U.S. patent application number 13/812248 was filed with the patent office on 2013-06-20 for rapid delivery and/or receiving of fluids.
This patent application is currently assigned to Seventh Sense Biosystems, Inc.. The applicant listed for this patent is Donald E. Chickering, Shawn Davis, Remin Haghgooie. Invention is credited to Donald E. Chickering, Shawn Davis, Remin Haghgooie.
Application Number | 20130158482 13/812248 |
Document ID | / |
Family ID | 45559964 |
Filed Date | 2013-06-20 |
United States Patent
Application |
20130158482 |
Kind Code |
A1 |
Davis; Shawn ; et
al. |
June 20, 2013 |
RAPID DELIVERY AND/OR RECEIVING OF FLUIDS
Abstract
The present invention generally relates to systems and methods
for delivering and/or receiving a substance or substances such as
blood, from subjects, e.g., from the skin and/or from beneath the
skin. In one aspect, the present invention is generally directed to
devices and methods for receiving or extracting blood from a
subject, e.g., from the skin and/or from beneath the skin, using
devices containing a fluid transporter (for example, one or more
microneedles), and a storage chamber having an internal pressure
less than atmospheric pressure prior to receiving blood. In some
cases, the device may be self-contained, and in certain instances,
the device can be applied to the skin, and activated to receive
blood from the subject. The device, or a portion thereof, may then
be processed to determine the blood and/or an analyte within the
blood, alone or with an external apparatus. For example, blood may
be received from the device, and/or the device may contain sensors
or agents able to determine the blood and/or an analyte suspected
of being contained in the blood. In another aspect, the present
invention is generally directed to arrangements of skin insertion
objects such as microneedles and methods of forming and arranging
skin insertion objects. Other aspects of the present invention are
directed at other devices for receiving blood (or other bodily
fluids, e.g., interstitial fluid), kits involving such devices,
methods of making such devices, methods of using such devices, and
the like.
Inventors: |
Davis; Shawn; (Boston,
MA) ; Chickering; Donald E.; (Framingham, MA)
; Haghgooie; Remin; (Arlington, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Davis; Shawn
Chickering; Donald E.
Haghgooie; Remin |
Boston
Framingham
Arlington |
MA
MA
MA |
US
US
US |
|
|
Assignee: |
Seventh Sense Biosystems,
Inc.
Cambridge
MA
|
Family ID: |
45559964 |
Appl. No.: |
13/812248 |
Filed: |
July 12, 2011 |
PCT Filed: |
July 12, 2011 |
PCT NO: |
PCT/US11/43698 |
371 Date: |
March 5, 2013 |
Related U.S. Patent Documents
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|
Application
Number |
Filing Date |
Patent Number |
|
|
61367607 |
Jul 26, 2010 |
|
|
|
Current U.S.
Class: |
604/173 ; 216/11;
29/527.1 |
Current CPC
Class: |
A61B 5/150526 20130101;
A61B 5/150511 20130101; A61B 5/150984 20130101; A61B 5/150282
20130101; A61B 5/150427 20130101; A61B 5/150221 20130101; A61B
5/150229 20130101; A61B 5/15113 20130101; A61M 2037/0053 20130101;
A61B 5/150503 20130101; A61M 37/0015 20130101; A61M 2037/0023
20130101; A61M 2037/0046 20130101; A61B 5/15144 20130101; A61B
5/150022 20130101; Y10T 29/4998 20150115; A61B 5/150435 20130101;
A61B 5/157 20130101 |
Class at
Publication: |
604/173 ;
29/527.1; 216/11 |
International
Class: |
A61M 37/00 20060101
A61M037/00 |
Claims
1. A microneedle structure comprising: a first plurality of
microneedles that each include a base portion and a penetrating
portion, the base portions of the first plurality of microneedles
being arranged at the periphery of a first closed loop lying in a
plane, the penetrating portions of the first plurality of
microneedles each extending at a respective angle away from the
plane of the first closed loop; and a second plurality of
microneedles that each include a base portion and a penetrating
portion, the base portions of the second plurality of microneedles
being arranged at a periphery of a second closed loop lying in the
plane, the second closed loop being larger than, and surrounding,
the first closed loop, the penetrating portions of the second
plurality of microneedles each extending at a respective angle away
from the plane of the second closed loop.
2. The structure of claim 1, wherein the first closed loop is a
circle, and the penetrating portions extend perpendicularly away
from the plane.
3. The structure of claim 1, wherein the first and second closed
loops are concentric circles.
4. The structure of claim 1, wherein the first closed loop has a
circular, elliptical, hexagonal, rectangular, pentagonal, octagonal
or irregular shape.
5. The structure of claim 1, wherein a packing density of the
microneedles is at least 2 microneedles per square millimeter.
6. (canceled)
7. The structure of claim 1, wherein the penetrating portion is
arranged to pierce human skin and extend at least 100 microns into
the skin.
8-10. (canceled)
11. The structure of claim 1, wherein the microneedles have a
combined skin-penetration area of at least about 500 square
nanometers.
12-14. (canceled)
15. The structure of claim 1, wherein each penetrating portion
includes a proximal portion that is formed integral with the base
portion and a distal portion having a point that is formed at an
intersection of at least four surfaces of the penetrating
portion;
16. The structure of claim 1, wherein each penetrating portion
includes a proximal portion that is formed integral with the base
portion and a distal portion, the distal portion having an
approximately hexagon-shaped cross section.
17. The structure of claim 1, wherein each penetrating portion has
a sword shape with a symmetrical V-type knife edge at a periphery
of the penetrating portion.
18. The structure of claim 1, wherein at least some of the
microneedles are coated with a substance.
19. The structure of claim 18, wherein the substance comprises one
or more of lidocaine, bupivacaine, and tetracaine.
20. A device comprising a plurality of the structures recited in
claim 1.
21. The structure of claim 1, wherein the base portions of the
first and second pluralities of microneedles are connected
together.
22. (canceled)
23. A method for forming a microneedle structure, comprising:
providing a layer of material having opposed substantially planar
sides; etching the layer of material to define a plurality of
microneedles such that bases of the microneedles are arranged at a
periphery of a first closed loop and each of the microneedles
extends toward a center of the first closed loop; and etching the
layer of material to define a second plurality of microneedles with
bases arranged at a periphery of a second closed loop that is
arranged around the first closed loop.
24. The method of claim 23, wherein the first closed loop has a
substantially circular, elliptical, hexagonal, rectangular,
pentagonal, octagonal or irregular shape.
25. The method of claim 23, wherein each of the microneedles has a
sword shape having a V-type knife edge at a periphery of the
microneedle.
26. The method of claim 23, wherein the step of etching is part of
a lithographic patterning process.
27. The method of claim 23, wherein the step of etching includes
isotropic etching of the layer.
28. The method of claim 23 wherein a distal end of at least one
microneedle has an approximately hexagon-shaped cross section.
29. The method of claim 23, wherein a distal end of at least one
microneedle has a point that is formed at an intersection of at
least four surfaces.
30. The method of claim 23, wherein the second plurality of
microneedles each extend away from the center of the first closed
loop.
31. The method of claim 23, further comprising: bending penetrating
portions of the first and second pluralities of microneedles away
from the plane of the first closed loop.
32. The method of claim 23, wherein a packing density of the
microneedles is at least 2 microneedles per square millimeter.
33-34. (canceled)
35. The method of claim 23, further comprising: exposing both sides
of the layer, separately or simultaneously, to etching conditions,
such that the steps of etching occurs on both sides of the layer of
material.
36. The method of claim 23, wherein at least some of the
microneedles are coated with a substance.
37. The method of claim 36, wherein the substance comprises one or
more of lidocaine, bupivacaine, and tetracaine.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/367607, filed Jul. 26, 2010,
entitled "Rapid Delivery and/or Withdrawal of Fluids," by
Chickering, et al. This application is incorporated herein by
reference.
FIELD OF INVENTION
[0002] The present invention generally relates to systems and
methods for delivering and/or receiving a substance or substances
such as blood and/or drugs, with respect to subjects, e.g., at
and/or beneath the skin, and in some cases, with relatively little
pain.
BACKGROUND
[0003] Phlebotomy or venipuncture is the process of obtaining
intravenous access for the purpose of intravenous therapy or
obtaining a sample of venous blood. This process is typically
practiced by medical practitioners, including paramedics,
phlebotomists, doctors, nurses, and the like. Substantial equipment
is needed to obtain blood from a subject, including the use of
evacuated (vacuum) tubes, e.g., such as the Vacutainer.TM. (Becton,
Dickinson and company) and Vacuette.TM. (Greiner Bio-One GmBH)
systems. Other equipment includes hypodermic needles, syringes, and
the like. However, such procedures are complicated and require
sophisticated training of practitioners, and often cannot be done
in non-medical settings. Accordingly, improvements in methods of
obtaining blood or other fluids from the skin are still needed.
SUMMARY OF THE INVENTION
[0004] The present invention generally relates to systems and
methods for delivering and/or receiving a substance or substances
such as blood, from subjects, e.g., from the skin and/or from
beneath 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] In one aspect of the invention, microneedles in an array may
be arranged to maximize a density of microneedles per unit area of
the array. For example, a number of microneedles in a circular
array according to one embodiment of the invention may be about two
times the number of microneedles in a rectangular array having the
same footprint size. Improved density may be achieved in some
embodiments by having microneedles arranged (while the microneedles
are lying in a common plane and prior to bending a penetrating
portion of the needles upward from the plane) so that the
microneedles generally "point" towards at least one other
microneedle in the array and such that the microneedles are
generally not parallel with each other. For example, in one
embodiment, a method for forming an array of microneedles may
include steps of providing a layer of material having opposed
substantially planar sides, and etching the layer of material to
define a plurality of microneedles. The microneedles may be formed
from the layer such that bases of the microneedles are arranged at
a periphery of a closed loop and each of the microneedles extends
toward a center of the closed loop. Since the microneedles in this
illustrative embodiment may point radially inwardly, the
microneedles will generally not be parallel with each other
(although some needles may be parallel with one or more other
needles). This configuration has been found to make efficient use
of material in the layer and provide a higher total number of
microneedles for a given area than other arrangements, such as a
rectangular array in which the microneedles are all parallel to
each other. After forming the microneedles from the layer, the
penetrating portions of the microneedles may be bent away from the
bases (i.e., out of the common plane of the layer) so that the
penetrating portions are arranged for insertion into skin or other
material. That is, the penetrating portions may be bent upwardly
from the common plane of the layer so that the penetrating portions
are arranged at an angle relative to the plane of the closed
loop.
[0006] In another illustrative embodiment, an array of microneedles
may include a plurality of microneedles that each include a base
portion and a penetrating portion. The base portions of the
plurality of needles may be arranged at the periphery of a closed
loop lying in a common plane, and the penetrating portions may
extend at an angle away from the plane of the closed loop. Such an
arrangement may help improve a packing density of needles for the
array, e.g., by allowing the needles to be formed from a sheet of
material while making efficient use of the material, and/or provide
for an array with improved material transfer properties, e.g., by
allowing the microneedles to provide a flow channel for fluid
exiting from skin penetrated by the needles.
[0007] In another aspect of the invention, the microneedle
arrangement includes a first plurality of microneedles that each
include a base portion and a penetrating portion, the base portions
of the first plurality of microneedles being arranged at the
periphery of a first closed loop lying in a plane, the penetrating
portions of the first plurality of microneedles each extending at a
respective angle away from the plane of the first closed loop. The
arrangement also includes a second plurality of microneedles that
each include a base portion and a penetrating portion, the base
portions of the second plurality of microneedles being arranged at
a periphery of a second closed loop lying in the plane, the second
closed loop being larger than, and surrounding, the first closed
loop, the penetrating portions of the second plurality of
microneedles each extending at a respective angle away from the
plane of the second closed loop. This arrangement may further
increase the packing density of needles. In some illustrative
embodiments, the closed loops are circles. In one illustrative
embodiment, the closed loops are concentric circles.
[0008] In another aspect of the invention, a method for forming a
microneedle arrangement includes providing a layer of material
having opposed substantially planar sides, etching the layer of
material to define a plurality of microneedles such that bases of
the microneedles are arranged at a periphery of a first closed loop
and each of the microneedles extends toward a center of the first
closed loop, and etching the layer of material to define a second
plurality of microneedles with bases arranged at a periphery of a
second closed loop that is arranged around the first closed
loop.
[0009] In one aspect, the present invention is generally directed
to microneedles for insertion into the skin for the purpose of
delivering therapeutics, such as medicines, drugs, etc., or
receiving fluids, such as blood or interstitial fluid. For example,
microneedles may be inserted into skin and then withdrawn, allowing
blood or other fluid to flow from the skin. In other arrangements,
the microneedles may remain in the skin after insertion (at least
temporarily), and be coated, have one or more channels, be capable
of degrading or dissolving, or otherwise be arranged to allow fluid
to flow from the skin. In one embodiment, microneedles may include
a tip having a point that serves as a leading contact surface.
Providing a leading contact surface on a microneedle in the form of
a point may help reduce a force needed to insert the microneedle
into skin or other material, may help the microneedle maintain a
straight or other desired trajectory when passing through skin,
and/or other features. In one embodiment, the point may be formed
at the intersection of four or more surfaces and may reduce a force
needed to insert the needle into skin or other material. In another
embodiment, a microneedle may have a knife edge, e.g., at least a
portion of the edge of the microneedle may be formed by beveled
surfaces. The knife edge may have a V-shape and may be symmetrical
or asymmetrical. The knife edge may be formed using an etching
process, e.g., an isotropic chemical etching process used in
combination with a photolithographic patterning or other
lithographic patterning process to form the microneedles from a
layer of metal or other material.
[0010] In yet another aspect, the invention is directed to a kit.
In one set of embodiments, the kit includes a fluid sample device
comprising a fluid transporter for receiving fluid from the subject
and a storage chamber for receiving fluid withdrawn from the
subject via the fluid transporter, and an external analytical
apparatus having a port for mating with a port on the fluid sample
device.
[0011] In another aspect, the present invention is directed to a
method of making one or more of the embodiments described herein,
for example, devices for receiving blood from a subject. In another
aspect, the present invention is directed to a method of using one
or more of the embodiments described herein, for example, devices
for receiving blood from a subject.
[0012] 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
[0013] 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:
[0014] FIGS. 1A-1B illustrate devices according to certain
embodiments of the invention;
[0015] FIGS. 2A-2C illustrate devices according to various
embodiments of the invention;
[0016] FIG. 2D illustrates a kit containing more than one device,
in yet another embodiment of the invention;
[0017] FIG. 2E illustrates a device according to still another
embodiment of the invention;
[0018] FIG. 3 illustrates a device in one embodiment of the
invention, having a vacuum chamber;
[0019] FIG. 4 illustrates a device in another embodiment of the
invention, having a vacuum chamber and a storage chamber;
[0020] FIG. 5 illustrates a device in yet another embodiment of the
invention, having a flow controller;
[0021] FIG. 6 illustrates a device in yet another embodiment of the
invention, having an exit port;
[0022] FIG. 7 illustrates a device according to another embodiment
of the invention;
[0023] FIG. 8 illustrates a device containing a fluid reservoir, in
another embodiment of the invention;
[0024] FIG. 9 illustrates an adaptor according to one embodiment of
the invention;
[0025] FIGS. 10A-10C illustrate a device in still another
embodiment illustrating a deployment actuator;
[0026] FIG. 11 illustrates yet another embodiment of the invention
in which a device is actuated by a deployment actuator;
[0027] FIGS. 12A and 12B illustrate yet another embodiment of the
invention, in which a device is actuated by a deployment actuator,
at different stages of operation of the device;
[0028] FIG. 13 is a perspective view of a microneedle that is
usable in some microneedle array arrangements in accordance with an
aspect of the invention;
[0029] FIG. 14 shows a perspective view of a microneedle having a
knife edge in an illustrative embodiment;
[0030] FIG. 15 is a cross sectional view of the microneedle of FIG.
14 along the line 15-15;
[0031] FIG. 16 is a top view of the microneedle in FIG. 14;
[0032] FIG. 17 shows a perspective view of a microneedle having a
knife edge in another illustrative embodiment;
[0033] FIGS. 18 and 19 schematically show two steps in a method for
forming microneedles in an illustrative embodiment;
[0034] FIG. 20 shows an illustrative array of microneedles in which
each microneedle has the configuration as shown in FIG. 14;
[0035] FIG. 21 shows an illustrative array of microneedles in which
each microneedle has the configuration as shown in FIG. 13;
[0036] FIG. 22 schematically shows steps in a method for forming
the array of FIG. 20;
[0037] FIG. 23 shows a plan view of the array of FIG. 21 prior to a
bending step
[0038] FIG. 24 shows a plan view of a rectangular microneedle array
prior to a bending step;
[0039] FIG. 25 shows a perspective view of a microneedle having a
beveled edge in an illustrative embodiment;
[0040] FIG. 26 is a cross sectional view of the microneedle of FIG.
25 along the line 26-26; and
[0041] FIG. 27 shows an illustrative array of microneedles having
two groups of microneedles arranged with respect to concentric
closed loops.
DETAILED DESCRIPTION
[0042] The present invention generally relates to systems and
methods for receiving a substance from a subject, e.g. received
from the skin and/or from beneath the skin of the subject, and/or
for delivering a substance to a subject, e.g. delivering a
substance to the skin and/or to a location beneath the skin of a
subject. Throughout the application, the phrase "from the skin" is
used to mean from the top or outer surface of the skin, from within
the skin, and/or from beneath the skin. Likewise, "to the skin" is
used to mean to the top or outer surface of the skin, to within the
skin, and/or to beneath the skin. The device, in some cases, may be
interfaced with external equipment to determine an analyte
contained within a fluid contained within or collected by the
device. For example, the device may be mounted on an external
holder, the device may include a port for transporting fluid out of
the device, the device may include a window for interrogating a
fluid contained within the device, or the like.
[0043] The received fluid may be any suitable bodily fluid, such as
interstitial fluid, other skin-associated material, mucosal
material or fluid, whole blood, perspiration, saliva, plasma,
tears, lymph, urine, plasma, or any other bodily fluid, or
combinations thereof. Substances received from a subject can
include solid or semi-solid material such as skin, cells, or any
other substance from the subject. Substances that can be delivered
to a subject in accordance with some embodiments of the invention
include diagnostic substances, therapeutic substances such as
drugs, and the like. Various embodiments of the invention are
described below in the context of delivering or receiving a fluid,
such as blood, from or through the skin. It is to be understood
that in all embodiments herein, regardless of the specific
exemplary language used (e.g., receiving blood), the devices and
methods of other embodiments of the invention can be used for
receiving any substance from the skin and/or from beneath the skin
of the subject, and/or for delivering any substance to the subject,
e.g. to the skin and/or a location beneath the skin of the
subject.
[0044] In one aspect, the present invention is generally directed
to devices and methods for receiving or extracting blood or other
bodily fluids from a subject, e.g., from the skin and/or from
beneath the skin, using devices having a substance transfer
component (which may include, for example, one or more microneedles
and/or other skin insertion objects). The device may also contain,
in some embodiments, a storage chamber having an internal pressure
less than atmospheric pressure prior to receiving blood or other
bodily fluids. In some cases, the device may pierce the skin of the
subject, and fluid can then be delivered and/or received from the
subject. 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.
[0045] In some cases, the device can be applied to the skin, and
activated to receive fluid from the subject. The device, or a
portion thereof, may then be processed to determine the fluid
and/or an analyte within the fluid, alone or with an external
apparatus. For example, fluid may be received from the device,
and/or the device may contain sensors or agents able to determine
the fluid and/or an analyte suspected of being contained in the
fluid.
[0046] The inventors have appreciated that the performance of
microneedles or other skin insertion objects when inserted into
skin to receive fluids, or to deliver therapeutics or fluids,
depends on the mechanical stability and sharpness of the needles
used, and that the force needed to insert microneedles into skin
depends on the interfacial area between the microneedle tip and the
skin contact surface. That is, needles for some applications should
have a suitably small interfacial area to reduce the force needed
to insert the needles into skin, and be strong enough to withstand
the force so as to prevent breaking or bending of the needles.
Also, an amount of fluid received or delivered via the needles
depends on the cross sectional area and number of microneedles
within a given array, as well as the length of the needles. In some
aspects of the invention, provided microneedles have a reduced
interfacial area (i.e., increased sharpness) and an increased
number of microneedles per unit area of an array (i.e., higher
packing density). This results in microneedle arrays that penetrate
the skin more easily and reliably than other arrays and/or allow
for the receiving or the delivery of greater volumes (and/or higher
flow rates) of fluid. In some cases, needles of greater length may
be more easily bent or damaged during insertion. Needles that
require smaller insertion forces (due to increased sharpness or
other factors) allow needles to be formed at longer lengths with
less risk of deformation during insertion.
[0047] One aspect of the invention relates to a microneedle
arrangement in which the microneedle, and/or an array of
microneedles, has improved penetration, fluid transfer or other
performance characteristics. In one embodiment, a microneedle may
have a point at its distal end that is formed at the intersection
of at least four surfaces. Such an arrangement may provide for
improved insertion characteristics, e.g., allow the microneedle to
more easily penetrate skin and/or maintain a straight trajectory
when being inserted into skin or other material. This is in
contrast to prior needle tip arrangements in which the needle has a
leading contact surface in the form of a line as opposed to a
point. For example, FIG. 13 shows a prior microneedle arrangement
as taught in U.S. Patent Publication 20070161964 in which the
microneedle 1 has a penetrating portion 2 that extends upwardly at
an angle relative to a base portion 3 and has a sword-like shape
with a tip 4 at a distal end of the penetrating portion 2. In this
arrangement, however, the penetrating portion 2 has flat surfaces 5
at its periphery configured such that the tip 4 has a line shape at
its extreme distal end. That is, the leading contact surface of the
penetrating portion 2 is a line formed by the intersection of two
surfaces 5. In some cases, a line-type leading contact surface may
not be ideal, e.g., may require relatively higher forces to be
placed on the microneedle 1 for insertion than desired.
[0048] In contrast, FIG. 14 shows one embodiment of a microneedle
having a tip with a leading contact surface in the form of a point
as opposed to a line like that in the FIG. 13 embodiment. That is,
in this embodiment, the periphery of the microneedle 1 is formed
having a symmetrical V-type knife edge that extends from the base 3
along the length of the penetrating portion 2 to the tip 4. (As
used herein, "periphery" refers to at least a portion of an outer
edge of the microneedle, and does not necessarily include the
entire outer edge of the microneedle.) Accordingly, the penetrating
portion 2 has an approximately hexagon-shaped cross-section as
shown in FIG. 15 (which is a lateral cross section along a line
15-15 shown in FIG. 14). As can also be seen in FIG. 15, the
opposed substantially planar sides 6 of the penetrating portion 2
are interconnected by the knife edge surfaces 5, which are arranged
at non-perpendicular angles to the sides 6, and are arranged at an
acute angle relative to each other. Thus, when viewed from the top
as shown in FIG. 16, the tip 4 has a point at its extreme distal
end that is formed at the intersection of four surfaces 5a, 5b, 5c
and 5d. Having the tip 4 arranged to have a point may provide
benefits, such as reduced force or friction when inserting the
penetrating portion 2 into skin or other material. Alternately, or
in addition, the surfaces 5a-5d may help maintain a straight
trajectory of the tip 4 and penetrating portion 2 when inserted
into skin or other material. That is, contact of the surfaces 5a-5d
with skin during penetration may exert balanced forces on the
penetrating portion 2 that helps to keep the tip 4 traveling along
a straight path. This is in contrast to an arrangement like that in
FIG. 13 where the tip 4 has no surfaces to provide balanced forces
on the tip in directions generally perpendicular to the width of
the penetrating portion 2, i.e., in directions parallel to the
planes of the side surfaces 5 of the penetrating portion 2 at the
tip 4. The pointed tip 4 of the FIG. 14 embodiment is also in
contrast to a microneedle arrangement like that shown in FIGS. 25
and 26, in which the microneedle has a single beveled surface 5 at
its periphery. Since the microneedle in FIG. 25 has single beveled
surfaces 5 at the tip 4, the tip 4 will generally not experience
balanced forces when inserted into skin or other material. This is
because the beveled surfaces 5 at the tip 4 will exert a force on
the tip 4 that tends to bend the penetrating portion away from the
base 3, tending to flatten the needle. Such forces can cause the
microneedle 1 to bend or break in some environments, rendering the
microneedle 1 less useful for its intended function. For example,
one of the possible consequences of bending is incomplete
insertion. Bending during insertion causes the needles to deflect
away from each other and results in a non-parallel arrangement
between the needles. This may, in turn, limit the insertion
depth.
[0049] It should be understood that embodiments in accordance with
the invention may be configured in ways other than that shown in
FIGS. 14-16. For example, FIG. 17 shows a microneedle 1 arrangement
having a chisel-like shape as opposed to the sword-like shape in
FIG. 14. However, as in the FIG. 14 embodiment, a periphery of the
penetrating portion 2 has a V-type knife edge formed by surfaces 5
that are arranged at an acute angle relative to each other and that
interconnect, or join, the relatively broad, opposed planar sides 6
of the penetrating portion 2. Also like the FIG. 14 embodiment, the
tip 4 in FIG. 17 has a point that is formed at the intersection of
four surfaces, i.e., the knife edge surfaces 5. However, it should
be noted that while the microneedle in FIG. 17 may experience
balanced forces on the tip 4 in directions generally perpendicular
to the sides 6, the longer, angled surfaces 5 on the right side of
the microneedle 1 may exert forces on the penetrating portion 2
that cause the microneedle 1 to bend toward the left (as shown in
FIG. 17) when being inserted into skin or other material. Other
arrangements are possible in accordance with aspects of the
invention, such as forming a knife edge on a periphery of the
penetrating portion in an asymmetrical way (e.g., so that the
surfaces 5 have a different width and/or are arranged at a
different angle with respect to the planar sides 6 of the
penetrating portion), forming the knife edge so as to include more
than two surfaces that interconnect the planar sides 6 (e.g., each
surface 5 may be arranged to be formed by two or more surfaces),
the penetrating portion 2 may be arranged to include two or more
points (e.g., the sword shaped penetrating portion 2 of FIG. 14 may
be split so that a slot extends from the tip 4 down toward the base
3, thus providing the penetrating portion 2 with two points), the
penetrating portion 2 may include one or more channels, holes,
grooves or other features (e.g., such as the opening in the needle
of FIG. 13 to facilitate fluid flow), and others.
[0050] Another aspect of the invention relates to a method for
forming a microneedle, e.g., so as to include a knife edge or other
multiple surface arrangement at a periphery of the microneedle. One
embodiment shown schematically in FIGS. 18 and 19 involves
providing a layer of material from which one or more microneedles
is to be formed. The layer may include any suitable material or
combination of materials, such as metals, polymers, ceramics, and
other materials. In this illustrative embodiment, the layer 7 is a
single layer of titanium (e.g., a roll formed sheet, a sputter or
vapor deposited layer, or otherwise formed), having top and bottom
(opposed) substantially planar sides. (It should be understood that
the term "planar" as used herein refers to a generally flat surface
or region that may, in some cases, include bumps, holes or other
relatively small surface irregularities. For example, chemical
etching can in some environments form pits, grooves or other
surface features on a sheet of material. Thus, a planar side or
surface need not be completely flat and/or smooth.) In this
embodiment, a pattern 8 is formed on both the top and bottom
surfaces of the layer 7 that corresponds to at least a portion of
the desired shape for the microneedle 1 (FIG. 14). In this case,
the patterns 8 have a sword-like shape so as to form a sword shaped
microneedle 1, although other shapes or configurations are
possible. The pattern 8 may be formed in any suitable way, such as
by a photolithographic process including depositing a layer of
photoresist on the layer 7, exposing the photoresist to a suitable
illumination pattern, and etching the resist to form the pattern 8
shown in FIG. 18. After providing the patterns 8, the layer 7 may
be etched (e.g., by chemical etching) from one or both sides
(whether simultaneously or consecutively) to form the microneedle 1
having edge surfaces 5 that form a knife edge at the periphery of
the microneedle 1. As is understood in the art, if the layer 7 is
an isotropic material (or otherwise suitably formed) and the
etching process is likewise isotropic (i.e., equal in etch rate in
all directions), beveled surfaces 5 will be formed as shown in FIG.
19. This arrangement can provide a convenient way to form a knife
edge around the microneedle 1 with a suitably sharp edge and other
characteristics. Moreover, the use of photolithographic processes
to form the microneedles allows for a flexibility in the shape,
size and other features of the needles.
[0051] Although the pattern and etching method shown schematically
in FIGS. 18 and 19 can be used to form a microneedle in accordance
with aspects of the invention, a microneedle can be formed using
other techniques. For example, a knife edge can be formed on a
microneedle using other techniques that do not involve a pattern
and/or chemical etching, such as grinding, molding, stamping, laser
etching, and others. Accordingly, aspects of the invention
regarding microneedles having certain physical features are not
necessarily limited in any way with respect to how those features
are formed.
[0052] Another aspect of the invention relates to an arrangement
for an array of microneedles. In one embodiment, a plurality of
microneedles may be configured so that the base of each microneedle
is arranged at a periphery of a closed loop that lies in a plane.
The penetrating portion of each microneedle may extend at an angle
away from the base and the plane of the closed loop, e.g., to form
an array of needles in a ring-like shape. For example, FIG. 20
shows a microneedle array including a plurality of microneedles 1
arranged in a circular array such that the base 3 of each needle 1
is arranged in a periphery of a closed loop (in this case a
circle). The penetrating portions 2 of the needles 1 all extend at
an angle (e.g., a 90 degree angle) away from the plane of the
closed loop. Although in this embodiment, the microneedles 1 have a
knife edge and other features like that shown in FIG. 14, the
microneedles 1 may be arranged in any suitable way. For example,
FIG. 21 shows a similar array of microneedles 1 in which the
needles have a distal end and tip arranged like that in FIG. 13. In
other embodiments, the microneedles may have an arrangement like
that shown in FIG. 25. Thus, an array of microneedles in accordance
with this aspect of the invention is not limited with respect to
how the tip or other features of the microneedle 1 are configured.
The closed loop may be of any suitable shape, including, but not
limited to, circular, elliptical, hexagonal, rectangular,
pentagonal, octagonal or other curved or irregular shape. Also, the
term "closed loop" does not require that the bases 3 of the
microneedles 1 in an array be connected together in a continuous
fashion like that shown in FIGS. 20 and 21. Rather, "closed loop"
is used to refer to a shape that is formed by drawing a line that
connects the bases of the microneedles in an array to each other.
Thus, for example, the array in FIG. 20 may be arranged so that the
bases 3 of the microneedles 1 are not connected together by an
annular ring as shown, but may instead be physically separate from
each other. In other embodiments, however, the array may be
arranged so that the bases 3 of the microneedles 1 are connected
together.
[0053] FIG. 22 shows schematic steps in an illustrative method for
forming an array of microneedles arranged like that in FIGS. 20 and
21. In an initial step, a layer of material is provided, e.g., a
layer of titanium or other suitable material or combination of
materials. Next, a pattern is provided on one or both sides of the
layer. In this embodiment, the pattern corresponds to a desired
shape of the microneedles. The pattern may be formed in any
suitable way, such as using a photolithographic process, a stamping
process, or other. Next, the layer is etched, e.g., using a
chemical etch or other suitable process, to form the layer into a
desired arrangement. Etching may be performed from one or both
sides of the layer. In this embodiment, a plurality of microneedles
are formed from the layer with each microneedle having its base
arranged in a periphery of a closed loop (in this case a circle)
and with the penetrating portions 2 of the needles 1 extending
toward a center of the closed loop. As can be seen in the third
step from the left in FIG. 22, the microneedles 1 each "point"
toward at least one other microneedle in the array, and the
microneedles are generally not parallel with each other (although
some microneedles may be parallel to one or more microneedles).
Although in this embodiment the penetrating portions 2 extend
toward an exact center of the closed loop, the penetrating portions
may generally extend toward a center of the closed loop. For
example, if the closed loop is in the form of an ellipse, the
penetrating portions may generally extend inwardly without having
all of the penetrating portions extending toward a precise,
geometric center of the ellipse. In other embodiments, the
penetrating portions 2 may generally extend away from the center of
the closed loop. Lastly, the penetrating portions 2 of the
microneedles 1 may be bent upwardly from the plane of the base and
closed loop so that the penetrating portions 2 extend at an angle
from the plane. In this embodiment, the penetrating portions 2 are
arranged at a 90 degree angle to the plane, but other angles may be
used. For example, the penetrating portions 2 may be bent upwardly
at a 45 degree angle at a point near the base 3, and then bent
upwardly again another 45 degrees at an upper region so that the
tip 4 extends generally perpendicularly to the plane of the closed
loop and the bases 3. This arrangement may allow the tips 4 of the
penetrating portions 2 to be more compliant, allowing the
penetrating portions 2 to bend elastically rather than plastically
when confronted with a material that is difficult to penetrate. In
another embodiment, a 90 degree bend may be made at a position
along the length of the needle away from the plane of the base.
[0054] Arranging microneedles such that the bases of the needles
are located at a periphery of a closed loop allows for an increased
packing density (e.g., number of needles per unit area) than prior
arrangements. In some embodiments, the packing density may be 2
microneedles per square millimeter or more, e.g., where the
microneedle length is greater than 500 microns. For example, FIG.
23 shows a plan view of a microneedle array formed like that in
FIG. 22 prior to bending the penetrating portions 2 upwardly away
from the bases 3 and the common plane of the layer in which the
microneedles are initially formed. This arrangement includes a
total of 16 microneedles. In one embodiment, the microneedles may
each be about 750 .mu.m long and the array may have a diameter of
about 3 mm. In contrast, FIG. 24 shows a rectangular array of 8
microneedles each having the same size and shape as in the FIG. 23
embodiment, i.e., the needles are 750 .mu.m long and are parallel
to each other, and the array has a diameter of about 3 mm. Since
the FIG. 23 array has twice the number of needles, the FIG. 23
array will have a larger capacity for fluid flow (whether total
fluid volume and/or flow rate) as compared to the FIG. 24 array
while having the same overall size. Moreover, the central void in
the FIG. 23 array (i.e., the central area containing no needles)
may provide additional benefits, such as channeling flow toward a
center of the array for easier collection. In some cases, a small
distance between microneedles may decrease ease of insertion. In
some cases, it may be desirable to maintain a minimum spacing
between microneedles. For example, the minimum spacing may be about
100 micrometers, about 200 micrometers, about 300 micrometers,
about 400 micrometers, about 500 micrometers, about 600
micrometers, about 700 micrometers, about 800 micrometers or about
900 micrometers. This minimum spacing limits the number of needles
that can be arranged in a confined area, for example, a base with a
small area. In some cases, a circular configuration may maximize
the number of needles that can fit in the confined area.
[0055] Aspects of the invention are not limited to microneedle
arrays in which only a single group of microneedles are arranged
with their bases at the periphery of a closed loop. For example, an
array may include two or more groups of needles that are arranged
with respect to different closed loops. Arrays may include a
plurality of groups of needles. FIG. 27 shows an illustrative
embodiment that includes a first group of microneedles 1 arranged
in an inner pattern (in this case a circular arrangement) and a
second group of microneedles 1 arranged in an outer pattern (also a
circular pattern in this embodiment. Other arrangements will occur
to those of skill in the art. For example, the closed loops for
concentric patterns like that in FIG. 27 may have different sizes
or shapes, such as a first inner group of needles arranged with
respect to a closed loop in a pentagonal shape and a second outer
group of needles arranged with respect to a closed loop in a
hexagonal shape. Moreover, the centers of the closed loops need not
be coincident, but instead may be offset from each other.
[0056] In yet other embodiments, an array may include three or more
closed loops of microneedles, such as a larger closed loop of
microneedles that surrounds two smaller closed loops of
microneedles. The closed loops need not be "concentric" in the
sense that a smallest closed loop is contained within a medium
sized closed loop, which is in turn contained within a larger
closed loop and so on. Instead, for example, two smaller closed
loops may be adjacent each other and contained within a larger
closed loop. In some illustrative embodiments, however, the closed
loops are concentric circles. In some embodiments, a needle
arrangement may include a plurality of these pairs of closed
loops.
[0057] The invention, in one set of embodiments, involves the
determination of a condition of a subject. Bodily fluids and/or
other 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. In one
aspect, accordingly, the present invention is generally directed to
various devices for delivering and/or receiving blood, or other
bodily fluids, from the skin and/or from beneath the skin of a
subject. Accordingly, in the description that follows, the
discussion of blood is by way of example only, and in other
embodiments, other fluids may be received from the skin in addition
to and/or instead of blood.
[0058] In one set of embodiments, the device includes a substance
transfer component able to deliver to or receive fluid from the
subject. As used herein, "substance transfer component" is any
component or combination of components that facilitates movement of
a substance or a fluid from one portion of the device to another,
and/or from the device to the subject or vice versa. The substance
transfer component may include an opening of any size and/or
geometry that is constructed to receive fluid into the device. For
example, an opening of a substance transfer component may lie in a
two-dimensional plane or the opening may include a
three-dimensional cavity, hole, groove, slit, etc. In some
embodiments, the substance transfer component may also include one
or more microneedles or other skin insertion objects, arranged to
cause fluid to be released from the subject, e.g., by piercing the
skin of a subject. In some embodiments, if fluid may partially or
fully fill an enclosure surrounding a skin insertion object or
other object, then the enclosure can define at least part of a
substance transfer component. A substance transfer component may
include any other suitable fluid transporter or flow activator.
Other components including partially or fully enclosed channels,
microfluidic channels, tubes, wicking members, vacuum containers,
etc. can be, or be a part of, a substance transfer component.
[0059] If needles or microneedles are used, they may be solid or
hollow, i.e., blood or other fluid may travel in and/or around the
needles or microneedles into or from the device. In some cases, the
needles or microneedles may also be removed from the subject, e.g.,
after insertion into the skin, for example, to increase the flow of
blood or other fluids from the subject. In one set of embodiments,
the substance transfer component includes solid needles that are
removed from the skin and a cup or channel to direct the flow of
blood or other bodily fluids.
[0060] It should be noted that a skin insertion object or other
flow activator need not be included with all embodiments as the
device may not necessarily employ a mechanism for causing fluid
release from the subject. For instance, the device may receive
fluid that has already been released due to another cause, such as
a cut or an abrasion, fluid release due to a separate and
independent device, such as a separate lancet, an open fluid access
such as during a surgical operation, and so on. Additionally, fluid
may be introduced into the device via urination, spitting, pouring
fluid into the device, etc. If included, a skin insertion object or
other substance transfer component may physically penetrate,
pierce, and/or or abrade, chemically peel, corrode and/or irritate,
release and/or produce electromagnetic, acoustic or other waves,
other otherwise operate to cause fluid release from a subject. The
substance transfer component may include a movable mechanism, e.g.,
to move a needle, or may not require movement to function. For
example, the substance transfer component may include a jet
injector or a "hypospray" that delivers fluid under pressure to a
subject, a pneumatic system that delivers and/or receives fluid, a
hygroscopic agent that adsorbs or absorbs fluid, a reverse
iontophoresis system, a transducer that emits ultrasonic waves, or
thermal, radiofrequency and/or laser energy, and so on, any of
which need not necessarily require movement of an element to cause
fluid release from a subject.
[0061] In some aspects, the device may include a support structure,
such as a housing. The housing may be used, as discussed herein,
for applying the substance transfer component to the surface of the
skin of the subject, e.g., so that fluid may be delivered and/or
received from the skin of the subject. In some cases, the housing
may immobilize the substance transfer component such that the
substance transfer component cannot move relative to the housing;
in other cases, however, the substance transfer component, or a
portion thereof, may be able to move relative to the housing. In
one embodiment, as a non-limiting example, the substance transfer
component is immobilized relative to the housing, and the
deployment actuator is positioned within the device such that
application of the device to the skin causes at least a portion of
the substance transfer component to pierce the skin of the subject.
In some cases, as previously discussed, the housing encloses a
deployment actuator.
[0062] In some embodiments, the deployment actuator, or a portion
of the deployment actuator, may move from a first position to a
second position. For example, the first position may be one where
the deployment actuator has attached thereto a substance transfer
component that is not in contact with the skin (e.g., a skin
insertion object of the substance transfer component may be
contained within a recess of the substance transfer component),
while the second position of the deployment actuator may be one
where the substance transfer component does contact the skin, e.g.,
to pierce the skin. The deployment actuator 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 deployment actuator may be
moved from a first position to a second position by pushing a
button on the device, which causes the deployment actuator to move
(either directly, or through a mechanism linking the button with
the deployment actuator). Other mechanisms (e.g., dials, levers,
sliders, etc., as discussed herein) may be used in conjunction of
or instead of a button. In another set of embodiments, the
deployment actuator 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
deployment actuator is activated electronically, moving the
deployment actuator from the first position to the second position.
In some cases, the deployment actuator may include a triggering
mechanism that initiates deployment.
[0063] In some cases, the deployment actuator and/or the substance
transfer component may also be moved from the second position to
the first position (or some other position). For example, after
fluid has been delivered and/or received from the skin, e.g., using
a substance transfer component, the deployment actuator may be
moved, which may move the substance transfer component away from
contact with the skin. The deployment actuator 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 deployment actuator from the second position to the
first position may be the same or different as that moving the
deployment actuator from the first position to the second
position.
[0064] In some cases, the device may be able to draw skin towards
the substance transfer component. For example, in one set of
embodiments, the device may include a vacuum interface or region.
The interface or region 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 device, e.g., for contact
with a substance transfer component, such as one or more needles or
microneedles.
[0065] In one set of embodiments, the device includes a deployment
actuator able to drive a substance transfer component into the
skin, e.g., so that the device can receive a fluid from the skin of
a subject, and/or so that the substance transfer component can
deliver a substance to a subject, e.g. deliver a substance to the
skin and/or to a location beneath the skin of a subject. The
deployment actuator may be a structure that can be deformed using
unaided force (e.g., by a human pushing the structure), or other
forces (e.g., electrically-applied forces, mechanical interactions
or the like), but is able to restore its original shape after the
force is removed or at least partially reduced. For example, the
structure may restore its original shape spontaneously, or some
action (e.g., heating) may be needed to restore the structure to
its original shape. In one set of embodiments, the deployment
actuator may include a flexible concave member or a reversibly
deformable structure that is movable between a first configuration
and a second configuration. The deployment actuator may be formed
out a suitable elastic material, in some cases. For instance, the
structure may be formed from a plastic, a polymer, a metal, etc. In
one set of embodiments, the structure may have a concave or convex
shape. For instance, the edges of the structure may be put under
compressive stress such that the structure "bows" out to form a
concave or convex shape. A person pushing against the concave or
convex shape may deform the structure, but after the person stops
pushing on the structure, the structure may be able to return to
its original concave or convex shape, e.g., spontaneously or with
the aid of other forces as previously discussed. In some cases, the
device may be bistable, i.e., having two different positions in
which the device is stable.
[0066] An example of a deployment actuator is now illustrated with
respect to FIG. 10. In FIG. 10A, structure 700 has a generally
concave shape, and is positioned on the surface of skin 710.
Structure 700 also includes a substance transfer component 720 for
insertion into the skin. In FIG. 10B, a person (indicated by finger
705) pushes onto structure 700, deforming at least a portion of the
structure and thereby forcing a substance transfer component 720
into at least a portion of the skin. In FIG. 10C, after the person
releases structure 700, the structure is allowed to return to its
original position, e.g., spontaneously, lifting substance transfer
component 720 out of the skin. In some cases, e.g., if the
substance transfer component includes needles or other skin
insertion objects that are sufficiently large or long, blood or
other fluids 750 may come out of the skin through the holes created
by the needles, and optionally the fluid may be collected by the
device for later storage and/or use, as discussed herein.
[0067] As another example, referring now to FIG. 11, a device 1100
is illustrated schematically in which a substance transfer
component is driven by a deployment actuator. In FIG. 11, device
1100 includes a housing 1102 defining a plurality of chambers and
channels. In other embodiments (not shown) a plurality of
components that can be separable from and attachable to each other
(e.g., modular components) can together define the device and
together define a series of channels and compartments necessary for
device function. See, e.g., U.S. patent application Ser. No.
12/716,233, filed Mar. 2, 2010, 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. patent
application Ser. No. 12/716,226, filed Mar. 2, 2010, entitled
"Techniques and Devices Associated with Blood Sampling," by
Levinson, et al.; or U.S. patent application Ser. No. 12/716,229,
filed Mar. 2, 2010, entitled "Devices and Techniques Associated
with Diagnostics, Therapies, and Other Applications, Including
Skin-Associated Applications," by Bernstein, et al., each
incorporated herein by reference.
[0068] In the specific device illustrated, device 1100 includes a
surface 1104 for positioning the device proximate the skin of a
subject during use. Where desired in certain embodiments, the
device can include an adhesive layer 1106 where the adhesive is
selected to be suitable for retaining the device in a relatively
fixed position relative to the skin during use, but may allow for
relatively easy removal of the device from the skin following use.
Specific non-limiting examples of adhesives are discussed below.
The adhesive also can be selected to assist in maintaining a vacuum
within portions of the device proximate the skin as will be
understood.
[0069] In FIG. 11, device 1100 includes a substance transfer
component 1108. The substance transfer component may be or include,
for example, a skin insertion object or other suitable object as
discussed herein. Specific non-limiting examples include needles or
microneedles, e.g., as shown in FIG. 11. The substance transfer
component can be or include, as described elsewhere herein and in
other documents incorporated herein by reference, any of a variety
of components able to receive a substance from the skin and/or from
beneath the skin of a subject, and or deliver a substance to the
skin and/or to a location beneath the skin of the subject. For
example, the substance transfer component may include one or more
needles and/or microneedles, a hygroscopic agent, a cutter or other
piercing element, an electrically-assisted system, or the like. In
the specific device illustrated, substance transfer component 1108
includes an array of skin insertion objects such as solid or hollow
microneedles. In one set of embodiments, substance transfer
component 1108 is selected to have a particular size and profile
for a particular use. For example, the substance transfer component
may include an array of skin insertion objects which, in the device
illustrated, emanate from a base 1110 which will be described
further below.
[0070] In certain embodiments, a plurality of skin insertion
objects of the substance transfer component 1108 and are relatively
small, and are relatively completely driven into the skin. The skin
insertion objects may be positioned to address the skin of the
subject, each protruding from a base and defining a length from the
base, and are able to be inserted into or through the skin to a
depth essentially equal to their length but are prevented, by the
base, from inserting at a depth greater than their length. In some
embodiments, the plurality of skin insertion objects have an
average length (measured from the base) of no more than about 1,000
microns or more than about 2,000 microns, although lengths can
differ between individual skin insertion objects. In one set of
embodiments, the skin insertion objects are of relatively uniform
length, together defining an average length and each differing from
the average length by no more than about 50%, about 40%, about 30%,
about 10%, or about 5%. The average length of the skin insertion
objects, in other embodiments, are no more than about 1,500
microns, no more than about 1,000 microns, no more than about 900
microns, no more than about 800 microns, no more than about 750
microns, no more than about 600 microns, no more than about 500
microns, no more than about 400 microns, or no more than about 350
microns. In some embodiments, a deployment actuator as discussed
herein is provided that is able to move the skin insertion objects
from a fully pre-deployed position to a fully deployed position
with a force sufficient to insert the plurality of skin insertion
object into or through the skin to an average insertion depth of at
least about 50% the average length of the plurality of skin
insertion objects. In other embodiments, the deployment actuator is
able to insert the plurality of skin insertion objects to an
average insertion depth of at least about 55%, at least about 60%,
at least about 65%, at least about 70%, at least about 75%, at
least about 80%, at least about 85%, at least about 90%, at least
about 92%, about 94%, about 96%, or about 98% of the average length
of the plurality of skin insertion objects.
[0071] In the device illustrated, the skin insertion objects of the
substance transfer component 1108 are mounted on a flexible
structure 1112 which, as illustrated, is maintained relatively
rigidly through various aspects of the device but which mounts
substance transfer component 1108 flexibly for up/down movement
relative to the skin. Flexible structure 1112 can be a membrane, a
single or multi-layer structure selected from various polymers or
the like to provide sufficient properties such as any combination
of flexibility, elasticity, gas permeability or impermeability,
fluid permeability or impermeability, or the like for desired
operation. Portions of flexible structure 1112, skin insertion
objects t 1108, and other interior walls of the device define a
region 1114 which allows for movement of skin insertion objects
1108 relative to the skin for delivery of a substance to and/or
receiving of a substance from the skin or beneath the skin, and,
where a substance is received from the skin or from beneath the
skin, region 1114 can serve as a reservoir for introduction of the
substance into the device. Where a vacuum is used to receive a
substance from the subject (as in the embodiment illustrated in
FIG. 11), region 1114, when positioned against the skin, can expose
vacuum to that portion of the skin proximate surface 1104 of the
device and abutting the chamber.
[0072] Device 1100 also includes a transfer component actuator 1116
which, as illustrated, includes a proximate portion 1118 which can
be addressed by a user of the device (who may be the same or
different from the subject the device is administered to) and a
distal portion 1120 for addressing skin insertion objects 1108 via
flexible structure 1112. Proximal portion 1118 and distal portion
1120 are, in the device illustrated, opposite ends of a single
component but, as would be understood by those of ordinary skill in
the art, the actuator can include a plurality of individual
components operably linked in any way necessary to perform
actuation as will be described.
[0073] As will be understood, FIG. 11 is a cross-section of a
device illustrating various components and channels within the
device. As will also be understood by those of ordinary skill in
the art, different arrangements of devices and channels are
contemplated herein so long as the purpose of the device described
herein is met. In this figure, device actuator 1116 is directly
connected to or otherwise operably linked to a deployment actuator
1122 which, in the device illustrated, is in the form of a "snap
dome," the function and use of which will be described below. The
snap dome in this figure has an approximately circular profile. The
structure may define an interior and a periphery which, if not
circular, may include a plurality of tabs, protrusions, or the like
sufficient for support of structure 1122 within the device. As
illustrated, a plurality of tabs (or the essentially circular
perimeter of) the device are supported within holders 1124, and the
center, snap dome portion of the device is operably linked to
device actuator 1116, such that movement of the central portion of
snap dome 1122 and the periphery of the snap dome can be controlled
independently of each other. Holders 1124 are directly connected to
or otherwise operably linked to a retraction actuator 1126 which,
in the device illustrated, can be a ring-shaped structure
positioned under and supporting holders 1124. Holders 1124 can be
individual holders and/or a ring-like structure surrounding the
periphery of snap dome 1122. A series of one, two, or more support
members (e.g., 1130) are positioned near the top of device 1100 and
serve to define a series of channels for sample flow, vacuum
control, or the like as will be described.
[0074] Turning now to channels defined within the device, as
described above, region 1114, when the device is positioned against
skin, can serve to expose a portion of the skin defined by the
periphery of the region to a vacuum, to substance transfer
component 1108 as it moves toward and/or away from the skin, and/or
to transfer a substance from or to the subject. Region 1114 can
house a substance for transfer to the subject, in the form of a
pharmaceutical composition or the like, optionally loaded on skin
insertion objects 1108. Where blood and/or interstitial fluid is
drawn from a subject, region 1114 can serve to introduce the
substance into the device from the subject.
[0075] A channel 1132 connects region 1114 to other portions of the
device in this example. Channel 1132 can be used to deliver a
substance to region 1114 for transfer to a subject, or for
application of a vacuum to region 1114, and/or for receiving of a
substance from a subject. The remainder of the description of
device 1100 will be made within the context of receiving a
substance such as blood and/or interstitial fluid from a subject,
but it is to be understood that substances can also be delivered
via various channels. Channel 1132 typically emanates in one
direction from region 1114 although a plurality of channels can
emanate from the region, arranged radially or otherwise relative to
the center of the device. In device 1100, channel 1132 first passes
laterally from the center of the device and then upwardly where,
near the top of the device, it can, optionally, include one wall
defining a window 1134 through which a user of the device can
observe transfer of a substance, or through which analysis of a
substance may occur. It can also itself define a reservoir, in
whole or in part, or be connected to an internal or an external
reservoir for maintaining, storing, and/or transferring a substance
drawn from a subject. As shown here, it can be connected to a
substance collection reservoir 1136 which, as illustrated, is a
disc-shaped reservoir formed in the device housing and surrounding
the center of the device including device actuator 1116 and related
components.
[0076] Device 1100, illustrated as one example of devices provided
by the invention, includes a vacuum chamber for applying a vacuum
proximate the skin of a subject for receiving a substance from the
skin. As illustrated, vacuum chamber 1138 is positioned in a
central portion of the device surrounding device actuator 1116,
although it can be provided anywhere in or proximate the device.
The vacuum chamber can be evacuated to an appropriate level just
prior to use, or the device can be pre-packaged under vacuum as
described elsewhere herein. As illustrated, vacuum chamber 1138 is
in fluid communication with substance collection reservoir 1136
but, in its initial state and prior to use, a membrane or other
component, such as support member 1128, separates channel 1132
connecting it to region 1102. In the device illustrated, a vacuum
actuation component 1140 can be actuated to puncture the membrane
or other component (e.g., 1128) and thereby connect vacuum chamber
1138 with channel 1132, at an appropriate time during use of the
device. In other embodiments, device actuator 1116 and vacuum
actuation component 1140 can be combined into a single button or
operably linked so that only one operation is needed to actuate
both the skin insertion objects and the vacuum.
[0077] Deployment actuator (or, as shown, a snap dome) 1122 can be
provided in a variety of forms including a monostable or bistable
configuration. In the embodiment illustrated, a bistable
configuration is illustrated including first and second low energy
or stable configurations separated by a relatively high energy or
unstable configuration. As shown, the deployment actuator 1122 is
shown in a "cocked" or pre-deployed position.
[0078] The deployment actuator may be formed from any suitable
material, for example, a metal such as stainless steel (e.g., 301,
301LN, 304, 304L, 304LN, 304H, 305, 312, 321, 321H, 316, 316L,
316LN, 316Ti, 317L, 409, 410, 430, 440A, 440B, 440C, 440F, 904L),
carbon steel, spring steel, spring brass, phosphor bronze,
beryllium copper, titanium, titanium alloy steels, chrome vanadium,
nickel alloy steels (e.g., Monel 400, Monel K 500, Inconel 600,
Inconel 718, Inconel x 750, etc.), a polymer (e.g.,
polyvinylchloride, polypropylene, polycarbonate, etc.), a composite
or a laminate (e.g., comprising fiberglass, carbon fiber, bamboo,
Kevlar, etc.), or the like. The deployment actuator may be of any
shape and/or size. For example, the deployment actuator may have a
generally domed shape (e.g., as in a snap dome), and be circular
(no legs), or the deployment actuator may have other shapes, e.g.,
oblong, triangular (3 legs), square (4 legs), pentagonal (5 legs),
hexagonal (6 legs), spiderlegged, starlike, clover-shaped (with any
number of lobes, e.g., 2, 3, 4, 5, etc.), or the like. The
deployment actuator may have, in some embodiments, a hole, dimple,
or button in the middle. The deployment actuator may also have a
serrated disc or a wave shape. In some cases, the substance
transfer component may be mounted on the deployment actuator. In
other cases, however, the substance transfer component is mounted
on a separate structure which is driven or actuated upon movement
of the deployment actuator.
[0079] In one set of embodiments, the deployment actuator is not
planar, and has a portion that can be in a first position (a
"cocked" or pre-deployed position) or a second position (a "fired"
or deployed position), optionally separated by a relatively high
energy configuration. In some cases, the pre-deployed position may
be at a higher energy level than the deployed position. In some
cases, both the first position and the second position are stable
(i.e., the structure is bistable), although conversion between the
first position and the second position requires the structure to
proceed through an unstable configuration.
[0080] In some cases, surprisingly, the distance or separation
between the first position and the second position is relatively
small. Such distances or separations may be achieved using snap
domes or other configurations such as those described herein, in
contrast to springs or other devices which require longer
translational or other movements. For example, the perpendicular
distance (i.e., in a direction away from the skin) in the
deployment actuator between the top of the structure and the bottom
of the structure (excluding the substance transfer component) when
the device containing the structure is placed on the skin of a
subject may be no more than about 5 mm, no more than about 4 mm, no
more than about 3 mm, no more than about 2 mm, no more than about 1
mm in some cases, no more than about 0.8 mm, no more than about 0.5
mm, or no more than about 0.3 mm. In one set of embodiments, the
distance is between about 0.3 mm and about 1.5 mm. In another set
of embodiments, the deployment actuator may have a greatest lateral
dimension (parallel to the skin) when the device containing the
structure is placed on the skin of a subject of no more than about
50 mm, no more than about 40 mm, no more than about 30 mm, no more
than about 25 mm, no more than about 20 mm, no more than about 15
mm, no more than about 5 mm, no more than about 4 mm, no more than
about 3 mm, no more than about 2 mm, no more than about 1 mm in
some cases, no more than about 0.8 mm, no more than about 0.5 mm,
or no more than about 0.3 mm. In one set of embodiments, the
distance is between about 0.3 mm and about 1.5 mm.
[0081] Use of device 1100 will now be described in the context of
receiving a substance such as blood from a subject. Device 1100 is
placed against the skin of a subject such that at least a portion
of surface 1104 contacts the skin. Prior to use, a cover member
(not shown) can cover surface 1104 of the device and can cover
region 1114, to protect surface 1104 and region 1114 from
contaminants, etc. optionally maintaining the interior of the
device in a sterile condition. The cover can be peeled off or
otherwise removed from the device, and the device placed against
the skin, optionally adhering to the skin. Vacuum actuation
component 1140 can be actuated to expose channel 1132 and region
1114 to vacuum at any time, including before, simultaneously, or
after actuation of substance transfer component 1108. In one
arrangement, vacuum actuation component 1140 is actuated to apply
vacuum to region 1114 prior to actuation to substance transfer
component 1108, thereby to create a vacuum against the skin
proximate region 1114 prior to use. Actuation of device actuator
1116 can take place before or after deployment of vacuum.
[0082] When device actuator 1116 is actuated by a user (e.g., when
proximal portion 1118 is depressed downwardly as shown in the
figure), distal portion 1120 engages skin insertion objects 1108
(optionally via flexible structure 1112) to drive it toward the
skin. In some embodiments, foil 1128 is first broken, then
retraction actuator 1126 is compressed, then retraction actuator
1126 is broken, before flexible structure 1112 is stretched and the
deployment actuator 1122 of the device fires or is actuated.
Membranes or other members 1112, 1128, or 1130 may have, in some
cases, sufficient flexibility and/or elasticity to allow actuator
1116 to drive skin insertion objects 1108 sufficiently distally
(downwardly, as shown) to engage the skin of the subject and carry
out the desired function of the device. Various gaskets, bearings,
or membranes as shown can be used for this function. Where support
member 1128 is a foil or the like used for the purpose of initially
separating vacuum reservoir 1138 from channel 1132 (e.g., prior to
use), when device actuator 1116 is moved downwardly, vacuum
actuation component 1140 may rupture support member 1128 proximate
actuator 1116, or flexibly deform as need be, so long as member
1130 (or another component) serves to allow device actuator 1116 to
move slidably within the device while maintaining sufficient vacuum
in vacuum reservoir 1138 and related channels for use of the
device.
[0083] When skin insertion objects 1108 engage the skin of the
subject and facilitates receiving of a substance from the skin
and/or from beneath the skin of the subject, a vacuum can draw the
substance into region 1114, through channel or channels 1132, and
into substance collection reservoir 1136. In this process, device
actuator 1116 first urges deployment actuator 1122 from its first
stable configuration to a relatively unstable configuration and
beyond that point, at which point the deployment actuator 1122
rapidly moves to a second stable configuration associated with
downward driving of device actuator 1116 to quickly drive access
substance transfer component 1108 proximate the skin.
[0084] After that point, if it is desirable for access substance
transfer component 1108 to be received from the skin, then a
variety of techniques can be used to do so. In the device
illustrated, retraction actuator 1126 drives holder 1124 upwardly,
retracting structure 1122 and device actuator 1116 from substance
transfer component 1108. At that point, device actuator 1116 can be
operably linked to transfer component 1108 and retract the transfer
component, or it can move freely relative to substance transfer
component 1108, whereby flexible structure 1112 (e.g., an elastic
membrane) or other component can retract substance transfer
component 1108 from the skin. The retraction actuator 1126 may
include any suitable retraction component. Again, in the device
illustrated, retraction actuator 1126 can itself be a reversibly
deformable structure such as a leaf spring, coil spring, foam, or
the like. During use, when device actuator 1116 is driven
downwardly, retraction actuator 1126 is first compressed and,
depending upon the size and arrangement of components 1126, 1124,
1122, 1116 and 1108, during compression, substance transfer
component 1108 can be driven downwardly to some extent. At the
point at which retraction actuator 1126 is compressed and provides
a sufficient resistance force, deployment actuator 1122 can be
urged from its first configuration through an unstable
configuration and can return to its second configuration, driving
substance transfer component 1108 against the skin. Then, upon
release of user pressure (or other actuation, which can be
automatic) from actuator 1116, retraction actuator 1126 can expand
and, with structure 1122 optionally remaining in its second,
downwardly-driven low-energy configuration, actuator 1116 can be
retracted and substance transfer component 1108 retracted from the
skin.
[0085] Referring now to FIGS. 12A and 12B, device 1150 is
illustrated schematically. Device 1150 is similar to and can be
considered essentially identical to device 1100 in all aspects
other than those described here with respect to FIGS. 12A and 12B.
As such, the reader will observe that not all components are
provided, although other components similar to those of device 1100
can exist. One way in which device 1150 differs from device 1100 is
that in device 1150, in the pre-deployment or post-deployment
retracted configuration, membrane 1112 is drawn proximally
(upwardly) as illustrated in FIG. 12B. Membrane 1112 is in a
less-stressed lower-energy configuration as shown in FIG. 12A when
retraction actuator 1126 is compressed and substance transfer
component 1108 is driven proximate the skin. Devices 1100, 1150,
and other similar devices are one way to enact a deployment
actuator that can move a substance transfer component 1108 relative
to the skin in particularly advantageous ways. Examples of
deployment actuators include, in addition to the examples shown in
FIGS. 11 and 12, blasting caps, explosives, other chemical
reactions, solenoids or other electrical interactions, pneumatics
(e.g., compressed air), other thermal interactions or mechanical
interactions, or the like.
[0086] In one set of embodiments, the deployment actuator may move
substance transfer component 1108 from a fully pre-deployed
position (e.g., as shown in FIG. 11) to a fully deployed position
in which substance transfer component 1108 is fully engaged with
the skin, in a short period of time. In one embodiment, that period
of time is less than about 0.01 seconds, and in other embodiments,
less than about 0.009 seconds, less than about 0.008 seconds, less
than about 0.007 seconds, less than about 0.006 seconds, less than
about 0.005 seconds, less than about 0.004 seconds, less than about
0.003 seconds, less than about 0.002 seconds, less than about 0.001
seconds, less than about 0.0005 seconds, less than about 0.00025,
or less than about 0.0001 seconds.
[0087] In some embodiments, the distance between the fully
pre-deployed position and the fully deployed position is no more
than about 1,000 microns, no more than about 2,500 microns, or no
more than about 5,000 microns.
[0088] In another embodiment, substance transfer component 1108
moves quickly relative to skin during deployment via the deployment
actuator, reaching a speed of at least about 4 m/s, at least about
5 m/s, at least about 6 m/s, at least about 7 m/s, at least about 8
m/s, at least about 10 m/s, at least about 12 m/s, at least about
15 m/s, or at least about 20 m/sat the point at which substance
transfer component 1108 first touches the skin during
deployment.
[0089] In some cases, substance transfer component 1108 achieves
relatively high accelerations due to the deployment actuator. For
example, in some cases, the deployment actuator can produce average
accelerations (e.g., average acceleration from start of movement to
a position where a substance transfer component first contacts a
subject) of at least about 4 m/s2, about 6 m/s2, about 8 m/s2,
about 10 m/s2, about 12 m/s2, about 15 m/s2, or about 20 m/s2, at
least about 30 m/s2, at least about 50 m/s2, at least about 100
m/s2, at least about 300 m/s2, at least about 500 m/s2, at least
about 1,000 m/s2, at least about 3,000 m/s2, at least about 5,000
m/s2, at least about 10,000 m/s2, at least about 30,000 m/s2, at
least about 50,000 m/s2, at least about 60,000 m/s2, at least about
70,000 m/s2, at least about 100,000 m/s2, at least about 200,000
m/s2, or at least about 300,000 m/s2. In some cases, the deployment
actuator can produce instantaneous accelerations of at least about
4 m/s2, about 6 m/s2, about 8 m/s2, about 10 m/s2, about 12 m/s2,
about 15 m/s2, or about 20 m/s2, at least about 30 m/s2, at least
about 50 m/s2, at least about 100 m/s2, at least about 300 m/s2, at
least about 500 m/s2, at least about 1,000 m/s2, at least about
3,000 m/s2, at least about 5,000 m/s2, at least about 10,000 m/s2,
at least about 30,000 m/s2, at least about 50,000 m/s2, at least
about 60,000 m/s2, at least about 70,000 m/s2, at least about
80,000 m/s2, at least about 80,000 m/s2, at least about 100,000
m/s2, at least about 200,000 m/s2, or at least about 300,000
m/s2.
[0090] Average acceleration is used to mean the rate of change of
velocity over the entire time period from the pre-deployed position
to the deployed position, and instantaneous acceleration is used to
mean the acceleration at a specific point in time during the time
period. The average acceleration and the instantaneous
accelerations may be determined using high-speed imaging analysis.
High speed imaging is used to capture a sequence of video frames
with very short time steps between frames. In one example, the time
step between frames may be 66 microseconds, although other time
steps are possible depending on imaging equipment capability and/or
the total capture time. Each video frame captures the position of a
moving object at a specific moment in time. Using this data,
position as a function of time may be plotted. An equation that is
fit to this data approximates position as a function of time. The
second derivative of the position equation is an equation for
instantaneous acceleration as a function of time. The acceleration
equation can then be used to calculate the instantaneous
acceleration at any given point in time.
[0091] In some embodiments, the substance transfer component 1108
is accelerated for relatively short periods of time, e.g., less
than about 1 second, less than about 300 milliseconds, less than
about 100 milliseconds, less than about 30 milliseconds, less than
about 10 milliseconds, less than about 3 milliseconds, or less than
about 1 millisecond, and/or over relatively short distances, e.g.,
less than about 5 millimeters, less than about 4 millimeters, less
than about 3 millimeters, less than about 2 millimeters, less than
about 1 millimeter, 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 100 micrometers, less than about 50 micrometers,
etc. Significant forces can be applied to substance transfer
component 1108 as it moves relative to the skin via the deployment
actuator. In another set of embodiments, substance transfer
component 1108, at the point at which it first contacts the skin,
is driven by a force created at least in part by the deployment
actuator of at least about 6 micronewtons, about 8 micronewtons,
about 10 micronewtons, about 12 micronewtons, or about 15
micronewtons.
[0092] Significant forces can be applied to substance transfer
component 1108 as it moves relative to the skin via the deployment
actuator. In another set of embodiments, substance transfer
component 1108, at the point at which it first contacts the skin,
is driven by a force created at least in part by the deployment
actuator of at least about 6 micronewtons, about 8 micronewtons,
about 10 micronewtons, about 12 micronewtons, or about 15
micronewtons.
[0093] In another set of embodiments, substance transfer component
1108 applies a pressure to the skin, during deployment caused by
the deployment actuator, of at least about 100 N/m2, at least about
300 N/m2, at least about 1,000 N/m2, at least about 3,000 N/m2,
etc. In force assessment, the area can be measured as the area of
skin displaced by the transfer component at full deployment, e.g.,
the area of the skin ruptured by the total of the cross sectional
area of all substance transfer components inserted into the skin,
at the top surface of the skin.
[0094] In some cases, the substance transfer component is forced
into the skin via the deployment actuator with a force sufficient
to insert the substance transfer component into or through the skin
to an average depth of at least about 60% of the substance transfer
component (or the average length of the substance transfer
components, if more than one is used, e.g., as in an array of
microneedles). In some cases, the depth is at least about 65%, at
least about 70%, at least about 75%, at least about 80%, at least
about 85%, at least about 90%, or at least about 95% of the
substance transfer component, e.g., the length of the needle or the
microneedle inserted into the skin.
[0095] Devices of the invention can provide significant advantage
in some embodiments. For example, deployment actuators able to move
substance transfer components in short time periods, and/or at high
velocities, and/or with high forces, and/or with high pressure,
and/or drive relatively short substance transfer components such as
skin insertion objects or microneedles relatively deeply into the
skin and/or through the skin, and/or any combination of the above
can provide significant advantage. In some embodiments, these
features can provide better control of substance delivery or
receipt. Better mechanical stability can be provided in some cases
by shorter substance transfer components (e.g., bending and/or
buckling can be avoided) and relatively shorter substance transfer
components, designed to be driven relatively completely (for
example, through nearly all of their entire length) into the skin
may offer better control of penetration in some embodiments. If
better control of penetration can be achieved, better delivery or
receiving can also be achieved in some cases, for example,
resulting in less pain or essentially painless deployment.
[0096] Moreover, if substance transfer components are used to
deliver a substance such as a pharmaceutical composition into or
through the skin, more precise delivery can be provided, according
to certain embodiments. With better, precise control over depth of
insertion of the substance transfer components (e.g., by using
devices designed to insert the substance transfer components
essentially fully), and/or the substance transfer components
contain and/or are coated with a pharmaceutical composition, then
more control exists over the amount of pharmaceutical substance
inserted into the skin by the substance transfer components, in
some embodiments. Furthermore, quick and/or high velocity, and/or
high force and/or pressure application of skin insertion objects to
the skin may in certain embodiments result in lower pain or
painless deployment.
[0097] According to one set of embodiments, many devices as
discussed herein use various techniques for delivering and/or
receiving fluid, for example, in connection with substance transfer
components, skin insertion objects, or the like. For example, one
or more needles and/or microneedles, a hygroscopic agent, a cutter
or other piercing element, an electrically-assisted system, or the
like may be used in conjunction with a snap dome or other device as
described above. Additional examples of such techniques are
described herein and/or in the applications incorporated herein. It
is to be understood that, generally, fluids may be delivered and/or
received in a variety of ways, and various systems and methods for
delivering and/or receiving fluid from the skin are discussed below
and/or in the applications incorporated herein. In some
embodiments, for example, techniques for piercing or altering the
surface of the skin to transport a fluid are discussed, for
example, using a needle such as a hypodermic needle or
microneedles, chemicals applied to the skin (e.g., penetration
enhancers), jet injectors or other techniques such as those
discussed below, etc.
[0098] As an example, in one embodiment, a needle such as a
hypodermic needle can be used to deliver and/or receive fluid to or
from the skin. 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.
[0099] 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. As an example,
microneedles 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., may be used to
deliver and/or receive fluids or other materials to or from 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.
[0100] 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 2 or more,
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. In some embodiments, the device
may have at least 3 but no more than 5 needles or microneedles (or
other skin insertion objects), at least 6 but no more than 10
needles or microneedles, or at least 11 but no more than 20 needles
or microneedles. Typically, a microneedle will have an average
cross-sectional dimension (e.g., diameter) of less than about a
micron. 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.
[0101] 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..
[0102] In some cases, the microneedles may be present in an array
selected such that the density of microneedles within the array is
between about 0.5 needles/mm.sup.2 and about 10 needles/mm.sup.2,
and in some cases, the density may be between about 0.6 needles/mm2
and about 5 needles/mm.sup.2, between about 0.8 needles/mm.sup.2
and about 3 needles/mm.sup.2, between about 1 needles/mm.sup.2 and
about 2.5 needles/mm.sup.2, or the like. In some cases, the needles
may be positioned within the array such that no two needles are
closer than about 1 mm, about 0.9 mm, about 0.8 mm, about 0.7 mm,
about 0.6 mm, about 0.5 mm, about 0.4 mm, about 0.3 mm, about 0.2
mm, about 0.1 mm, about 0.05 mm, about 0.03 mm, about 0.01 mm,
etc.
[0103] In another set of embodiments, the needles (or microneedles)
may be chosen such that the area of the needles (determined by
determining the area of penetration or perforation on the surface
of the skin of the subject by the needles) allows for adequate flow
of fluid to or from the subject. The microneedles may be chosen to
have smaller or larger areas (or smaller or large diameters), so
long as the area of contact for the microneedles to the skin is
sufficient to allow adequate blood flow from the subject to the
device. The needles or microneedles may have any suitable
cross-sectional area. For example, in certain embodiments, each
microneedle may be selected to have a cross-sectional area of at
least 5 nm.sup.2, at least about 100 nm.sup.2, at least about 500
nm.sup.2, at least about at least about 1,000 nm.sup.2, at least
about 3,000 nm.sup.2, at least about 10,000 nm.sup.2, at least
about 30,000 nm.sup.2, at least about 100,000 nm.sup.2, at least
about 300,000 nm.sup.2, at least about 1 microns.sup.2, at least
about 3 microns.sup.2, at least about 10 microns.sup.2, at least
about 30 microns.sup.2, at least about 100 microns.sup.2, at least
about 300 microns.sup.2, at least about 500 microns.sup.2, at least
about 1,000 microns.sup.2, at least about 2,000 microns.sup.2, at
least about 2,500 microns.sup.2, at least about 3,000
microns.sup.2, at least about 5,000 microns.sup.2, at least about
8,000 microns.sup.2, at least about 10,000 microns.sup.2, or at
least about 25,000 microns.sup.2. For example, in certain
embodiments, the microneedles may be selected to have a combined
skin-penetration area of at least about 500 nm.sup.2, at least
about 1,000 nm.sup.2, at least about 3,000 nm.sup.2, at least about
10, nm.sup.2nm2, at least about 30,000 nm.sup.2, at least about
100,000 nm.sup.2, at least about 300,000 nm.sup.2, at least about 1
microns.sup.2, at least about 3 microns.sup.2, at least about 10
microns.sup.2, at least about 30 microns.sup.2, at least about 100
microns.sup.2, at least about 300 microns.sup.2, at least about 500
microns.sup.2, at least about 1,000 microns.sup.2, at least about
2,000 microns.sup.2, at least about 2,500 microns.sup.2, at least
about 3,000 microns.sup.2, at least about 5,000 microns.sup.2, at
least about 8,000 microns.sup.2, at least about 10,000
microns.sup.2, at least about 35,000 microns.sup.2, at least about
100,000 microns.sup.2, etc., depending on the application.
[0104] The needles or microneedles may have any suitable length,
and the length may be, in some cases, dependent on the application.
For example, needles designed to only penetrate the epidermis may
be shorter than needles designed to also penetrate the dermis, or
to extend beneath the dermis or the skin. In certain embodiments,
the needles or microneedles may have a maximum penetration into the
skin, or insertion depth, of no more than about 3 mm, no more than
about 2 mm, no more than about 1.75 mm, no more than about 1.5 mm,
no more than about 1.25 mm, no more than about 1 mm, no more than
about 900 microns, no more than about 800 microns, no more than
about 750 microns, no more than about 1500 microns, no more than
about 600 microns, no more than about 500 microns, no more than
about 400 microns, no more than about 300 microns, no more than
about 200 microns, no more than about 175 micrometers, no more than
about 150 micrometers, no more than about 125 micrometers, no more
than about 100 micrometers, no more than about 75 micrometers, no
more than about 50 micrometers, etc. In certain embodiments, the
needles or microneedles may be selected so as to have a maximum
insertion depth of at least about 50 micrometers, at least about
100 micrometers, at least about 300 micrometers, at least about 500
micrometers, at least about 1 mm, at least about 2 mm, at least
about 3 mm, etc.
[0105] In one set of embodiments, the needles (or microneedles) may
be coated. For example, the needles may be coated with a substance
that is delivered when the needles are inserted into the skin. For
instance, the coating may comprise heparin, an anticoagulant, an
anti-inflammatory compound, an analgesic, an anti-histamine
compound or a vasodilator to assist with the flow of blood from the
skin of the subject. The coating may comprise a drug or other
therapeutic agent such as those described herein. The drug or other
therapeutic agent may be one used for localized delivery (e.g., of
or proximate the region to which the coated needles or microneedles
are applied), and/or the drug or other therapeutic agent may be one
intended for systemic delivery within the subject.
[0106] At least some the skin insertion objects may be at least
partially coated by a substance such as a drug, analgesic or agent
by using dip or spray coating or other suitable technique. Thus,
the substance may be delivered to the skin by the substance
dissolving or otherwise detaching from the substance transfer
component at or in the skin or other subject site. Alternately, the
substance may be delivered after a substance transfer component
penetrates the subject, e.g., in a way similar to a hypodermic
needle. For example, a skin insertion object of the substance
transfer component may be inserted into the skin, and a substance
may be pumped or pushed through a hole, groove or other channel of
the skin insertion object (e.g., by a high pressure gas).
[0107] A drug may be any composition which possesses therapeutic,
prophylactic, or diagnostic properties in vivo, for example when
administered to an animal, including mammals, such as humans. The
drug can be for local treatment or for regional or systemic
therapy. The drug can be or include a peptide, protein,
carbohydrate (including monosaccharides, oligosaccharides, and
polysaccharides), nucleoprotein, mucoprotein, lipoprotein,
glycoprotein, nucleic acid molecules (including any form of DNA
such as cDNA, RNA, or a fragment thereof, oligonucleotides, and
genes), nucleotide, nucleoside, lipid, biologically active organic
or inorganic molecules, or combination thereof. Examples of
suitable therapeutic and/or prophylactic active agents include
anti-infectives, analgesics, anti-inflammatories, steroids,
decongestants, neuroactive agents, anesthetics, and sedatives.
Examples of suitable diagnostic agents include radioactive isotopes
and radioopaque agents, metals, gases, labels including
chromatographic, fluorescent, or enzymatic labels.
[0108] Examples of biologically active polypeptides or proteins
include, but are not limited to, glucagon, glucagon-like peptides
such as, GLP-1, GLP-2 or other GLP analogs, derivatives or agonists
of Glucagon Like Peptides, exendins such as, exendin-3 and
exendin-4, derivatives, agonists and analogs thereof, vasoactive
intestinal peptide (VIP), immunoglobulins, antibodies, cytokines
(e.g., lymphokines, monokines, chemokines), interleukins,
macrophage activating factors, interferons, erythropoietin,
nucleases, tumor necrosis factor, colony stimulating factors (e.g.,
G-CSF), insulin, enzymes (e.g., superoxide dismutase, plasminogen
activator, etc.), tumor suppressors, blood proteins, hormones and
hormone analogs and agonists (e.g., follicle stimulating hormone,
growth hormone, adrenocorticotropic hormone, and luteinizing
hormone releasing hormone (LHRH)), vaccines (e.g., tumoral,
bacterial and viral antigens), antigens, blood coagulation factors,
growth factors (NGF and EGF), gastrin, GRH, antibacterial peptides
such as defensin, enkephalins, bradykinins, calcitonin and muteins,
analogs, truncation, deletion and substitution variants and
pharmaceutically acceptable salts of all the foregoing. Suitable
analgesics include but are not limited to lidocaine, bupivacaine,
and tetracaine. Suitable steroids include but are not limited to
cortisone, betametasone, budesonide and fluticasone.
[0109] In one set of embodiments, the needles or microneedles may
be used to deliver a drug into the skin of a subject. The needles
or microneedles may be at least partially coated, and the coating
may comprise a drug or other therapeutic agent such as those
described herein. For example, in one set of embodiments, at least
about 50%, at least about 60%, at least about 70%, at least about
80%, at least about 90%, or substantially all of a needle or a
microneedle may be coated, and one or more than one needle or
microneedle may be coated in a device as discussed herein. For
instance, at least about 25%, at least about 50%, at least about
60%, at least about 70%, at least about 80%, at least about 90%, or
substantially all of the needles or microneedles in a device may
comprise a coating.
[0110] Without wishing to be bound by any theory, it is believed
that, at least in some cases, longer needles or microneedles may be
useful for the delivery of a drug or other therapeutic agent. For
example, a needle having a greater depth of penetration into the
skin may be useful for delivering the drug or other therapeutic
agent deeper into the skin, e.g., closer to capillaries within or
below the skin, which may minimize the distance the drug needs to
travel before being available systemically and allow a more rapid
onset of the drug effect. In addition, greater depth of penetration
can be useful for delivering greater amounts of drug. A longer
needle can have more surface area exposed internally of the
subject, relative to a shorter needle (e.g., of the same diameter),
and the increased surface area may allow more of the coating
containing drug to be exposed internally of the skin. Thus, for
example, a greater amount of drug may be delivered per needle or
microneedle that enters the skin.
[0111] Accordingly, in certain embodiments, relatively long needles
or microneedles may be used for the delivery of a drug or other
therapeutic agent into the skin, for example. For instance, the
average length of the needles or microneedles in the device may be
at least about 200 micrometers, at least about 300 micrometers, at
least about 400 micrometers, at least about 500 micrometers, at
least about 600 micrometers, at least about 750 micrometers, at
least about 800 micrometers, at least about 900 micrometers, at
least about 1,000 micrometers, at least about 1,200 micrometers, at
least about 1,500 micrometers, at least about 1,700 micrometers, or
at least about 2,000 micrometers in some embodiments.
[0112] Any of a variety of suitable techniques may be used to coat
a needle or a microneedle. For instance, the needle or microneedle
may be coated by exposing the needles or microneedles to a liquid
containing a substance to be coated thereon. For example, the
needles or microneedles may be dipped into a liquid, a liquid may
be sprayed on or aerosolized onto the needles or microneedles, an
electric field may be used to attract a charged liquid onto the
needles or microneedles, etc.
[0113] In one embodiment, the fluid is delivered and/or received
manually, e.g., by manipulating a plunger on a syringe. In another
embodiment, the fluid can be delivered and/or received from the
skin mechanically or automatically, e.g., using a piston pump or
the like. Fluid may also be received using vacuums such as those
discussed herein. For example, vacuum may be applied to a conduit,
such as a needle, in fluidic communication with a bodily fluid in
order to draw up at least a portion of the fluid from the pooled
region. In yet another embodiment, fluid is received using
capillary action (e.g., using a microfluidic channel or hypodermic
needle having a suitably narrow inner diameter). In still another
embodiment, pressure may be applied to force fluid out of the
needle.
[0114] In some embodiments, a substance is delivered to a subject
from a device. In cases where the needle or other skin insertion
object is coated with a drug or other substance, the device may
deliver the drug or substance to a subject by penetrating the skin
with the coated needle. The substance may be delivered to or
beneath the skin by the substance dissolving or otherwise detaching
from the substance transfer component at the skin or other subject
site. The device may or may not cause fluid release from the
subject. In some cases, fluid from the subject is not received into
the device and a vacuum source is not needed. Also, in some cases,
the device may additionally or alternatively deliver a fluid drug
or other fluid substance to a subject. The fluid substance may
delivered to or beneath the skin through hollow needles that
transfer fluid from the device to the subject.
[0115] 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.
[0116] In some embodiments, fluid may be received using a
hygroscopic agent applied to the surface of the skin, or proximate
the skin. For example, a device as described herein may contain a
hygroscopic agent. 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.
[0117] In some embodiments, 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 through which fluids may be
delivered and/or received from the skin. For example, the cutter
may comprise a hypodermic needle, a blade (e.g., a knife blade, a
serrated blade, etc.), a piercing element (e.g., a lancet or a
solid or a hollow needle), or the like, which can be applied to the
skin to create a suitable conduit for the delivery and/or receiving
of fluid from the skin. In one embodiment, a cutter is used to
create such a pathway and removed, then fluid may be delivered
and/or received via this pathway. In another embodiment, the cutter
remains in place within the skin, and fluid may be delivered and/or
received through a conduit within the cutter.
[0118] In some embodiments, fluid may be received 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.
[0119] A current may be applied to induce reverse iontophoresis,
thereby receiving 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.
[0120] In one set of embodiments, the device may comprise a
substance transfer component in the form of 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.
[0121] In some embodiments, the device may comprise a substance
transfer component in the form of 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, surfactants, etc.
[0122] The device may also contain, in some embodiments, a vacuum
source. In some cases, the vacuum source is one that is
self-contained within the device, i.e., the device need not be
connected to an external vacuum source (e.g., a house vacuum)
during use of the device to receive blood from the skin. For
example, in one set of embodiments, the vacuum source may include a
vacuum chamber having a pressure less than atmospheric pressure
before blood (or other fluid) is received into the device, i.e.,
the vacuum chamber is at a "negative pressure" (that is, negative
relative to atmospheric pressure) or a "vacuum pressure" (or just
having a "vacuum"). For example, the vacuum in the vacuum chamber
may be 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, i.e., below atmospheric
pressure. However, in other embodiments, it should be understood
that other pressures may be used and/or that different methods may
be used to produce other pressures (greater than or less than
atmospheric pressure). As non-limiting examples, an external vacuum
or a mechanical device may be used as the vacuum source; various
additional examples are discussed in detail herein.
[0123] As a specific, non-limiting example, in one embodiment, a
device may be used to receive fluid without an external power
and/or a vacuum source. Examples of such devices include 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 deliver and/or receive 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.
[0124] 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. 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.
[0125] In one set of embodiments, the device may be able to create
a pressure differential (e.g. a vacuum). The pressure differential
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.
[0126] 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. In some cases, vacuum may be created
manually, e.g., by manipulating a syringe pump, a plunger, 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. 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. 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.
[0127] 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.
[0128] 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.
[0129] 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. 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 chambers, where a seal is punctured in some
manner to create a vacuum. For instance, upon puncturing the seal,
a vacuum chamber may be in fluidic communication with a needle,
which can be used to move the skin towards the device, receive
fluid from the skin, or the like.
[0130] 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.
[0131] 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 some embodiments, the device may be used to create a
vacuum automatically, once activated, without any external control
by a user.
[0132] In one set of embodiments, the device contains a vacuum
chamber that is also used as a storage chamber to receive blood or
other fluid received from the subject into the device. For
instance, blood received from a subject through or via the
substance transfer component may enter the vacuum chamber due to
its negative pressure (i.e., because the chamber has an internal
pressure less than atmospheric pressure), and optionally stored in
the vacuum chamber for later use. A non-limiting example is
illustrated in FIG. 3. In this figure, device 600 contains vacuum
chamber 610, which is connected to substance transfer component 620
(which may include, e.g., one or more microneedles). Upon
activation of vacuum chamber 610 (e.g., using actuator 660, as
discussed below), vacuum chamber 610 may be put into fluidic
communication with substance transfer component 620. Substance
transfer component 620 may accordingly cause negative pressure to
be applied to the skin of the subject, for instance, due to the
internal pressure within vacuum chamber 610. Fluid (e.g., blood)
exiting the skin via substance transfer component 620 may
accordingly be drawn into the device and into vacuum chamber 610,
e.g., through conduit 612. The fluid collected by the device can
then be analyzed within the device or removed from the device for
analysis, storage, etc.
[0133] In another set of embodiments, however, the device may
include separate vacuum chambers and storage chambers (e.g.,
chambers to store fluid such as blood from the subject). The vacuum
chamber and storage chambers may be in fluid communication, and may
have any suitable arrangement. In some embodiments, the vacuum from
the vacuum chamber may be used, at least in part, to receive fluid
from the skin, which is then directed into a storage chamber, e.g.,
for later analysis or use, for example, as discussed below. As an
example, blood may be received into the device, flowing towards a
vacuum chamber, but the fluid may be prevented from entering the
vacuum chamber. For instance, in certain embodiments, a material
permeable to gas but not to a liquid such as blood may be used. For
example, the material may be a membrane such as a hydrophilic or
hydrophobic membrane having a suitable porosity, a porous
structure, a porous ceramic frit, a dissolvable interface (e.g.,
formed from a salt or a polymer, etc.), or the like.
[0134] One non-limiting example is illustrated in FIG. 4. In this
figure, device 600 contains vacuum chamber 610 and storage chamber
615. Vacuum chamber 610 can be put in fluidic communication with
storage chamber 615 via conduit 612, which contains material 614.
Material 614 may be any material permeable to gas but not to a
liquid in this example, e.g., material 614 may be a membrane such
as a hydrophilic membrane or a hydrophobic membrane that has a
porosity that allows gas exchange to occur but does not allow the
passage of blood from the subject. When device 600 is actuated
using actuator 660, blood (or other fluid) flows through substance
transfer component 620 via conduit 661 into collection chamber 615
because of the internal vacuum pressure from vacuum chamber 610,
which is not completely impeded by material 614 since it is
permeable to gases. However, because of material 614, blood (or
other suitable bodily fluid) is prevented from entering vacuum
chamber 610, and instead remains in storage chamber 615, e.g., for
later analysis or use.
[0135] In some embodiments, the flow of blood (or other fluid) into
the storage chamber may be controlled using a flow controller. The
flow controller may be manually and/or automatically controlled to
control the flow of blood. The flow controller may activate or
deactivate when a certain amount or volume of fluid has entered the
storage chamber in certain cases. For instance, the flow controller
may stop blood flow after a predetermined amount or volume of blood
has entered the storage chamber, and/or the flow controller may be
able to control the internal pressure of the storage chamber, e.g.,
to a specific level, such as a predetermined level. Examples of
suitable flow controllers for the device include, but are not
limited to, a membrane, a valve, a dissolvable interface, a gate,
or the like.
[0136] One non-limiting example of a flow controller is now
illustrated with reference to FIG. 5. In this example figure,
device 600 includes a vacuum chamber 610 and a storage chamber 615.
Fluid entering device 600 via substance transfer component 620 is
prevented from entering storage chamber 615 due to flow controller
645 present within conduit 661. However, under suitable conditions,
flow controller 645 may be opened, thereby allowing at least some
fluid to enter storage chamber 615. In some cases, for instance,
storage chamber 615 also contains at least a partial vacuum,
although this vacuum may be greater or less than the pressure
within chamber 610. In other embodiments, flow controller 645 may
initially be open, or be externally controllable (e.g., via an
actuator), or the like. In some cases, the flow controller may
control the flow of fluid into the device such that, after
collection, at least some vacuum is still present in the
device.
[0137] Thus, in some cases, the device may be constructed and
arranged to reproducibly obtain from the subject a controlled
amount of fluid, e.g., a controlled amount or volume of blood. The
amount of fluid reproducibly obtained from the subject may be
controlled, for example, using flow controllers, materials
permeable to gas but not to liquids, membranes, valves, pumps,
gates, microfluidic systems, or the like, as discussed herein. In
particular, it should be noted that the volume of blood or other
fluid obtained from the subject need not be strictly a function of
the initial vacuum pressure or volume within the device. For
example, a flow controller may initially be opened (e.g., manually,
automatically, electronically, etc.) to allow fluid to begin
entering the device; and when a predetermined condition is reached
(e.g., when a certain volume or amount of blood has entered the
device), the flow controller may be closed at that point, even if
some vacuum pressure remains within the device. In some cases, this
control of fluid allows the amount of fluid reproducibly obtained
from the subject to be controlled to a great extent. For example,
in one set of embodiments, the amount of fluid received from the
subject may be controlled to be less than about 1 ml, may be less
than about 300 microliters, less than about 100 microliters, less
than about 30 microliters, less than about 10 microliters, less
than about 3 microliters, less than about 1 microliter, etc.
[0138] Further examples of various embodiments of the invention are
illustrated in FIGS. 6 and 8. In FIG. 7, device 500 is illustrated.
In this example, device 500 includes a housing 501, an adhesive 502
for adhesion of the device to the skin, and a substance transfer
component 503. In this figure, substance transfer component 503
includes a plurality of microneedles 505, although other substance
transfer components as discussed herein may also be used.
Microneedles 505 are contained within recess 508. Also shown in
FIG. 7 is vacuum chamber 513 which, in this example, is
self-contained within device 500. Vacuum chamber 513 is in fluidic
communication with recess 508 via channel 511, for example, as
controlled by a controller or an actuator. Device actuator 560 is
shown at the top of device 500. Device actuator 560 may be, for
example, a button, switch, slider, dial, etc. and may cause
microneedles 505 to move towards the skin when the device is placed
on the skin. For example, the microneedles may be moved
mechanically (e.g., compression spring, Belleville spring, etc.),
electrically (e.g., with the aid of a servo, which may be
computer-controlled), pneumatically, etc. In some cases, device
actuator 560 (or another actuator) may be used to cause the
microneedles to be received from the skin, and/or the microneedles
may be received automatically after delivering and/or receiving
fluid from the subject, e.g., without any intervention by the
subject, or by another person. Non-limiting examples of such
techniques are discussed in detail below.
[0139] Another example is illustrated with reference to FIG. 8. In
this figure, device 500 includes a housing 501, an adhesive 502 for
adhesion of the device to the skin, and a substance transfer
component 503. In FIG. 8, substance transfer component 503 includes
a plurality of microneedles 505 within recess 508, although other
substance transfer components as discussed herein may also be used.
Device actuator 560 is shown at the top of device 500. Device
actuator 560 may be, for example, a button, switch, slider, dial,
etc. and may cause microneedles 505 to move towards the skin when
the device is placed on the skin. For example, the microneedles may
be moved mechanically (e.g., compression spring, Belleville spring,
etc.), electrically (e.g., with the aid of a servo, which may be
computer-controlled), pneumatically, etc., e.g., via component 584
(e.g., a piston, a screw, a mechanical linkage, etc.). In some
cases, device actuator 560 may also be able to receive the
microneedles from the skin after use, e.g., after a fluid is
delivered and/or received from the skin.
[0140] Chamber 513, in this figure, is a self-contained vacuum
chamber. Vacuum chamber 513 is in fluidic communication with recess
508 via channel 511, for example, as controlled by a controller or
an actuator. Also illustrated in FIG. 8 is fluid reservoir 540,
which may contain a fluid such as an anticoagulant. The fluid may
be introduced into blood or other fluid received from the skin.
Controlling fluid flow from fluid reservoir may be one or more
suitable fluidic control elements, e.g., pumps, nozzles, valves, or
the like, for example, pump 541 in FIG. 8.
[0141] In certain embodiments, the substance transfer component may
be fastened on a deployment actuator. In some cases, the deployment
actuator can bring the substance transfer component to the skin,
and in certain instances, insert the substance transfer component
into the skin. For example, the substance transfer component can be
moved mechanically, electrically (e.g., with the aid of a servo,
which may be computer-controlled), pneumatically, via a piston, a
screw, a mechanical linkage, or the like. In one set of
embodiments, the deployment actuator can insert the substance
transfer component into the skin at a speed of at least about 0.1
cm/s, at least about 0.3 cm/s, about 1 cm/s, at least about 3 cm/s,
at least about 10 cm/s, at least about 30 cm/s, at least about 1
m/s, at least about 2 m/s, at least about 3 m/s, at least about 4
m/s, at least about 5 m/s, at least about 6 m/s, at least about 7
m/s, at least about 8 m/s, at least about 9 m/s, at least about 10
m/s, at least about 12 m/s, etc., at the point where the substance
transfer component initially contacts the skin. Without wishing to
be bound by any theory, it is believed that relatively faster
insertion speeds may increase the ability of the substance transfer
component to penetrate the skin (without deforming the skin or
causing the skin to move in response), and/or decrease the amount
of pain felt by the application of the substance transfer component
to the skin. Any suitable method of controlling the penetration
speed into the skin may be used, include those described
herein.
[0142] As mentioned, in some embodiments, blood or other bodily
fluids may be stored within the device for later use and/or
analysis. For example, the device may be attached to a suitable
external apparatus able to analyze a portion of the device (e.g.,
containing the fluid), and/or the external apparatus may remove at
least some of the blood or other fluid from the device for
subsequent analysis and/or storage. In some cases, however, at
least some analysis may be performed by the device itself, e.g.,
using one or more sensors, etc., contained within the device.
[0143] For example, as discussed in detail below, in some cases, a
storage chamber may contain a reagent or a reaction entity able to
react with an analyte suspected of being present in the blood (or
other fluid) entering the device, and in some cases, the reaction
entity may be determined to determine the analyte. In some cases,
the determination may be made externally of the device, e.g., by
determining a color change or a change in fluorescence, etc. The
determination may be made by a person, or by an external apparatus
able to analyze at least a portion of the device. In some cases,
the determination may be made without removing blood from the
device, e.g., from the storage chamber. (In other cases, however,
blood or other fluid may first be removed from the device before
being analyzed.) For example, the device may include one or more
sensors (e.g., ion sensors such as K+ sensors, colorimetric
sensors, fluorescence sensors, etc.), and/or contain "windows" that
allow light to penetrate the device. The windows may be formed of
glass, plastic, etc., and may be selected to be at least partially
transparent to one or a range of suitable wavelengths, depending on
the analyte or condition to be determined. As a specific example,
the entire device (or a portion thereof) may be mounted in an
external apparatus, and light from the external apparatus may pass
through or otherwise interact with at least a portion of the device
(e.g., be reflected or refracted via the device) to determine the
analyte and/or the reaction entity.
[0144] In one aspect, the device may be interfaced with an external
apparatus able to determine an analyte contained within a fluid in
the device, for example within a storage chamber as discussed
herein. For example, the device may be mounted on an external
holder, the device may include a port for transporting fluid out of
the device, the device may include a window for interrogating a
fluid contained within the device, or the like. Examples may be
seen in U.S. patent application Ser. No. 13/006,165 filed on Jan.
13, 2011, entitled "Sampling Device Interfaces," incorporated
herein by reference in its entirety.
[0145] Thus, the device, in certain embodiments, may contain a
portion able to determine a fluid received 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 received fluid from the subject, for example, a
marker for a disease state. The sensor may be 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 chamber within or fluid from the device.
For example, the sensor may be in fluidic communication with fluid
received 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 received
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 chamber within the device.
As another example, a sensor may be positioned on or within the
device, and may sense activity in a chamber by being connected
optically to the chamber. Sensing communication can also be
provided where the chamber 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 chamber. As one example, the sensor may be positioned
downstream of a chamber, within a channel such a microfluidic
channel, on an external apparatus, or the like. Thus, the invention
provides, in certain embodiments, sensors able to determine an
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. "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. The species may
be, for example, a bodily fluid and/or an analyte suspected of
being present in the bodily fluid. "Determining" also means
detecting or quantifying interaction between species.
[0146] Non-limiting examples of sensors 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 suitable sensors. 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.
[0147] Examples of sensors include, but are not limited to, pH
sensors, optical sensors, ion sensors, colorimetric sensors, a
sensor able to detect the concentration of a substance, or the
like, e.g., as discussed herein. For instance, in one set of
embodiments, the device may include an ion selective electrode. The
ion selective electrode may be able to determine a specific ion
and/or ions such as K+, H+, Na+, Ag+, Pb2+, Cd2+, or the like.
Various ion selective electrodes can be obtained commercially. As a
non-limiting example, a potassium-selective electrode may include
an ion exchange resin membrane, using valinomycin, a potassium
channel, as the ion carrier in the membrane to provide potassium
specificity.
[0148] Examples of analytes that the sensor may be used to
determine include, but are not limited to, 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. Other conditions that can be determined
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, e.g., legal prescription levels of drugs such as coumadin,
other drugs such as nicotine, or illegal such as cocaine. 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. Still other potentially
suitable analytes include various pathogens such as bacteria or
viruses, and/or markers produced by such pathogens.
[0149] As additional 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 received 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.
[0150] In one set of embodiments, a sensor in the device may be
used to determine a condition of the blood present within the
device. For example, the sensor may indicate the condition of
analytes commonly found within the blood, for example, O2, K+,
hemoglobin, Na+, glucose, or the like. As a specific non-limiting
example, in some embodiments, the sensor may determine the degree
of hemolysis within blood contained within the device. Without
wishing to be bound by any theory, it is believed that in some
cases, hemolysis of red blood cells may cause the release of
potassium ions and/or free hemoglobin into the blood. By
determining the levels of potassium ions, and/or hemoglobin (e.g.,
by subjecting the device and/or the blood to separate cells from
plasma, then determining hemoglobin in the plasma using a suitable
colorimetric assay), the amount of blood lysis or "stress"
experienced by the blood contained within the device may be
determined. Accordingly, in one set of embodiments, the device may
indicate the usability of the blood (or other fluid) contained
within the device, e.g., by indicating the degree of stress or the
amount of blood lysis. Other examples of devices suitable for
indicating the usability of the blood (or other fluid) contained
within the device are also discussed herein (e.g., by indicating
the amount of time blood has been contained in the device, the
temperature history of the device, etc.).
[0151] For instance, fluids received from the subject will often
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+ (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. As discussed herein, certain embodiments of the
present invention are generally directed at methods for receiving
fluids from the body, and optionally determining one or more
analytes within the received fluid. Thus, in some embodiments, 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 received from the skin may be subjected to
such uses, and/or one or more materials previously delivered to the
skin may be subject to such uses.
[0152] 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 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.
[0153] In some embodiments, the device may connected to an external
apparatus for determining at least a portion of the device, a fluid
removed from the device, an analyte suspected of being present
within the fluid, or the like. For example, the device may be
connected to an external analytical apparatus, and fluid removed
from the device for later analysis, or the fluid may be analyzed
within the device in situ, e.g., by adding one or more reaction
entities to the device, for instance, to a storage chamber, or to
analytical chamber within the device. For example, in one
embodiment, the external apparatus may have a port or other
suitable surface for mating with a port or other suitable surface
on the device, and blood or other fluid can be removed from the
device using any suitable technique, e.g., using vacuum or
pressure, etc. The blood may be removed by the external apparatus,
and optionally, stored and/or analyzed in some fashion. For
example, in one set of embodiments, the device may include an exit
port for removing a fluid from the device (e.g., blood). In some
embodiments, fluid contained within a storage chamber in the device
may be removed from the device, and stored for later use or
analyzed outside of the device. In some cases, the exit port may be
separate from the substance transfer component. An example is shown
with exit port 670 and substance transfer component 620 in device
600 in FIG. 6. As shown in this figure, the exit port can be in
fluidic communication with vacuum chamber 610, which can also serve
as a fluid reservoir in some cases.
[0154] In one set of embodiments, the device may include an
anticoagulant or a stabilizing agent for stabilizing the fluid
received from the skin. For example, the fluid may be stored within
the device for a certain period of time, and/or the device (or a
portion thereof) may be moved or shipped to another location for
analysis or later use. For instance, a device may contain
anticoagulant or a stabilizing agent in a storage chamber. In some
cases, more than one anticoagulant may be used, e.g., in the same
storage chamber, or in more than one storage chamber.
[0155] As a specific non-limiting example, an anticoagulant may be
used for blood received from the skin. Examples of anticoagulants
include, but are not limited to, heparin, citrate, thrombin,
oxalate, ethylenediaminetetraacetic acid (EDTA), sodium polyanethol
sulfonate, acid citrate dextrose. Other agents may be used in
conjunction or instead of anticoagulants, for example, stabilizing
agents such as solvents, diluents, buffers, chelating agents,
antioxidants, binding agents, preservatives, antimicrobials, or the
like. Examples of preservatives include, for example, benzalkonium
chloride, chlorobutanol, parabens, or thimerosal. Non-limiting
examples of antioxidants include ascorbic acid, glutathione, lipoic
acid, uric acid, carotenes, alpha-tocopherol, ubiquinol, or enzymes
such as catalase, superoxide dismutase, or peroxidases. Examples of
microbials include, but are not limited to, ethanol or isopropyl
alcohol, azides, or the like. Examples of chelating agents include,
but are not limited to, ethylene glycol tetraacetic acid or
ethylenediaminetetraacetic acid. Examples of buffers include
phosphate buffers such as those known to ordinary skill in the
art.
[0156] In one set of embodiments, at least a portion of the device
may be colored to indicate the anticoagulant(s) contained within
the device. In some cases, the colors used may be identical or
equivalent to that commercially used for Vacutainers.TM.,
Vacuettes.TM., or other commercially-available phlebotomy
equipment. For example, lavender and/or purple may indicate
ethylenediaminetetraacetic acid, light blue may indicate citrate,
dark blue may indicate ethylenediaminetetraacetic acid, green may
indicate heparin, gray may indicate a fluoride and/or an oxalate,
orange may indicate a thrombin, yellow may indicate sodium
polyanethol sulfonate and/or acid citrate dextrose, black may
indicate citrate, brown may indicate heparin, etc. In other
embodiments, however, other coloring systems may be used.
[0157] Other coloring systems may be used in other embodiments of
the invention, not necessarily indicative of anti-coagulants. For
example, in one set of embodiments, the device carries a color
indicative of a recommended bodily use site for the device, e.g., a
first color indicative of a device suitable for placement on the
back, a second color indicative of a device suitable for placement
on a leg, a third color indicative of a device suitable for
placement on the arm, etc.
[0158] As mentioned, in one set of embodiments, a device of the
invention as discussed herein may be shipped to another location
for analysis. In some cases, the device may include an
anticoagulant or a stabilizing agent contained within the device,
e.g., within a storage chamber for the fluid. Thus, for example,
fluid such as blood received from the skin may be delivered to a
chamber (e.g., a storage chamber) within the device, then the
device, or a portion of the device (e.g., a module) may be shipped
to another location for analysis. Any form of shipping may be used,
e.g., via mail.
[0159] Non-limiting examples of various devices of the invention
are shown in FIG. 1. In FIG. 1A, device 90 is used for receiving a
fluid from a subject when the device is placed on the skin of a
subject. Device 90 includes sensor 95 and substance transfer
component 92, e.g., including a needle, a microneedle, etc., as
discussed herein. In fluidic communication with substance transfer
component 92 via fluidic channel 99 is sensing chamber 97. In one
embodiment, sensing chamber 97 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
received using substance transfer component 92 by a vacuum, for
example, a self-contained vacuum contained within device 90.
Optionally, device 90 also contains a display 94 and associated
electronics 93, batteries or other power supplies, etc., which may
be used to display sensor readings obtained via sensor 95. In
addition, device 90 may also optionally contain memory 98,
transmitters for transmitting a signal indicative of sensor 95 to a
receiver, etc.
[0160] In the example shown in FIG. 1A, device 90 may contain a
vacuum source (not shown) that is self-contained within device 90,
although in other embodiments, the vacuum source may be external to
device 90. (In still other instances, other systems may be used to
deliver and/or receive 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 of the
substance transfer component 92, 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 90, 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 due to the vacuum. Skin
drawn into the recess may come into contact with a skin insertion
object (e.g., solid or hollow needles), which may, in some cases,
pierce the skin and allow a fluid to be delivered and/or received
from the skin. In another embodiment, a skin insertion object may
be actuated and moved downward to come into contact with the skin,
and optionally retracted after use.
[0161] Another non-limiting example of a device is shown in FIG.
1B. This figure illustrates a device useful for delivering a fluid
to the subject. Device 90 in this figure includes substance
transfer component 92, e.g., including a needle, a microneedle,
etc., as discussed herein. In fluidic communication with substance
transfer component 92 via fluidic channel 99 is chamber 97, 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 received using substance transfer component 92 by a vacuum,
for example, a self-contained vacuum contained within device 90.
For instance, upon creating a vacuum, skin may be drawn up towards
substance transfer component 92, and the substance transfer
component 92 may pierce the skin. Fluid from chamber 97 can then be
delivered into the skin through fluid channel 99 and substance
transfer component 92. Optionally, device 90 also contains a
display 94 and associated electronics 93, batteries or other power
supplies, etc., which may be used control delivery of fluid to the
skin. In addition, device 90 may also optionally contain memory 98,
transmitters for transmitting a signal indicative of device 90 or
fluid delivery to a receiver, etc.
[0162] Yet another non-limiting example of a device of the
invention is shown in FIG. 2. FIG. 2A illustrates a view of the
device (with the cover removed), while FIG. 2B schematically
illustrates the device in cross-section. In FIG. 2B, device 50
includes a needle 52 contained within a recess 55. Needle 52 may be
solid or hollow, depending on the embodiment. Device 50 also
includes a self-contained vacuum chamber 60, which wraps around the
central portion of the device where needle 52 and recess 55 are
located. A channel 62 connects vacuum chamber 60 with recess 55,
separated by a foil or a membrane 67. Also shown in device 50 is
button 58. When pushed, button 58 breaks foil 67, thereby
connecting vacuum chamber 50 with recess 55, creating a vacuum in
recess 55. The vacuum may be used, for example, to draw skin into
recess 55, preferably such that it contacts needle 52 and pierces
the surface, thereby gaining access to an internal fluid. The fluid
may be controlled, for example, by controlling the size of needle
52, 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 50 on the surface of the skin, and/or to assist in
the receiving of fluid from the skin. For instance, fluid may flow
into channel 62 under action of the vacuum, and optionally to
sensor 61, e.g., for detection of an analyte contained within the
fluid. For instance, sensor 61 may produce a color change if an
analyte is present, or otherwise produce a detectable signal.
[0163] Other components may be added to the example of the device
illustrated in FIG. 2, in some embodiments of the invention. For
example, device 50 may contain a cover, displays, ports,
transmitters, sensors, channels such as microfluidic channels,
chambers, and/or various electronics, e.g., to control or monitor
fluid transport into or out of device 50, to determine an analyte
present within a fluid delivered and/or received 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 50
may contain an adhesive, e.g., on surface 54, for adhesion of the
device to the skin.
[0164] Yet another non-limiting example is illustrated with
reference to FIG. 2C. In this example, device 500 includes a
housing 501, and an associated substance transfer component 503.
Substance transfer component 503 includes a plurality of needles or
microneedles 505, although other skin insertion objects or flow
activators as discussed herein may also be used. Also shown in FIG.
5 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, preferably 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 example, 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 on display
525 a suitable signal. 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.
[0165] In some cases, more than one substance transfer component
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 receive 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 receive fluid
to and from a subject. A non-limiting example of a device having
more than one substance transfer component is illustrated with
reference to FIG. 2E. In this example, device 500 contains a
plurality of structures such as those described herein for
delivering and/or receiving 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 substance transfer components 575.
Each of these substance transfer components may independently have
the same or different structures, depending on the particular
application, and they may have structures such as those described
herein. 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. 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, a cyanoacrylate, a glue, a gum, hot melts, an epoxy, or
the like. In some cases, the adhesive is chosen to be biocompatible
or hypoallergenic.
[0166] 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.
[0167] 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.
[0168] 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 in a
variety of ways. In one embodiment, a device can be applied to a
subject and a region of the device activated (e.g., pushed,
pressed, or 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 accesses
interstitial fluid and draws interstitial fluid into an analysis
region) or the 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. 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.
[0169] In some 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.
[0170] 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.
[0171] 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. 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. 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. 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.
[0172] According to one aspect of the invention, the device is of a
relatively small size. In some embodiments, the device may be sized
such that it is wearable and/or carryable by a subject. For
example, the device may be self-contained, needing no wires,
cables, tubes, external structural elements, or other external
support. The device may be positioned on any suitable position of
the subject, for example, on the arm or leg, on the back, on the
abdomen, etc. As mentioned, in some embodiments, the device may be
affixed or held onto the surface of the skin using any suitable
technique, e.g., using adhesives, mechanical elements such as
straps, belts, buckles, strings, ties, elastic bands, or the like.
In some cases, the device may be positioned on the subject such
that the subject is able to move around (e.g., walking, exercising,
typing, writing, drinking or eating, using the bathroom, etc.)
while wearing the device. For example, the device may have a mass
and/or dimensions such that the subject is able to wear the device
for at least about 5 minutes, and in some cases for longer periods
of time, e.g., at least about 10 minutes, at least about 15
minutes, at least about 30 minutes, at least about 45 minutes, at
least about 1 hour, at least about 3 hours, at least 5 hours, at
least about 8 hours, at least about 1 day, at least about 2 days,
at least about 4 days, at least about 1 week, at least about 2
weeks, at least about 4 weeks, etc.
[0173] In some embodiments, the device is relatively lightweight.
For example, the device may have a mass of no more than about 1 kg,
no more than about 300 g, no more than about 150 g, no more than
about 100 g, no more than about 50 g, no more than about 30 g, no
more than about 25 g, no more than about 20 g, no more than about
10 g, no more than about 5 g, or no more than about 2 g. For
instance, in various embodiments, the device has a mass of between
about 2 g and about 25 g, a mass of between about 2 g and about 10
g, a mass of between 10 g and about 50 g, a mass of between about
30 g and about 150 g, etc.
[0174] The device, in some cases, may be relatively small. For
example, the device may be constructed and arranged to lie
relatively close to the skin. Thus, for instance, the device may
have a largest vertical dimension, extending from the skin of the
subject when the device is positioned on the skin, of no more than
about 25 cm, no more than about 10 cm, no more than about 7 cm, no
more than about 5 cm, no more than about 3 cm, no more than about 2
cm, no more than about 1 cm, no more than about 8 mm, no more than
about 5 mm, no more than about 3 mm, no more than about 2 mm, no
more than about 1 mm, or no more than about 0.5 mm. In some cases,
the device may have a largest vertical dimension of between about
0.5 cm and about 1 cm, between about 2 and about 3 cm, between
about 2.5 cm and about 5 cm, between about 2 cm and about 7 cm,
between about 0.5 mm and about 7 cm, etc.
[0175] In another set of embodiments, the device may have a
relatively small size. For example, the device may have a largest
lateral dimension (e.g., parallel to the skin) of no more than
about 25 cm, no more than about 10 cm, no more than about 7 cm, no
more than about 5 cm, no more than about 3 cm, no more than about 2
cm, or no more than about 1 cm. In some cases, the device may have
a largest lateral dimension of between about 0.5 cm and about 1 cm,
between about 2 and about 3 cm, between about 2.5 cm and about 5
cm, between about 2 cm and about 7 cm, etc.
[0176] Combinations of these and/or other dimensions are also
possible in other embodiments. As non-limiting examples, the device
may have a largest lateral dimension of no more than about 5 cm, a
largest vertical dimension of no more than about 1 cm, and a mass
of no more than about 25 g; or the device may have a largest
lateral dimension of no more than about 5 cm, a largest vertical
dimension of no more than about 1 cm, and a mass of no more than
about 25 g; etc.
[0177] In certain embodiments, the may also include a device
actuator. The device actuator may be constructed and arranged to
cause exposure of the substance transfer component to the skin upon
actuation of the device actuator. For example, the activator may
cause the substance transfer component to release a chemical to
contact the skin, a microneedle or other substance transfer
component 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
device actuator may be actuated by the subject, and/or by another
person (e.g., a health care provider), or the device itself may be
self-actuating, e.g., upon application to the skin of a subject.
The actuator may be actuated once, or multiple times in some
cases.
[0178] The device may be actuated, 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 actuate the actuator.
In some cases, the device may be remotely actuated. 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 radio signal, etc.
[0179] In one set of embodiments, the device may include channels
such as microfluidic channels, which may be used to deliver and/or
receive fluids and/or other materials 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 substance
transfer component that is used to deliver and/or receive 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 received 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
receive fluid from the skin, e.g., for delivery to an analytical
chamber within the device, to a reservoir for later analysis, or
the like.
[0180] In some cases, more than one chamber may be present within
the device, and in some cases, some or all of the chambers may be
in fluidic communication, e.g., via channels such as microfluidic
channels. In various embodiments, a variety of chambers and/or
channels may be present within the device, depending on the
application. For example, the device may contain chambers for
sensing an analyte, chambers for holding reagents, chambers for
controlling temperature, chambers for controlling pH or other
conditions, chambers for creating or buffering pressure or vacuum,
chambers for controlling or dampening fluid flow, mixing chambers,
or the like.
[0181] 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 example, 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.
[0182] 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.
[0183] A channel may have any aspect ratio, e.g., an aspect ratio
(length to average cross-sectional dimension) of 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.
[0184] 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 substance transfer
components and/or one or more microfluidic channels. For instance,
the device may contain a chamber for collecting fluid received 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.
[0185] After receipt of the fluid into the device, the device, or a
portion thereof, may be removed from the skin of the subject, e.g.,
by the subject or by another person. For example, the entire device
may be removed, or a portion of the device containing the storage
reservoir may be removed from the device, and optionally replaced
with another storage reservoir. Thus, for instance, in one
embodiment, the device may contain two or more modules, for
example, a first module that is able to cause receiving of fluid
from the skin into a storage reservoir, and a second module
containing the storage module. In some cases, the module containing
the storage reservoir may be removed from the device. Other
examples of modules and modular systems are discussed below; other
examples are discussed in U.S. Provisional Patent Application Ser.
No. 61/256,931, filed Oct. 30, 2009, entitled "Modular Systems for
Application to the Skin," incorporated by reference herein in its
entirety.
[0186] The received fluid may then be sent to a clinical and/or
laboratory setting, e.g., for analysis. In some embodiments, the
entire device may be sent to the clinical and/or laboratory
setting; in other embodiments, however, only a portion of the
device (e.g., a module containing a storage reservoir containing
the fluid) may be sent to the clinical and/or laboratory setting.
In some cases, the fluid may be shipped using any suitable
technique (e.g., by mail, by hand, etc.). In certain instances, the
subject may give the fluid to appropriate personnel at a clinical
visit. For instance, a doctor may prescribe a device as discussed
above for use by the subject, and at the next doctor visit, the
subject may give the doctor the received fluid, e.g., contained
within a device or module.
[0187] In some aspects, the device may contain an indicator. The
indicator may be used for determining a condition of a fluid
contained within the device, e.g., within a fluid storage chamber
or a fluid reservoir. In some embodiments, the indicator may
indicate one or more conditions associated with the introduction of
fluid into the storage component and/or one or more conditions
associated with storage of fluid in the storage component. For
example, the indicator may indicate the condition of blood or ISF
within the device, e.g., as the device is being transported or
shipped to a clinical or a laboratory setting. The indicator may
indicate the condition of the blood through any suitable technique,
e.g., visually (such as with a color change), using a display, by
producing a sound, etc. For instance, the indicator may have a
display that is green if the fluid has not been exposed to certain
temperatures or if there is no adverse chemical reaction present
within the fluid (e.g., a change in pH, growth of microorganisms,
etc.), but is yellow or red if adverse conditions are or have been
present (e.g., exposure to temperatures that are too extreme,
growth of microorganisms, etc.). In other embodiments, the display
may display a visual message, a sound may be produced by the
device, or the like.
[0188] In some cases, the indicator may be activated upon the
accessing of fluid by the access component and/or introduction of
fluid into the storage component. In one set of embodiments, the
indicator may be activated upon the introduction of fluid within a
fluid storage reservoir, upon activation of the device (e.g., to
receive fluid from a subject, as discussed below), upon activation
by a user (e.g., by the subject, or another person), etc.
[0189] In some cases, the indicator may determine the condition of
fluid within a fluid storage reservoir within the device using one
or more suitable sensors, for example, pH sensors, temperature
sensors (e.g., thermocouples), oxygen sensors, or the like. For
instance, a sensor may be present within or proximate the fluid
storage reservoir for determining the temperature of the fluid
within the fluid storage reservoir. In some cases, for example,
more than one sensor measurement may be taken, e.g., at multiple
points of time or even continuously. In some cases, the indicator
may also record the sensor determinations, e.g., for analysis or
later study.
[0190] In certain embodiments, time information may be determined
and/or recorded by the indicator. For example, the time fluid
enters a fluid storage reservoir may be recorded, e.g., using a
time/date stamp (e.g., absolute time), and/or using the duration of
time that fluid has been present within the fluid storage
reservoir. The time information may also be recorded in some
embodiments.
[0191] As discussed, in one set of embodiments, information from
sensors and/or time information may be used to determine a
condition of the fluid within the fluid storage reservoir. For
example, if certain limits are met or exceeded, the indicator may
indicate that, as discussed above. As a specific non-limiting
example, if the temperature of the device is too low (e.g., reaches
0.degree. C.) or too high (e.g., reaches 100.degree. C. or
37.degree. C.), this may be displayed by a display on the
indicator. Thus, fluid exposed to temperature extremes may be
identified, e.g., as being problematic or spoiled. As a another
non-limiting example, it may be desired to keep the pH of fluid
within the device within certain conditions, and if the pH is
exceeded (e.g., too acidic or too basic), this may be displayed by
a display on the indicator, for example, if the pH is less than 6
or 5, or greater than 8 or 9. In some cases, the time that fluid is
present within the device may be kept within certain limits as
well, as another condition. For example, the indicator may indicate
that fluid has been present within the device for more than about
12 hours, more than about 18 hours, or more than about 24 hours,
which may indicate the fluid as being problematic, spoiled,
etc.
[0192] In one set of embodiments, conditions such as these may also
be combined (e.g., time and temperature). Thus, for example, fluid
exposed to a first temperature may be allowed to be present within
the device for a first time, while fluid exposed to a second
temperature may be allowed to be present within the device for a
second time, before the indicator displays this.
[0193] In some embodiments, the indicator may record and/or
transmit sensor or time information. This may be recorded and/or
transmitted using any suitable format. For instance, the
information may be transmitted using a wireless signal, a radio
signal, etc., or recorded on any suitable electronic media, e.g.,
on a microchip, flash drive, optically, magnetically, etc.
[0194] A variety of materials and methods, according to certain
aspects of the invention, can be used to form the device, e.g.,
microfluidic channels, chambers, etc. 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).
[0195] 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).
[0196] Other examples of potentially suitable polymers include, but
are not limited to, polyethylene terephthalate (PET), polyacrylate,
polymethacrylate, polycarbonate, polystyrene, polyethylene,
polypropylene, polyvinylchloride, cyclic olefin copolymer (COC),
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.
[0197] 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.
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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 or generators
include, but are not limited to, displays (visual, LED, light,
etc.), speakers, chemical-releasing chambers (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
substance transfer component for application to the skin of the
subject, e.g., such as a needle or a microneedle), or the signal
structure may not be integrally connected with the substance
transfer component. 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.
[0202] 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.
[0203] 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 radio signal, etc.
[0204] 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 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.
[0205] 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 (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.
[0206] 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.
[0207] 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.
[0208] 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
received 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 received from a subject, the amount of fluid
received 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).
[0209] 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.
[0210] 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.
[0211] 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 attach it to a medical record associated
with the subject.
[0212] According to various sets of embodiments, the device may be
used once, 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).
[0213] 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.
[0214] 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. 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.
[0215] In one set of embodiments, one or more materials, such as
particles, are 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
particles may be, for example, nanoparticles or microparticles, and
in some cases, the particles may be anisotropic particles. 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.
[0216] 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.
[0217] In some cases, materials such as particles may become
embedded within the skin, for example, due to physical properties
of the materials (e.g., size, hydrophobicity, etc.). 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 is
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.
[0218] 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. Other 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. Other
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.
[0219] In some cases, a pooled region of fluid, such as a suction
blister, may be formed in the skin to facilitate delivery and/or
receiving of fluid from the skin. 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.
[0220] 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
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 microneedle or microneedles can be applied to the
interstitial region and fluid can be drawn there from.
[0221] Pooled regions of fluids 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 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
received 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 or less than about 1 ml 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.
[0222] A variety of techniques may be used to cause pooled regions
of fluid to form within the skin. In one set of embodiments, vacuum
is applied to create a suction blister, or otherwise used to
collect interstitial fluid from a subject. In other embodiments,
however, other methods may be used to create as a pooled region of
fluid within 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, 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 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. 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.
[0223] 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 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
received 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.
[0224] 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., at
least about 55.degree. C., or at least about 60.degree. C., using
any suitable technique, to cause such separation to occur. 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.
[0225] 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.
[0226] 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).
[0227] 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.
[0228] 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.
[0229] One aspect of the present invention is directed to an
adaptor able to position a device of the invention in apparatuses
designed to contain Vacutainer.TM. tubes or Vacuette.TM. tubes. In
some cases, the Vacutainer or Vacuette tube sizes have a maximum
length of no more than about 75 mm or about 100 mm and a diameter
of no more than about 16 mm or about 13 mm. In some cases, the
adaptor may be able to immobilize a device of the invention
therein, e.g., for subsequent use or processing. In some cases, as
previously discussed, devices of the invention may have a largest
lateral dimension of no more than about 50 mm, and/or a largest
vertical dimension, extending from the skin of the subject when the
device is applied to the subject, of no more than about 10 mm. An
example of such a device is shown in FIG. 9, with device 800
contained within adapter 850. The device may contained within the
adaptor using any suitable technique, e.g., using clips, springs,
braces, bands, or the application of force to the device present
within the adaptor.
[0230] 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 device for the delivery and/or receiving 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. 2D, 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.
[0231] 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.
[0232] 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.
[0233] 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. The
following documents are incorporated herein by reference: U.S.
Provisional Patent Application Ser. No. 61/058,796, filed Jun. 4,
2008, entitled "Compositions and Methods for Diagnostics,
Therapies, and Other Applications"; U.S. Provisional Patent
Application Ser. No. 61/163,791, filed Mar. 26, 2009, entitled
"Composition and Methods for Rapid One-Step Diagnosis"; U.S.
Provisional Patent Application Ser. No. 61/163,793, filed Mar. 26,
2009, entitled "Compositions and Methods for Diagnostics,
Therapies, and Other Applications"; 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. 61/163,733, filed Mar. 26, 2009,
entitled "Determination of Tracers within Subjects"; U.S.
Provisional Patent Application Ser. No. 61/163,750, filed Mar. 26,
2009, entitled "Monitoring of Implants and Other Devices"; U.S.
Provisional Patent Application Ser. No. 61/154,632, filed Mar. 2,
2009, entitled "Oxygen Sensor"; and 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." Also
incorporated by reference herein are U.S. Provisional Patent
Application Ser. No. 61/263,882, filed Nov. 24, 2009, entitled
"Patient-Enacted Sampling Technique"; U.S. Provisional Patent
Application Ser. No. 61/294,543, filed Jan. 13, 2010, entitled
"Blood Sampling Device and Method"; U.S. patent application Ser.
No. 12/716,222, filed Mar. 2, 2010, entitled "Oxygen Sensor," by
Levinson, et al.; U.S. patent application Ser. No. 12/716,233,
filed Mar. 2, 2010, 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. patent application Ser. No.
12/716,226, filed Mar. 2, 2010, entitled "Techniques and Devices
Associated with Blood Sampling," by Levinson, et al.; and U.S.
patent application Ser. No. 12/716,229, filed Mar. 2, 2010,
entitled "Devices and Techniques Associated with Diagnostics,
Therapies, and Other Applications, Including Skin-Associated
Applications," by Bernstein, et al; U.S. Provisional Patent
Application Ser. No. 61/256,880, filed Oct. 30, 2009, entitled
"Systems and Methods for Altering or Masking Perception of
Treatment of a Subject," by Chickering, et al.; U.S. Provisional
Patent Application Ser. No. 61/256,874, filed Oct. 30, 2009,
entitled "Systems and Methods for Application to Skin and Control
of Use Thereof," by Benstein, et al.; U.S. Provisional Patent
Application Ser. No. 61/256,871, filed Oct. 30, 2009, entitled
"Packaging Systems and Methods for Devices Applied to the Skin," by
Bernstein, et al.; U.S. Provisional Patent Application Ser. No.
61/334,533, filed May 13, 2010, entitled "Blood Sampling Device and
Method," by Chickering, et al.; U.S. Provisional Patent Application
Ser. No. 61/334,529, filed May 13, 2010, entitled "Sampling Device
Interfaces," by Chickering, et al.; and U.S. patent application
Ser. No. 13/006,165, filed Jan. 13, 2011, entitled "Sampling Device
Interfaces" by Chickering, et al.
[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.
* * * * *