell. In some embodiments,
the electrodes are not in direct contact with the skin.
[0166] A current may be applied to induce reverse iontophoresis,
thereby extracting a fluid from the skin. The current applied may
be, for example, greater than 0.01 mA, greater than 0.3 mA, greater
than 0.1 mA, greater than 0.3 mA, greater than 0.5 mA, or greater
than 1 mA. It should be understood that currents outside these
ranges may be used as well. The current may be applied for a set
period of time. For example, the current may be applied for greater
than 30 seconds, greater than 1 minute, greater than 5 minutes,
greater than 30 minutes, greater than 1 hour, greater than 2 hours,
or greater than 5 hours. It should be understood that times outside
these ranges may be used as well.
[0167] In one set of embodiments, the device may comprise an
apparatus for ablating the skin. Without wishing to be bound by any
theory, it is believed that ablation comprises removing a
microscopic patch of stratum corneum (i.e., ablation forms a
micropore), thus allowing access to bodily fluids. In some cases,
thermal, radiofrequency, and/or laser energy may be used for
ablation. In some instances, thermal ablation may be applied using
a heating element. Radiofrequency ablation may be carried out using
a frequency and energy capable of heating water and/or tissue. A
laser may also be used to irradiate a location on the skin to
remove a portion. In some embodiments, the heat may be applied in
pulses such that a steep temperature gradient exists essentially
perpendicular to the surface of the skin. For example, a
temperature of at least 100.degree. C., at least 200.degree. C., at
least 300.degree. C., or at least 400.degree. C. may be applied for
less than 1 second, less than 0.1 seconds, less than 0.01 seconds,
less than 0.005 seconds, or less than 0.001 seconds.
[0168] In some embodiments, the device may comprise a mechanism for
taking a solid sample of tissue. For example, a solid tissue sample
may be acquired by methods such as scraping the skin or cutting out
a portion. Scraping may comprise a reciprocating action whereby an
instrument is scraped along the surface of the skin in two or more
directions. Scraping can also be accomplished by a rotating action,
for example parallel to the surface of the skin and in one
direction (i.e., with a roller drum) or parallel to the surface of
the skin and in a circular manner (i.e., with a drilling
instrument). A cutting mechanism may comprise a blade capable of
making one or more incisions and a mechanism for removing a portion
of tissue (i.e., by suction or mechanically picking up) or may use
a pincer mechanism for cutting out a portion of tissue. A cutting
mechanism may also function by a coring action. For example, a
hollow cylindrical device can be penetrated into the skin such that
a cylindrical core of tissue may be removed. A solid sample may be
analyzed directly or may be liquefied prior to analysis.
Liquefaction can comprise treatment with organic solvents,
enzymatic solutions, etc.
[0169] In some cases, the device may contain a shape memory polymer
and/or metal, for example, one that is sensitive to heat. Upon
insertion into the skin between the epidermis and dermis, the shape
memory polymer may expand in some fashion, allowing separation of
the epidermis and the dermis to occur. Non-limiting examples of
shape-memory polymers and metals include Nitinol, compositions of
oligo(epsilon-caprolactone)diol and crystallisable
oligo(rho-dioxanone)diol, or compositions of
oligo(epsilon-caprolactone)dimethacrylate and n-butyl acrylate. For
example, the shape memory polymer (or metal) may have a first,
condensed shape at a temperature below the body temperature of the
subject, but upon insertion into the skin, the cutter heats and
assumes a second, larger shape that causes at least some separation
to occur between the epidermis and dermis.
[0170] The device, in certain embodiments, may also contain a
portion able to determine the fluid removed from the skin. For
example, a portion of the device may contain a sensor, or reagents
able to interact with an analyte contained or suspected to be
present within the withdrawn fluid from the subject, for example, a
marker for a disease state. As non-limiting examples, the sensor
may contain an antibody able to interact with a marker for a
disease state, an enzyme such as glucose oxidase or glucose
1-dehydrogenase able to detect glucose, or the like. The analyte
may be determined quantitatively or qualitatively, and/or the
presence or absence of the analyte within the withdrawn fluid may
be determined in some cases. Those of ordinary skill in the art
will be aware of many suitable commercially-available sensors, and
the specific sensor used may depend on the particular analyte being
sensed. For instance, various non-limiting examples of sensor
techniques include pressure or temperature measurements,
spectroscopy such as infrared, absorption, fluorescence,
UV/visible, FTIR ("Fourier Transform Infrared Spectroscopy"), or
Raman; piezoelectric measurements; immunoassays; electrical
measurements, electrochemical measurements (e.g., ion-specific
electrodes); magnetic measurements, optical measurements such as
optical density measurements; circular dichroism; light scattering
measurements such as quasielectric light scattering; polarimetry;
refractometry; chemical indicators such as dyes; or turbidity
measurements, including nephelometry.
[0171] As mentioned, certain aspects of the present invention are
generally directed to particles such as anisotropic particles or
colloids, which can be used in a wide variety of applications. For
instance, the particles may be present within the skin, or
externally of the skin, e.g., in a device on the surface of the
skin. The particles may include microparticles and/or
nanoparticles. As discussed above, a "microparticle" is a particle
having an average diameter on the order of micrometers (i.e.,
between about 1 micrometer and about 1 mm), while a "nanoparticle"
is a particle having an average diameter on the order of nanometers
(i.e., between about 1 nm and about 1 micrometer. The particles may
be spherical or non-spherical, in some cases. For example, the
particles may be oblong or elongated, or have other shapes such as
those disclosed in U.S. patent application Ser. No. 11/851,974,
filed Sep. 7, 2007, entitled "Engineering Shape of Polymeric Micro-
and Nanoparticles," by S. Mitragotri, et al.; International Patent
Application No. PCT/US2007/077889, filed Sep. 7, 2007, entitled
"Engineering Shape of Polymeric Micro- and Nanoparticles," by S.
Mitragotri, et al., published as WO 2008/031035 on Mar. 13, 2008;
U.S. patent application Ser. No. 11/272,194, filed Nov. 10, 2005,
entitled "Multi-phasic Nanoparticles," by J. Lahann, et al.,
published as U.S. Patent Application Publication No. 2006/0201390
on Sep. 14, 2006; or U.S. patent application Ser. No. 11/763,842,
filed Jun. 15, 2007, entitled "Multi-Phasic Bioadhesive Nan-Objects
as Biofunctional Elements in Drug Delivery Systems," by J. Lahann,
published as U.S. Patent Application Publication No. 2007/0237800
on Oct. 11, 2007, each of which is incorporated herein by
reference.
[0172] An "anisotropic" particle, as used herein, is one that is
not spherically symmetric (although the particle may still exhibit
various symmetries), although the particle may have sufficient
asymmetry to carry out at least some of the goals of the invention
as described herein. On the basis of the present disclosure, this
will be clearly understood by those of ordinary skill in the art.
The asymmetry can be asymmetry of shape, of composition, or both.
As an example, a particle having the shape of an egg or an American
football is not perfectly spherical, and thus exhibits anisotropy.
As another example, a sphere painted such that exactly one half is
red and one half is blue (or otherwise presents different surface
characteristics on different sides) is also anisotropic, as it is
not perfectly spherically symmetric, although it would still
exhibit at least one axis of symmetry.
[0173] Accordingly, a particle may be anisotropic due to its shape
and/or due to two or more regions that are present on the surface
of and/or within the particle. For instance, the particle may
include a first surface region and a second surface region that is
distinct from the first region in some way, e.g., due to
coloration, surface coating, the presence of one or more reaction
entities, etc. The particle may include different regions only on
its surface or the particle may internally include two or more
different regions, portions of which extend to the surface of the
particle. The regions may have the same or different shapes, and be
distributed in any pattern on the surface of the particle. For
instance, the regions may divide the particle into two hemispheres,
such that each hemisphere has the same shape and/or the same
surface area, or the regions may be distributed in more complex
arrangements.
[0174] Non-limiting examples of particles can be seen in U.S.
patent application Ser. No. 11/272,194, filed Nov. 10, 2005,
entitled "Multi-phasic Nanoparticles," by J. Lahann, et al.,
published as U.S. Patent Application Publication No. 2006/0201390
on Sep. 14, 2006; U.S. patent application Ser. No. 11/763,842,
filed Jun. 15, 2007, entitled "Multi-Phasic Bioadhesive Nan-Objects
as Biofunctional Elements in Drug Delivery Systems," by J. Lahann,
published as U.S. Patent Application Publication No. 2007/0237800
on Oct. 11, 2007; or U.S. Provisional Patent Application Ser. No.
61/058,796, filed Jun. 4, 2008, entitled "Compositions and Methods
for Diagnostics, Therapies, and Other Applications," by D.
Levinson, each of which is incorporated herein by reference.
[0175] The particles (which may be anisotropic, or not anisotropic)
may be formed of any suitable material, depending on the
application. For example, the particles may comprise a glass,
and/or a polymer such as polyethylene, polystyrene, silicone,
polyfluoroethylene, polyacrylic acid, a polyamide (e.g., nylon),
polycarbonate, polysulfone, polyurethane, polybutadiene,
polybutylene, polyethersulfone, polyetherimide, polyphenylene
oxide, polymethylpentene, polyvinylchloride, polyvinylidene
chloride, polyphthalamide, polyphenylene sulfide, polyester,
polyetheretherketone, polyimide, polymethylmethacylate and/or
polypropylene. In some cases, the particles may comprise a ceramic
such as tricalcium phosphate, hydroxyapatite, fluorapatite,
aluminum oxide, or zirconium oxide. In some cases (for example, in
certain biological applications), the particles may be formed from
biocompatible and/or biodegradable polymers such as polylactic
and/or polyglycolic acids, polyanhydride, polycaprolactone,
polyethylene oxide, polyacrylamide, polyacrylic acid, polybutylene
terephthalate, starch, cellulose, chitosan, and/or combinations of
these. In one set of embodiments, the particles may comprise a
hydrogel, such as agarose, collagen, or fibrin. The particles may
include a magnetically susceptible material in some cases, e.g., a
material displaying paramagnetism or ferromagnetism. For instance,
the particles may include iron, iron oxide, magnetite, hematite, or
some other compound containing iron, or the like. In another
embodiment, the particles can include a conductive material (e.g.,
a metal such as titanium, copper, platinum, silver, gold, tantalum,
palladium, rhodium, etc.), or a semiconductive material (e.g.,
silicon, germanium, CdSe, CdS, etc.). Other particles potentially
useful in the practice of the invention include ZnS, ZnO,
TiO.sub.2, AgI, AgBr, HgI.sub.2, PbS, PbSe, ZnTe, CdTe,
In.sub.2S.sub.3, In.sub.2Se.sub.3, Cd.sub.3P.sub.2,
Cd.sub.3As.sub.2, InAs, or GaAs. The particles may include other
species as well, such as cells, biochemical species such as nucleic
acids (e.g., RNA, DNA, PNA, etc.), proteins, peptides, enzymes,
nanoparticles, quantum dots, fragrances, indicators, dyes,
fluorescent species, chemicals, small molecules (e.g., having a
molecular weight of less than about 1 kDa), or the like.
[0176] As an example, certain particles or colloids such as gold
nanoparticles can be coated with agents capable of interacting with
an analyte. Such particles may associate with each other, or
conversely, dissociate in the presence of analyte in such a manner
that a change is conferred upon the light absorption property of
the material containing the particles. This approach can also be
used as a skin-based visual sensor, in one embodiment. A
non-limiting example of a technique for identifying aggregates is
disclosed in U.S. patent application Ser. No. 09/344,667, filed
Jun. 25, 1999, entitled "Nanoparticles Having Oligonucleotides
Attached Thereto and Uses Therefor," by Mirkin, et al., now U.S.
Pat. No. 6,361,944, issued Mar. 26, 2002.
[0177] The particles may also have any shape or size. For instance,
the particles may have an average diameter of less than about 5 mm
or 2 mm, or less than about 1 mm, or less than about 500 microns,
less than about 200 microns, less than about 100 microns, less than
about 60 microns, less than about 50 microns, less than about 40
microns, less than about 30 microns, less than about 25 microns,
less than about 10 microns, less than about 3 microns, less than
about 1 micron, less than about 300 nm, less than about 100 nm,
less than about 30 nm, or less than about 10 nm. As discussed, the
particles may be spherical or non-spherical. The average diameter
of a non-spherical particle is the diameter of a perfect sphere
having the same volume as the non-spherical particle. If the
particle is non-spherical, the particle may have a shape of, for
instance, an ellipsoid, a cube, a fiber, a tube, a rod, or an
irregular shape. In some cases, the particles may be hollow or
porous. Other shapes are also possible, for instance, core/shell
structures (e.g., having different compositions), rectangular
disks, high aspect ratio rectangular disks, high aspect ratio rods,
worms, oblate ellipses, prolate ellipses, elliptical disks, UFOs,
circular disks, barrels, bullets, pills, pulleys, biconvex lenses,
ribbons, ravioli, flat pills, bicones, diamond disks, emarginate
disks, elongated hexagonal disks, tacos, wrinkled prolate
ellipsoids, wrinkled oblate ellipsoids, porous ellipsoid disks, and
the like. See, e.g., International Patent Application No.
PCT/US2007/077889, filed Sep. 7, 2007, entitled "Engineering Shape
of Polymeric Micro- and Nanoparticles," by S. Mitragotri, et al.,
published as WO 2008/031035 on Mar. 13, 2008, incorporated herein
by reference.
[0178] In one aspect of the invention, a particle may include one
or more reaction entities present on the surface (or at least a
portion of the surface) of the particle. The reaction entity may be
any entity able to interact with and/or associate with an analyte,
or another reaction entity. For instance, the reaction entity may
be a binding partner able to bind an analyte. For example, the
reaction entity may be a molecule that can undergo binding with a
particular analyte. The reaction entities may be used, for example,
to determine pH or metal ions, proteins, nucleic acids (e.g. DNA,
RNA, etc.), drugs, sugars (e.g., glucose), hormones (e.g.,
estradiol, estrone, progesterone, progestin, testosterone,
androstenedione, etc.), carbohydrates, or other analytes of
interest.
[0179] The term "binding partner" refers to a molecule that can
undergo binding with a particular molecule, e.g., an analyte. For
example, the binding may be highly specific and/or non-covalent.
Binding partners which form highly specific, non-covalent,
physiochemical interactions with one another are defined herein as
"complementary." Biological binding partners are examples. For
example, Protein A is a binding partner of the biological molecule
IgG, and vice versa. Other non-limiting examples include nucleic
acid-nucleic acid binding, nucleic acid-protein binding,
protein-protein binding, enzyme-substrate binding, receptor-ligand
binding, receptor-hormone binding, antibody-antigen binding, etc.
Binding partners include specific, semi-specific, and non-specific
binding partners as known to those of ordinary skill in the art.
For example, Protein A is usually regarded as a "non-specific" or
semi-specific binder. As another example, the particles may contain
an enzyme such as glucose oxidase or glucose 1-dehydrogenase, or a
lectin such as concanavalin A that is able to bind to glucose.
[0180] As additional examples, binding partners may include
antibody/antigen pairs, ligand/receptor pairs, enzyme/substrate
pairs and complementary nucleic acids or aptamers. Examples of
suitable epitopes which may be used for antibody/antigen binding
pairs include, but are not limited to, HA, FLAG, c-Myc,
glutathione-S-transferase, His.sub.6, GFP, DIG, biotin and avidin.
Antibodies may be monoclonal or polyclonal. Suitable antibodies for
use as binding partners include antigen-binding fragments,
including separate heavy chains, light chains Fab, Fab',
F(ab').sub.2, Fabc, and Fv. Antibodies also include bispecific or
bifunctional antibodies. Exemplary binding partners include
biotin/avidin, biotin/streptavidin, biotin/neutravidin and
glutathione-S-transferase/glutathione.
[0181] The term "binding" generally refers to the interaction
between a corresponding pair of molecules or surfaces that exhibit
mutual affinity or binding capacity, typically due to specific or
non-specific binding or interaction, including, but not limited to,
biochemical, physiological, and/or chemical interactions. The
binding may be between biological molecules, including proteins,
nucleic acids, glycoproteins, carbohydrates, hormones, or the like.
Specific non-limiting examples include antibody/antigen,
antibody/hapten, enzyme/substrate, enzyme/inhibitor,
enzyme/cofactor, binding protein/substrate, carrier
protein/substrate, lectin/carbohydrate, receptor/hormone,
receptor/effector, complementary strands of nucleic acid,
protein/nucleic acid repressor/inducer, ligand/cell surface
receptor, virus/ligand, virus/cell surface receptor, etc. As
another example, the binding agent may be a chelating agent (e.g.,
ethylenediaminetetraacetic acid) or an ion selective polymer (e.g.,
a block copolymer such as poly(carbonate-b-dimethylsiloxane), a
crown ether, or the like). As another example, the binding partners
may be biotin and streptavidin, or the binding partners may be
various antibodies raised against a protein.
[0182] The term "specifically binds," when referring to a binding
partner (e.g., protein, nucleic acid, antibody, etc.), refers to a
reaction that is determinative of the presence and/or identity of
one or other member of the binding pair in a mixture of
heterogeneous molecules (e.g., proteins and other biologics). Thus,
for example, in the case of a receptor/ligand binding pair, the
ligand would specifically and/or preferentially select its receptor
from a complex mixture of molecules, or vice versa. An enzyme would
specifically bind to its substrate, a nucleic acid would
specifically bind to its complement, an antibody would specifically
bind to its antigen, etc. The binding may be by one or more of a
variety of mechanisms including, but not limited to ionic
interactions or electrostatic interactions, covalent interactions,
hydrophobic interactions, van der Waals interactions, etc.
[0183] Thus, the invention provides, in certain embodiments,
particles that are able to bind to an analyte, e.g., via a binding
partner to the analyte, and such particles can be used to determine
the analyte. Such determination may occur within the skin, and/or
externally of the subject, e.g., within a device on the surface of
the skin, depending on the embodiment. "Determine," in this
context, generally refers to the analysis of a species, for
example, quantitatively or qualitatively, and/or the detection of
the presence or absence of the species. The species may be, for
example, a bodily fluid and/or an analyte suspected of being
present in the bodily fluid. "Determining" may also refer to the
analysis of an interaction between two or more species, for
example, quantitatively or qualitatively, and/or by detecting the
presence or absence of the interaction, e.g. determination of the
binding between two species. "Determining" also means detecting or
quantifying interaction between species. As an example, an analyte
may cause a determinable change in a property of the particles,
e.g., a change in a chemical property of the particles, a change in
the appearance and/or optical properties of the particles, a change
in the temperature of the particles, a change in an electrical
property of the particles, etc. In some cases, the change may be
one that is determinable by a human, unaided by any equipment that
may be directly applied to the human. For instance, the
determinable change may be a change in appearance (e.g., color), a
change in temperature, the production of an odor, etc., which can
be determined by a human without the use of any equipment (e.g.,
using the eyes). Non-limiting examples include temperature changes,
chemical reactions or other interactions (e.g., with capsaicin)
that can be sensed, or the like. Examples of capsaicin and
capsaicin-like molecules include, but are not limited to,
dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,
homocapsaicin, or nonivamide. Without wishing to be bound by any
theory, it is believed that interactions with capsaicin and
capsaicin-like molecules can be sensed by a subject, since such
molecules may interact with certain nerve endings, which produces a
sensation of burning.
[0184] In one set of embodiments, more than one particle may be
able to bind an analyte, and/or more than one analyte may bind to a
particle. In some cases, such multiple binding properties may
result in the clustering of more than one particle to an analyte
and/or more than one analyte to a particle. Such clustering can be
determined in some fashion, e.g., via a change in an optical
property. As an example, an aggregate of particles may form in the
absence of analyte, but disaggregate (at least partially) in the
presence of the analyte, e.g., if the analyte and the particles
exhibit competitive or non-competitive inhibition. Such binding
and/or aggregation may be equilibrium-based in some cases, i.e.,
the binding and/or aggregation occurs in equilibrium with unbinding
or disaggregation processes. Thus, when the environment surrounding
the particles is altered in some fashion (e.g., a change in
concentration of an analyte), the equilibrium may shift in
response, which can be readily determined (e.g., as a change in
color). It should be noted that such equilibrium-based systems may
be able to determine such changes in environment, in some cases,
without the need to apply any energy to determine the environmental
change. In another example, aggregation may cause a change in an
electrical or a magnetic property.
[0185] As an example, an optical property of the medium containing
the clusters may be altered in some fashion (e.g., exhibiting
different light scattering properties, different opacities,
different degrees of transparency, etc.), which can be correlated
with the analyte. In some cases, the color may change in intensity,
for example, the clustering of particles may bring two or more
reactants into close proximity
[0186] Other properties may also be determined besides color.
Accordingly, it should be understood that the use of "color" with
respect to particles as used herein is by way of example only, and
other properties may be determined instead of or in addition to
color. For instance, clustering of aniostropic particles may cause
a change in an electrical or a magnetic property of the particles,
which can be determined by determining an electrical or a magnetic
field. As another example, the first region and the second region
may have different reactivities (e.g., the first region may be
reactive to an enyzme, an antibody, etc.), and aggregation of the
particles may cause a net change in the reactivity. As still
another example, size may be used to determine the particles and/or
the analyte. For instance, the aggregates may be visually
identifiable, the aggregates may form a precipitant, or the like.
Thus, for example, the particles (which may be anisotropic or not
anisotropic) may appear to be a first color when separate, and a
second color when aggregation occurs. In some cases, an assay
(e.g., an agglutination assay) may be used to determine the
aggregation. In another set of embodiments, an ordering of the
particles may be determined For example, in the absence of an
analyte, the particles may be ordered on the surface of a
substrate; while in the presence of an analyte, the particles may
bind to the analyte and become disordered relative to the surface.
This ordering may be determined, for example, as a change in an
optical property of the surface (e.g., index of refraction, color,
opacity, etc.). As yet other examples, a shape change may be
produced using a shape memory polymer or a "smart polymer," and
this may be able to be sensed by feel. Alternatively, a color may
be released, a hydrolysis reaction may occur, or aggregation of the
particles may occur.
[0187] In one embodiment, the binding or presence of the analyte,
e.g. present in interstitial fluid optionally created using a
suction blister device, results in a tactile change (e.g., change
in shape or texture). For example, shape memory polymer (SMPs) can
be used to detect the presence of one or more analytes. SMPs are
generally characterized as phase segregated linear block
co-polymers having a hard segment and a soft segment. The hard
segment is typically crystalline, with a defined melting point, and
the soft segment is typically amorphous, with a defined glass
transition temperature. In some embodiments, however, the hard
segment is amorphous and has a glass transition temperature rather
than a melting point. In other embodiments, the soft segment is
crystalline and has a melting point rather than a glass transition
temperature. The melting point or glass transition temperature of
the soft segment is substantially less than the melting point or
glass transition temperature of the hard segment.
[0188] When the SMP is heated above the melting point or glass
transition temperature of the hard segment, the material can be
shaped. This (original) shape can be "memorized" by cooling the SMP
below the melting point or glass transition temperature of the hard
segment. When the shaped SMP is cooled below the melting point or
glass transition temperature of the soft segment while the shape is
deformed, that (temporary) shape is fixed. The original shape is
recovered by heating the material above the melting point or glass
transition temperature of the soft segment but below the melting
point or glass transition temperature of the hard segment. The
recovery of the original shape, which is induced by an increase in
temperature, is called the thermal shape memory effect. Properties
that describe the shape memory capabilities of a material include
the shape recovery of the original shape and the shape fixity of
the temporary shape
[0189] Shape memory polymers can contain at least one physical
crosslink (physical interaction of the hard segment) or contain
covalent crosslinks instead of a hard segment. The shape memory
polymers also can be interpenetrating networks or
semi-interpenetrating networks. In addition to changes in state
from a solid to liquid state (melting point or glass transition
temperature), hard and soft segments may undergo solid to solid
state transitions, and can undergo ionic interactions involving
polyelectrolyte segments or supramolecular effects based on highly
organized hydrogen bonds.
[0190] Other polymers that can shape or phase change as a function
of temperature include PLURONICS.RTM.. These are also known as
poloxamers, nonionic triblock copolymers composed of a central
hydrophobic chain of polyoxypropylene (poly(propylene oxide))
flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene
oxide)). Because the lengths of the polymer blocks can be
customized, many different poloxamers exist that have slightly
different properties. For the generic term "poloxamer," these
copolymers are commonly named with the letter "P" (for poloxamer)
followed by three digits, the first two digits .times.100 give the
approximate molecular mass of the polyoxypropylene core, and the
last digit .times.10 gives the percentage polyoxyethylene content
(e.g., P407=Poloxamer with a polyoxypropylene molecular mass of
4,000 g/mol and a 70% polyoxyethylene content). For the
PLURONICS.RTM. tradename, coding of these copolymers starts with a
letter to define its physical form at room temperature (L=liquid,
P=paste, F=flake (solid)) followed by two or three digits. The
first digit (two digits in a three-digit number) in the numerical
designation, multiplied by 300, indicates the approximate molecular
weight of the hydrophobe; and the last digit .times.10 gives the
percentage polyoxyethylene content (e.g., L61=Pluronic with a
polyoxypropylene molecular mass of 1,800 g/mol and a 10%
polyoxyethylene content).
[0191] Other temperature sensitive polymers that form gels that
have a distinct phase change at its lower critical solution
temperature (LCST) including the cross-linked copolymers comprising
hydrophobic monomers, hydrogen bonding monomers, and
thermosensitive monomers.
[0192] Additional thermal responsive, water soluble polymers
including the co-polymerization product of N-isopropyl acrylamide
(NIP); 1-vinyl-2-pyrrolidinone (VPD); and optionally, acrylic acid
(AA), change shape as a function of temperature. As the proportion
of component AA increases, the Lower Critical Solution Temperature
(LCST) decreases and the COOH reactive groups increase, which
impart high reactivity to the copolymer. By adjusting the
proportion of the monomers, a broad range of LCST can be
manipulated from about 20.degree. C. to 80.degree. C.
[0193] While the shape memory effect is typically described in the
context of a thermal effect, the polymers can change their shape in
response to application of light, changes in ionic concentration
and/or pH, electric field, magnetic field or ultrasound. For
example, a SMP can include at least one hard segment and at least
one soft segment, wherein at least two of the segments, e.g., two
soft segments, are linked to each other via a functional group that
may be cleavable under application of light, electric field,
magnetic field, or ultrasound. The temporary shape may be fixed by
crosslinking the linear polymers. By cleaving those links the
original shape can be recovered. The stimuli for crosslinking and
cleaving these bonds can be the same or different.
[0194] In one embodiment, the shape memory polymer composition
binds, complexes to, or interacts with an analyte, which can be a
chromophore. The hard and/or soft segments can include double bonds
that shift from cis to trans isomers when the chromophores absorb
light. Light can therefore be used to detect the presence of a
chromophore analyte by observing whether or not the double bond
isomerizes.
[0195] The shape memory effect can also be induced by changes in
ionic strength or pH. Various functional groups are known to
crosslink in the presence of certain ions or in response to changes
in pH. For example, calcium ions are known to crosslink amine and
alcohol groups, i.e., the amine groups on alginate can be
crosslinked with calcium ions. Also, carboxylate and amine groups
become charged species at certain pHs. When these species are
charged, they can crosslink with ions of the opposite charge. The
presence of groups, which respond to changes in the concentration
of an ionic species and/or to changes in pH, on the hard and/or
soft segments results in reversible linkages between these
segments. One can fix the shape of an object while crosslinking the
segments. After the shape has been deformed, alteration of the
ionic concentration or pH can result in cleavage of the ionic
interactions which formed the crosslinks between the segments,
thereby relieving the strain caused by the deformation and thus
returning the object to its original shape. Because ionic bonds are
made and broken in this process, it can only be performed once. The
bonds, however, can be re-formed by altering the ionic
concentration and/or pH, so the process can be repeated as desired.
Thus, in this embodiment, the presence of an analyte which changes
the ionic strength or pH can induce a shape memory effect in the
polymer confirming the presence of the analyte.
[0196] Electric and/or magnetic fields can also be used to induce a
shape memory effect. Various moieties, such as chromophores with a
large number of delocalized electrons, increase in temperature in
response to pulses of applied electric or magnetic fields as a
result of the increased electron flow caused by the fields. After
the materials increase in temperature, they can undergo temperature
induced shape memory in the same manner as if the materials were
heated directly. These compositions are useful in biomedical
applications where the direct application of heat to an implanted
material may be difficult, but the application of an applied
magnetic or electric field would only affect those molecules with
the chromophore, and not heat the surrounding tissue. For example,
the presence of a chromophore analyte with a large number of
delocalized electrons can cause an increase in temperature in the
microenvironment surrounding the shape memory polymer implant in
response to pulses of applied electric or magnetic fields. This
increase in temperature can in turn cause a thermal shape memory
effect, thus confirming the presence of a particular analyte.
[0197] Other types of "smart polymers" may also be used. The
combination of the capabilities of stimuli-responsive components
such as polymers and interactive molecules to form site-specific
conjugates are useful in a variety of assays, separations,
processing, and other uses. The polymer chain conformation and
volume can be manipulated through alteration in pH, temperature,
light, or other stimuli. The interactive molecules can be
biomolecules like proteins or peptides, such as antibodies,
receptors, or enzymes, polysaccharides or glycoproteins which
specifically bind to ligands, or nucleic acids such as antisense,
ribozymes, and aptamers, or ligands for organic or inorganic
molecules in the environment or manufacturing processes. The
stimuli-responsive polymers are coupled to recognition biomolecules
at a specific site so that the polymer can be manipulated by
stimulation to alter ligand-biomolecule binding at an adjacent
binding site, for example, the biotin binding site of streptavidin,
the antigen-binding site of an antibody or the active,
substrate-binding site of an enzyme. Binding may be completely
blocked (i.e., the conjugate acts as an on-off switch) or partially
blocked (i.e., the conjugate acts as a rheostat to partially block
binding or to block binding only of larger ligands). Once a ligand
is bound, it may also be ejected from the binding site by
stimulating one (or more) conjugated polymers to cause ejection of
the ligand and whatever is attached to it. Alternatively, selective
partitioning, phase separation or precipitation of the
polymer-conjugated biomolecule can be achieved through exposure of
the stimulus-responsive component to an appropriate environmental
stimulus.
[0198] Liquid crystal polymeric materials can also be used to
provide a signal for detection or quantification of analyte. Liquid
crystals are materials that exhibit long-range order in only one or
two dimensions, not all three. A distinguishing characteristic of
the liquid crystalline state is the tendency of the molecules, or
mesogens, to point along a common axis, known as the director. This
feature is in contrast to materials where the molecules are in the
liquid or amorphous phase, which have no intrinsic order, and
molecules in the solid state, which are highly ordered and have
little translational freedom. The characteristic orientational
order of the liquid crystal state falls between the crystalline and
liquid phases. These can be pressure or temperature sensitive, and
react by producing a change in color or shape.
[0199] In some cases, the particles may contain a diagnostic agent
able to determine an analyte. An example of an analyte within a
subject is glucose (e.g., for diabetics); other potentially
suitable analytes include ions such as sodium, potassium, chloride,
calcium, magnesium, and/or bicarbonate (e.g., to determine
dehydration); gases such as carbon dioxide or oxygen; pH;
metabolites such as urea, blood urea nitrogen or creatinine;
hormones such as estradiol, estrone, progesterone, progestin,
testosterone, androstenedione, etc. (e.g., to determine pregnancy,
illicit drug use, or the like); or cholesterol. Still other
potentially suitable analytes include various pathogens such as
bacteria or viruses, and/or markers produced by such pathogens. For
example, a particle may include an antibody directed at a marker
produced by bacteria. In addition, more than one analyte may be
determined in a subject, e.g., through the use of different
particle types and/or through the use of particles able to
determine more than one analyte, such as those discussed above. For
instance, a first set of particles may determine a first analyte
and a second set of particles may determine a second analyte. In
some cases, such particles may be used to determine a physical
condition of a subject. For instance, the particles may exhibit a
first color indicating a healthy state and a second color
indicating a disease state. In some cases, the appearance of the
particles may be used to determine a degree of health. For
instance, the particles may exhibit a first color indicating a
healthy state, a second color indicating a warning state, and a
third color indicating a dangerous state, or the particles may
exhibit a range of colors indicating a degree of health of the
subject.
[0200] Binding partners to these and/or other species are
well-known in the art. Non-limiting examples include pH-sensitive
entities such as phenol red, bromothymol blue, chlorophenol red,
fluorescein, HPTS, 5(6)-carboxy-2',7'-dimethoxyfluorescein SNARF,
and phenothalein; entities sensitive to calcium such as Fura-2 and
Indo-1; entities sensitive to chloride such as
6-methoxy-N-(3-sulfopropyl)-quinolinim and lucigenin; entities
sensitive to nitric oxide such as
4-amino-5-methylamino-2',7'-difluorofluorescein; entities sensitive
to dissolved oxygen such as
tris(4,4'-diphenyl-2,2'-bipyridine)ruthenium (II) chloride
pentahydrate; entities sensitive to dissolved CO.sub.2; entities
sensitive to fatty acids, such as BODIPY 530-labeled
glycerophosphoethanolamine; entities sensitive to proteins such as
4-amino-4'-benzamidostilbene-2-2'-disulfonic acid (sensitive to
serum albumin), X-Gal or NBT/BCIP (sensitive to certain enzymes),
Tb.sup.3+ from TbCl.sub.3 (sensitive to certain calcium-binding
proteins), BODIPY FL phallacidin (sensitive to actin), or BOCILLIN
FL (sensitive to certain penicillin-binding proteins); entities
sensitive to concentration of glucose, lactose or other components,
or entities sensitive to proteases, lactates or other metabolic
byproducts, entities sensitive to proteins, antibodies, or other
cellular products.
[0201] In one set of embodiments, at least some of the particles
used in the subject to determine the analyte are anisotropic
particles (in other cases, however, the particles are not
necessarily anisotropic), and in some cases, substantially all of
the particles are anisotropic particles. In certain cases, at least
about 10%, at least about 30%, at least about 40%, at least about
50%, at least about 60%, at least about 70%, at least about 80%, at
least about 90%, at least about 95%, or at least about 99% of the
particles are anisotropic particles. In one embodiment, the
anisotropic particles may have a first region having a first color
and a second region having a second color distinct from the first
color, and the particles, upon exposure to the analyte within the
subject, may form clusters that exhibit an excess of the second
region or second color relative to the first region or first color,
as discussed above. The particles may be present, for example, in
the bloodstream and/or within the skin of the subject.
[0202] In some cases, the particles, after delivery into the skin
may give the appearance of a "tattoo" or a permanent mark within
the skin, and the tattoo or other mark may be of any color and/or
size. For instance, in one embodiment, anisotropic particles such
as those described above that are able to bind glucose may be
delivered into the skin of a subject, and such particles, after
deposition within the skin, may react to the presence or absence of
glucose by exhibiting a change in color. The particles may exhibit
a color change based on the presence or absence of glucose, and/or
the concentration of glucose. For instance, the particles may
exhibit a first color (e.g., green) when not aggregated, and a
second color (e.g., red or brown) when aggregated, or the particles
may be invisible when not aggregated, but visible (e.g., exhibiting
a color) when aggregated. The particles may be, for example,
anisotropic particles having a first surface region having a first
color (e.g., green) and a second surface region having a second
color (e.g., red), and the first surface region may contain a
binding partner to glucose. At low levels of glucose, the particles
may exhibit a combination of the first and second colors, while at
higher levels of glucose, the particles may exhibit more of the
second color.
[0203] It should be noted that causing clustering of particles to
occur is not limited to only the exposure of particles to an
analyte. In another set of embodiments, for example, the clustering
or aggregation properties of the particles is externally controlled
in some fashion. For instance, an electrical, magnetic, and/or a
mechanical force can be used to bring the particles closer together
and/or cause the particles to separate. Thus, in some cases, the
application of an electrical, magnetic, and/or a mechanical force
to the particles causes the particles to exhibit a change in color.
The clustering or aggregation of particles as discussed herein is
not limited to generally spherical aggregations. In some cases, the
particles may cluster onto a surface, or the particles may be
aligned in some fashion relative to the surface due to an analyte
or other external force.
[0204] In addition, it should be noted that the particles may
contain reaction entities that are not necessarily binding partners
to an analyte. For instance, there may be first particles
containing a first reaction entity and a second reaction entity
that reacts with the first reaction entity; when the particles are
brought together in some fashion (e.g., by exposure to an analyte
or other chemical that is recognized by binding partners on each of
the particles, by the application of an electrical, magnetic,
and/or a mechanical force to bring the particles closer together,
etc.), the first and second reaction entities may react. As a
specific example, the reaction between the first and second
reaction entities may be an endothermic or an exothermic reaction;
thus, when the particles are brought together, a temperature change
is produced, which can be determined in some fashion. As another
example, a reaction between the first and second reactants may
cause the release of a material. In some cases, the material may be
one that can be sensed by a subject, e.g., capsaicin, an acid, an
allergen, or the like. Thus, the subject may sense the change as a
change in temperature, pain, itchiness, swelling, or the like.
[0205] In some cases, the particles may be suspended in a carrying
fluid, e.g., saline, or the particles may be contained within a
matrix, e.g., a porous matrix that is or becomes accessible by
interstitial fluid after delivery, or a hydrogel matrix, etc. For
instance, the matrix may be formed from a biodegradable and/or
biocompatible material such as polylactic acid, polyglycolic acid,
poly(lactic-co-glycolic acid), etc., or other similar
materials.
[0206] In some cases, the matrix may prevent or at least inhibit an
immunological response by the subject to the presence of the
particles, while allowing equilibration of analytes, etc. with the
particles to occur, e.g., if the matrix is porous. For instance,
the pores of a porous matrix may be such that immune cells are
unable to penetrate, while proteins, small molecules (e.g.,
glucose, ions, dissolved gases, etc.) can penetrate. The pores may
be, for instance, less than about 5 micrometers, less than about 4
micrometers, less than about 3 micrometers, less than about 2
micrometers, less than about 1.5 micrometers, less than about 1.0
micrometers, less than about 0.75 micrometers, less than about 0.6
micrometers, less than about 0.5 micrometers, less than about 0.4
micrometers, less than about 0.3 micrometers, less than about 0.1
micrometers, less than about 0.07 micrometers, and in other
embodiments, or less than about 0.05 micrometers. The matrix may
comprise, for example, biocompatible and/or biodegradable polymers
such as polylactic and/or polyglycolic acids, polyanhydride,
polycaprolactone, polyethylene oxide, polybutylene terephthalate,
starch, cellulose, chitosan, and/or combinations of these, and/or
other materials such as agarose, collagen, fibrin, or the like.
[0207] Thus, in one set of embodiments, particles are provided
which can be analogized to a light on an automotive dashboard,
e.g., green for normal, yellow for suspicious, slightly low or
slightly high, and red for abnormal. The subject then knows that
they need to be seen, and the degree of urgency, by appropriate
medical personnel. The particles may be placed and read at the site
of detection. For example, the devices may provide a visual
colorimetic signal, but other signals are possible, such as smell
(released upon change in pH or temperature, for example), or
tactile (shape change due to chemical reaction).
[0208] Signals from the particles can be used to generate a pattern
or color which is indicative of the presence and/or amount of
analyte. The density, shape, color, or intensity of the pattern or
color may provide a yes-no type answer or may be graduated to
provide quantitative amounts. This could also be effected by
exposure to a pH or temperature change in some embodiments. Other
patterns include, for example, + and - signs, arrows (e.g., up
arrows or down arrows), faces (smiley, neutral, sad), etc., or the
like.
[0209] In one set of embodiments, the skin surface may change in
feel when there is a reaction. For example, shape memory polymers
may say "OK" when the cholesterol level is below 150 mg/dl. These
may change to ready "HIGH" when the cholesterol level exceeds 200
mg/dl. The device may be blank or lack definition at values between
these levels.
[0210] The particles may change when reacted with analyte. This may
result in a smell such as a food odor being released as a function
of a pH or temperature change. For instance, an encapsulated scent
may be released. In some cases, FDA GRAS ingredients may be used as
signals.
[0211] These may be applied to the skin to measure a change in
temperature indicative of disease or inflammation. In one
embodiment, the device may be colorless or a color indicative of
normal temperature (for example, green), or the device will display
a message such as "OK." In the event the temperature exceeds a
certain level, such as 101.degree. F., the color changes (for
example, yellow for caution or red for warning or critical) or the
message changes (for example, if shape memory polymers are used) to
read "HOT." These are particularly useful in a setting such as a
day care, where there are a number of babies or young children to
supervise, and fevers can occur rapidly.
[0212] In another embodiment, the particles may be used to measure
a decrease in blood oxygen, or measure the amount of molecules such
as glucose, cholesterol, triglycerides, cancer markers, or
infectious agents, by providing agents that specifically react with
the molecules, and signal generating agents which produce signal in
an amount correlated with the amounts of the molecules that react.
As another non-limiting example, analogous to the temperature
monitor, a pre-set level can be used to create a message that says
"C high," for example, or "insulin!" for example, which effects a
color change.
[0213] As discussed above, the devices may, instead of a color
change or message change, change shape, emit a scent or flavor, or
otherwise notify the person of a need to seek further information.
In some cases, this might be to seek medical attention where the
indicator of a disorder can be confirmed and appropriate medical
intervention obtained. In the case of temperature indicative of a
fever, the caregiver might measure the temperature using a standard
thermometer. In the case of a hormone change, indicative of
pregnancy or ovulation, an ELISA test might be performed using a
urine sample. In the case of high glucose, this could be confirmed
using a standard glucose monitor and a blood sample.
[0214] In another aspect, the particles may be delivered for
cosmetic purposes, e.g., as a permanent or temporary tattoo. In
some cases, the "tattoo" or particles contained within the skin may
be alterable by the administration of an electrical, magnetic,
and/or a mechanical force to the subject. For instance, by applying
such forces, the particles may be caused to cluster, which may
result in a change in color, as discussed above. Thus, one
embodiment of the invention is directed to a cosmetic mark in the
skin that can be altered by application of an external stimulus,
such as an electrical, magnetic, and/or a mechanical force, and/or
a chemical applied to the skin (e.g., a chemical which is a binding
partner of a species on the particle).
[0215] The tattoo (or other mark) present in the skin may have any
function, e.g., as a decorative art, or as an identification
system. For instance, a tattoo may be verified by applying a
stimulus to the subject (e.g., an electric field, a magnetic field,
a mechanical force, a chemical, etc.), and confirming the tattoo by
identifying a change in the mark, such as a change in color. The
change in the mark may be permanent or temporary. As a specific
example, a stimulus may be applied to anisotropic particles
containing a first region exhibiting a first color and a second
region exhibiting a second color. In the absence of the stimulus,
the particles exhibit a blend of the first and second colors;
however, under application of the stimulus, only one color may be
exhibited as the particles are aligned. This identification of a
change in color may be used, for example, artistically, or as an
identifying mark. As mentioned, in some cases, such a mark may be
permanent or temporary. As another example, the particles may be
invisible (e.g., non-aggregated) in the absence of a stimulus, but
become visible (e.g., aggregated) when a stimulus is applied. In
some cases, the particles change their appearance while the
stimulus is applied, but revert to their original appearance once
the stimulus is removed; in other cases, however, the particles may
be able to retain their altered appearance for some time following
removal of the stimulus, and in some cases, the particles
permanently retain their altered appearance.
[0216] In another aspect, the present invention is directed to a
kit including one or more of the compositions previously discussed,
e.g., a kit including a particle, a kit including a device for the
delivery and/or withdrawal of fluid from the skin, a kit including
a device able to create a pooled region of fluid within the skin of
a subject, a kit including a device able to determine a fluid, or
the like. An example of a kit containing more than one device of
the invention is illustrated in FIG. 11B, with kit 150 containing
devices 152. A "kit," as used herein, typically defines a package
or an assembly including one or more of the compositions or devices
of the invention, and/or other compositions or devices associated
with the invention, for example, as previously described. For
example, in one set of embodiments, the kit may include a device
and one or more compositions for use with the device. Each of the
compositions of the kit, if present, may be provided in liquid form
(e.g., in solution), or in solid form (e.g., a dried powder). In
certain cases, some of the compositions may be constitutable or
otherwise processable (e.g., to an active form), for example, by
the addition of a suitable solvent or other species, which may or
may not be provided with the kit. Examples of other compositions or
components associated with the invention include, but are not
limited to, solvents, surfactants, diluents, salts, buffers,
emulsifiers, chelating agents, fillers, antioxidants, binding
agents, bulking agents, preservatives, drying agents,
antimicrobials, needles, syringes, packaging materials, tubes,
bottles, flasks, beakers, dishes, frits, filters, rings, clamps,
wraps, patches, containers, tapes, adhesives, and the like, for
example, for using, administering, modifying, assembling, storing,
packaging, preparing, mixing, diluting, and/or preserving the
compositions components for a particular use, for example, to a
sample and/or a subject.
[0217] A kit of the invention may, in some cases, include
instructions in any form that are provided in connection with the
compositions of the invention in such a manner that one of ordinary
skill in the art would recognize that the instructions are to be
associated with the compositions of the invention. For instance,
the instructions may include instructions for the use,
modification, mixing, diluting, preserving, administering,
assembly, storage, packaging, and/or preparation of the
compositions and/or other compositions associated with the kit. In
some cases, the instructions may also include instructions for the
delivery and/or administration of the compositions, for example,
for a particular use, e.g., to a sample and/or a subject. The
instructions may be provided in any form recognizable by one of
ordinary skill in the art as a suitable vehicle for containing such
instructions, for example, written or published, verbal, audible
(e.g., telephonic), digital, optical, visual (e.g., videotape, DVD,
etc.) or electronic communications (including Internet or web-based
communications), provided in any manner.
[0218] In some embodiments, the present invention is directed to
methods of promoting one or more embodiments of the invention as
discussed herein. As used herein, "promoted" includes all methods
of doing business including, but not limited to, methods of
selling, advertising, assigning, licensing, contracting,
instructing, educating, researching, importing, exporting,
negotiating, financing, loaning, trading, vending, reselling,
distributing, repairing, replacing, insuring, suing, patenting, or
the like that are associated with the systems, devices,
apparatuses, articles, methods, compositions, kits, etc. of the
invention as discussed herein. Methods of promotion can be
performed by any party including, but not limited to, personal
parties, businesses (public or private), partnerships,
corporations, trusts, contractual or sub-contractual agencies,
educational institutions such as colleges and universities,
research institutions, hospitals or other clinical institutions,
governmental agencies, etc. Promotional activities may include
communications of any form (e.g., written, oral, and/or electronic
communications, such as, but not limited to, e-mail, telephonic,
Internet, Web-based, etc.) that are clearly associated with the
invention.
[0219] In one set of embodiments, the method of promotion may
involve one or more instructions. As used herein, "instructions"
can define a component of instructional utility (e.g., directions,
guides, warnings, labels, notes, FAQs or "frequently asked
questions," etc.), and typically involve written instructions on or
associated with the invention and/or with the packaging of the
invention. Instructions can also include instructional
communications in any form (e.g., oral, electronic, audible,
digital, optical, visual, etc.), provided in any manner such that a
user will clearly recognize that the instructions are to be
associated with the invention, e.g., as discussed herein.
[0220] U.S. Provisional Patent Application Ser. No. 61/058,796,
filed Jun. 4, 2008, entitled "Compositions and Methods for
Diagnostics, Therapies, and Other Applications," by D. Levinson, is
incorporated herein by reference. Also incorporated herein by
reference are U.S. Provisional Patent Application Ser. No.
61/163,733, filed on Mar. 26, 2009, entitled "Determination of
Tracers within Subjects," by D. Levinson; U.S. Provisional Patent
Application Ser. No. 61/163,750, filed on Mar. 26, 2009, entitled
"Monitoring of Implants and Other Devices," by D. Levinson, et al.;
U.S. Provisional Patent Application Ser. No. 61/058,682, filed on
Mar. 26, 2009, entitled "Compositions and Methods for Diagnostics,
Therapies, and other Applications," by D. Levinson; U.S.
Provisional Patent Application Ser. No. 61/163,793, filed Mar. 26,
2009, entitled "Compositions and Methods for Diagnostics,
Therapies, and Other Applications," by D. Levinson; U.S. patent
application Ser. No. 12/478,756, filed Jun. 4, 2009, entitled
"Compositions and Methods for Diagnostics, Therapies, and Other
Applications"; International Patent Application No.
PCT/US09/046333, filed Jun. 4, 2009, entitled "Compositions and
Methods for Diagnostics, Therapies, and Other Applications"; U.S.
Provisional Patent Application Ser. No. 61/163,710, filed Mar. 26,
2009, entitled "Systems and Methods for Creating and Using Suction
Blisters or Other Pooled Regions of Fluid within the Skin"; U.S.
Provisional Patent Application Ser. No. 61/156,632, filed Mar. 2,
2009, entitled "Oxygen Sensor"; U.S. Provisional Patent Application
Ser. No. 61/269,436, filed Jun. 24, 2009, entitled "Devices and
Techniques associated with Diagnostics, Therapies, and Other
Applications, Including Skin-Associated Applications"; U.S.
Provisional Patent Application Ser. No. 61/163,791, filed on Mar.
26, 2009, entitled "Compositions and Methods for Rapid One-Step
Diagnosis," by D. Levinson; U.S. Provisional Patent Application
Ser. No. 61/257,731, filed Nov. 3, 2009, entitled "Devices and
Techniques Associated with Diagnostics, Therapies, and Other
Applications, Including Skin-Associated Applications"; and U.S.
Provisional Patent Application Ser. No. 61/294,543, filed Jan. 13,
2010, entitled "Blood Sampling Device and Method." Also
incorporated herein by reference are the following U.S. patent
applications being filed on even date herewith: "Oxygen Sensor," by
Levinson, et al.; "Systems and Methods for Creating and Using
Suction Blisters or Other Pooled Regions of Fluid within the Skin,"
by Levinson, et al.; and "Devices and Techniques Associated with
Diagnostics, Therapies, and Other Applications, Including
Skin-Associated Applications," by Bernstein, et al.
[0221] In one aspect of the present invention, methods of forming
particles such as those described herein are provided. For
instance, in one set of embodiments, electrospraying or
electrospinning techniques are used to prepare particles. In some
cases, two or more fluid streams (including liquid jets) are
combined together such that the two or more fluid streams contact
over spatial dimensions sufficient to form a composite stream. In
some cases, there is little or no mixing of the two or more fluid
streams within the composite stream. In some variations, the fluid
streams are electrically conductive, and in certain cases, a
cone-jet may be formed by combining the two or more fluid streams
under the influence of an electric field.
[0222] In some cases, the composite stream is directed at a
substrate, e.g., by the application of a force field such as an
electric field. For instance, if the composite stream is charged,
an electric field may be used to urge the composite stream towards
a substrate. The composite stream may be continuous or
discontinuous in some cases, e.g., forming a series of droplets
(which may be spherical or non-spherical). In some cases, the
composite stream is hardened prior to and/or upon contact with the
substrate. For example, the composite stream may be urged towards
the substrate under conditions in which at least a portion of the
composite stream (e.g., a solvent) is able to evaporate, causing
the remaining stream to harden and/or precipitate, e.g., to form
particles, spheres, rods, fibers, or the like. In some variations,
the composite stream fragments in droplets that can lead to
particle, sphere, rod, and/or fiber formation.
[0223] Additional examples of techniques for forming such particles
or fibers can be found in U.S. patent application Ser. No.
11/272,194, filed Nov. 10, 2005, entitled "Multi-Phasic
Nanoparticles," by Lahann, et al., published as U.S. Patent
Application Publication No. 2006/0201390 on Sep. 14, 2006; or
priority to U.S. patent application Ser. No. 11/763,842, filed Jun.
15, 2007, entitled "Multiphasic Biofunctional Nano-Components and
Methods for Use Thereof," by Lahann, published as U.S. Patent
Application Publication No. 2007/0237800 on Oct. 11, 2007, each of
which is incorporated herein by reference.
[0224] In one set of embodiments, solvent evaporation techniques
may be used. In one embodiment, a polymer may be dissolved in a
volatile organic solvent, such as methylene chloride. Drugs or
other suitable species are added to the solution, and the mixture
is suspended in an aqueous solution that contains a surface active
agent such as poly(vinyl alcohol). The resulting emulsion can be
stirred until most of the organic solvent evaporated, leaving solid
particles. The resulting particles may be washed with water and
dried overnight in a lyophilizer Particles with different sizes or
morphologies can be obtained by this method. This method is useful
for relatively stable polymers like polyesters and polystyrene.
[0225] In another set of embodiments, solvent removal techniques
may be used, e.g., for polymers such as polyanhydrides. In one
embodiment, a polymer may be dissolved in a volatile organic
solvent like methylene chloride. The mixture can be suspended by
stirring in an organic oil (such as silicon oil) to form an
emulsion. This can be used to make particles from polymers with
high melting points and different molecular weights. Particles that
range, for example, between 1-2000 microns, 1-1000 microns, 1-500
microns, 1-300 microns, 1-100 microns, 1-30 microns, 1-10 microns,
etc. in diameter can be obtained by this procedure. The external
morphology of spheres produced with this technique may be
controlled by controlling the type of polymer used.
[0226] In yet another set of embodiments, spray-drying techniques
may be used. In one embodiment, a polymer is dissolved in organic
solvent. The solution or the dispersion is then spray-dried.
Particles ranging between, for example, between 1-2000 microns,
1-1000 microns, 1-500 microns, 1-300 microns, 1-100 microns, 1-30
microns, 1-10 microns, etc. in diameter can be obtained with a
morphology which depends on the type of polymer used.
[0227] In still another set of embodiments, interfacial
polycondensation techniques may be used. In one embodiment, a
monomer is dissolved in a solvent. A second monomer is dissolved in
a second solvent (typically aqueous) which is immiscible with the
first. An emulsion may be formed by suspending the first solution
through stirring in the second solution. Once the emulsion is
stabilized, an initiator can be added to the aqueous phase causing
interfacial polymerization at the interface of each droplet of
emulsion.
[0228] In yet another set of embodiments, phase inversion
techniques may be used. In one set of embodiments, particles can be
formed from polymers using a phase inversion method wherein a
polymer is dissolved in a solvent and the mixture is poured into a
non-solvent for the polymer, to spontaneously produce particles
under favorable conditions. The method can be used to produce
particles in a wide range of diameters, including, for example,
about 100 nanometers to about 10 microns. Examples of polymers
which can be used include polyvinylphenol and polylactic acid. In
some cases, the polymer can be dissolved in an organic solvent and
then contacted with a non-solvent, which causes phase inversion of
the dissolved polymer to form particles, optionally incorporating
an antigen or other substance.
[0229] In still another set of embodiments, phase separation
techniques may be used. In one set of embodiments, the polymer is
dissolved in a solvent to form a polymer solution. While
continually stirring, a nonsolvent for the polymer may be added to
the solution to decrease the polymer's solubility. Depending on the
solubility of the polymer in the solvent and nonsolvent, the
polymer may precipitate and/or phase separate into a polymer-rich
and a polymer-poor phase. Under proper conditions, the polymer in
the polymer-rich phase may migrate to the interface with the
continuous phase, forming particles.
[0230] In yet another set of embodiments, spontaneous
emulsification techniques can be used. One set of embodiments
involves solidifying emulsified liquid polymer droplets by changing
temperature, evaporating solvent, and/or adding chemical
cross-linking agents. In still another set of embodiments, hot melt
techniques may be used.
[0231] In some cases, the particles may comprise a gel. For
instance, in one set of embodiments, particles made of gel-type
polymers, such as alginate and hyaluronic acid, can be produced
through ionic gelation techniques. In one embodiment, polymers can
be first dissolved in an aqueous solution and then extruded through
a droplet forming device, which in some instances employs a flow of
nitrogen and/or other gases to break off the droplet. A slowly
stirred (approximately 100-170 RPM) ionic hardening bath may be
positioned below the extruding device to catch the forming
droplets. The particles are left to incubate in the bath to allow
gelation to occur. Particle size may be controlled, for example, by
using various size extruders or varying nitrogen gas or polymer
solution flow rates. In one embodiment, chitosan particles can be
prepared by dissolving the polymer in acidic solution and
crosslinking it with tripolyphosphate. In another embodiment,
carboxymethyl cellulose (CMC) nanoparticles can be prepared by
dissolving the polymer in acid solution and precipitating the
nanoparticle with lead ions. In some cases where negatively charged
polymers (e.g., alginate, CMC) are used, positively charged ligands
(e.g., polylysine, polyethyleneimine) of different molecular
weights can be ionically attached.
[0232] Other methods known in the art that can be used to prepare
nanoparticles include, but are not limited to, polyelectrolyte
condensation, single and double emulsion (probe sonication),
nanoparticle molding, or electrostatic self-assembly (e.g.,
polyethylene imine-DNA or liposomes).
[0233] In some cases, the particles may include functional groups
used to bind or complex the analyte, and such functional groups can
be introduced prior to particle formation (e.g., monomers can be
functionalized with one or more functional groups for binding or
complexing the analyte) or the functional groups can be introduced
after particle formation (e.g., by functionalizing the surface of
the microparticle with reactive functional groups). The particles
may optionally have encapsulated therein one or more core
materials. In one embodiment, the particles may be present in an
effective amount to provide a signal detectable to the user without
the need for additional equipment. For example, the articles should
be present in an effective amount to provide a change in taste,
smell, shape, and/or color upon binding or complexing the analyte
that is easily detectable by the user.
[0234] While several embodiments of the present invention have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present invention. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present invention
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. It is, therefore, to be understood that the foregoing
embodiments are presented by way of example only and that, within
the scope of the appended claims and equivalents thereto, the
invention may be practiced otherwise than as specifically described
and claimed. The present invention is directed to each individual
feature, system, article, material, kit, and/or method described
herein. In addition, any combination of two or more such features,
systems, articles, materials, kits, and/or methods, if such
features, systems, articles, materials, kits, and/or methods are
not mutually inconsistent, is included within the scope of the
present invention.
[0235] All definitions, as defined and used herein, should be
understood to control over dictionary definitions, definitions in
documents incorporated by reference, and/or ordinary meanings of
the defined terms.
[0236] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0237] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0238] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0239] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0240] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0241] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
* * * * *