U.S. patent application number 15/707971 was filed with the patent office on 2018-01-04 for apparatus for mass producing a monodisperse microbubble agent.
The applicant listed for this patent is Universidad de Sevilla, Universiteit Twente. Invention is credited to Elena de Castro Hernandez, Jose Manuel Gordillo Arias de Saveedra, Detlof Lohse, Willem van Hoeve, Andreas Michael Versluis.
Application Number | 20180001282 15/707971 |
Document ID | / |
Family ID | 45937521 |
Filed Date | 2018-01-04 |
United States Patent
Application |
20180001282 |
Kind Code |
A1 |
van Hoeve; Willem ; et
al. |
January 4, 2018 |
APPARATUS FOR MASS PRODUCING A MONODISPERSE MICROBUBBLE AGENT
Abstract
An apparatus for mass producing monodisperse microbubbles
includes a microfluidic flow focusing device, which includes a
dispersed phase fluid supply channel having an outlet that
discharges into a flow focusing junction, a continuous phase fluid
supply channel having an outlet that discharges into the flow
focusing junction, and a bubble formation channel having an inlet
disposed at the flow focusing junction. The configuration of the
flow focusing junction is such that, in operation, a flow of
dispersed phase fluid discharging from the outlet of the dispersed
phase fluid supply channel is engageable in co-flow by a focusing
flow of continuous phase fluid discharging from the outlet of the
at least one continuous phase fluid supply channel under formation
of a gradually thinning jet of dispersed phase fluid that extends
into the inlet of the bubble formation channel.
Inventors: |
van Hoeve; Willem;
(Enschede, NL) ; de Castro Hernandez; Elena;
(Sevilla, ES) ; Gordillo Arias de Saveedra; Jose
Manuel; (Sevilla, ES) ; Versluis; Andreas
Michael; (Enschede, NL) ; Lohse; Detlof;
(Enschede, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Universiteit Twente
Universidad de Sevilla |
Enschede
Sevilla |
|
NL
ES |
|
|
Family ID: |
45937521 |
Appl. No.: |
15/707971 |
Filed: |
September 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14386318 |
Dec 26, 2014 |
9782733 |
|
|
PCT/NL2012/050179 |
Mar 22, 2012 |
|
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15707971 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 2219/00894
20130101; B01F 2215/0034 20130101; B01F 13/0084 20130101; B01J
19/0093 20130101; B01J 2219/0086 20130101; B01F 3/0446 20130101;
B01F 2003/04858 20130101; B01F 13/0062 20130101; B01F 2005/0097
20130101; B01J 2219/00995 20130101; B01F 5/0602 20130101; B01J
2219/0084 20130101; B01J 2219/00959 20130101; A61K 49/223 20130101;
B01F 3/04985 20130101; B01F 13/0064 20130101; B01F 13/0086
20130101 |
International
Class: |
B01F 5/06 20060101
B01F005/06; A61K 49/22 20060101 A61K049/22; B01J 19/00 20060101
B01J019/00; B01F 3/04 20060101 B01F003/04; B01F 13/00 20060101
B01F013/00 |
Claims
1. An apparatus for mass producing monodisperse microbubbles,
comprising: at least one microfluidic flow focusing device
including: a dispersed phase fluid supply channel having an outlet
that discharges into a flow focusing junction; at least one
continuous phase fluid supply channel having an outlet that
discharges into the flow focusing junction; and a bubble formation
channel having an inlet disposed at the flow focusing junction, the
configuration of the flow focusing junction being such that, in
operation, a flow of dispersed phase fluid discharging from the
outlet of the dispersed phase fluid supply channel is engageable in
co-flow by a focusing flow of continuous phase fluid discharging
from the outlet of the at least one continuous phase fluid supply
channel under formation of a gradually thinning jet of dispersed
phase fluid that extends into the inlet of the bubble formation
channel, wherein said bubble formation channel has a length that is
much greater than its hydraulic diameter by a factor of at least
ten.
2. The apparatus according to claim 1, further comprising: a source
of dispersed phase fluid, operably connected to an inlet of the
dispersed phase fluid supply channel; and a source of continuous
phase fluid, operably connected to an inlet of the at least one
continuous phase fluid supply channel.
3. The apparatus according to claim 2, wherein the dispersed phase
fluid is a gas, and the continuous phase fluid is a liquid
4. The apparatus according to claim 2, wherein the dispersed phase
fluid is a liquid, and the continuous phase fluid is a gas.
5. The apparatus according to claim 2, wherein at least one of the
dispersed phase fluid and the continuous phase fluid contains a
surfactant suitable to populate a fluid interface between the
dispersed phase fluid and the continuous phase fluid, and to thus
stabilize bubbles of dispersed phase fluid within the continuous
phase fluid.
6. The apparatus according to claim 2, wherein the bubble formation
channel is bounded by a wall having a portion of inner wall surface
that extends substantially from the inlet of the bubble formation
channel and in a longitudinal direction thereof, and that has a low
wettability with respect to the continuous phase fluid.
7. The apparatus according to claim 6, wherein the bubble formation
channel is bounded by a wall having a portion of inner wall surface
that extends substantially from the inlet of the bubble formation
channel and in a longitudinal direction thereof, and that defines
an inner wall surface enlarging provision.
8. The apparatus according to claim 7, wherein the inner wall
surface enlarging provision includes at least one of a
longitudinally extending ridge, a longitudinally extending slot,
and a roughened inner wall surface area.
9. The apparatus according to claim 7, wherein said portion of
inner wall surface with low wettability defines said inner wall
surface enlarging provision.
10. The apparatus according to claim 1, wherein bubble formation
channel is substantially straight and substantially uniform in
cross-section over its length.
11. The apparatus according to claim 1, wherein the length of the
bubble formation channel is greater than 1 mm.
12. The apparatus according to claim 1, wherein the hydraulic
diameter of the bubble formation channel is between 10 .mu.m and
100 .mu.m.
13. The apparatus according to claim 1, further comprising: a
bubble harvesting reservoir; a transition channel, wherein said
transition channel fluidly connects an outlet of the bubble
formation channel to the bubble harvesting reservoir, and wherein
said transition channel has a gradually increasing hydraulic
diameter.
14. The apparatus according to claim 1, wherein the at least one
microfluidic flow focusing device has a substantially planar flow
focusing geometry, such that the respective channels at least
partially extend in a same plane.
15. The apparatus according to claim 1, wherein the at least one
microfluidic flow focusing device includes two continuous phase
fluid supply channels, wherein the outlet of the dispersed phase
fluid supply channel, the outlets of the two continuous phase fluid
supply channels, and the inlet of the bubble formation channel
define the flow focusing junction, wherein the dispersed phase
fluid supply channel is substantially aligned with the bubble
formation channel, such that the inlet of the bubble formation
channel is disposed opposite the outlet of the dispersed phase
fluid supply channel, and wherein the outlets of the two continuous
phase fluid channels join the flow focusing junction from
substantially opposite sides.
16. The apparatus according to claim 1, wherein the continuous
phase fluid supply channels include a tapering portion just
upstream of their respective outlets.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional Application of U.S.
application Ser. No. 14/386318, filed Sep. 18, 2014 (35 U.S.C.
.sctn.371 requirements completed on Dec. 26, 2014), which is the
U.S. National Stage Application under 35 U.S.C. .sctn.371 of
International Application No. PCT/NL2012/050179, filed Mar. 22,
2012, designating the U.S. and published in English as WO
2013/141695 A1 on Sep. 26, 2013. Any and all applications for which
a foreign or a domestic priority is claimed is/are identified in
the Application Data Sheet filed herewith and is/are hereby
incorporated by reference in their entirety under 37 C.F.R.
.sctn.1.57.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of microfluidics,
and more in particular to an apparatus and a method for the mass
production of monodisperse microbubbles.
BACKGROUND
[0003] Microbubble production is an area of growing interest due to
its countless applications in food processing, material science,
pharmacy and medicine. In the field of medicine, for instance,
microbubbles are used as contrast agent for medical ultrasound
imaging, and as carriers for targeted drug delivery. Microbubbles
for such therapeutic applications may preferably have a diameter in
the range of 1-10 .mu.m. Bubbles with larger diameters may not
safely flow through the smallest capillaries of a patient's blood
vessel system and provoke edema. Smaller bubbles may possess poor
ultrasound reflectivity, or be inefficient as drug carriers.
[0004] Microbubbles with diameters in the desired range may be
produced by either sonication or mechanical agitation. These
methods, however, are only capable of generating colloids of
polydisperse gaseous microbubbles within a liquid. The
polydispersity of the microbubbles limits their potential use in
therapeutic purposes. In ultrasound imaging applications, for
example, monodispersity is required to provide an ultrasound image
of sufficient quality; in drug transport applications,
monodispersity is necessary to precisely control the amount of the
drug to be delivered to the patient.
SUMMARY OF THE INVENTION
[0005] It is therefore an object of the present invention to
provide for an apparatus and a method that enable the mass
production of monodisperse microbubbles with controllable diameters
below 10 .mu.m, and preferably in the range of 2-5 .mu.m.
[0006] The term `monodisperse`, where used in this text to
characterize a collection of microbubbles, may be construed to mean
that the polydispersity index (PDI) of the collection,
mathematically defined as PDI=s/r.sub.b wherein r.sub.b denotes the
average bubble radius and s the standard deviation of the bubble
radii, is smaller than 510.sup.-2. That is, a collection of bubbles
having a PDI<5% may be considered to be monodisperse.
[0007] To this end, a first aspect of the present invention is
directed to an apparatus for mass producing monodisperse
microbubbles. The apparatus may comprise at least one microfluidic
flow focusing device including a dispersed phase fluid supply
channel having an outlet that discharges into a flow focusing
junction; at least one continuous phase fluid supply channel having
an outlet that discharges into the flow focusing junction; and a
bubble formation channel having an inlet disposed at the flow
focusing junction. The configuration of the flow focusing junction
may be such that, in operation, a flow of dispersed phase fluid
discharging from the outlet of the dispersed phase fluid supply
channel is engageable in co-flow by a focusing flow of continuous
phase fluid discharging from the outlet of the at least one
continuous phase fluid supply channel under formation of a
gradually thinning jet of dispersed phase fluid that extends into
the inlet of the bubble formation channel. The bubble formation
channel may have a length L.sub.bfc and a hydraulic diameter
D.sub.bfc, wherein L.sub.bfc/D.sub.bfc>>1.
[0008] A second aspect of the present invention is directed to a
method of mass producing monodisperse microbubbles. The method may
include providing an apparatus according to the first aspect of the
invention. The method may also include supplying a flow of
dispersed phase fluid through the outlet of the dispersed phase
fluid supply channel into the flow focusing junction, and supplying
a flow of continuous phase fluid through the outlet of the at least
one continuous phase fluid supply channel into the flow focusing
junction, such that, at the junction, the flow of dispersed phase
fluid is engaged in co-flow by the focusing flow of continuous
phase fluid under formation of a gradually thinning jet of
dispersed phase fluid that extends into the inlet of the bubble
formation channel, and monodisperse microbubbles, having a diameter
smaller than the hydraulic diameter of the bubble formation channel
break off a tip of said jet.
[0009] A third aspect of the present invention is directed to an
agent, for instance a contrast agent for use in ultrasound imaging,
including a plurality of monodisperse microbubbles manufactured by
means of the apparatus according to the first aspect of the
invention, and/or through the method according to the second aspect
of the invention.
[0010] The apparatus according to the first aspect of the present
invention is structurally simple and may be manufactured very
economically, if desired as a disposable device. It enables the
mass production of microbubbles with an extremely narrow size
distribution and accurately controlled diameter well below 10
.mu.m, e.g. in the range of 2-5 .mu.m, in particular through the
method according to the second aspect of the present invention.
Microbubbles may be produced fast, at rates above 10.sup.5
microbubbles per second per microbubble-generating jet. In one
embodiment, the apparatus may include multiple microfluidic flow
focusing devices that may operate in parallel to boost the overall
microbubble production rate further. The agent according to the
third aspect of the present invention, comprising stable
(optionally surfactant encapsulated), monodisperse microbubbles,
may thus be produced rapidly in a single step, and in particular
without any size-sorting steps that may be necessary with some
conventional bubble production methods to obtain a monodisperse
distribution.
[0011] These and other features and advantages of the invention
will be more fully understood from the following detailed
description of certain embodiments of the invention, taken together
with the accompanying drawings, which are meant to illustrate and
not to limit the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows a schematic perspective view of an exemplary
embodiment of an apparatus according to the present invention;
[0013] FIGS. 2A-B show a schematic top view of the base body of the
microfluidic flow focusing device of the apparatus shown in FIG.
1;
[0014] FIG. 3A-D shows four alternative schematic cross-sectional
views of the bubble formation channel of the microfluidic flow
focusing device of the apparatus shown in FIGS. 1 and 2; and
[0015] FIG. 4 shows a schematic top view of the microfluidic flow
focusing device of the apparatus in FIG. 1 in operation.
DETAILED DESCRIPTION
[0016] FIG. 1 shows a schematic perspective view of an exemplary
embodiment of a microbubble mass production apparatus 1 according
to the present invention. The apparatus 1 may include at least one
microfluidic flow focusing device 2, a source of dispersed phase
fluid 10 and a source of continuous phase fluid 20. The flow
focusing device 2 may comprise two generally planar bodies, a base
body 100 and a cover body 200, which, in an assembled condition of
the flow focusing device 2, may be attached to one another, such
that the structures indicated with reference numbers 112, 122 and
160 in the base body 100 are in registry with respective,
geometrically corresponding passages through the cover body 200
labelled 212, 222 and 260. FIG. 2 shows a schematic top view of the
base body 100.
[0017] Referring now to in particular FIGS. 1 and 2A-B to
illustrate the construction of the apparatus 1.
[0018] The generally plate-shaped base body 100 may include a main
surface 102 defining a planar arrangement of open-top surface
channels; in an assembled condition of the flow focusing device 2,
the flat, lower main surface 204 of the cover body 200 may close
the top-side of the channels, so as to fully define them. The
arrangement of channels may include a dispersed phase fluid supply
channel 110, at least one continuous phase fluid supply channel
120, 120', and a bubble formation channel 130. The channels 110,
120, 120', 130 of the arrangement may join one another at a flow
focusing junction 140.
[0019] Each of the channels 110, 120, 120', 130 may be a
microchannel, i.e. a channel having a hydraulic diameter that is
preferably smaller than 1 mm, or at least smaller than 10 mm. In
the depicted embodiment all channels 110, 120, 120', 130 have a
depth of 50 .mu.m (measured perpendicular to the main surface 102
of the base body 100), while the widths of the respective channels
(measured parallel to the main surface 102 of the base body 100)
differ, ranging from several tens to several hundreds of
micrometers. The transverse cross-sectional shape of each of the
channels 110, 120, 120', 130 in the depicted embodiment is
rectangular. It is contemplated, however, that the channels in
different embodiments may have different dimensions, e.g. a
different depths and widths, and that their transverse
cross-sectional shapes may be different, e.g. otherwise polygonal
or circular.
[0020] The dispersed phase fluid supply channel 110 may extend from
an inlet 112, which may be fluidly connected to the source of
dispersed phase fluid 10, to an outlet 114 that discharges into the
flow focusing junction 140. The dispersed phase fluid supply
channel 110 may preferably be straight, and at least its outlet 114
may extend in a dispersed phase fluid jet direction I.sub.dpf. A
hydraulic diameter of the dispersed phase fluid supply channel 100,
D.sub.dpf, may preferably be substantially uniform over its length,
and be in the range of about 40-120 .mu.m; in the depicted
embodiment the dispersed phase fluid supply channel 100 has a
uniform width of 200 .mu.m. The two continuous phase fluid supply
channels 120, 120' may extend from a common inlet 122, which may be
fluidly connected to a source of continuous phase fluid 20, to
respective outlets 124, 124' that discharge into the flow focusing
junction 140. At least the outlets 124, 124' of the continuous
phase fluid supply channels 120, 120' may extend in respective
continuous phase fluid discharge directions I.sub.cpf, I.sub.cpf'.
The outlets 124, 124' may further have a substantially identical
geometry, and be disposed symmetrically opposite to each other with
respect to a central axis A of the dispersed phase fluid supply
channel 110, such that their respective continuous phase fluid
discharge directions I.sub.cpf, I.sub.cpf' are aligned/in parallel
and extend substantially perpendicular to the dispersed phase fluid
jet direction I.sub.dpf. Upstream of their respective outlets 124,
124', the continuous phase fluid supply channels 120, 120' may
preferably have a relatively large hydraulic diameter D.sub.cpfsc,
e.g. D.sub.cpfsc>90 .mu.m, so as to ensure little resistance in
the supply of continuous phase fluid 22, and to warrant stable
dispersed phase fluid-continuous phase fluid interfaces 30 at the
flow focusing junction 140 during operation (see FIG. 4). Just
upstream of their outlets 124, 124' the continuous phase fluid
supply channels 120, 120' may include a tapering portion 126, 126'
that tapers off in the downstream directions (.delta.45.degree.),
causing their hydraulic diameters to gradually decrease up to a
hydraulic diameter D.sub.cpfsc,outlet<D.sub.cpfsc. The opposing,
aligned outlets 124, 124' may thus define a cross-channel 128 with
a hydraulic diameter D.sub.cpfsc,outlet, that, as part of the flow
focusing junction 140, joins at right angles with the outlet 114 of
the dispersed phase fluid supply channel 110. D.sub.cpfsc,outlet
may preferably be in the range of about 50-80 .mu.m. In the
depicted embodiment, upstream portions of the continuous phase
fluid supply channels 120, 120' have a width of about 600 .mu.m,
while at their outlets 124, 124', their width is approximately 100
.mu.m. The bubble formation channel 130 may extend from an inlet
132, which may be disposed at the flow focusing junction 140, to an
outlet 134. The bubble formation channel 130 may preferably be
straight, and have a hydraulic diameter D.sub.bfc that is smaller
than the hydraulic diameter D.sub.bfsc of the dispersed phase fluid
supply channel 110. At the same time, D.sub.bfc may preferably be
significantly greater, e.g. about one order of magnitude, than a
diameter d.sub.b of the microbubbles 36 to be formed inside during
operation, such that these bubbles 36 can be transported through
the channel 130 without being squeezed between the walls thereof
(see FIG. 4). This latter condition avoids clogging of the bubble
formation channel 130 with bubbles 36, but is also of general
importance to the bubble formation process, as will be clarified
below. In a preferred embodiment D.sub.bfsc may preferably be in
the range of 10-100 .mu.m, and more preferably in the range of
25-75 .mu.m. In the depicted embodiment, the bubble formation
channel 130 has a square transverse cross-section, with a width
w.sub.bfc and D.sub.bfc of 50 .mu.m. Furthermore, the bubble
formation channel 130 may preferably have a length L.sub.bfc that
is much greater than its hydraulic diameter, i.e.
L.sub.bfc>>D.sub.bfc; in the depicted embodiment, for
instance, L.sub.bfc is 1500 .mu.m, such that
L.sub.bfc/D.sub.bfc=30. The relatively great length L.sub.bfc of
the bubble formation channel 130 ensures that the (laminar) flow of
continuous phase fluid 22 that is forced through the bubble
formation channel 130 during operation is enabled to develop an at
least approximately parabolic velocity profile. Full development is
not necessary, but may be desirable. As will be elucidated in some
more detail below, the development of the flow of continuous phase
fluid is important to the optimal functioning of the apparatus 1.
The inlet of the bubble formation channel 132 may be disposed
opposite the outlet of the dispersed phase fluid supply channel
114, across the cross-channel 128 defined by the outlets 124, 14'
of the continuous phase fluid supply channels 120, 120', such that
a central axis of the bubble formation channel 130 is aligned with
a central axis A of the dispersed phase fluid supply channel 110,
and extends in the dispersed phase fluid jet direction I.sub.dpf.
At the point where the inlet 132 of the bubble formation channel
130 connects to the flow focusing junction 140, and more
specifically to the cross-channel 128, the walls of the respective
channels 128, 130 may meet at approximately right angles to define
an inlet angle .phi.90.degree. that maximizes a continuous phase
fluid pressure gradient along the bubble formation channel 130
during operation.
[0021] Accordingly, the flow focusing junction 140 defined by the
four channels 110, 120', 120', 130 may preferably be substantially
symmetrical relative to the central axis A of the bubble fluid
supply channel 110, and hence to the dispersed phase fluid jet
direction I.sub.dpf. More specifically, the configuration of the
flow focusing junction 140 may be such that, in operation, a flow
of dispersed phase fluid 12 discharging from the outlet of the
dispersed phase fluid supply channel 114 is engageable in co-flow
by a flow of continuous phase fluid 22 discharging from the outlets
124, 124' of the continuous phase fluid supply channels 120, 120'
under formation of a gradually thinning jet 32 of dispersed phase
fluid 12 that extends into the inlet 132 of the bubble formation
channel 130 (see FIG. 4).
[0022] Inside the bubble formation channel 130, the jet 32 may be
inherently unstable, as a result of which bubbles 36 may break or
pinch off its tip 34. This is the principle bubble formation
mechanism on which the apparatus 1 is based. However, as the
dimensions of the bubbles 36 may be directly related to the
dimensions of the tip of the jet 34, which thins as it extends
further into the longitudinal direction, undesired early break up
of the unstable tip 32 may prevent or hinder the formation of
monodisperse bubbles below a certain diameter threshold. To
overcome this problem, the bubble formation channel 130 may be
fitted with one or more dispersed phase fluid jet stabilization
provisions to stabilize the jet 32 in the downstream direction, so
as to allow it to thin further and enable the formation of smaller
bubbles 36.
[0023] FIGS. 3A-D schematically illustrate four cross-sectional
perspective views of the bubble formation channel 130. FIG. 3A
illustrates the bubble formation channel 130 without any particular
dispersed phase fluid jet stabilization provision, and during
operation. FIGS. 3B-D schematically illustrate three alternative
embodiments of the bubble formation channel 130 including dispersed
phase fluid jet stabilization provisions. In all embodiments, the
bubble formation channel 130 has a rectangular cross-section, such
that the inner surface of the channel wall 136 defines four flat,
longitudinally extending faces.
[0024] FIG. 3A schematically shows how, during operation, a wobbly
dispersed phase fluid jet 32 extends into the bubble formation
channel 130. The jet 32 is shown to adhere to the upper face 137 of
the channel wall 136, but without particular stabilization
provisions the choice for any face is essentially arbitrary. Where
the jet 32 is not in contact with the upper face 137 of the channel
wall 136, it is in contact with the co-flow of continuous phase
fluid 22 that flanks and largely surrounds it.
[0025] To stabilize the jet 32 against the upper face 137 of the
channel wall 136, the face may be manufactured from a material,
possibly in the form of a coating, that possesses a low wettability
with respect to the continuous phase fluid 22, or preferably at
least a lower wettability than that provided by the materials from
which the other faces are manufactured. For instance, in case the
continuous phase fluid 22 is (distilled) water, the face 137 may be
made of a (relatively) hydrophobic material. In general terms, the
channel wall 136 of the bubble formation channel 130 may define a
portion of inner surface area 137, such as a wall face in the case
of prismatic channel, that extends substantially from the inlet 132
of the bubble formation channel 130 and in the longitudinal
direction of that channel, and that has a low wettability with
respect to the continuous phase fluid 22, or at least a lower
wettability than adjacent inner surface area portions defined by
the wall. The portion of surface area 137 need not extend of over
the entire length L.sub.bfc of the bubble formation channel 130,
but preferably over a distance of at least several tens of
micrometers. The term `low wettability` of a surface may be
construed in terms of the contact angle of a droplet of continuous
phase fluid on the respective surface; for a surface of low
wettability, the contact angle may be .gtoreq.90.degree.,
preferably .gtoreq.110.degree., and more preferably
.gtoreq.130.degree..
[0026] Alternatively or in addition to manufacturing the upper face
137 of a material with an absolute or relative low wettability, the
upper face 137 of the channel wall 136 may be provided with a
longitudinally extending surface enlarging provision. FIGS. 3B-D
schematically illustrate, by way of example, how the upper surface
137, and more generally any longitudinally extending inner surface
portion of the wall 136 defining the bubble formation channel 130,
may be provided with a surface enlarging provision in the form of a
longitudinally extending rim or ridge 138a, a longitudinally
extending slot or groove 138b, and a roughened inner wall surface
area 138c (e.g. surface area defined by nanopillars), respectively.
A ridge 138a or groove 138b may preferably have transverse
dimensions, e.g. width and depth, that are on the order of the
diameter of bubbles 36 to be formed, i.e. 1-10 .mu.m. The inner
surface enlarging provision need not extend over the entire length
L.sub.bfc of the bubble formation channel 130, but preferably over
a distance of at least several tens of micrometers, and
substantially from the inlet 132 on. The outlet 134 of the bubble
formation channel 130 may discharge into a bubble harvesting
reservoir 160, 260, from which the bubbles 36 may be collected or
harvested. The sudden release of a monodisperse microbubbles
carrying flow of continuous phase fluid 22 from a bubble formation
channel 130 into a reservoir 160 with relatively large dimensions,
however, may cause (heavy) swirling of the continuous phase fluid
22, which may in turn cause the microbubbles 36 to coalesce. As a
result, the microbubbles 36 may loose their monodispersity. To
prevent such coalescence of bubbles 36, the outlet 134 of the
bubble formation channel 130 may preferably be fluidly connected to
the bubble harvesting reservoir 160, 260 via a transition channel
150 that is characterized by a design that prevents the bubbles 36
from being subjected to high shear rates, and hence a
geometry/hydraulic diameter that varies only gradually, avoiding,
for instance sudden expansions or constrictions. In the depicted
embodiment, the planar transition channel 150 has essentially the
shape of a truncated triangle with an apex angle 2.theta., wherein
.theta.=30.degree.. For such truncated triangle-shaped transition
channels 150, 0 may preferably satisfy the condition
.theta..ltoreq.45.degree., and more preferably
.theta..ltoreq.30.degree.. The condition is, of course, mutatis
mutandis applicable to non-planar truncated cone-shaped transition
channels.
[0027] It will be clear that the microfluidic flow focusing device
2 described above exhibits an essentially planar geometry in which
the relevant channels 110, 120, 120', 130, and 150 are all disposed
in a same plane. Although such planar geometry is advantageous from
the point of manufacture, it is noted that the apparatus and method
according to the present invention are not limited to planar flow
focusing geometry. The apparatus and method may in particular also
employ an axisymmetric, generally cylindrical (as opposed to
planar) flow geometry; one embodiment with such a geometry would,
for example, be obtained by revolving the above-described
microfluidic flow focusing device 2 around the central axis A of
the dispersed phase fluid supply channel 110.
[0028] An advantage of the depicted planar flow focusing device 2
is that it may be manufactured very economically. The base body
100, including the channel arrangement 100, 120, 120', 130, may for
example be produced by soft lithography or photolithography
techniques. The cover body 200, which may typically include only
macroscopic structures 212, 222, 260, may be manufactured through
conventional machining.
[0029] To supply the microfluidic flow focusing device 2 with
fluids to run it, the apparatus 1 may include a dispersed phase
fluid source 10, and a continuous phase fluid source 20. The
dispersed phase fluid source 10 may supply pressurized dispersed
phase fluid 12, which, in the context of flow focusing and bubble
generation, may also be referred to as the core fluid or the
focused fluid. The continuous phase fluid source 20 may supply
pressurized continuous phase fluid 22, which, may also be referred
to as the sheath fluid or focusing fluid. The sources 10, 20 may be
any suitable source device for the chosen fluid, e.g. a pressurized
vessel, a syringe pump, etc., and may include suitable regulators
to enable control over the pressure and/or flow rate at which a
respective fluid is supplied. The dispersed phase fluid source 10
may be fluidly connected to the inlet 112 of the dispersed phase
fluid supply channel 110, in particular via the passage 212 in the
cover body 200. Similarly, the continuous phase fluid source 20 may
be fluidly connected to the inlet 122 of the continuous phase fluid
supply channels 120, 120', in particular via the passage 222 in the
cover body 200.
[0030] In case the dispersed phase fluid 12 is a gas, the
continuous phase fluid 22 may be a liquid. The dispersed phase
fluid 12 may, for example, include (biocompatible) gases such as
air, nitrogen, oxygen, carbon dioxide, noble or inert gases, and
fluorinated gases (e.g. C.sub.3F.sub.8, C.sub.4F.sub.10,
C.sub.5F.sub.12); the continuous phase fluid may, for instance, be
distilled water. Alternatively, in case the dispersed phase fluid
12 is a liquid, the continuous phase fluid 22 may be a gas.
[0031] In a preferred embodiment, at least one of the dispersed
phase fluid 12 and the continuous phase fluid 22 may contain a
surfactant suitable to populate a fluid interface 30 between the
dispersed phase fluid 12 and the continuous phase fluid 22, and to
thus encapsulate and stabilize bubbles 36 of dispersed phase fluid
12 within the continuous phase fluid 22 immediately upon formation.
The surfactant may, for example, include a film-forming (mixture
of) phospholipid(s), e.g. a mixture of DPPC, DPPA, and
DPPE-PEG5000.
[0032] Now that the construction of the apparatus 1 according to
the present invention has been described in some detail, attention
is invited to its operation.
[0033] FIG. 4 schematically illustrates a top view of the
microfluidic flow focusing device 2, and more specifically of a
portion thereof including the flow focusing junction 140, during
operation. The source of dispersed phase fluid 10, operably
connected to the inlet 112 of the dispersed phase fluid supply
channel 110, may force a flow of dispersed phase fluid 12 through
the channel and into the junction 140 at a flow rate Q.sub.dpf.
Simultaneously, the source of continuous phase fluid 20, operably
connected to the inlet 122 of the continuous phase fluid supply
channels 120, 120', may force a flow of continuous phase fluid 22
through each of the two channels at a respective flow rate
Q.sub.cpf/2. Accordingly, continuous phase fluid 22 may be
discharged into the flow focusing junction 140 at an overall flow
rate Q.sub.cpf. The flow rates Q.sub.dpf and Q.sub.cpf may satisfy
the condition Q.sub.dpf/Q.sub.cpf<<1. In addition the overall
configuration, including in particular the channel geometry of the
flow focusing device 2 and the choice of fluids, may be such that
the dimensionless Reynolds number Re and the dimensionless Weber
number We of the flow of continuous phase fluid 22 within the
bubble formation channel 130 satisfy the conditions
Re.gtoreq.10.sup.2 and We>1. Here, the Reynolds number Re may be
defined as Re=.rho.vs/.mu., wherein .rho. denotes the density of
the continuous phase fluid 22, v denotes the mean velocity of the
continuous phase fluid 22, w denotes the transversal dimension or
hydraulic diameter of the bubble formation channel 130, and .mu.
denotes the viscosity of the continuous phase fluid 22. The Weber
number We may be defined as We=.rho.v.sup.2w/.sigma., wherein
.rho., v, and w denote the same quantities as in the Reynolds
number, and .sigma. denotes the surface tension coefficient.
[0034] As is apparent from FIG. 4, the flows of continuous phase
fluid 22 engage the flow of dispersed phase fluid 12 in co-flow at
the flow focusing junction 140. The flows of continuous phase fluid
22 thereby mould the interface between the dispersed phase fluid 12
and the continuous phase fluid 22 into a cusp that, under the
influence of a relatively large pressure gradient, may give rise to
a gradually thinning jet 32 of dispersed phase fluid 12 that
extends into the inlet 132 of the bubble formation channel 130. A
cross-sectional area of the jet 32 may be significantly smaller
than a cross-sectional area of the bubble formation channel 130,
preferably at least a factor five. Within the bubble formation
channel 130, the laminar flow of continuous phase fluid 22 may
develop a parabolic velocity profile. In this respect, it is noted
that the configuration of the flow focusing device 2 in combination
with the operational parameters that define its use (in particular
the flow rates Q.sub.dpf and Q.sub.cpf) may preferably be chosen to
maximize the aforementioned pressure gradient in the direction of
the flow at the inlet 132 of the bubble formation channel 130. The
relatively large pressure gradient helps to ensure proper
development of the continuous phase fluid 22 from a flat velocity
profile at the inlet 132 to a parabolic velocity profile further
downstream. A centerline of the parabolic velocity profile may
substantially coincide with a centerline of the jet 32, such that
the jet 32 is effective stretched thinner as it extends further
into the bubble formation channel 130. As the jet 32 is inherently
unstable, bubbles 36 may spontaneously pinch off or break off its
tip 34.
[0035] The point at which the bubbles 36 pinch off may be dependent
on the presence of the aforementioned jet stabilization provisions,
such as the inner wall surface portion 137 of low wettability
and/or the inner wall surface enlarging provisions 138a-c (e.g.
rim, groove, roughened surface area). As discussed, these features
may prevent early break up of the jet 32 at its tip 34 and enable
further thinning thereof in the flow direction, such that it may
develop into an elongate, thin thread from which, eventually, even
smaller bubbles may pinch off.
[0036] In case either one of the dispersed phase fluid 12 and the
continuous phase fluid 22 contains a suitable surfactant, the
surfactant molecules may spontaneously populate the dispersed phase
fluid-continuous phase fluid interfaces of the bubbles 36 upon
their formation, and thus encapsulate and stabilize them against
dissolution. The bubbles 36 may then be carried along in the flow
of continuous phase fluid 22 towards the bubble harvesting
reservoir 160, 260. In preparation of discharge into the
(relatively large) reservoir 160, 260, the bubbles 36 may
preferably pass through a transition channel 150 with a
slowly/gradually increasing hydraulic diameter to prevent the
bubbles 36 from being subjected to high shear rates that might
damage them and/or cause their coalescence. Once the bubbles 36 are
discharged into the bubble harvesting reservoir 160, 260, they may
easily be harvested, e.g. by sucking up desired amounts of
bubble-comprising continuous phase fluid 22 and bottling them,
optionally after evaporating at least part of the continuous phase
fluid 22.
[0037] Microbubble generation experiments carried out by the
inventors of the present invention, using an apparatus and method
identical or in some respects similar to the embodiments of the
invention discussed above, are described in detail in E.
Castro-Hernandez, W. Van Hoeve, D. Lohse, J. M. Gordillo,
Microbubble generation in a co-flow device operated in a new
regime, Lab on a Chip, 2011, 11, 2023-2029, which publication is
hereby incorporated by reference in its entirety.
[0038] With regard to the terminology used in this text and not
elaborated on above, the following may be noted. The term `bubble`
may be construed to refer to a typically globular body of a first
fluid (the dispersed phase), disposed within a second fluid (the
continuous phase). In case the first fluid is a gas, the second
fluid may be a liquid. In case the first fluid is liquid, the
second fluid may be a gas; the body of the first fluid may then
also be referred to as a `droplet`. The term `channel` may be
construed to refer to a microchannel, i.e. a channel having a
hydraulic diameter that is preferably smaller than 1 mm, or at
least smaller than 10 mm. The mathematical symbols "<<" and
">>" may be construed to mean `much smaller than` and `much
greater than`, respectively.
[0039] More precisely, the symbols may indicate a difference factor
of at least ten; i.e. the mathematical expression "a>>b" may
be construed to mean that a is at least ten times greater than b,
or: "a.gtoreq.10b". The `hydraulic diameter` of a channel may be
defined as 4A/P, wherein A denotes the cross-sectional area of the
channel, and P the wetted perimeter of the cross-section. For a
channel with a circular cross-section, the hydraulic diameter
simply amounts to the diameter of the channel; for a channel with a
square cross-section, the hydraulic diameter amounts to the side
length of the square.
[0040] Although illustrative embodiments of the present invention
have been described above, in part with reference to the
accompanying drawings, it is to be understood that the invention is
not limited to these embodiments. Variations to the disclosed
embodiments can be understood and effected by those skilled in the
art in practicing the claimed invention, from a study of the
drawings, the disclosure, and the appended claims. Reference
throughout this specification to "one embodiment" or "an
embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, it
is noted that particular features, structures, or characteristics
of one or more embodiments may be combined in any suitable manner
to form new, not explicitly described embodiments.
LIST OF ELEMENTS
[0041] 1 apparatus [0042] 2 flow focusing device [0043] 10 source
of dispersed phase fluid [0044] 12 dispersed phase fluid [0045] 20
source of continuous phase fluid [0046] 22 continuous phase fluid
[0047] 30 interface between dispersed phase fluid and continuous
phase fluid [0048] 32 jet of dispersed phase fluid [0049] 34 tip of
jet [0050] 36 microbubble [0051] 100 base body [0052] 102 main
(top) surface of base body [0053] 110 dispersed phase fluid supply
channel [0054] 112 inlet of dispersed phase fluid supply channel
[0055] 114 outlet of dispersed phase fluid supply channel [0056]
120 continuous phase fluid supply channel [0057] 122 inlet of
continuous phase fluid supply channel [0058] 124 outlet of
continuous phase fluid supply channel [0059] 126 tapering portion
of continuous phase fluid supply channel [0060] 128 cross-channel
[0061] 130 bubble formation channel [0062] 132 inlet of bubble
formation channel [0063] 134 outlet of bubble formation channel
[0064] 136 channel wall [0065] 137 face of low wettability [0066]
138a ridge [0067] 138b groove [0068] 138c roughened inner wall
surface area [0069] 140 flow focusing junction [0070] 150
transition channel [0071] 160 bubble harvesting reservoir (bottom
portion) [0072] 200 cover body [0073] 202 main (top) surface of
cover body [0074] 204 main (bottom) surface of cover body [0075]
212 passage for dispersed phase fluid [0076] 222 passage for
continuous phase fluid [0077] 260 bubble harvesting reservoir (top
portion) [0078] A central axis of dispersed phase fluid supply
channel [0079] D.sub.bfc hydraulic diameter of bubble formation
channel [0080] D.sub.cpfsc hydraulic diameter of continuous phase
fluid supply channel [0081] D.sub.cpfsc,outlet hydraulic diameter
of continuous phase fluid supply channel outlet [0082] d.sub.b
(average) bubble diameter [0083] I.sub.dpf dispersed phase fluid
jet direction [0084] I.sub.cpf, I.sub.cpf' continuous phase fluid
discharge direction [0085] L.sub.bfc length of bubble formation
channel [0086] Q.sub.dpf flow rate of dispersed phase fluid [0087]
Q.sub.cpf of flow rate of continuous phase fluid [0088] w.sub.bfc
width of bubble formation channel [0089] .delta. angle of tapering
portion of continuous phase fluid supply channel [0090] .sigma.
wall angle at inlet of bubble formation channel [0091] .theta.
angle of widening transition channel
* * * * *