U.S. patent application number 13/456546 was filed with the patent office on 2012-11-01 for systems and methods for collection and/or manipulation of blood spots or other bodily fluids.
This patent application is currently assigned to Seventh Sense Biosystems, Inc.. Invention is credited to Howard Bernstein, Donald E. Chickering, III, Shawn Davis, Ping Gong, Kristin Horton, Scott James.
Application Number | 20120277629 13/456546 |
Document ID | / |
Family ID | 46148950 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277629 |
Kind Code |
A1 |
Bernstein; Howard ; et
al. |
November 1, 2012 |
SYSTEMS AND METHODS FOR COLLECTION AND/OR MANIPULATION OF BLOOD
SPOTS OR OTHER BODILY FLUIDS
Abstract
The present invention generally relates to systems and methods
for receiving blood (or other bodily fluids) from a subject, e.g.,
from or beneath the skin of a subject. In some cases, the blood (or
other bodily fluids) may be deposited on a membrane or other
substrate. For example, blood may be absorbed in a substrate, and
dried in some cases to produce a dried blood spot. In one aspect,
the present invention is generally directed to devices and methods
for receiving blood from a subject, e.g., from the skin, using
devices including a substance transfer component (which may
contain, for example, one or more microneedles), and directing the
blood on a substrate, e.g., for absorbing blood. The substrate, in
some embodiments, may comprise filter paper or cotton-based paper.
After absorption of some blood onto the substrate, the substrate
may be removed from the device and shipped or analyzed.
Inventors: |
Bernstein; Howard;
(Cambridge, MA) ; Chickering, III; Donald E.;
(Framingham, MA) ; Davis; Shawn; (Boston, MA)
; Gong; Ping; (Melrose, MA) ; Horton; Kristin;
(Brighton, MA) ; James; Scott; (Epping,
NH) |
Assignee: |
Seventh Sense Biosystems,
Inc.
Cambridge
MA
|
Family ID: |
46148950 |
Appl. No.: |
13/456546 |
Filed: |
April 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61480941 |
Apr 29, 2011 |
|
|
|
61549437 |
Oct 20, 2011 |
|
|
|
Current U.S.
Class: |
600/578 |
Current CPC
Class: |
B01L 3/502753 20130101;
G01N 33/1826 20130101; A61M 1/3687 20130101; A61B 5/15105 20130101;
B01L 2300/0681 20130101; A61B 5/14514 20130101; B01L 2300/087
20130101; A61B 5/150412 20130101; A61B 5/150755 20130101; B01L
2400/049 20130101; A61M 2202/0415 20130101; A61B 5/1455 20130101;
A61B 10/0045 20130101; A61B 5/150984 20130101; A61B 5/154 20130101;
A61B 5/150343 20130101; B01L 2300/0672 20130101; A61B 5/1411
20130101; A61M 2205/3334 20130101; A61B 5/150221 20130101; G01N
33/18 20130101; A61B 5/14546 20130101; B01L 2300/0874 20130101;
A61B 5/150022 20130101; A61M 1/34 20130101; A61B 5/150213 20130101;
A61B 5/150358 20130101; B01L 2300/0816 20130101; A61B 2562/0295
20130101; A61B 5/151 20130101; A61B 5/1486 20130101; A61B 5/150099
20130101; B01L 2400/0655 20130101; A61B 5/150419 20130101; A61B
5/14539 20130101; A61B 5/150503 20130101; A61B 5/15142 20130101;
A61B 5/14532 20130101; A61B 5/150229 20130101; A61B 5/150969
20130101; B01L 2400/0688 20130101; A61M 1/3486 20140204; A61B
5/1438 20130101 |
Class at
Publication: |
600/578 |
International
Class: |
A61B 5/153 20060101
A61B005/153 |
Claims
1. A device for receiving blood from the skin and/or from beneath
the skin of a subject, the device comprising: a substance transfer
component for receiving blood from the skin of the subject; a
vacuum chamber having an internal pressure less than atmospheric
pressure before blood is received into the device from the
substance transfer component; and a substrate for absorbing blood
received from the subject.
2. The device of claim 1, wherein the substrate is a blood spot
membrane.
3. The device of claim 1, wherein the substrate comprises filter
paper.
4. The device of claim 1, wherein the substrate comprises
cotton-based paper.
5. The device of claim 1, wherein the substrate comprises Whatman
903.TM. paper.
6. The device of claim 1, wherein the device comprises a recess,
wherein the recess contains the substrate for absorbing blood.
7. The device of claim 1, wherein the substrate for absorbing blood
is positioned proximate the vacuum chamber.
8-12. (canceled)
13. The device of claim 1, wherein the substrate has an area of no
more than about 5 cm.sup.2.
14. The device of claim 1, wherein the device comprises a plurality
of substrates for absorbing blood received from the subject.
15-17. (canceled)
18. The device of claim 1, wherein the device further comprises
desiccant.
19. (canceled)
20. The device of claim 1, wherein a portion of the device is
sealable to create an airtight portion surrounding the substrate
for absorbing blood.
21. The device of claim 20, wherein a portion of the device
comprises a movable portion that sealingly creates the airtight
portion when moved into position.
22. The device of claim 1, wherein the device comprises a cover for
covering at least a portion of the substance transfer
component.
23. (canceled)
24. The device of claim 1, further comprising a tracking
apparatus.
25. (canceled)
26. The device of claim 1, wherein the substrate further comprises
a stabilizer.
27. The device of claim 26, wherein the stabilizer comprises a
chelating agent.
28. The device of claim 26, wherein the stabilizer comprises an
enzyme inhibitor.
29. The device of claims 26, wherein the stabilizer comprises a
lysing agent.
30. A device for receiving a bodily fluid from the skin and/or from
beneath the skin of a subject, the device comprising: a substance
transfer component for receiving the bodily fluid from the skin of
the subject; a vacuum chamber having an internal pressure less than
atmospheric pressure before the bodily fluid is received into the
device from the substance transfer component; and a substrate for
absorbing the bodily fluid received from the subject.
31. A method, comprising: applying a device to the skin of a
subject, wherein the device applies reduced pressure to the skin of
the subject; and withdrawing blood from the skin of the subject
into the device such that at least a portion of the blood contacts
a substrate for absorbing the blood.
32. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/480,941, filed Apr. 29, 2011,
entitled "Plasma or Serum Production and Removal of Fluids under
Reduced Pressure," by Haghgooie, et al.; and of U.S. Provisional
Patent Application Ser. No. 61/549,437, filed Oct. 20, 2011,
entitled "Systems and Methods for Collection and/or Manipulation of
Blood Spots or Other Bodily Fluids," by Bernstein, et al. Each of
these is incorporated herein by reference.
FIELD OF INVENTION
[0002] The present invention generally relates to systems and
methods for receiving blood (or other bodily fluids) from a
subject, e.g., from or beneath the skin of a subject. In some
cases, the blood (or other bodily fluids) may be deposited on a
membrane or other substrate.
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
[0004] The present invention generally relates to systems and
methods for receiving blood (or other bodily fluids) from a
subject, e.g., from or beneath the skin of a subject. In some
cases, the blood (or other bodily fluids) may be deposited on a
membrane or other substrate. 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, the present invention is generally directed
to a device for receiving blood from the skin and/or from beneath
the skin of a subject. In one set of embodiments, the device
includes a substance transfer component for receiving blood from
the skin of the subject, a vacuum chamber having an internal
pressure less than atmospheric pressure before blood is received
into the device from the substance transfer component, and a
substrate for absorbing blood received from the subject
[0006] In another set of embodiments, the device includes a
substance transfer component for receiving the bodily fluid from
the skin of the subject, a vacuum chamber having an internal
pressure less than atmospheric pressure before the bodily fluid is
received into the device from the substance transfer component, and
a substrate for absorbing the bodily fluid received from the
subject
[0007] The invention, in another set of embodiments, is generally
directed to a method. In one set of embodiments, the method
includes acts of applying a device to the skin of a subject, where
in some cases, the device may apply reduced pressure to the skin of
the subject, and withdrawing blood from the skin of the subject
into the device such that at least a portion of the blood contacts
a substrate for absorbing the blood.
[0008] The method in another set of embodiments, includes an act of
receiving blood into a device by applying reduced pressure to the
skin of the subject, where at least a portion of the blood within
the device contacts a substrate for absorbing the blood.
[0009] In one aspect, the present invention is generally directed
to a simple, one-piece, low-profile, high acceleration, high
energy, actuation mechanism for inserting microneedles (or other
objects) into the skin for the purpose of receiving substances,
such as blood or interstitial fluid. In one set of embodiments, a
device of the invention is actuated by a deployment actuator which
can provide advantages in ease of operation, speed of operation,
reduction or elimination of pain, etc.
[0010] 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 a fluid such as 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 a fluid such as blood from a
subject.
[0011] 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
[0012] 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:
[0013] FIGS. 1A-1B illustrate devices including a substrate for
absorbing blood or other bodily fluids, according to certain
embodiments of the invention;
[0014] FIGS. 2A-2B illustrate additional devices including a
substrate for absorbing blood or other bodily fluids, according to
various embodiments of the invention
[0015] FIG. 3 illustrates one embodiment including a plurality of
substrates;
[0016] FIG. 4 illustrates various substrates including tabs or
handles, in certain embodiments of the invention;
[0017] FIGS. 5A-5B illustrate an applicator region in accordance
with certain embodiments of the invention;
[0018] FIGS. 6A-6B illustrate the formation of a pool of bodily
fluid on the surface of the skin, in certain embodiments of the
invention;
[0019] FIGS. 7A-7B illustrate various capillaries in accordance
with certain embodiments of the invention; and
[0020] FIGS. 8A-8C illustrate a device in still another embodiment,
illustrating a deployment actuator.
DETAILED DESCRIPTION
[0021] The present invention generally relates to systems and
methods for receiving blood (or other bodily fluids) from a
subject, e.g., from or beneath the skin of a subject. In some
cases, the blood (or other bodily fluids) may be deposited on a
membrane or other substrate. For example, blood may be absorbed in
a substrate, and dried in some cases to produce a dried blood spot.
In one aspect, the present invention is generally directed to
devices and methods for receiving blood from a subject, e.g., from
the skin, using devices including a substance transfer component
(which may contain, for example, one or more microneedles), and
directing the blood on a substrate, e.g., for absorbing blood. The
substrate, in some embodiments, may comprise filter paper or
cotton-based paper. After absorption of some blood onto the
substrate, the substrate may be removed from the device and shipped
or analyzed. In some cases, the device itself may be shipped or
analyzed. For example, in some embodiments, a portion of the device
may be sealed such that the substrate is contained within an
airtight portion of the device, optionally containing desiccant.
Other aspects are generally directed at other devices for receiving
blood (or other bodily fluids), kits involving such devices,
methods of making such devices, methods of using such devices, and
the like.
[0022] As mentioned, certain aspects of the present invention are
directed to substrates for absorbing blood and/or other bodily
fluids, for example, a blood spot membrane. Thus, in some
embodiments, blood spots may be produced on a blood spot membrane.
In these cases, a channel within the device may have a small volume
relative to the volume of a blood spot membrane which may be very
porous and may collect fluid. The blood spot membrane is used to
collect fluid in certain embodiments. The blood spot membrane is
not used to separate cells/plasma (as opposed to the separation
membranes discussed herein), in certain cases. Fluid may fill all,
or a portion of, the blood spot membrane. A second hydrophobic
membrane may be positioned on top of the collection membrane in
some embodiments. Once fluid contacts the hydrophobic membrane,
fluid collection may cease. The blood spot membrane may remain in
the device to dry and can then be removed from the device. In some
embodiments, the blood spot membrane may be removed from the device
and dried outside of the device. In some cases, the membrane is not
dried. If a vacuum is used to draw blood towards the blood spot
membrane, the vacuum may be released prior to removal of the blood
spot membrane from the device, at least in some embodiments.
[0023] In one set of embodiments, the substrate is contained within
a device for receiving blood from the skin of a subject. Examples
of such devices, and details of such devices able to contain a
substrate for absorbing blood and/or other bodily fluids, are
discussed in detail below. Additional examples of devices in which
a substrate for absorbing blood and/or other bodily fluids may be
utilized can be found in U.S. Provisional Patent Application Ser.
No. 61/480,977, filed Apr. 29, 2011, entitled "Delivering and/or
Receiving Fluids," by Gonzales-Zugasti, et al., incorporated herein
by reference in its entirety for all purposes.
[0024] In one set of embodiments, the substrate for absorbing blood
may comprise paper, e.g., that is able to absorb blood or other
bodily fluids received by the device. The substrate may be able to
partially or wholly absorb any blood (or other bodily fluid) that
it comes into contact with. For example, the substrate may comprise
filter paper, cellulose filters, cotton-based paper, e.g., made
from cellulose filters, cotton fibers (e.g., cotton linters), glass
fibers, or the like. Specific non-limiting examples that are
commercially available include Schleicher & Schuell 903.TM. or
Whatman 903.TM. paper (Whatman 903.TM. Specimen Collection Paper)
(Whatman International Limited, Kent, UK), or Ahlstrom 226 specimen
collection paper (Ahistrom Filtration LLC, Mount Holly Springs,
Pa.). In some embodiments, the paper may be one that is validated
in compliance with the requirements of the CLSI (Clinical and
Laboratory Standards Institute) LA4-A5 consensus standard. However,
other materials may also be used for the substrate for absorbing
blood, instead of and/or in addition to paper. For example, the
substrate for absorbing blood (or other bodily fluids) may comprise
gauze, cloth, cardboard, foam, foamboard, paperboard, a polymer, a
gel, or the like. In some cases, the absorbent substrate may have a
surface area of at least about 0.001 m.sup.2/g, at least about
0.003 m.sup.2/g, at least about 0.005 m.sup.2/g, at least about
0.01 m.sup.2/g, at least about 0.03 m.sup.2/g, at least about 0.05
m.sup.2/g, at least about 0.1 m.sup.2/g, at least about 0.3
m.sup.2/g, at least about 0.5 m.sup.2/g, or at least about 1
m.sup.2/g. In some cases, the absorbent substrate may have a
surface area of about 100 g/m.sup.2 to about 200 g/m.sup.2, or
about 150 g/m.sup.2 to about 200 g/m.sup.2.
[0025] The blood (or other bodily fluid) may be absorbed into the
substrate such that the blood becomes embedded within fibers or
other materials forming the substrate, and/or such that the blood
becomes embedded in spaces between the fibers or other materials
forming the substrate. For example, the blood may be held within or
on the substrate mechanically and/or chemically (e.g., via clotting
and/or reaction with fibers or other materials forming the
substrate).
[0026] In some cases, the substrate may absorb a relatively small
amount of blood. For example, less than about 1 ml, less than about
800 microliters, less than about 600 microliters, less than about
500 microliters, less than about 400 microliters, less than about
300 microliters, less than about 200 microliters, less than about
100 microliters, less than about 80 microliters, less than about 60
microliters, less than about 40 microliters, less than about 30
microliters, less than about 20 microliters, less than about 10
microliters, or less than about 1 microliter of blood may be
absorbed into the substrate.
[0027] The substrate may be of any shape or size. In some
embodiments, the substrate may be substantially circular, although
in other embodiments, other shapes are possible, e.g., square or
rectangular. The substrate may have any suitable area. For example,
the substrate may be large enough to contain only one spot, of
blood (e.g., of the above volumes), or more than one spot in some
embodiments. For example, the substrate may have an area of no more
than about 1 cm.sup.2, no more than about 3 cm.sup.2, no more than
about 5 cm.sup.2, no more than about 7 cm.sup.2, no more than about
10 cm.sup.2, no more than about 30 cm.sup.2, no more than about 50
cm.sup.2, no more than about 100 cm.sup.2, no more than about 300
cm.sup.2, no more than about 500 cm.sup.2, no more than about 1000
cm.sup.2, or no more than about 3000 cm.sup.2.
[0028] In some embodiments, a "tab" or a handle, or other separate
portion, may be present on or proximate the substrate, e.g., to
facilitate analysis and/or manipulation of the absorbed blood or
other bodily fluid. The handle may be any portion that can be used
to manipulate the substrate. For example, a handle may be used to
remove the substrate from the device for subsequent shipping and/or
analysis, e.g., without requiring a person to touch the blood spot
itself in order to manipulate the substrate. The handle may be
formed from the substrate, and/or different material, for example,
plastic, cardboard, wood, metal, etc. In some cases, the handle may
surround all, or at least a portion of, the substrate. Non-limiting
examples of such handles are illustrated in FIG. 4. For instance,
in FIG. 4A, a tab 41 is formed as an integral part of the substrate
20. In FIG. 4B, a separate handle 44 surrounds substrate 20,
including a separate tab 41.
[0029] In certain embodiments, the substrate may include
stabilizers or other agents, e.g., for stabilizing and/or treating
the blood in the substrate. Non-limiting examples of stabilizers
include chelating agents, enzyme inhibitors, or lysing agents.
Examples of chelating agents include, but are not limited to, EDTA
(ethylenediaminetetraacetic acid) or dimercaprol. Examples of
enzyme inhibitors include, but are not limited to, protease
inhibitors (e.g., aprotinin, bestatin, calpain inhibitor I and II,
chymostatin, E-64, leupeptin or
N-acetyl-L-leucyl-L-leucyl-L-argininal, alpha-2-macroglobuline,
Pefabloc SC, pepstatin, PMSF or phenylmethanesulfonyl fluoride,
TLCK, a trypsin inhibitor, etc.) or reverse transcriptase
inhibitors (e.g., zidovudine, didanosine, zalcitabine, stavudine,
lamivudine, abacavir, emtricitabine, entecavir, apricitabine,
etc.). Non-limiting examples of lysing agents include distilled
water or guanidinium thiocyanate.
[0030] One non-limiting example of a substrate able to absorb blood
and/or other bodily fluids within a device may be seen in FIG. 1A.
In this figure, device 10 is placed on the surface of skin 15.
Additional examples of such devices are discussed in more detail
below, and/or in documents incorporated herein by reference. In
FIG. 1A, blood 30 (or another bodily fluid, such as interstitial
fluid) from skin 15 enters device 10 via a substance transfer
component 25. For example, a flow activator of the substance
transfer component 25, such as one or more microneedles (not shown
here) may be used to cause blood to flow into device 10 towards
substrate 20. In this figure, substrate 20 is positioned so that
blood entering device 10 will come into contact with substrate 20.
At least a portion of the blood entering the device may be absorbed
into the substrate. It should be understood, however, that other
configurations are also possible. Thus, the substrate may be
positioned at any suitable location within a device, e.g., such
that blood (or other bodily fluid) is able to come into contact
with at least a portion of the substrate when blood is received
into the device. As non-limiting examples, a substrate may be
positioned flush with the skin or in a recess, e.g., of the of the
substance transfer component, the substrate may be positioned
further away from the substance transfer component such that the
blood flows through a portion of the device (e.g., through one or
more channels) in order to reach the substrate, or the like. In
some embodiments, the substrate may be positioned no more than
about 1 mm, no more than about 2 mm, no more than about 3 mm, no
more than about 4 mm, or no more than about 5 mm away from the
surface of the skin when the device is applied to the surface of
the skin of a subject.
[0031] Another embodiment is now described with reference to FIG.
1B; further details of this and other devices in accordance with
certain aspects of the present invention are also described in
further detail below. In this example figure, device 10 is applied
to the skin 15 of a subject. The device in this figure is
self-contained, i.e., such that the device is able to function to
withdraw blood from a subject to produce plasma or serum without
requiring external connections such as an external source of
vacuum, an external source of power, or the like. In other
embodiments, however, the device need not be self-contained.
[0032] A vacuum or a reduced pressure less than atmospheric or
ambient pressure may be used to facilitate the movement of blood 30
into the device, as follows. The vacuum may be contained within
device 10, for example, within vacuum chamber 35. Blood 30 on the
skin 15 of the subject may become exposed to the vacuum or reduced
pressure, which causes the blood to enter device 10, e.g., through
applicator region 40 into inlet 42 of channel 45, moving towards
substrate 50, which can be a substrate for absorbing blood, e.g.,
as previously discussed. Thus, when blood 30 reaches substrate 50,
at least a portion of the blood may become absorbed into substrate
50. In some cases, some blood may also pass through substrate 50
into vacuum chamber 35.
[0033] Upon actuation of the device shown in FIG. 1B, for example,
remotely or by pressing button 22, flow activators 25 are deployed
into skin 15 of the subject. The flow activators may include one or
more needles or microneedles, or other flow activators as discussed
in detail below and/or in documents incorporated herein by
reference. As shown in this figure, the deployment of flow
activators 25 into skin 15 of the subject may be accomplished using
a deployment actuator 28, or by other techniques such as those
described herein. The deployment actuator 28 may include suitable
components to deploy the flow activators 25, such as a button, a
switch, a lever, a slider, a dial, a compression spring, a
Belleville spring, a servo, rotary or linear electric motor, and/or
a pneumatic apparatus, or other suitable device.
[0034] As another non-limiting example, FIG. 2A shows an underside
of a fluid receiving device 10 according to another embodiment of
the invention; a top view of the device may be seen in FIG. 2B.
FIG. 2A shows a fluid transporter 120 that includes an opening 130,
an applicator region 131, and a flow activator 90. In this
embodiment, the flow activator 90 includes one or more needles. As
described in more detail below, the needles may be extended from
the opening 130 to pierce a subject's skin, and then retracted back
into the opening to allow blood or other fluid to enter the opening
130. That is, to use device 10 to receive blood from a subject, the
base 100 may be placed on the skin so that the opening 130 is
adjacent the skin. Thereafter, a device actuator may be depressed
to cause the needles to be deployed, piercing the skin and causing
blood to be released. Blood may enter the opening and be collected
in the storage chamber 140. In one embodiment, blood may flow into
the storage chamber 140 as a result of a relatively low pressure
(vacuum) in the device 10 that draws blood from the opening 130 and
into a storage chamber internally of the device (not shown here). A
substrate 20 for absorbing blood and/or other bodily fluids may be
positioned within the storage chamber, and/or as part of base 100
of the device as is shown in FIG. 2B.
[0035] After being absorbed on the substrate, the blood (or other
bodily fluid) may be allowed to dry and/or clot, in certain
embodiments of the invention. Clotting of blood may occur
naturally, e.g., upon exposure to air. Drying or clotting, in some
cases, may occur through gaseous exchange with the external
environment, and/or with an internal environment contained within
the device, e.g., an environment with a relatively low relative
humidity. For example, the internal or external environment may be
one in which the relative humidity is less than about 50%, less
than about 30%, less than about 25%, less than about 20%, less than
about 15%, less than about 10%, or less than about 5%. As a
specific example, the internal environment may be "pre-packaged"
such that the device has a relatively low relative humidity before
use, and/or a dessicant may be used to control the relative
humidity within the device. In some cases, the device may include a
heat source, such as a resistive heater, to facilitate drying
and/or clotting.
[0036] Thus, in some embodiments, the device may contain desiccant.
The desiccant may be "pre-packaged" in the device, and/or desiccant
may be added after blood or other bodily fluids has been received
into the device. For example, a cover or a lid may be put on the
device after blood has been received into the device, where the
cover or lid contains desiccant. Non-limiting examples of desiccant
potentially suitable for the device include solid desiccants such
as P.sub.2O.sub.5, CaSO.sub.4, CaCl.sub.2, silica, or the like. The
desiccant may be present in the same chamber within the device as
the substrate comprising absorbed blood (or other bodily fluids),
and/or the desiccant may be present in a different chamber within
the device, e.g., one in gaseous communication with the
substrate.
[0037] In one set of embodiments, after blood is received on the
substrate, the device may be manipulated in order to create an
airtight seal around the substrate. For example, an internal
portion of the device may be sealed off to create an airtight seal,
e.g., forming an enclosed airtight chamber surrounding the
substrate. In some embodiments, for instance, a portion of the
device may be moveable or sealable to create an airtight portion
within the device, or a cover or a lid may be added to the device,
and/or brought into position on the device to create an airtight
portion. A user of the device may manipulate the device to create
the airtight portion, and/or the device may itself create the
airtight portion, for example, upon removal of at least a portion
of the substance transfer component from the subject. For example,
in one set of embodiments, a cover or lid may be used to seal the
substance transfer component from the external environment
surrounding the device, thereby preventing exchange of gases from
the substrate with the external environment. The cover or lid may
be formed out of any suitable material, e.g., plastic, rubber,
metal, or the like. As another example, a valve may be closed or
the device may close a valve in order to form an airtight portion
within the device containing the substrate. For example, a valve
may be positioned on channel 45 in FIG. 1B that can be closed
(manually or automatically) in order to form an airtight seal
around substrate 50.
[0038] In some embodiments, blood or other bodily fluids may be
stored within the device for later use and/or analysis, e.g., on a
substrate such as previously discussed. For example, the substrate
and/or the device may, in some embodiments, be sent to a clinical
and/or laboratory setting, e.g., for analysis or storage. In some
embodiments, the entire device and/or substrate may be sent to a
clinical and/or laboratory setting; in other embodiments, however,
only a portion of the device and/or substrate may be sent to a
clinical and/or laboratory setting. For example, the substrate may
be removed from the device, or a module containing the substrate
may be removed from the device, e.g., for shipping or other
transport. In some cases, the substrate and/or the device may be
shipped using any suitable technique (e.g., by mail, by hand,
etc.). Blood or other bodily fluids may be present during shipping
in dried form (e.g., clotted), or while at least partially liquid,
in some cases. In certain instances, the subject may give the
substrate and/or the device 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 substrate and/or the device.
[0039] According to certain embodiments, the substrate and/or the
device may be shipped with only minimal preparation, for example,
where blood or other bodily fluids are present as spots (e.g., dry
spots) on the substrates. In some cases, as discussed herein, the
spots may be relatively small. For instance, the volume of the
blood in a spot, prior to drying, may be less than about 100
microliters, less than about 80 microliters, less than about 60
microliters, less than about 40 microliters, less than about 30
microliters, less than about 20 microliters, less than about 10
microliters, or less than about 1 microliter. In certain
embodiments, shipping may occur at room or ambient temperature,
without the need for ice or dry ice to maintain constant or colder
temperatures. In some cases, shipping may also be performed without
the need for biohazard labeling.
[0040] In some embodiments, the substrate and/or the device may be
contained within a suitable shipping container, for instance, an
envelope or a box. For example, the envelope may be a paper
envelope, a cardboard envelope, or the like. The box may be, for
example, a paper box, a cardboard box, a plastic box, a metal box,
etc. In some cases, the shipping container may be padded, e.g.,
with cloth, plastic bubbles, Styrofoam pellets, etc. In some cases,
the shipping container may be airtight and/or the shipping
container may contain a desiccant. In some embodiments, the device
and/or the substrate may be placed in a shipping container in such
a form that the substrate is exposed to at least the air within the
shipping container, and the use of an airtight container and/or
desiccant may serve to preserve blood or other bodily fluids
absorbed within the substrate in a relatively dry state. Examples
of desiccant include those described herein. In other embodiments,
however, desiccant and/or an airtight container may not be
necessary. For example, as previously discussed, the device itself
may contain desiccant, or the blood may be dried on the substrate
such that further precautions are unnecessary and the substrate may
be shipped or otherwise manipulated (e.g., analyzed) while exposed
to ambient conditions, and/or without any subsequent preservation
steps.
[0041] In one aspect, the device and/or the substrate may include,
and/or may be shipped with, a tracking apparatus. The tracking
apparatus may be present as part of the device or as a part of a
cover or lid for the device, and/or the tracking apparatus may be
separate from the device but designed to be shipped with the device
and/or the substrate. For example, the tracking apparatus may be
formed as or be contained within a shipping container such as an
envelope or a box for shipping the device and/or the substrate. In
some cases, for example, the tracking apparatus may be attached to
the envelope or box, or the tracking apparatus may be part of a
holder designed to be shipped with the device and/or the
substrate.
[0042] In one set of embodiments, the tracking apparatus may
include an RFID transmitter or "tag." A suitable scanner may be
able to determine the RFID tag, e.g., when a shipping container
such as an envelope or a box for shipping the device and/or the
substrate is received, e.g., at a clinical and/or laboratory
setting. As another example, a scannable target may be used as a
tracking apparatus. For example, the scannable target may be a bar
code, such as a 1- or 2-dimensional barcode, and may code
information based on lines, colors, patterns, shapes, or any other
features or combinations of features. In some embodiments, a
scanner able to scan the scannable target may also be used. For
example, in one set of embodiments, prior to or during use, the
device may be held next to the scannable target such that the
device is able to scan the scannable target, e.g., in order to
activate the device, or to record data from the device, etc. As
additional non-limiting examples, in other embodiments, the
scannable target may be formed as part of the substrate, and the
scannable target may be tracked after the substrate has received
blood, before or after the substrate has been shipped, before or
after analysis of blood (or other bodily fluid) on the substrate,
etc.
[0043] In some cases, more than one substrate for absorbing blood
and/or other fluids may be present in the device. For instance,
more than one substrate for absorbing blood and/or other bodily
fluids may be stacked together. For instance, in certain cases,
excess blood (or other bodily fluid) is received by the device, and
blood is able to saturate some of the substrates within the device.
By use of multiple substrates in a stacked configuration, some
substrates (e.g., a middle substrate) may be used for subsequent
analysis, while other substrates (e.g., on the top and/or bottom)
are simply present to absorb excess blood.
[0044] However, as mentioned, in some embodiments, more than one
substrate may be used for subsequent analysis. In some cases, the
substrates may also be arranged separately from each other, e.g.,
as is illustrated with respect to FIG. 3. In this figure,
substrates 31, 32, 33, and 34 are arranged about a central region
39. Blood received into the device may pass through central region
35 to some or all of substrates 31, 32, 33, and 34, and some or all
of these may then be subsequently analyzed, e.g., for different
analytes such as those discussed herein.
[0045] Other types of substrates or blood spot membranes may also
be present within the device. For example, in some embodiments, the
device may include a separation membrane that is impermeable to
blood cells and other substances. The separation membrane may be
positioned anywhere in the device, e.g., before or after blood
contacts a substrate for absorbing blood within the device. Fluid
received from the subject may flow through a separation membrane,
and the received fluid may include components of various sizes. For
example, the device may receive blood that includes blood cells,
clotting factors, proteins, and blood plasma, among other
components. Larger components such as blood cells and other larger
substances may not be able to pass through the separation membrane
while blood plasma is free to pass. If anticoagulant is not
introduced to the blood plasma, the blood plasma, which contains
clotting factors such as fibrinogen, may clot, thereby resulting in
a solid clot component and a liquid component. This liquid
component is known as serum, which is blood plasma without
fibrinogen or other clotting factors. This serum can be collected
via aspiration or other suitable method out of the storage chamber,
leaving the blood clots in the storage chamber. If anticoagulant is
introduced to the blood plasma, the blood plasma will not clot and
blood plasma can be collected out of the storage chamber instead.
Thus, the embodiments described throughout the specification may be
used to produce plasma or serum. More details regarding plasma and
serum production can be found in U.S. Provisional Pat. Apl. Ser.
No. 61/480,941, entitled "Plasma or Serum Production and Removal of
Fluids Under Reduced Pressure," filed on Apr. 29, 2011 by
Haghgooie, et al., incorporated herein by reference in its
entirety.
[0046] Also shown in FIG. 3 are optional beading disruptors 51, 52,
53, and 54. Beading disruptors generally disrupt the "pooling" of
bodily fluids such as blood on the surface of the skin and allow
blood to flow to a desired location, e.g., to a substrate. Thus, as
is shown in FIG. 3, beading disruptors 51, 52, 53, and 54 are used
to direct blood towards substrates 31, 32, 33, and 34. It should be
understood that this is by way of example only; in other
embodiments, there may be 1, 2, 3, or any other suitable number of
beading disruptors. In yet other embodiments, there may be no
beading disruptors present. Non-limiting examples of additional
beading disruptors suitable for use in certain embodiments of the
invention are disclosed in U.S. Provisional Patent Application Ser.
No. 61/480,960, filed Apr. 29, 2011, entitled "Systems and Methods
for Collecting Fluid from a Subject," by Haghgooie, et al.,
incorporated herein by reference in its entirety.
[0047] One non-limiting example of such a device comprising a
beading disruptor is now described with reference to FIGS. 5A and
5B. In these figures, device 10 is used to receive blood or other
bodily fluids from the skin and/or from beneath the skin of a
subject. Device 10 is shown positioned on skin 15 of a subject.
Bodily fluid 30 is caused to reach the surface of the skin using
one or more flow activators that include, for example, microneedles
25 as shown in this figure. In other embodiments, however, as
discussed below and/or in documents incorporated herein by
reference, other flow activator arrangements may be used in
addition to and/or instead of flow activators that include
microneedles 25. The bodily fluid collects on the surface of skin
15 within applicator region 40, and at least some of the bodily
fluid may enter device 10 through inlet 42. FIG. 5A shows a side
view while FIG. 5B shows an angled view of a cross-section of an
applicator region of certain devices.
[0048] The bodily fluid 30 on the surface of the skin typically
will from a "pool" or a "bead" of liquid on the surface of the
skin. However, this beading of the liquid may prevent, or at least
delay, the movement of the bodily fluid 30 to inlet 42. To counter
the natural tendency of the bodily fluid to form a bead on the
surface, one or more beading disruptors may be used. As depicted in
FIGS. 5A and 5B, beading disruptor 80 can take the form of one or
more protrusions extending from a portion of the surface defining
applicator region 40. However, in other embodiments, the beading
disruptor may take other forms, instead of and/or in addition to
one or more protrusions. Upon contact of bodily fluid 30 with
beading disruptor 80, at least a portion of the bead of fluid may
be deformed or otherwise be caused to move towards inlet 42 for
entry into the device, e.g., for processing, analysis, storage,
etc. as is discussed in detail below.
[0049] In some embodiments, the applicator region may include a
capillary that may facilitate fluid flow. Fluid may move along the
capillary with, or without, capillary action, e.g. it may be moved
due to a vacuum, pneumatic force, gravity feed, or other suitable
manner. Additionally, the capillary may be of any cross-sectional
shape, length, diameter, and is not limited to any particular
arrangement. The some cases, the capillary may be a capillary slit,
e.g., including a relatively narrow groove. However, a capillary
slit is only one arrangement and others are possible. For example,
fluid may flow through a closed tube of any suitable
cross-sectional shape. Also, it should be noted that beading
disruptor 80 and capillary slit 90 are not necessarily required in
all embodiments; in certain cases, one or both of these may be
absent. As shown in FIG. 5B, capillary slit 90 may be positioned
such that it is in fluidic communication with inlet 42. In this
embodiment, a single capillary slit is shown that forms a closed
circuit or circle along the surface of the applicator region 40
(note that FIG. 5B has been cut in half for clarity). However, in
other embodiments, more than one capillary may be present and/or
the capillary may not necessarily form a closed circuit along the
surface of the applicator region 40. In addition, in this figure,
capillary slit 90 is depicted as being oriented substantially
parallel to the opening of the applicator region and skin 15 of the
subject, although in other embodiments, other orientations are also
possible. Capillary slit 90, in this example, is illustrated as
having two substantially parallel walls 92, 93, and a
cross-sectional shape that is substantially rectangular.
[0050] A bodily fluid 30 on the surface of the skin may come into
contact with capillary slit 90 during use, and at least a portion
of the bodily fluid may then flow along capillary slit 90, e.g.,
due to capillary action. The capillaries may thereby guide bodily
fluid 30 towards inlet 42 into the device. As shown in FIG. 5,
beading disruptor 80 is formed as part of the bottom plane of
capillary slit 90, such that at least a portion of the bead of
bodily fluid may be caused to enter capillary slit 90, and the
fluid can then be moved towards inlet 42, e.g., as previously
discussed.
[0051] The applicator region may contain, in one set of
embodiments, one or more beading disruptors for disrupting the
pooling of bodily fluids on the surface of the skin. This is now
illustrated with reference to the example shown in FIG. 6. In FIG.
6A, a bodily fluid 30, such as blood, is present on the surface of
the skin 15, e.g., transported thereto by one or more flow
activators such as is discussed herein. The bodily fluid typically
forms a bead or pool on the surface of the skin, instead of wetting
the skin. The shape of the bead (e.g., the contact angle) may be
controlled by the condition of the skin (for example, its
hydrophobicity) and/or the bodily fluid on the skin. For example,
the bodily fluid may pool on the skin of the subject at a contact
angle of about 30.degree., about 40.degree., about 45.degree.,
about 50.degree., about 55.degree., etc. in a substantially
circular region on the surface of the skin. In many cases, the skin
is relatively hydrophobic, thereby causing the bodily fluid to form
a bead instead of wetting or spreading on the surface of the skin.
Furthermore, as more bodily fluid enters the bead, the bead
typically grows in size while keeping substantially the same shape.
Thus, before the bead is able to contact a surface of the
applicator region, a certain amount of bodily fluid must flow from
the body into the bead on the surface of the skin.
[0052] In FIG. 6B, beading disruptor 80 is also shown, in addition
to bodily fluid 30 on the surface of skin 15. Beading disruptor 80
is shaped and positioned to disrupt the shape of bodily fluid 30 to
prevent or at least alter the ability of bodily fluid 30 to pool on
the surface of the skin. Thus, in this example, bodily fluid
exiting the skin within the applicator region (e.g., from the
center of the applicator region) will first come into contact with
the beading disruptor, which can disrupt the shape of the pool of
bodily fluid on the surface of the skin. In some cases, as is shown
in this figure, at least a portion of bodily fluid 30 may be caused
to move away from the pool of fluid, e.g., towards an inlet of the
device, or another suitable location as is shown by arrow 88, due
to the presence of beading disruptor 80.
[0053] The beading disruptor may take any of a variety of forms. In
one set of embodiments, the beading disruptor is present within an
applicator region, such as a recess, in which a bodily fluid is
transported thereto by a flow activator, for example, one or more
needles and/or microneedles. More than one beading disruptor may
also be present, in some embodiments.
[0054] In one set of embodiments, in a protrusion having a first
end in contact with the applicator region and a second end that is
located closest to the geometrical center of the applicator region,
a ratio of the width of the first end to the distance between the
first end and the second end, may be about 1, greater than 1, or
less than 1. This ratio may have any suitable value. For example,
the ratio may be about 1 (i.e., such that the protrusion is
substantially square), less than 1, or greater than 1. As specific
non-limiting examples, this ratio may be less than or greater than
1, less than or greater than 2, less than or greater than 3, less
than or greater than 4, less than or greater than 5, less than or
greater than 7, less than or greater than 10, etc.
[0055] It should be understood, however, that the beading disruptor
is not necessarily limited to projections or protrusions. For
example, in certain embodiments, the beading disruptor may be
connected at two portions to the applicator region, e.g., forming a
"span" across the applicator region. In some embodiments the
beading disruptor includes the geometric center of the applicator
region, but in other embodiments, the geometric center of the
applicator region is not included. More complex shapes may also be
used in some embodiments, for example, where the beading disruptor
physically contacts the applicator region at three ends, at four
ends (e.g., defining an "X" or a cross shape), or more in some
cases.
[0056] In one set of embodiments, the beading disruptor may
comprise a "shelf" or a "lip" along a portion of the applicator
region. In some, the beading disruptor may be positioned along a
portion of the applicator region, for example, such that an
imaginary plane can be positioned that divides the applicator
region into two halves that have the same volume such that only one
of the two halves comprises the beading disruptor.
[0057] In some embodiments, the beading disruptor can be positioned
to facilitate the flow of a bodily fluid to an inlet to the device,
e.g., to the inlet of a channel such as a microfluidic channel
within the device. In some cases, as is discussed below, the
beading disruptor may form a portion of a capillary that
facilitates the flow of a bodily fluid to an inlet to the
device.
[0058] In one set of embodiments, the applicator region contains
one or more capillaries that can facilitate the flow of a bodily
fluid to an inlet of the device, or to a substrate for absorbing
blood or other fluids. A non-limiting example of a capillary is
shown with respect to FIG. 7A. In this figure, the surface of a
portion of applicator region 40 of device 10 is illustrated,
including a capillary 90 that is in fluid communication with inlet
42 of the device. In this figure, capillary 90 is defined by walls
92, 93 which are substantially parallel to each other, thereby
forming capillary 90. In some embodiments, at least a portion of
capillary 90, such as one or both of walls 92, 93, may also be used
as a beading disruptor.
[0059] Although only one capillary is shown in FIG. 7A, in other
embodiments, more than one capillary may be present, which may be
lead to one or more inlets of the device. The capillary can have
any suitable configuration to facilitate the flow of a bodily fluid
along at least a portion of the capillary, e.g., through capillary
action. In some cases, the capillary may encircle or circumscribe
at least a portion of the applicator region. For instance, the
capillary may form a closed circuit such that the flow of bodily
fluid in any direction along the capillary will reach the inlet.
One example of this can be seen in FIG. 7B with capillary 90 and
inlet 42.
[0060] The capillary may have any suitable size. For example, the
capillary may have an average cross-sectional dimension (e.g.,
perpendicular to the flow of fluid therein) 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, less than about
1 mm, less than about 500 microns, less than about 300 microns, or
less than about 100 microns. For example, the capillary may have an
average cross-sectional diameter of between about 100 and about 700
micrometers, or between about 300 and about 500 micrometers. The
average cross-sectional dimension may be constant or may change
along the capillary, e.g., to promote flow towards the inlet. The
capillary can have any cross-sectional shape, for example,
circular, oval, triangular, irregular, square or rectangular
(having any aspect ratio), or the like. The capillary may have, in
certain embodiments, a cross-sectional shape and/or area that
remains substantially constant throughout the capillary.
[0061] In some embodiments, the entire capillary may be exposed to
the applicator region; in other embodiments, however, a portion of
the capillary may not necessarily be open to or exposed to the
applicator region. In some cases, some or all of the capillary is
in fluidic communication with the applicator region, for example
such that substantially each portion of the capillary can be
reached by a fluid within the applicator region. For instance, in
certain embodiments, no portion of the capillary is further than
about 10 micrometers, about 5 micrometers, about 3 micrometers, or
about 1 micrometer away from a portion of the applicator region, as
determined by flow of a fluid from the applicator region to the
capillary. In some embodiments, no portion of the capillary may be
further than about 5 mm, about 3 mm, about 1 mm, about 500
micrometers, about 300 micrometers, about 100 micrometers, about 50
micrometers, about 30 micrometers, or about 10 micrometers away
from a portion of the applicator region, as determined by flow of a
fluid from the applicator region to the capillary, e.g., depending
on the size of the applicator region. In some embodiments, no
portion of the applicator region is greater than about 5 mm, about
3 mm, about 1 mm, about 500 micrometers, about 300 micrometers,
about 100 micrometers, about 50 micrometers, about 30 micrometers,
or about 10 micrometers away from a portion of the capillary
[0062] The capillary may be positioned in any suitable location
within the applicator region. In some cases, a capillary may be
positioned near an inlet in the applicator region, or near a
substrate for absorbing blood such that at least some blood is
directed towards the substrate.
[0063] The invention, in one set of embodiments, involves the
determination of a condition of a subject. Blood or other bodily
fluids associated with the skin, for example, absorbed on a
substrate, may be analyzed, e.g., for the presence of one or more
analytes, 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 receiving blood, or other bodily fluids, from
the skin and/or from beneath the skin of a subject. 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, for
example, interstitial fluid.
[0064] In some cases, blood or other bodily fluids (e.g.,
interstitial fluid) received from the subject, e.g., on a
substrate, 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.
[0065] In one set of embodiments, blood (or other bodily fluid) on
a substrate may accordingly be determined, e.g., to determine a
past, present and/or future condition of the subject. Any suitable
method may be used to determine or analyze the blood present on the
substrate. For example, one or more portions of the substrate may
be used (e.g., cut out or punched), or the entire substrate may be
used, e.g., without requiring any punching out of portions of the
substrate. In some cases, for instance, the blood may be present as
one or more dried spots, and portions of the substrate may be cut
off (e.g., punched out as holes, cut with scissors, etc.) for
analysis. As mentioned, in some embodiments, more than one
substrate may be present within the device, and in some cases, some
or all of the substrates can be used.
[0066] In some embodiments, the blood (or other bodily fluid) on
the substrate may be analyzed on the substrate, e.g., using
techniques such as spectroscopy, microscopy, etc. In other
embodiments, the substrate (or cut portions thereof) may be eluted
to remove at least a portion of the blood (or other bodily fluids)
on the substrate. As one example, blood can be eluted out from the
substrate using saline, such as phosphate buffered saline,
optionally containing detergents such as Tween. The resultant
eluent can be subsequently analyzed to determine analytes within
the blood. Any suitable technique can be used for analysis, many of
which are commercially available or are known to those of ordinary
skill in the art, for example, spectroscopy, HPLC analysis, ELISA,
etc.
[0067] Non-limiting examples of such analytes include, but are not
limited to: acarboxyprothrombin; acylcarnitine; adenine
phosphoribosyl transferase; adenosine deaminase; albumin;
a-fetoprotein; amino acids such as arginine (Krebs cycle),
histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, or
tryptophan, etc.; andrenostenedione; antipyrine; arabinitol
enantiomers; arginase; benzoylecgonine (cocaine); biotinidase;
biopterin; C-reactive protein; carnitine; carnosinase; CD4;
ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;
cholinesterase; conjugated 1-b hydroxycholic acid; cortisol;
creatine kinase; creatine kinase MM isoenzyme; cyclosporin A;
D-penicillamine; de-ethylchloroquine; dehydroepiandrosterone
sulfate; DNA (PCR), e.g., to detect acetylator polymorphism,
alcohol dehydrogenase, a 1-antitrypsin, cystic fibrosis,
Duchenne/Becker (e.g., muscular dystrophy), glucose-6-phosphate
(e.g., dehydrogenase), hemoglobinopathies (e.g., A, S, C, E,
D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,
Leber hereditary optic, neuropathy, MCAD, mRNA, PKU, plasmodium
vivax, sexual differentiation); 21-deoxycortisol;
desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus
antitoxin; erythrocyte arginase; erythrocyte protoporphyrin;
esterase D; fatty acids/acylglycines; free b-human chorionic
gonadotropin; free erythrocyte prophyrin; free thyroxine (FT4);
free tri-iodothyroine (FT3); fumarylacetoacetase;
galactose/gal-1-phosphate; galactose-1-phosphate uridyl
transferase; gentamicin; glucose; glucose-6-phosphate
dehydrogenase; glutathione; glutathione perioxidase; glycocholic
acid; glycosylated hemoglobin; halofantrine; hemoglobin variants;
hexosaminidase A; human erythrocyte carbonic anhydrase i; 17-a
hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;
Immunoreactive trypsin (CF); lactate; lead; lipoproteins (a),
B/A-1, and b; lysozyme; mefloquine; netilmicin; phenobarbitone;
phenytoin; phytanic/pristanic acid; progesterone; prolactin;
prolidase; purine nucleoside; phosphorylase; quinine; reverse
tri-iodothyronine (rT3); selenium; serum pancreatic lipase;
sissomicin; somatomedin C; specific antibodies (e.g., adenovirus,
anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's
disease virus, dengue virus, Dracunculus medinensis, Echinococcus
granulosus, Entamoeba histolytica, enterovirus, Giardia
duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus,
HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani,
leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma
pneumoniae, Onchocerca volvulus, parainfluenza virus, Plasmodium
falciparum, poliovirus, Pseudomonas aeruginosa, respiratory
syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni,
Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli,
vesicular stomatis virus, Wuchereria bancrofti, or yellow fever
virus); spectic antigens (e.g., hepatitis B virus or HIV-1);
succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); or
throxine (T4).
[0068] As mentioned, in certain aspects, the substrate may be
contained within a device for receiving blood from the skin of a
subject. As used herein, 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. In some embodiments, for example, 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 and/or a vacuum chamber having an internal pressure
less than atmospheric pressure prior to receiving blood or other
bodily fluids. Additional non-limiting examples of devices can be
found in U.S. Provisional Patent Application Ser. No. 61/480,977,
filed Apr. 29, 2011, entitled "Delivering and/or Receiving Fluids,"
by Gonzales-Zugasti, et al., incorporated herein by reference in
its entirety. In various embodiments, those devices may include one
or more substrates as discussed herein, e.g., for absorbing blood
or other bodily fluids.
[0069] 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.
[0070] The device may be used once, or multiple times, depending on
the application. For instance, a device may be used once to receive
blood, then the device and/or substrate, or a portion thereof, may
be shipped, or a device may be used multiple times, e.g., by
replacing a module or a substrate and replacing it with a fresh
module or substrate.
[0071] In some embodiments, the device may be relatively small. For
example, the device may be handheld or be applied to the skin of a
subject, e.g., using an adhesive, as is discussed below. The device
may be self-contained in some embodiments, i.e., such that the
device is able to function to withdraw blood (or other bodily
fluids) from a subject and cause at least some of the blood to be
absorbed into the substrate, e.g., without requiring external
connections such as an external source of vacuum, an external
source of power, or the like. For instance, a vacuum source within
the device, e.g., a vacuum chamber, may be used to draw blood to
the substrate.
[0072] 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.
[0073] 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.
[0074] In some embodiments, the substance transfer component may
include one or more skin insertion objects, such as needles,
microneedles, lancets, blades, knives, protrusions, or other
suitable object. As used herein, a "skin insertion object," may be
inserted into any organ, tissue or portion of a subject and is not
restricted for use with only skin.
[0075] 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.
[0076] 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.
[0077] 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 moveable 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] 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 moveable 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.
[0083] In certain embodiments, quick and/or high velocity, and/or
high force and/or pressure application of skin insertion objects to
the skin, such as microneedles, or other substance transfer
components, may in certain embodiments result in lower pain or
painless deployment. Without wishing to be bound by any theory, it
is believed that higher velocities, forces, etc., may result in
faster penetration of the objects into the skin, which results in
less damage to the skin, and thus less pain. In addition,
relatively rapid insertions may give a subject less sensation of
pain, and/or less time to become apprehensive to the insertion,
thereby resulting in lower perceived pain. Examples of devices able
to deliver objects quickly and/or at high velocity, and/or with
high force and/or pressure are disclosed in detail herein, and
include, but are not limited to, snap domes and other deployment
actuators such as those described below.
[0084] An example of a deployment actuator is now illustrated with
respect to FIG. 8. In FIG. 8A, 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. 8B, 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. 8C, 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.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] In some cases, more than one microneedle may be used. For
example, arrays of microneedles may be used, and the microneedles
may be arranged in the array in any suitable configuration, e.g.,
periodic, random, etc. In some cases, the array may have 3 or more,
4 or more, 5 or more, 6 or more, 10 or more, 15 or more, 20 or
more, 35 or more, 50 or more, 100 or more, or any other suitable
number of microneedles. 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.
[0092] 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..
[0093] 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/mm.sup.2 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.
[0094] 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.
[0095] 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 10,000 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, at least about
35,000 microns.sup.2, at least about 100,000 microns.sup.2, etc.,
depending on the application.
[0096] 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 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.
[0097] In certain embodiments, relatively long needles or
microneedles may be used. 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.
[0098] 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.
[0099] 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).
[0100] In one embodiment, the fluid is 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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. patent application Ser. No.
12/915,735, filed Oct. 29, 2010, entitled "Modular Systems for
Application to the Skin," published as U.S. Patent Application
Publication No. 2011/0105872 on May 5, 2011, incorporated by
reference herein in its entirety.
[0138] 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).
[0139] 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).
[0140] 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.
[0141] 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.
[0142] 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.
[0143] 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.
[0144] 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.
[0145] 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. 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] The following documents are incorporated herein by
reference: U.S. Provisional Patent Application Ser. No. 61/480,977,
filed Apr. 29, 2011, entitled "Delivering and/or Receiving Fluids,"
by Gonzales-Zugasti, et al.; U.S. Provisional Pat. Apl. Ser. No.
61/480,941, entitled "Plasma or Serum Production and Removal of
Fluids Under Reduced Pressure," filed on Apr. 29, 2011 by
Haghgooie, et al.; U.S. Provisional Patent Application Ser. No.
61/480,960, filed Apr. 29, 2011, entitled "Systems and Methods for
Collecting Fluid from a Subject," by Haghgooie, et al.; U.S. patent
application Ser. No. 12/478,756, filed Jun. 4, 2009, entitled
"Compositions and Methods for Diagnostics, Therapies, and Other
Applications," by Levinson, published as U.S. Pat. Apl. Pub. No.
2010/0069726 on Mar. 18, 2010; U.S. patent application Ser. No.
12/716,222, filed Mar. 2, 2010, entitled "Oxygen Sensor," by
Levinson, et al., published as U.S. Pat. Apl. Pub. No. 2010/0249560
on Sep. 30, 2010; 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., published as U.S. Pat. Apl. Pub. No.
2011/0009847 on Jan. 13, 2011; 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., published as
U.S. Pat. Apl. Pub. No. 2010/0256524 on Oct. 7, 2010; 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., published as U.S. Pat. Apl. Pub. No.
2010/0256465 on Oct. 7, 2010; U.S. patent application Ser. No.
12/953,744, filed Nov. 24, 2010, entitled "Patient-Enacted Sampling
Technique," by Levinson, et al.; U.S. patent application Ser. No.
12/915,735, filed Oct. 29, 2010, entitled "Systems and Methods for
Application to Skin and Control of Actuation, Delivery, and/or
Perception Thereof," by Chickering, et al.; U.S. patent application
Ser. No. 12/915,789, filed Oct. 29, 2010, entitled "Systems and
Methods for Treating, Sanitizing, and/or Shielding the Skin or
Devices Applied to the Skin," by Bernstein, et al.; U.S. patent
application Ser. No. 12/915,820, filed Oct. 29, 2010, entitled
"Relatively Small Devices Applied to the Skin, Modular Systems, and
Methods of Use Thereof," by Bernstein, et al.; U.S. patent
application Ser. No. 13/006,177, filed Jan. 13, 2011, entitled
"Rapid Delivery and/or Withdrawal of Fluids," by Chickering, et
al.; U.S. patent application Ser. No. 13/006,165, filed Jan. 13,
2011, entitled "Sampling Device Interfaces," by Chickering, et al.;
U.S. Prov. Pat. Apl. Ser. No. 61/357,582, filed Jun. 23, 2010,
entitled "Sampling Devices and Methods Involving Relatively Little
Pain," by Chickering, et al.; U.S. Prov. Pat. Apl. Ser. No.
61/367,607, filed Jul. 26, 2010, entitled "Rapid Delivery and/or
Withdrawal of Fluids," by Davis, et al.; U.S. Prov. Pat. Apl. Ser.
No. 61/373,764, filed Aug. 13, 2010, entitled "Clinical and/or
Consumer Techniques and Devices," by Chickering, et al.; and U.S.
Prov. Pat. Apl. Ser. No. 61/411,566, filed Nov. 9, 2010, entitled
"Systems and Interfaces for Blood Sampling," by Brancazio, et al.
Also incorporated herein by reference in their entireties are an
international patent application entitled "Delivering and/or
Receiving Fluids," and an international patent application entitled
"Methods and Devices for Withdrawing Fluids from a Subject Using
Reduced Pressure," each filed on even date herewith. In addition,
U.S. Provisional Patent Application Ser. No. 61/480,941, filed Apr.
29, 2011, entitled "Plasma or Serum Production and Removal of
Fluids under Reduced Pressure," by Haghgooie, et al., and U.S.
Provisional Patent Application Ser. No. 61/549,437, filed Oct. 20,
2011, entitled "Systems and Methods for Collection and/or
Manipulation of Blood Spots or Other Bodily Fluids," by Bernstein,
et al. are each incorporated herein by reference in its
entirety.
[0150] 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.
[0151] 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.
[0152] 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."
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
* * * * *