U.S. patent application number 13/193004 was filed with the patent office on 2012-02-02 for methods and apparatus for acoustic treatment of samples for heating and cooling.
This patent application is currently assigned to Covaris, Inc.. Invention is credited to James A. Laugharn, JR..
Application Number | 20120024867 13/193004 |
Document ID | / |
Family ID | 45525667 |
Filed Date | 2012-02-02 |
United States Patent
Application |
20120024867 |
Kind Code |
A1 |
Laugharn, JR.; James A. |
February 2, 2012 |
METHODS AND APPARATUS FOR ACOUSTIC TREATMENT OF SAMPLES FOR HEATING
AND COOLING
Abstract
Methods and systems relate to enhancing heat transfer between a
vessel wall and a sample or coupling medium during focused acoustic
processing. The vessel containing the sample may include a heat
exchanger on an inner surface and/or an outer surface of the vessel
that can have any suitable shape or dimension that increases the
surface area of the vessel wall. In some embodiments, heat
exchanger features may disrupt a boundary layer of a liquid sample
at the vessel wall during focused acoustic processing. Accordingly,
the temperature of the liquid sample can be appropriately
controlled. In some cases, heating and/or cooling of the liquid
sample may be performed efficiently. In an embodiment, a liquid
sample may be heated at a rate of at least about 25 degrees C. per
ml per minute.
Inventors: |
Laugharn, JR.; James A.;
(Winchester, MA) |
Assignee: |
Covaris, Inc.
Woburn
MA
|
Family ID: |
45525667 |
Appl. No.: |
13/193004 |
Filed: |
July 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61368410 |
Jul 28, 2010 |
|
|
|
Current U.S.
Class: |
220/592.01 ;
165/138 |
Current CPC
Class: |
F28F 13/00 20130101;
F28F 1/18 20130101; F28F 1/26 20130101 |
Class at
Publication: |
220/592.01 ;
165/138 |
International
Class: |
B65D 90/00 20060101
B65D090/00; F28F 7/00 20060101 F28F007/00 |
Claims
1. A method for acoustic treatment of a sample contained in a
vessel, comprising: providing a vessel containing a liquid sample,
the vessel having a wall in contact with the liquid sample, the
wall including a heat exchanger on an inner surface that is in
contact with the liquid sample; applying acoustic energy from an
acoustic energy source to the liquid sample to cause movement of
portions of the liquid sample near the vessel wall; and using the
heat exchanger on the inner surface of the vessel wall to interact
with moving portions of the liquid sample and disrupt a boundary
layer of the liquid sample at the vessel wall, disruption of the
boundary layer enhancing heat transfer between the vessel wall and
the liquid sample.
2. The method of claim 1, further comprising: simultaneous with
disrupting the boundary layer, applying acoustic energy from the
acoustic energy source to the vessel wall to heat the vessel wall
and increase the vessel wall's temperature above a temperature of
the liquid sample.
3. The method of claim 2, wherein heating the vessel wall causes
heat transfer from the vessel wall to the liquid sample to raise
the temperature of the liquid sample above a temperature of a
coupling medium in contact with an exterior of the vessel.
4. The method of claim 1, wherein a temperature of the vessel wall
is below a temperature of the liquid sample, and disrupting the
boundary layer causes heat transfer from the liquid sample to the
vessel wall so as to lower a temperature of the liquid sample.
5. The method of claim 1, wherein the heat exchanger includes a
plurality of raised areas and/or grooves on the vessel wall.
6. The method of claim 1, wherein the heat exchanger extends around
an entire internal periphery of the vessel wall and extends along
at least a portion of a length of the vessel.
7. The method of claim 1, wherein the heat exchanger includes
features that are molded integrally with the vessel wall.
8. The method of claim 1, wherein the vessel wall includes a heat
exchanger on an outer surface to interact with an environment
outside of the vessel.
9. The method of claim 1, simultaneous with disrupting the boundary
layer, applying acoustic energy from the acoustic energy source to
the vessel wall to heat the vessel wall and heat the liquid sample
at a rate of at least about 25 degrees C. per ml per minute.
10. A method for acoustic treatment of a sample contained in a
vessel, comprising: providing a vessel containing a liquid sample,
the vessel having a wall in contact with the liquid sample, the
wall including a heat exchanger on an outer surface; providing a
coupling medium in contact with the heat exchanger of the vessel,
the coupling medium having a temperature that is different from a
temperature of the liquid sample; and disrupting a boundary layer
between the liquid sample and the wall by transmitting acoustic
energy through the coupling medium and to the vessel and liquid
sample to cause movement of portions of the liquid sample,
disruption of the boundary layer enhancing heat transfer between
the liquid sample and the vessel wall.
11. The method of claim 10, wherein the heat exchanger includes a
plurality of raised areas and/or grooves on the outer surface of
the vessel wall.
12. The method of claim 10, further comprising: simultaneous with
disrupting the boundary layer, applying acoustic energy from the
acoustic energy source to the vessel wall to heat the vessel wall
and increase the vessel wall's temperature above a temperature of
the liquid sample.
13. The method of claim 12, wherein heating the vessel wall causes
heat transfer from the vessel wall to the liquid sample to raise
the temperature of the liquid sample above the temperature of the
coupling medium.
14. The method of claim 10, wherein a temperature of the vessel
wall is below a temperature of the liquid sample, and disrupting
the boundary layer causes heat transfer from the liquid sample to
the vessel wall so as to lower a temperature of the liquid
sample.
15. The method of claim 10, wherein the vessel is one of a
plurality of vessels in a multi-well plate.
16. The method of claim 10, wherein the heat exchanger extends
around an entire external periphery of the vessel wall and extends
along at least a portion of a length of the vessel.
17. The method of claim 10, wherein the heat exchanger includes
features that are molded integrally with the vessel wall.
18. The method of claim 10, wherein the vessel wall includes a heat
exchanger on an inner surface to interact with the liquid
sample.
19. The method of claim 10, simultaneous with disrupting the
boundary layer, applying acoustic energy from the acoustic energy
source to the vessel wall to heat the vessel wall and heat the
liquid sample at a rate of at least about 25 degrees C. per ml per
minute.
20. The method of claim 10, wherein the temperature of the coupling
medium is lower than a temperature of the liquid sample, and the
step of disrupting causes a temperature of the liquid sample to be
reduced.
21. A method for acoustic treatment of a sample contained in a
vessel, comprising: providing a vessel containing a liquid sample,
the vessel having a wall with an inner surface in contact with the
liquid sample; providing a coupling medium in contact with an outer
surface of the vessel; applying acoustic energy from an acoustic
energy source through the coupling medium to the vessel wall to
heat the vessel wall and increase the vessel wall's temperature
above a temperature of the liquid sample; and simultaneous with
applying acoustic energy to heat the vessel wall, applying acoustic
energy from the acoustic energy source to the liquid sample to
disrupt a boundary layer of the liquid sample at the vessel wall so
as to enhance heat transfer from the vessel wall to the liquid
sample and to raise the temperature of the liquid sample above a
temperature of the coupling medium, heating of the liquid sample
being performed at a rate of at least about 25 degrees C. per ml
per minute.
22. The method of claim 21, wherein the coupling medium that
couples acoustic energy from the acoustic energy source to the
vessel wall is a liquid.
23. The method of claim 21, wherein the coupling medium is at a
temperature that is lower than a temperature of the liquid
sample.
24. The method of claim 21, further comprising: subsequent to
heating the liquid sample to a temperature greater than the
temperature of the coupling medium, stopping heating of the vessel
wall to cool the vessel wall, and applying acoustic energy to the
liquid sample to disrupt a boundary layer of the liquid sample at
the vessel wall so as to enhance heat transfer from the vessel wall
to the liquid sample and to cool the liquid sample.
25. The method of claim 21, wherein the coupling medium includes
liquid water and the acoustic energy source includes a transducer
in contact with the liquid water.
26. The method of claim 21, wherein the acoustic energy is focused
to form a focal zone of acoustic energy that is located at least in
part at the vessel wall.
27. The method of claim 21, wherein the acoustic energy is focused
to form a focal zone of acoustic energy that is located inside the
vessel.
28. The method of claim 21, wherein the liquid sample increases in
temperature at a rate of at least 50 degrees C. per ml per
minute.
29. The method of claim 21, further comprising: subsequent to
raising the temperature of the liquid sample above a temperature of
the coupling medium, transferring heat from the vessel wall to the
coupling medium via the heat exchanger so as to lower the
temperature of the vessel wall; and subsequent to raising the
temperature of the liquid sample, applying acoustic energy from the
acoustic energy source to the liquid sample to disrupt the boundary
layer of the liquid sample at the vessel wall to transfer heat from
the liquid sample to the vessel wall and lower the temperature of
the liquid sample.
30. A vessel for holding a liquid sample to be treated with
acoustic energy, comprising: a vessel having a wall with an inner
surface and an outer surface and defining an interior volume to
hold a liquid sample; and a heat exchanger feature at the inner
surface of the wall, the heat exchanger feature including physical
structure that disrupts a boundary layer of the liquid sample at
the vessel wall in response to sample movement caused by acoustic
energy applied to the sample.
31. The vessel of claim 30, wherein the heat exchanger feature
includes a plurality of raised areas on the vessel wall.
32. The vessel of claim 30, further comprising a heat exchanger
feature on the outer surface of the wall.
33. The vessel of claim 30, wherein the interior volume is between
1 .mu.L and 100 milliliters.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/368,410, filed Jul. 28, 2010, which is hereby
incorporated by reference in its entirety.
BACKGROUND
[0002] 1. Field of Invention
[0003] Aspects described herein relate to acoustic treatment of
samples, such as liquid material contained in a well of a
microtiter plate or other similar vessel. In some cases, acoustic
treatment of a sample may involve enhancing heat transfer between
the vessel wall and the sample, such as through the disruption of a
boundary layer at a vessel wall.
[0004] 2. Related Art
[0005] Analytical techniques for biological and chemical samples
often require an extreme physicochemical preparatory step to enable
the desired analysis to be fully achieved. For example,
extraction/digestion of herbicides and pesticides from plant tissue
may require organic solvents (e.g., alcohols) and elevated
temperatures (e.g., 50 degrees C.). This requirement to elevate the
temperature of a sample to aid extraction of a desired component or
constituent of a sample is a commonly used technique. For example,
many environmental sample analysis techniques require thermal
energy to aid extraction. Another area whereby thermal energy is
utilized to aid sample preparation is in microbial analysis;
difficult cell wall disruption is aided by thermal energy.
[0006] Typically, transfer of thermal energy for such processes is
achieved when heat is transferred from an area at higher
temperature to a region of the sample at a lower temperature. For a
biological or chemical sample contained in an isolated environment
within a sample vessel, such heat transfer occurs by
convection-based diffusion processes (Brownian motion and eddy
diffusion) and advective fluid bulk transport (larger-scale current
flow) processes. This is inherently a slow process and is
exacerbated as the sample volume is increased (i.e., where the
volume increases at a greater rate than the contact thermal surface
area).
[0007] For example, a standard extraction/digestion process often
used with sample slurries employs a combination of a stirring
magnetic field to rotate a magnetic stir-bar in the sample fluid
contained in a glass vessel and a hot plate to heat the vessel. The
stir-bar imparts large scale currents, which ideally uniformly
transfer the heat at the vessel wall to the entire fluid. An
alternative means to transfer thermal energy is to use focused
microwave techniques for biological and chemical processing.
Indeed, even with closed vessel microwave heat exchange techniques,
a magnetic stir-bar is utilized to impart large scale currents in
the sample to be processed.
SUMMARY
[0008] In accordance with aspects of the invention, control of
acoustic energy enables both heating of the vessel wall to heat a
sample and disruption of a boundary layer of a sample liquid at the
vessel wall to enhance heat transfer between the vessel wall and
the sample. In other words, acoustic peak positive and peak
negative zones may impart fluid movement for large-scale current
formation as well as heating of the vessel wall. Heating of the
vessel wall may be caused by an intrinsic acoustic impedance
mismatch between materials (e.g., between the vessel wall and a
surrounding acoustic coupling medium) such that a portion of the
acoustic compression/rarefaction energy is absorbed by the vessel
wall. The acoustic energy may also cause portions of the sample
located at the vessel wall to flow, thereby enhancing heat transfer
from the vessel wall to the sample. As a result, both mixing and
heating of the sample can be performed without physically
contacting the sample with any structure aside from the vessel.
Also, some processes may benefit from exposing the sample to both
elevated pressures and temperatures (i.e., pressures and
temperatures above ambient). Aspects described herein may be useful
with such processes since the sample may be both thermally heated
as well as exposed to elevated pressures by way of cavitation or
other conditions caused by the acoustic energy.
[0009] In one aspect of the invention, a method for acoustic
treatment of a sample contained in a vessel includes providing a
vessel containing a liquid sample where the vessel has a wall in
contact with the liquid sample. The vessel wall may include a heat
exchanger on an inner surface that is in contact with the liquid
sample and/or a heat exchanger on an outer surface of the wall that
is in contact with an acoustic coupling medium. The heat exchanger
on the inner and/or outer surfaces may take a variety of forms,
such as fins, bumps, grooves and/or other physical features that
help increase a surface area of the vessel wall in contact with the
sample or a coupling medium. The heat exchanger features at the
inner surface of the vessel may also, or alternately, be arranged
to help disrupt a boundary layer of the liquid sample at the vessel
wall, e.g., to help induce large scale mixing or other flow of the
sample to enhance heat transfer. Thus, the method may further
include applying acoustic energy from an acoustic energy source to
the liquid sample to cause movement of portions of the liquid
sample near the vessel wall, and using a heat exchanger on the
inner surface of the vessel wall to interact with moving portions
of the liquid sample and disrupt a boundary layer of the liquid
sample at the vessel wall, such that disruption of the boundary
layer enhances heat transfer between the vessel wall and the liquid
sample.
[0010] Heat transfer between the vessel wall and the sample may be
used to heat or cool the sample. For example, simultaneous with
disrupting the boundary layer of the sample at the vessel wall,
acoustic energy may be applied from the acoustic energy source to
the vessel wall to heat the vessel wall and increase the vessel
wall's temperature above a temperature of the liquid sample. As
will be understood, heating the vessel wall causes heat transfer
from the vessel wall to the liquid sample to raise the temperature
of the liquid sample. In some embodiments, the temperature of the
sample may be raised above a temperature of a coupling medium in
contact with an exterior of the vessel. The temperature of the
sample may be detected, e.g., by an infrared detector, and the
acoustic energy controlled so as to maintain the sample temperature
constant, or to vary the temperature of the sample.
[0011] In other embodiments, the sample may be cooled. For example,
a temperature of the vessel wall may be below a temperature of the
liquid sample, and the boundary layer may be disrupted to cause
heat transfer from the liquid sample to the vessel wall so as to
lower a temperature of the liquid sample. The vessel wall may be
cooled in any suitable way, such as by transferring heat from the
vessel wall to a coupling medium in contact with the vessel wall.
In one embodiment, the coupling medium may be liquid water,
although other liquid, solid and semi-solid materials may be used
to couple acoustic energy to the vessel.
[0012] When heating or cooling the sample by transfer of heat
between the vessel wall and a coupling medium, a heat exchanger at
the outer surface of the vessel wall may be employed. The heat
exchanger may include physical features on the vessel wall, such as
fins, ribs, grooves, a metal element or other relatively highly
thermally conductive member, and so on. Disruption of a boundary
layer of the liquid sample at the vessel wall as discussed above
may also assist in enhancing heat transfer between the sample and
the vessel wall.
[0013] In another aspect of the invention, a method for acoustic
treatment of a sample contained in a vessel includes providing a
vessel containing a liquid sample where the vessel has a wall with
an inner surface in contact with the liquid sample. A coupling
medium, which may be a single material such as liquid water, or two
or more materials, may be provided in contact with an outer surface
of the vessel such that the coupling medium may transmit acoustic
energy to the vessel. Acoustic energy may be applied from an
acoustic energy source through the coupling medium to the vessel
wall to heat the vessel wall and increase the vessel wall's
temperature above a temperature of the liquid sample. As discussed
above, for some embodiments, the acoustic energy may take advantage
of impedance mismatches between the vessel wall and the coupling
medium and/or the sample to heat the vessel wall. Simultaneous with
applying acoustic energy to heat the vessel wall, acoustic energy
may be applied from the acoustic energy source to the liquid sample
to disrupt a boundary layer of the liquid sample at the vessel wall
so as to enhance heat transfer from the vessel wall to the liquid
sample and to raise the temperature of the liquid sample above a
temperature of the coupling medium. In one embodiment, heating of
the liquid sample may be performed at a rate of at least about 25
degrees C. per ml per minute. This rapid heating capability is
unknown in the prior art, and may be enabled by the use of a heat
exchanger or other element to disrupt the boundary layer of the
liquid sample at the vessel wall. That is, by physically disrupting
the boundary layer, more effective sample flow or other movement
may be caused, which results in more efficient heat transfer.
[0014] These and other aspects of the invention will be apparent
from the following description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Aspects of the invention are shown and described with
reference to illustrative embodiments and the following drawings,
in which like numerals reference like elements, and wherein:
[0016] FIG. 1 shows a schematic diagram of an acoustic treatment
system in accordance with an aspect of the invention;
[0017] FIG. 2 shows a schematic cross sectional diagram of a vessel
having a heat exchanger element at an inner surface in a
illustrative embodiment; and
[0018] FIG. 3 shows a vessel having a heat exchanger at an outer
surface in an illustrative embodiment.
DETAILED DESCRIPTION
[0019] Although aspects of the invention are described with
reference to embodiments in which acoustic energy is used to heat
and/or cool a sample, the sample may be subjected to other
treatments or other processes by the acoustic energy. For example,
the acoustic energy may also be suitable, or be adjusted, to cause
other effects in the liquid, such as fluidizing the sample, mixing
the sample, stirring the sample, catalyzing the sample, disrupting
the sample (such as shearing or fragmenting DNA molecules or other
compounds, lysing cells, etc.), permeabilizing a component of the
sample, enhancing a reaction in the sample (such as binding of
material to the material supports), causing crystal growth in the
sample (e.g., by nucleating crystal growth sites and/or enhancing
the rate of crystal growth), preparing formulations (e.g.,
suspensions and/or emulsions suitable for therapeutic use), causing
flow in a conduit, and/or sterilizing the sample. Thus, the
acoustic energy may be used for other purposes than merely heating
and/or cooling a sample. In other embodiments, the acoustic energy
may facilitate chemical or other reactions in the liquid, which
generate an end product that is to be separated from the liquid and
other substances in the liquid, e.g., using beads or other
structures that bind to the end product to be separated. In
addition, under the applied acoustic energy, a controlled active
turbulent regime may exist, whereby the collision frequency between
binding partners in the sample and on beads or other structures is
increased. This actively controlled turbulence may accelerate
desired processes, as opposed to passive diffusion dominated
processes of paramagnetic or other currently available bead
products.
[0020] The samples can be treated in any suitable vessel provided
that the vessel in at least some embodiments includes one or more
aspects of the invention. Vessels can be sealed for the duration of
the treatment to prevent contamination of the sample or of an
environment outside of the vessel, and arrays of vessels can be
used for processing large numbers of samples. These arrays can be
arranged in one or more high throughput configurations. Examples
include microtiter plates, optionally with a temporary sealing
layer to close the wells, blister packs, similar to those used to
package pharmaceuticals such as pills and capsules, and arrays of
polymeric bubbles, similar to bubble wrap, preferably with a
similar spacing to typical microtiter wells. Vessels containing the
samples can be sealed during the processing, and hence can be
sterile throughout, or after, the procedure. Moreover, the use of
focused ultrasound allows the samples in the vessels to be
processed, including processing by stirring, without contacting the
samples, even when the vessels are not sealed. Thus, a sample
vessel can be a membrane pouch, thermopolymer well, polymeric
pouch, hydrophobic membrane, microtiter plate, microtiter well,
test tube, centrifuge tube, microfuge tube, ampoule, capsule,
bottle, beaker, flask, and/or capillary tube.
[0021] Any suitable sample material can be included in a vessel,
and the sample may include any suitable combination of a liquid
(such as a solvent), a solid material (such as pieces of bone,
tissue or plant materials), a dissolved material (such as a salt)
and so on. Some example materials that may be included in a sample
are DNA, RNA, nucleic acids, or other genetic material, antibodies,
receptors and/or ligands associated with cellular functions,
proteins, polymers, amino acid monomers, an amino acid chain,
enzymes, nucleic acid monomers or chains, saccharides or
polysaccharides, lipids, organic or inorganic molecules, vectors,
plasmids, pharmaceutical agents, compositions suitable for crystal
growth, prions, bacteria, and/or viruses. This is not intended to
be an exhaustive list, but rather to provide a few examples of
sample material that may be used with aspects of the invention.
[0022] FIG. 1 shows a schematic diagram of an acoustic treatment
system 100 that incorporates one or more aspects of the invention.
In this illustrative embodiment, the system 100 includes an
acoustic transducer 1 that is arranged to emit sonic energy through
a coupling medium 2, such as a liquid (e.g., water, organic
solution, etc.) held in a container 3 or a solid material (e.g.,
elastomeric material, gel, silicone, rubber, etc.) in contact with
the transducer 1, and form a focal zone 11 of acoustic energy near
or at a vessel 4. The acoustic energy at the focal zone may be
suitable to cause heating, mixing, cavitation or other effects in a
sample 6 located in the vessel 4. Cavitation or other conditions
induced by acoustic energy at the focal zone may create localized
relatively high pressure (and/or low pressure) conditions that may
be useful in enhancing reactions in sample materials. The vessel 4
may have an interior volume of any suitable size, e.g., between 1
.mu.L and 100 milliliters.
[0023] A controller 5 may provide suitable control signals to the
transducer 1 to generate desired acoustic energy, and control the
relative position of the vessel 4 and the transducer 1 (e.g., in 3
dimensions) so that the sample 6 in the vessel 4 may be suitably
positioned relative to the focal zone 11. Further details regarding
an illustrative embodiment for an acoustic treatment system 100 are
provided below, and in U.S. Pat. No. 6,948,843, which is
incorporated herein by reference in its entirety. For example, the
focal zone 11 may have a spherical, egg-like, or elongated rod-like
shape, may include two or more focal zones or focal lines (e.g.,
focal zones with high aspect ratios), and so on.
[0024] In accordance with an aspect of the invention, the vessel 4
may include one or more heat exchanger features that are located in
contact with the sample 6 and/or in contact with the coupling
medium 2. When used at the inner surface of the vessel, the heat
exchanger features can enable rapid heating of the sample, e.g., by
enabling the disruption of a boundary layer of the sample at the
vessel wall. Generally, the boundary layer may be considered herein
as a layer of fluid immediately adjacent to a solid surface where
certain effects (e.g., due to viscosity) arising from the presence
of the solid surface play a non-negligible role. For example, a
boundary layer may be a fluid layer adjacent a vessel wall that, in
the absence of acoustic mixing/agitation, remains relatively
stagnant, substantially does not transfer heat between the vessel
wall and the fluid by convection, and instead transfers heat
between the vessel wall and the fluid by radiation and/or
conduction. When the boundary layer is sufficiently disrupted
(e.g., by focused acoustic treatment), convective heat transfer
between the vessel wall and the fluid occurs more freely. In some
embodiments, for a vessel lacking a heat exchanger or similar
feature at the inner wall, the boundary layer of sample at the
vessel wall may remain undisturbed, essentially forming a region
that behaves as a blanket of insulation that forces heat transfer
by radiation or conduction processes only. In contrast, the heat
exchanger features in accordance with an aspect of the invention at
the inner wall of a vessel allow the acoustic energy to disrupt
this boundary layer, thereby enabling convective heat transfer in
addition to radiation and conduction modes.
[0025] Disruption of the boundary layer enabled by a heat exchanger
feature creates large scale flow at the vessel wall and thus
permits rapid heat transfer between the sample and the vessel. In
cases where the vessel wall is at a higher temperature than the
sample, the sample can be heated quickly, particularly where the
vessel wall is being heated by acoustic energy. FIG. 2 shows a
cross sectional view of a vessel 4 that includes heat exchanger
features 7 in the form of an array of raised areas on the inner
surface of the vessel wall. In this embodiment, the raised areas
are arranged in a regular pattern of individual bumps that extends
around the inner periphery of the vessel 4 and along at least part
of the length of the vessel 4. These bumps 7 cause turbulence in
flow occurring near the vessel wall, thereby breaking up a
relatively stagnant boundary layer that might otherwise form. This
breakup induces improved convective heat flow, allowing the sample
to be heated or cooled more rapidly. The inventor has found that
these features can enable extremely rapid heating of at least 25
degrees C. per milliliter of liquid per minute (degrees C. per ml
per min). Heating this rapid is unknown in prior art applications
that do not involve focused acoustics and one or more aspects of
the invention.
[0026] The heat exchanger features 7 can be formed in any suitable
way such as by molding, thermoforming, machining, etching, applying
with an adhesive, and so on. For example, the heat exchanger 7 may
be formed as part of a sleeve that is inserted into the vessel and
bonded (e.g., with an adhesive, application of pressure, mechanical
fit, etc.) to the inner wall. In another embodiment, the heat
exchanger 7 may be molded integrally with the vessel wall. In
addition, the shape, size and arrangement of heat exchanger
features may be arranged in any suitable way. In the embodiment of
FIG. 2, the heat exchanger features have a mesa-type shape, but may
be arranged as fins, rods, smooth bumps, grooves, holes, pits,
tabs, and others. Also, in this embodiment, the raised areas have a
size of about 1 sq. millimeter, a height of about 100 micrometers
and are separated from each other by a spacing of about 3
millimeters, but other sizings and spacings are possible. For
example, the size, shape and/or space between features may be
varied according to a frequency or set of frequencies used to treat
the sample 6. In one embodiment, a variety of differently sized and
spaced features may be used so that different sets of features may
selectively interact with acoustic energy within a certain
frequency range. That is, features of a first size/shape/spacing
may interact most strongly with acoustic energy in a first
frequency range, features of a second size/shape/spacing may
interact most strongly with acoustic energy in a second frequency
range, and so on. As a result, the different features may be
activated at different times, e.g., if the sample 6 is treated with
a sweep of varying frequency acoustic energy.
[0027] Heat exchanger features may be formed as positive features
that extend from the vessel wall into the vessel and/or negative
features that extend into the vessel wall. Different types of heat
exchanger features may be used together, such as an array of bumps
combined with an array of grooves. In short, the heat exchanger
features may be arranged so as to maximize boundary layer
disruption for one or more particular applications. Since different
applications may involve different materials in the sample and/or
different sample viscosities, the heat exchanger features may be
arranged to work best with a specific sample viscosity range and/or
particle sizes.
[0028] As noted above, a vessel 4 may include heat exchanger
features at an inner surface of the vessel wall or at an outer
surface of the wall. FIG. 3 shows another embodiment in which a
vessel 4 includes heat exchanger features 8 on an exterior of the
vessel. In this embodiment, the heat exchanger features 8 are
arranged as longitudinal fins that extend along a length of the
vessel. In contrast to the heat exchanger features 7 at the
interior of the vessel, the heat exchanger features 8 on the
exterior of the vessel need not necessarily function to disrupt a
boundary layer of a coupling medium or other liquid at the exterior
of the vessel. Instead, heat exchanger features 8 at the vessel
exterior may function to help increase surface area and heat
transfer to a liquid, solid or semi-solid coupling medium (such as
water, a silica material, and/or a silicone rubber). By exchanging
heat with the coupling medium, the vessel can be heated and/or
cooled so long as there is a temperature difference between the
vessel and the coupling medium. As discussed above, heat transfer
between the vessel and the sample can heat and cool the sample, and
thus the coupling medium can be used to cool and/or heat the sample
in certain circumstances. By providing heat exchanger features 8 on
the vessel exterior, heat transfer between the vessel and the
coupling medium can be better controlled, allowing for more
accurate and efficient thermal cycling treatments of the sample to
be performed.
[0029] As with the heat exchanger features 7 at the vessel
interior, the heat exchanger features 8 can be arranged in any
suitable way, with any suitable size, shape and/or configuration.
Although the FIG. 3 embodiment shows the heat exchanger features 8
in the form of longitudinal fins, the heat exchanger features may
include bumps, grooves, pits, circumferential or spiral fins (e.g.,
having a washer-like shape), plates, mushroom-like structures,
studs, and others. The heat exchanger features 8 may be formed
unitarily with the vessel (e.g., molded into the vessel wall),
attached to the vessel wall (e.g., by an adhesive, sonic welding,
or other) and so on. For example, in one embodiment, heat exchanger
features 8 may be formed on a sleeve (such as a highly conductive
metal sheath) that is slid over the vessel and bonded in place. In
other embodiments, the heat exchanger features may be attached to
the vessel using an interference or friction fit, such as metallic
washer-shaped elements that are pressed onto the vessel wall such
that the hole of the washer element fits tightly to the vessel
outer surface. The heat exchanger may have portions that extend
through the vessel wall, such as metallic stud elements that extend
from outside the vessel wall, through the wall and into the vessel
interior. In one embodiment, such heat exchanger features may be
molded with a plastic material to make the vessel. For example, the
metallic studs may be mounted in a mold and molten plastic injected
so that the studs are formed integrally with the vessel and extend
from inside to outside of the vessel. In one embodiment, such studs
or similar elements may form both heat exchanger features at the
inner surface of the vessel wall and heat exchanger features at the
outer surface of the vessel wall.
[0030] When using a vessel in accordance with aspects of the
invention, the temperature of the external environment of the
sample vessel (e.g., the coupling medium) may be below the
temperature of the sample during a treatment process. This
arrangement enables the sample to be intermittently elevated in
temperature for a desired process. For example, a sample in a
polypropylene plastic tube and cap may initially be at 4 degree C.
with the tube placed in a 96 tube rack. A focused acoustic field
may be directed to the sample, which is contained in one of the
tubes in the rack. During an acoustic dose, the internal
temperature of the sample may be increased to 50 degree C. within
seconds (e.g., less than 10 seconds). If the sample is initially
frozen, this thermal energy may be used to quickly thaw the frozen
sample. In accordance with an aspect of the invention, only one of
the samples in the rack may be thawed while other samples remain
frozen. This would be of benefit if the rack of samples (e.g., 96
tubes) were at -20 degree C., but only one sample was required to
be thawed for processing. Rapid heating enabled by aspects of the
invention has been found by the inventor to be significantly faster
than other prior processes. For example, compare a process of
thawing a biological fluidic sample (e.g., serum) that is initially
at (-70) degrees C. in which the sample is placed in a water bath
at 20 degree C. to a process in accordance with aspects of the
invention. Simply placing the sample in a 20 degree C. water bath
typically requires several minutes before the sample reaches a
temperature at 20 degree C. However, with an applied acoustic field
and heat exchanger elements used with the vessel, a sample thaw may
occur within 10 seconds even with the coupling medium at a
relatively lower temperature of 5 degrees C.
[0031] In other embodiments, the temperature of the external
environment of the sample vessel (e.g., the coupling medium
temperature) may be elevated above the sample temperature, at least
initially. In this situation, a rise in temperature of the sample,
if desired, may be further accelerated. For example, a -70 degree
C. frozen sample may be placed into a water bath of 20 degrees C.
and an acoustic dose applied to the vessel. As the vessel wall is
heated by the acoustic energy, the fluid motion turbulence
generated by the acoustic energy and a heat exchanger in the vessel
further aids the heat transfer from the vessel wall and the
coupling medium to the sample. Similar is true where the sample is
to be cooled where the sample temperature is higher than the
coupling medium. Thus, the heat transfer process may be accelerated
for both heating and cooling of the sample by appropriate setting
of the coupling medium temperature. This may be of value in thermal
cycling of biological processes, such as thermo-stabile
enzymes.
[0032] The controller 5 may be arranged to control the transducer 1
in any suitable way, e.g., generate a variety of alternating
voltage waveforms to drive the transducer 1. For instance, a high
power "treatment" interval consisting of about 5 to 1,000 sine
waves, for example, at 1.1 MHz, may be followed by a low power
"convection mixing" interval consisting of about 1,000 to 1,000,000
sine waves, for example, at the same frequency. (Although there is
a short time period separation between treatment and mixing
intervals, the intervals are referred to herein as occurring
simultaneously, i.e., acoustic energy to cause heating is said to
be applied simultaneously with acoustic energy to cause mixing.) It
is during the convective mixing interval that heat exchanger
elements in the vessel may maximally assist in disrupting the
boundary layer at the vessel wall. "Dead times" or quiescent
intervals of about 100 microseconds to 100 milliseconds, for
example, may be programmed to occur between the treatment and
convection mixing intervals. Also, the focal zone 11 may be
arranged in any suitable way, e.g., may be small relative to the
dimensions of the vessel 4 to avoid heating of the treatment vessel
during some intervals, or may be larger than the vessel 4. In one
embodiment, the focal zone 11 may have a width of about 2 cm or
less, a height of about 6 cm or less and a length of 5 cm or more.
In another embodiment, the focal zone 11 may have an ellipsoidal
shape, with a width or diameter of about 2 cm or less and a length
of about 6 cm or less.
[0033] Acoustic energy in the focal zone 11 may generate a shock
wave that is characterized by a rapid shock front with a positive
peak pressure in the range of about 15 MPa, and a negative peak
pressure in the range of about negative 5 MPa. This waveform may be
of about a few microseconds duration, such as about 5 microseconds.
If the negative peak is greater than about 1 MPa, cavitation
bubbles may form in liquid in the sample. Cavitation bubble
formation may also be dependent upon the surrounding medium 2, the
vessel material, or other features. For example, glycerol is a
cavitation inhibitive medium, whereas liquid water is a cavitation
promotive medium. The collapse of cavitation bubbles may form
"microjets" and turbulence that impinge on the surrounding
material. These cavitation bubbles may contribute to sample liquid
movement during a treatment. Moreover, the localized high and low
pressure regions may expose portions of the sample to suitable
pressures and temperatures that are useful for causing some
chemical reactions or other results.
[0034] In the embodiments shown, the acoustic energy is transmitted
from the transducer 1 to the vessel 4 through a medium 2, such as
water. However, other media or combinations of media may be used,
such as a solid or semi-solid material and others. For example, the
transducer 1 may be mated to a solid silica-based material that
conducts acoustic energy toward the sample vessel. A semi-solid
material, such as a silicone rubber or gel, may be used to couple
the silica material to the vessel. The water bath or other acoustic
coupling media (e.g., silicone rubber) may be at room temperature
and the sample may be contained in a vessel which readily transfers
heat (e.g., borosilicate glass), but allows the acoustic energy to
couple directly with the internal sample for heat transfer. For
example, a 20% glycerol sample will be more sensitive to acoustic
energy-mediated temperature elevation than a 2% glycerol sample. In
this embodiment, the vessel wall may be more transparent to
acoustic energy, and thereby resulting in the sample or sample
constituents absorbing the acoustic energy and impart thermal
energy transfer directly to the sample. An example of a vessel wall
material with desired acoustic properties is the low density,
transparent thermoplastic polymer of methylpentene monomer units
(polymethylpentene or TPX).
[0035] The geometry and material choice of the vessel wall may also
affect the performance of the non-contact, acoustic treatment. In
addition, the internal vessel volume and the ratio of sample to
headspace will also affect the performance of the device. For
example, a 1.5 milliliter conical polypropylene tube with 1.0
milliliter of sample when placed into a 0.5 MHz focused acoustic
field converging on the cone of the tube would enable the internal,
starting temperature of 20 degree C. (external water bath
temperature) to be elevated to 90 degree C. in less than 120
seconds at a high acoustic dose. The temperature may quickly be
lowered to 20 degree C. with a lower acoustic dose to dissipate the
thermal energy.
[0036] Many types of acoustic systems may be used to generate the
appropriate wave-train to impart the thermal energy transfer. For
example, an unfocused acoustic source (15 kHz) directed toward the
vessel would result in the vessel wall temperature rise, which
would thereby heat the internal fluidic sample. Alternatively, a
focused acoustic source (e.g., 0.5 MHz) may also be used. In both
situations, a feedback loop algorithm may be utilized to automate
and control the process, e.g., monitoring the external temperature
of the vessel wall may indirectly indicate the appropriate dose to
be applied to the sample. In one embodiment, the apparatus may have
an external non-contact infrared meter monitoring the external
temperature of the sample vessel. For example, during an acoustic
extraction dose, the vessel wall temperature will increase and the
fluidic sample will be turbulent. The turbulence will effectively
transfer the temperature throughout the sample and thereby enable
external thermal measurements to provide an indication of internal
temperature. This is particularly valid if the sample is thoroughly
washing the internal walls of the vessel during the acoustic dose.
Thus, a heat exchanger 7 at the vessel inner surface may enable
more accurate temperature measurement of the sample.
[0037] Many biological and other materials can be treated according
to aspects of the invention. For example, such materials for
treatment include, without limitation, growing plant tissue such as
root tips, meristem, and callus, bone, yeast and other
microorganisms with tough cell walls; bacterial cells and/or
cultures on agar plates or in growth media, stem or blood cells,
hybridomas and other cells from immortalized cell lines, and
embryos. Additionally, other biological materials, such as serum
and protein preparations, can be treated with the processes of the
invention, including sterilization.
[0038] Many binding reactions can be enhanced with treatments in
accordance with aspects of the present disclosure. Binding
reactions involve binding together two or more molecules, for
example, two nucleic acid molecules, by hybridization or other
non-covalent binding. Binding reactions are found, for example, in
an assay to detect binding, such as a specific staining reaction,
in a reaction such as the polymerase chain reaction where one
nucleotide molecule is a primer and the other is a substrate
molecule to be replicated, or in a binding interaction involving an
antibody and the molecule it binds, such as an immunoassay.
Reactions also can involve binding of a substrate and a ligand. For
example, a substrate such as an antibody or receptor can be
immobilized on a support surface, for use in purification or
separation techniques of epitopes, ligands, and other
molecules.
[0039] In certain embodiments, temperature, mixing, or both can be
controlled with ultrasonic energy to enhance a chemical reaction.
For example, the association rate between a ligand present in a
sample to be treated and a binding partner on a bead or other
support in the sample can be accelerated. In another example, an
assay is performed where temperature is maintained and mixing is
increased to improve association of two or more molecules compared
to ambient conditions. It is possible to combine the various
aspects of the process described herein by first subjecting a
mixture to heat and mixing in order to separate a ligand or analyte
in the mixture from endogenous binding partners in the mixture. The
temperature, mixing, or both, are changed from the initial
condition to enhance ligand complex formation with a binding
partner relative to ligand/endogenous binding partner complex
formation at ambient temperature and mixing. Generally, the second
temperature and/or mixing conditions are intermediate between
ambient conditions and the conditions used in the first separating
step above. At the second temperature and mixing condition, the
separated ligand may be reacted with the binding partner.
[0040] Focused sonic fields can be used to enhance separations. As
noted elsewhere, sonic foci can be used to diminish or eliminate
wall effects in fluid flow, which is an important element of many
separation processes, such as chromatography including gas
chromatography, size exclusion chromatography, ion exchange
chromatography, and other known forms, including filed-flow
fractionation. The ability to remotely modulate and/or reduce or
eliminate the velocity and concentration gradients of a flowing
stream is applicable in a wide variety of situations, such as those
described in relation to FIG. 2.
[0041] Sonic energy fields can be used to enhance reaction rates in
a viscous medium, by providing remote stirring on a micro scale
with minimal heating and/or sample damage. Heat exchanger features
in a vessel may be useful in promoting micro and larger scale
stirring whether with or without significant heat transfer.
Likewise, any bimolecular (second-order) reaction where the
reactants are not mixed at a molecular scale, each homogenously
dissolved in the same phase, potentially can be accelerated by
sonic stirring. At scales larger than a few nanometers, convection
or stirring can potentially minimize local concentration gradients
and thereby increase the rate of reaction. This effect can be
important when both reactants are macromolecules, such as an
antibody and a large target for the antibody, such as a cell, since
their diffusion rates are relatively slow and desorption rates may
not be significant.
[0042] These advantages may be realized inexpensively on multiple
samples in an array, such as a microtiter plate. The use of remote
sonic mixing provides a substantially instantaneous start time to a
reaction when the sample and analytical reagents are of different
densities, because in small vessels, such as the wells of a 96 or
384 well plate, little mixing will occur when a normal-density
sample (about 1 g/cc) is layered over a higher-density reagent
mixture. Remote sonic mixing can start the reaction at a defined
time and control its rate, when required. Stepping and dithering
functions may allow multiple readings of the progress of the
reaction to be made. The mode of detecting reaction conditions can
be varied between samples if necessary. In fact, observations by
multiple monitoring techniques, such as the use of differing
optical techniques, can be used on the same sample at each pass
through one or more detection regions.
[0043] By focusing and positioning sonic energy near a wall of a
vessel, e.g., at heat exchanger features, many local differences in
the distribution of materials within a sample and/or
spatially-derived reaction barriers, particularly in reactive and
flowing systems, can be reduced to the minimum delays required for
microscopic diffusion. Put differently, enhanced mixing can be
obtained in situations where imperfect mixing is common. For
example, if sonic energy is focused in, on, or near the wall of the
vessel, near the fluid/wall boundary, then local turbulence can be
obtained without a high rate of bulk fluid flow. Excitation of the
near-wall fluid in a continuous, scanned, or burst mode can lead to
rapid homogenization of the fluid composition just downstream of
the excited zone, e.g., a short distance away from a boundary layer
at a heat exchanger feature.
[0044] This effect is useful in several areas, including
chromatography; fluid flow in analytical devices, such as clinical
chemistry analyzers; and conversion of the fluid in a pipeline from
one grade or type to another. Since most of the effect occurs in a
narrow zone, only a narrow zone of the conduit typically needs to
be sonically excited, and only the narrow zone need include heat
exchanger features at the vessel wall. For example, in some
applications, the focal zone of the sonic energy can be the region
closest to a valve or other device which initiates the switch of
composition. In any of these applications, feedback control can be
based on local temperature rise in the fluid at a point near to or
downstream of the excitation region.
[0045] Focused acoustics and heat exchanger features in accordance
with aspects of the present disclosure may be useful for preparing
formulations having a narrow particle size distribution. Such
formulations may include suspensions and/or emulsions having
particles that are submicron in size and may have applications for
therapeutic use, such as delivery systems for bioactive agents
(e.g., liposomes, micelles, etc.). Controlling heat transfer in a
focused acoustic processing system using heat exchanger features
contemplated may enhance the ability to suitably prepare
formulations in an advantageous manner (e.g., repeatable, short
processing times, high yield, etc.).
[0046] In some embodiments, enhancing heat transfer between the
wall of a processing vessel and a fluid upon focused acoustic
treatment may also be useful for initiating (e.g., forming
nucleation sites) and augmenting (nano)crystalline growth. For
example, crystalline particles may be formed as a suspension of
particles (e.g., submicron in size) in a liquid solution. In some
cases, though not required, (nano)crystalline particles prepared in
accordance with aspects described herein may be useful for
therapeutic delivery of bioactive agents.
[0047] While there has been described herein what are considered to
be exemplary and preferred embodiments of the invention, other
modifications and alternatives of the inventions will be apparent
to those skilled in the art from the teachings herein. All such
modifications and alternatives are considered to be within the
scope of the invention.
* * * * *