U.S. patent application number 12/410724 was filed with the patent office on 2009-10-01 for temperature control system.
Invention is credited to Peter MITCHELL, Gary Phillips, Thomas Smeltzer, Samuel C. Williams.
Application Number | 20090242173 12/410724 |
Document ID | / |
Family ID | 41115361 |
Filed Date | 2009-10-01 |
United States Patent
Application |
20090242173 |
Kind Code |
A1 |
MITCHELL; Peter ; et
al. |
October 1, 2009 |
TEMPERATURE CONTROL SYSTEM
Abstract
An improved system and method for controlling the temperature of
fluids during a mixing procedure or a chemical, pharmaceutical, or
biological process is disclosed. One embodiment of the system
comprises: a first collapsible bag including a perimeter and a
maximum dimension thereacross measured at full expansion of the
first collapsible bag; a first interior surface portion; a second
interior surface portion; one or more welds connecting the first
and second interior surface portions of the first collapsible bag
so as to form a channel between the first and second interior
surface portions, an inlet connected to a first portion of the
channel; an outlet connected to a second portion of the channel,
the channel defining a bulk fluid flow pathway through the first
collapsible bag from the inlet to the outlet; and a first
temperature-controlling surface in contact with a first exterior
surface portion of the first collapsible bag. A heat exchanger in
fluid communication with another vessel that can hold or store the
heated or cooled fluid is also disclosed.
Inventors: |
MITCHELL; Peter; (East
Greenwich, RI) ; Phillips; Gary; (Northborough,
MA) ; Smeltzer; Thomas; (Northborough, MA) ;
Williams; Samuel C.; (Acton, MA) |
Correspondence
Address: |
Xcellerex, Inc.;Attention: Jacqueline Arendt
170 Locke Drive
Marlborough
MA
01752
US
|
Family ID: |
41115361 |
Appl. No.: |
12/410724 |
Filed: |
March 25, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61039382 |
Mar 25, 2008 |
|
|
|
Current U.S.
Class: |
34/402 ; 222/94;
34/408 |
Current CPC
Class: |
F28F 7/00 20130101; F28F
2255/02 20130101; C12M 41/12 20130101; C12M 23/14 20130101 |
Class at
Publication: |
165/104.19 ;
222/94; 165/46 |
International
Class: |
F28D 15/00 20060101
F28D015/00; B65D 35/22 20060101 B65D035/22; F28F 7/00 20060101
F28F007/00 |
Claims
1. A system configured for use in a chemical, biological, or
pharmaceutical process, the system comprising: a first collapsible
bag comprising: a perimeter and a maximum dimension thereacross
measured at full expansion of the first collapsible bag; a first
interior surface portion; a second interior surface portion; one or
more welds connecting the first and second interior surface
portions of the first collapsible bag so as to form a channel
between the first and second interior surface portions, an inlet
connected to a first portion of the channel; an outlet connected to
a second portion of the channel, the channel defining a bulk fluid
flow pathway through the first collapsible bag from the inlet to
the outlet; and a first temperature-controlling surface in contact
with a first exterior surface portion of the first collapsible
bag.
2. The system of claim 1, wherein the channel comprises a
serpentine configuration.
3. The system of claim 1, wherein the channel comprises a spiral
configuration.
4. The system of claim 1, wherein the first collapsible bag has a
volume equal to from about 1 liter to about 10,000 liters.
5. The system of claim 1, wherein the average cross-sectional area
of the channel at full expansion of the first collapsible bag is
from about one tenth to about one fourth of the maximum dimension
of the bag, the system further comprising a reusable support
structure for supporting and containing the first collapsible
bag.
6. The system of claim 1, wherein the channel comprises from about
4 channel segments to about 10 channel segments.
7. The system of claim 1, wherein the first temperature-controlling
surface is selected from: a thermally-conductive material, a
plurality of particles embedded in a surface of the bag, and a
plate comprising channels for allowing fluid to flow therethrough,
and combinations of the foregoing.
8. The system of claim 1, further comprising a second
temperature-controlling surface in contact with a second exterior
surface portion of the first collapsible bag.
9. The system of claim 8, wherein the second
temperature-controlling surface is selected from a
thermally-conductive material, a plurality of particles embedded in
a surface of the bag, and a plate comprising channels for allowing
fluid to flow therethrough, and combinations of the foregoing.
10. The system of claim 8, wherein the system is configured and
arranged to allow variation of the distance between the first and
second temperature-controlling surfaces.
11. The system of claim 8, further comprising a component
associated with the collapsible bag that inhibits full expansion of
the collapsible bag during use.
12. The system of claim 11, wherein the component that inhibits
full expansion of the collapsible bag during use comprises the
first and second temperature-controlling surfaces maintained at a
separation distance from one another that does not allow full
expansion of the collapsible bag.
13. The system of claim 1, wherein the first collapsible bag
comprises a second exterior surface portion, the system further
comprising: a second collapsible bag having a first exterior
surface portion and a second exterior surface portion, the second
collapsible bag comprising an impeller in fluid communication with
the first collapsible bag.
14. The system of claim 13, wherein the first
temperature-controlling surface is in contact with the first
exterior surface portion of the second collapsible bag.
15. The system of claim 13, further comprising a second
temperature-controlling surface in contact with the second exterior
surface portion of the first collapsible bag.
16. The system of claim 15, further comprising a third
temperature-controlling surface in contact with the second exterior
surface portion of the second collapsible bag.
17. The system of claim 13, configured and arranged to allow
recirculation of fluid between the first and second collapsible
bags.
18. The system of claim 13, further comprising a collapsible heat
exchanger bag positioned in contact with the first or the second
exterior surface portion of the first collapsible bag and in
contact with the first or the second exterior surface portion of
the second collapsible bag.
19. A method, comprising: flowing a reaction fluid having a first
temperature from a chemical, biological or pharmaceutical reactor
into the collapsible bag of the system of claim 1, the collapsible
bag in fluid communication with the reactor; changing a temperature
of the reaction fluid in the collapsible bag by at least 5 degrees
Celsius while the reaction fluid is flowing in the collapsible bag;
and flowing the reaction fluid from the collapsible bag into a
container in fluid communication with the collapsible bag.
20. The method of claim 19, further comprising flowing a heating or
a cooling fluid adjacent the first temperature-controlling surface
for a period of time sufficient to cause a change in temperature of
the reaction fluid.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/039,382 filed on Mar. 25, 2008, the teachings of
which are incorporated herein by reference in their entirety.
BACKGROUND
[0002] A variety of vessels for manipulating fluids and/or for
carrying out chemical or biological reactions are available. For
example, biological materials such as mammalian, plant or insect
cells and microbial cultures can be processed using traditional or
disposable bioreactors. Although such bioreactors and other fluid
manipulating systems incorporating temperature control systems are
known, there is a need for improvements to such systems.
SUMMARY OF THE INVENTION
[0003] The present invention relates to the discovery of an
improved system for controlling the temperature of fluids during a
mixing procedure or a chemical or biological process. One
embodiment of the invention provides a system configured for use in
a chemical, biological, or pharmaceutical process, the system
comprising: a first collapsible bag comprising: perimeter and a
maximum dimension thereacross measured at full expansion of the
first collapsible bag; a first interior surface portion; a second
interior surface portion; one or more welds connecting the first
and second interior surface portions of the first collapsible bag
so as to form a channel between the first and second interior
surface portions; an inlet connected to a first portion of the
channel; an outlet connected to a second portion of the channel,
the channel defining a bulk fluid flow pathway through the first
collapsible bag from the inlet to the outlet; and a first
temperature-controlling surface in contact with a first exterior
surface portion of the first collapsible bag.
[0004] In accordance with a second aspect of the invention, a
method of changing the temperature of fluids during mixing or
during a chemical or biological process is disclosed. The method
comprises: flowing a reaction fluid having a first temperature from
a chemical, biological or pharmaceutical reactor into the
collapsible bag of the system described above, the collapsible bag
in fluid communication with the reactor; changing a temperature of
the reaction fluid in the collapsible bag by at least 5 degrees
Celsius while the reaction fluid is flowing in the collapsible bag;
and flowing the reaction fluid from the collapsible bag into a
container in fluid communication with the collapsible bag.
[0005] The present invention has many advantages, including an
improved heat exchanger system having improved temperature control
for a bioreactor or mixer. In the process of growing cells, it is
often necessary to dissipate some of the heat generated by the
cells, or in some cases, to warm the fluid in the bioreactor or
mixer. For example, in one embodiment, the presence of the welds in
a bioreactor bag provides a longer flow path for reaction, or for
efficient heating or cooling for a longer period of time. Another
advantage is that channels provided in various embodiments of the
invention can reduce the amount of random or non-directed fluid
flow, for example, turbulence and eddies, in a fluid in a
bioreactor or mixer. Yet another advantage is that the disclosed
channel configurations can also prevent or reduce "dead zones" that
may lead to non-uniform heating or cooling of fluid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The foregoing and other non-limiting objects, features and
advantages of the invention will be apparent from the following
more particular description of illustrative embodiments of the
invention, as illustrated in the accompanying drawings in which
like reference characters refer to the same parts throughout the
different views. The drawings are schematic and not intended to be
drawn to scale, emphasis instead being placed upon illustrating the
principles of the invention. For purposes of clarity, not every
component is labeled in every figure, nor is every component of
each embodiment of the invention shown where illustration is not
necessary to allow those of ordinary skill in the art to understand
the invention. In the figures:
[0007] FIG. 1 is a schematic representation of a system comprising
a container contained within a support structure according to one
embodiment of the invention.
[0008] FIG. 2 is a schematic representation of a system for
carrying out fluid manipulations including biological, chemical,
and biochemical processes, according to another embodiment of the
invention.
[0009] FIG. 3A is a schematic representation of an elevational view
of a heat exchanger comprising a collapsible bag having a channel
within, according to one embodiment of the invention.
[0010] FIG. 3B shows a cross-sectional view of a collapsible bag
without welds according to one embodiment of the invention.
[0011] FIG. 3C depicts a cross-sectional view of a collapsible bag
having welds and channel segments according to one embodiment of
the invention.
[0012] FIGS. 4A-4C depict various configurations of heat exchangers
in the form of collapsible bags according to some embodiments of
the invention.
[0013] FIGS. 4D-4G illustrate cross-sectional views of a channel
segment of a collapsible bag according to some embodiments of the
invention.
[0014] FIG. 5 depicts an elevational, cutaway view of a heat
exchange system in fluid communication with a container for holding
or storing a fluid according to one embodiment of the
invention.
[0015] FIG. 6 depicts a perspective view of the heat exchange
system shown in FIG. 5 according to one embodiment of the
invention.
[0016] FIG. 7 depicts a perspective view of a heat exchange system
according to one embodiment of the invention.
[0017] FIG. 8 depicts a temperature-controlling surface that
includes a channel for flowing a heating or cooling fluid
therethrough according to one embodiment of the invention.
[0018] FIG. 9 depicts a heat exchanger and containers in the form
of modules according to one embodiment of the invention.
DETAILED DESCRIPTION
[0019] A description of preferred embodiments of the invention
follows. It will be understood that the particular embodiments of
the invention are shown by way of illustration and not as
limitations of the invention. At the outset, the invention is
described in its broadest overall aspects, with a more detailed
description following. The features and other details of the
compositions and methods of the invention will be further pointed
out in the claims.
[0020] Disclosed herein are systems and methods for containing and
manipulating fluids, and for regulating the temperature of fluids
associated with a chemical, biological, or pharmaceutical reaction
or process. Certain embodiments of the invention involve a series
of improvements and features for fluid containment systems, for
example, by providing a vessel including a heat exchanger which may
be in the form of a flexible, collapsible bag.
[0021] Although much of the description herein involves an
exemplary application of the present invention related to
bioreactors and chemical, reaction systems, the invention and its
uses are not so limited, and it should be understood that aspects
of the invention can also be used in other settings, including
those involving containment systems in general, as well as systems
for containment or for mixing or other processing.
The Collapsible Bag or Other Container
[0022] Many disclosed examples include the use of collapsible bags,
liners, or flexible containers. In addition, an embodiment of the
invention can include systems utilizing non-collapsible bags, rigid
containers, semi-flexible containers and other configurations
involving liquid containment.
[0023] "Flexible container", "flexible bag", or "collapsible bag"
as used herein, indicates that the container or bag is unable to
maintain its shape and/or structural integrity when subjected to
the internal pressures, for example, pressures resulting from the
weight or hydrostatic pressure of liquids or gases contained
therein without the benefit of a separate support structure. A
reusable support structure may be utilized to surround and support
the collapsible bag.
[0024] The collapsible bag may be made out of inherently flexible
materials, such as many plastics, or may be made out of what are
normally considered rigid materials such as glass or certain
metals, but having a thickness or other physical properties
rendering the container as a whole unable to maintain its shape or
structural integrity when subjected to the internal pressures
expected during operation without the benefit of a separate support
structure. In some embodiments, collapsible bags include a
combination of flexible materials and substantially rigid materials
such as a rigid polymer, metal, or glass. For example, the
collapsible bag, liner or other container may include rigid
components such as connections, ports, supports for a mixing and/or
antifoaming system.
[0025] In some embodiments, a rigid container or a collapsible bag
comprises a polymeric material, for example, as a bulk material.
Polymeric materials, such as the ones described herein, can be
selected or formulated to have suitable physical and mechanical
characteristics, for example, by tailoring the amounts of
components of polymer blends to adjust the degree of any expected
cross-linking. For instance, those of ordinary skill in the art can
choose suitable polymers for use in containers based on factors
such as the polymer's thermal conductivity, compatibility with
certain processing techniques, compatibility with
thermally-conductive materials, compatibility with any materials,
such as cells, nutrients, solvents, contained in the container, and
compatibility with sterilizations or other treatments or
pre-treatments associated with performing a reaction inside the
container.
[0026] In some embodiments, a collapsible bag is formed of a
suitable flexible material, such as a homopolymer or a copolymer.
The flexible material may be one that is USP Class VI certified,
for example., silicone, polycarbonate, polyethylene, and
polypropylene. Non-limiting examples of flexible materials include
polymers such as polyethylene (for example, linear low density
polyethylene and ultra low density polyethylene), polypropylene,
polyvinylchloride, polyvinyldichloride, polyvinylidene chloride,
ethylene vinyl acetate, polycarbonate, polymethacrylate, polyvinyl
alcohol, nylon, silicone rubber, other synthetic rubbers and/or
plastics. Portions of the flexible container may comprise a
substantially rigid material such as a rigid polymer, for example,
high density polyethylene, metal, or glass. Substantially rigid
materials may be utilized in areas for supporting fittings, for
example.
[0027] In other embodiments, the container is a substantially rigid
material. Optionally, all or portions of the container may be
optically transparent to allow viewing of contents inside the
container. The materials or combination of materials used to form
the container may be chosen based on one or more properties such as
flexibility, puncture strength, tensile strength, liquid and gas
permeability, opacity, and adaptability to certain processes such
as blow molding for forming seamless collapsible bags. The
container may be disposable in some cases.
[0028] The container may have any suitable thickness for holding a
liquid and may be designed to have a certain resistance to
puncturing during operation or while being handled. The thickness
of a material such as a container wall is often specified in
"mils." A mil is a unit of length equal to one thousandth
(10.sup.-3) of an inch, which is equivalent to 0.0254 millimeter.
The unit "millimeter" is abbreviated herein as "mm." For example, a
thickness of the flexible wall portions of a collapsible bag
suitable for use in an embodiment of the invention may be less than
10 mils (less than 0.254 mm), or from about 10 mils to about 100
mils (from about 0.254 mm to about 2.54 mm) or from about 15 mils
to about 70 mils (from about 0.38 mm to about 1.78 mm), or from
about 25 mils to about 50 mils (from about 0.64 mm to about 1.27
mm). In yet another example, the walls of a container may have a
total thickness of about 250 mils.
[0029] In some embodiments, the container includes more than one
layer of material that may be laminated together or otherwise
attached to one another in order to impart certain properties to
the container. For instance, one layer may be formed of a material
that is substantially oxygen impermeable. Another layer may be
formed of a material to impart strength to the container. Yet
another layer may be included to impart chemical resistance to a
fluid that may be contained in the container. One or more layers of
the container may include a thermally-conductive material to
facilitate heat transfer to and from the interior of the container
to an environment outside of the container, as described in more
detail below.
[0030] A container, liner, or other article disclosed herein may be
formed of any suitable combinations of layers. Non-limiting
examples include an article comprising from 1 layer to about 5
layers of the same or different materials. Each layer may have a
thickness of, for example, from about 3 mils to about 200 mils
(from about 0.076 mm to about 5.08 mm), or combinations
thereof.
[0031] The containers, for example, collapsible bags, may be
adapted to include components of various sizes. In certain
embodiments, the thickness of a collapsible bag or other container
and the thickness of a portion of a component to be joined, for
example, fused, with the collapsible bag are, relative to the
thickest portion, within about 5 percent to about 30 percent, or
from about 10 percent to about 20 percent of one another.
[0032] A component to be incorporated with the container may have
at least one cross-sectional dimension, thickness, or height of,
for example, from about 0.05 centimeter (cm) to about 10 cm, or
from about 1 cm to about 5 cm, or from about 1.5 cm to about 2 cm.
A suitable thickness or height of a component may also be from
about 15 cm to about 30 cm, or from about 20 cm to about 25 cm. A
suitable thickness or height of a component can also be greater
than 30 cm.
[0033] Components that are integrated with collapsible bags or
other containers may be formed in any suitable material, that may
be the same or different from the material of the bag or container.
In one embodiment, a container is formed in a first polymer and a
component is formed in a second polymer that is different, for
example, in composition, molecular weight, or chemical structure,
from the first polymer. Those of ordinary skill in the art will be
familiar with material processing techniques and will be able to
use such techniques in the methods described herein to choose
suitable materials and combinations of materials.
[0034] A rigid container or a collapsible bag suitable for use in
an embodiment of the invention may have any size for containing a
liquid. For example, the container may have a volume from about 0.1
liter to about 10,000 liters (from about 100 cubic centimeters to
about 1.times.10.sup.7 cubic centimeters.) The term "cubic
centimeter" will be abbreviated herein as "cm.sup.3." In other
non-limiting examples, the container may have a volume from about 5
liters to about 5,000 liters (from about 5,000 cm.sup.3 to about
5.times.10.sup.6 cm.sup.3), or from about 40 liters to about 1,000
liters (from about 4.times.10.sup.4 cm.sup.3 to about
1.times.10.sup.6 cm.sup.3). Volumes greater than 10,000 liters
(1.times.10.sup.7 cm.sup.3) are also possible. The suitable volumes
may depend on the particular use of the container. For example, a
collapsible bag used as a heat exchanger may have a smaller volume
than a collapsible bag used to hold and store a large amount of
fluid.
[0035] A suitable container as part of a heat exchange system may
be in fluid communication with a second container that is used to
store or hold fluids. Either container or both containers may be in
the form of a collapsible bag. The two containers may have about
the same volume, or may have significantly different volumes. For
example, the volume of the larger container may be from about 5
times to about 100 times greater than the volume of the smaller
container. Other combinations of containers having different
volumes are also possible.
[0036] In certain embodiments, especially in certain embodiments
involving fluid manipulations or for carrying out a chemical or
biological reaction in a container, the container is substantially
closed, for example, substantially sealed from the environment
outside of the container. As used herein, the term "sealed" is used
to describe containers that are completely sealed from the
environment such that no substances can move out of the container
or into the container; containers that are essentially sealed such
that only trace amounts of substances can move into or out of the
container; and containers including one or more inlet or outlet
ports that allow addition to, or withdrawal of contents from the
container.
[0037] If a collapsible bag is used, it may be substantially
deflated prior to being filled with a liquid, and may begin to
inflate as it is filled with liquid. In other embodiments, the
invention may include open container systems.
[0038] Many existing collapsible bags are constructed from two
sheets of a plastic material joined by thermal or chemical bonding
to form a container having two longitudinal seams. The open ends of
the sheets are then sealed using known techniques, and access
apertures are formed through the container wall. During use,
collapsible bags having seams can cause the formation of crevices
at or near the seams where materials contained therein are not
thoroughly mixed. Such unmixed reagents can cause a reduction in
yield of a desired product of a chemical or biological process. The
presence of the seams in a collapsible bag can also result in
non-uniform heat distribution of fluids or the inability of the
collapsible bag to conform to the shape of a reusable support
structure surrounding the bag.
Seamless Collapsible Bags
[0039] The above-described problems can be avoided by using
collapsible bags without any seams. In one embodiment, seamless
collapsible bags can be made specifically to fit a particular
reusable support structure having a unique shape and configuration.
Substantially perfect-fitting collapsible bags can be used, for
example, as part of a bioreactor system or a biochemical or
chemical reaction system. Seamless rigid or semi-rigid containers
may also be beneficial in some instances.
[0040] A seamless collapsible bag suitable for use in an embodiment
of the invention is a collapsible bag that does not include any
seams joining two or more wall portions of the collapsible bag. The
collapsible bag may be produced by blow molding, injection molding,
or spin cast molding. In some embodiments, the referenced seamless
collapsible bag may have one or more of a rigid, a semi-rigid, and
a flexible wall portion.
[0041] A functional pre-made component may be formed integrally
with the seamless collapsible bag as the seamless bag is produced.
For example, a method of forming a seamless collapsible bag having
a pre-made component embedded in a wall portion of the bag may
include the steps of: positioning a pre-made component in a mold
having a shape configured to mold a container having a pre-selected
volume; introducing a at least one polymer precursor into the mold;
forming a seamless container within the mold by solidifying the
polymer precursor to form the container, while embedding at least a
portion of the pre-made component with one or more wall portions of
the container to form an integral piece of material without
seams.
[0042] In another embodiment, a functional component such as an
impeller shaft may be formed simultaneously and integrally with the
seamless collapsible bag as the seamless bag is produced. For
example, the method may include introducing a first polymer
precursor into a mold having a shape configured to mold a
collapsible bag having a pre-selected volume, and also configured
to mold a base including a shaft configured to support a magnetic
impeller; forming a collapsible bag within the mold; introducing a
second polymer precursor into the mold; forming the shaft by
solidifying the second polymer precursor; and joining the shaft and
the collapsible bag without welding. In one embodiment of the
invention, the first and second polymers are introduced into the
mold approximately simultaneously.
[0043] Additional description of seamless containers can be found
in U.S. patent application Ser. No. 11/818,901, filed Jun. 15,
2007, entitled, "Gas Delivery Configurations, Foam Control Systems,
and Bag Molding Methods and Articles for Collapsible Bag Vessels
and Bioreactors," by G. Hodge, et al., published as US2008/0068920
A1 on Mar. 20, 2008, the entire teachings of which are incorporated
herein by reference.
Exemplification
[0044] The invention is described in more detail in the following
examples, which are provided by way of illustration and are not
intended to limit the invention in any way. In one embodiment, a
vessel configured to contain a volume of liquid is a part of a
bioreactor system. Turning now to the drawings, the schematic
diagram of FIG. 1 depicts vessel 10, which includes a reusable
support structure 14. An example of the support structure 14 is a
stainless steel tank that surrounds and contains a container 18. In
some embodiments, the container 18 is configured as a collapsible
bag or liner, for example, a polymeric bag, and may optionally
include tubing, a magnetic drive pump, and/or a foam breaker. In
other embodiments, the container 18 is made of a substantially
rigid material. The container 18 may be disposable, and may be
configured to be easily removable from the support structure, or
configured to be irreversibly connected to the support
structure.
[0045] If a collapsible bag is used as container 18, it may be
constructed and arranged for containing a liquid 22, which may
contain reactants, media, or other components necessary for
carrying out a desired process such as a chemical, biochemical or
biological reaction. The collapsible bag may also be configured
such that liquid 22 remains substantially in contact only with the
collapsible bag during use and not in contact with support
structure 14. In such embodiments, the collapsible bag may be
disposable and used for a single reaction or a single series of
reactions, after which the bag is discarded. Because the liquid in
the collapsible bag in such embodiments does not come into contact
with the support structure 14, the support structure 14 can be
reused without cleaning. After a reaction takes place in container
18, the container 18 can be removed from the reusable support
structure 14 and replaced by a second disposable container. A
second reaction can be carried out in the second container without
having to clean either the first container 18 or the reusable
support structure 14. If any liquid 22 does come into contact with
the reusable support structure due to leakage from the bag, in
certain embodiments, one or more leak detection systems that are
associated with vessel 10 detect the leak and notify the user so
that appropriate measures can be taken.
[0046] Also shown in FIG. 1 are an optional inlet port 42 and
optional outlet port 46, which can be formed in the container 18 or
reusable support structure 14, and can facilitate more convenient
introduction and removal of a liquid 14 or gas from the container
18. The container 18 may have any suitable number of inlet ports 42
and any suitable number of outlet ports 46. For example, a
plurality of inlet ports 42 may be used to provide different gas
compositions via a plurality of spargers 47, or to allow separation
of gases prior to their introduction into the container 18. These
ports may be positioned in any suitable location with respect to
container 18. For instance, for certain vessels including spargers
47, the container 18 may include one or more gas inlet ports
located at a bottom portion of the container 18. Tubing may be
connected to the inlet and outlet ports 42 and 46 to form delivery
and harvest lines, respectively, for introducing and removing
liquid from the container 18. Optionally, the container 18 or
support structure 14 may include a utility tower 50, which
facilitates interconnection of one or more devices internal to the
container 18 or support structure 14 with one or more pumps,
controllers, or electronics, such as sensor electronics, electronic
interfaces, and pressurized gas controllers or other devices. Such
devices may be controlled using a control system 34. The control
system 34 may also be used to send signals to and receive signals
from a leak detection system and a wrinkle removal system.
[0047] For systems including multiple spargers 47, control system
34 may be operatively associated with each of the spargers 47 and
configured to operate the spargers 47 independently of each other.
This can allow control of multiple gases being introduced into the
container 18.
[0048] In general, as used herein, a component of an inventive
system that is "operatively associated with" one or more other
components indicates that such components are directly connected to
each other, in direct physical contact with each other without
being connected or attached to each other, or are not directly
connected to each other or in contact with each other, but are
interconnected mechanically, electrically, fluidically, or remotely
via electromagnetic signals, so as to cause or enable the
components so associated to perform their intended
functionality.
[0049] The vessel 10 may optionally include a mixing system such as
an impeller 51, which can be rotated about an axis using a motor 52
that can be external to the container 18. In some embodiments, as
described in more detail below, the impeller 51 and motor 52 are
magnetically coupled. The mixing system can be controlled by
control system 34. Mixing systems are described in further detail
below.
[0050] Additionally or alternatively, the vessel 10 may include an
antifoaming system such as a mechanical antifoaming device. As
shown in the embodiment illustrated in FIG. 1, an antifoaming
device may include, for example, an impeller 61 that can be rotated
magnetically using a motor 62, which may be external to the
container 18. The impeller 61 can be used to collapse a foam
contained in a head space 63 of the container 18. In some
embodiments, the antifoaming system is in electrical communication
with a sensor 43, for example, a foam sensor, via control system
34. The sensor 43 may determine, for instance, the level or amount
of foam in the head space 63 or the pressure in the container 18.
The determination by the sensor 43 can trigger regulation or
control of the antifoaming system. In other embodiments, the
antifoaming system is operated independently of any sensors.
[0051] The support structure 14 and/or the container 18 may also
include, in some embodiments, one or more ports 54 that can be used
for sampling, determining and/or analyzing conditions such as pH or
the amount of dissolved gases in the liquid 22 or for other
purposes. The support structure 14 may also include one or more
site windows 60 for viewing a level of liquid 22 within the
container 18. One or more connections 64 may be positioned at a top
portion of the container 18 or at any other suitable location.
Connections 64 may include openings, tubes, and/or valves for
adding or withdrawing liquids, gases, and the like from the
container 18, each of which may optionally include a flow sensor
and/or filter (not shown). The support structure 14 may further
include a plurality of legs 66, optionally with wheels 68 for
facilitating transport of the vessel 10.
[0052] It should be understood that not all of the features shown
in FIG. 1 need be present in all embodiments of the invention and
that the illustrated elements may be otherwise positioned or
configured. Also, additional elements may be present in other
embodiments, such as the elements described herein. For example, in
some embodiments, a vessel 10 or one or more components of the
vessel 10 is associated with an "identifier". The identifier may be
used to guide proper assembly of system components, verify that the
system components are correctly assembled, and protect against the
use of counterfeit, improper or unauthorized components, for
example. Each identifier may itself be "encoded with" information.
In other words, the encoded information may be carry or contain
information about the component including the identifier, such as
by use of an information-carrying, storing, generating, or
conveying device, such as a radio frequency identification (RFID)
tag or bar code. In another embodiment, each identifier may not
itself be encoded with any information about the component, but
rather may only be associated with information that may be
contained in, for example, a database on a computer or on a
computer readable medium. In the latter instance, detection of such
an identifier can trigger retrieval and usage of the associated
information from the database.
[0053] Additional examples and uses of identifiers are described in
more detail in U.S. patent application Ser. No. 12/011,492, filed
on Jan. 25, 2008, entitled, "Information Acquisition and Management
Systems and Methods in Bioreactor Systems and Manufacturing
Facilities", which is incorporated herein by reference.
[0054] In other embodiments, one or more components shown in FIG. 1
are configured to be a part of a bioreactor system 100, as
illustrated in FIG. 2 and as described in more detail below.
Bioreactor or Mixer with Heat Exchange System
[0055] In some embodiments, a heat exchange system described herein
is in fluid communication with one or more components of a
bioreactor system, such as bioreactor system 100 shown in FIG. 2.
For example, container 18 may be operatively associated with and/or
in fluid communication with a temperature controller 106 which may
comprise a heat exchanger 200 described in connection with FIGS.
3-9. In other embodiments, however, a closed loop water jacket, an
electric heating blanket, a PELTIER heater or cooler, or other
temperature control system known to those of ordinary skill in the
art can also be used in combination with container 18. The
temperature control system may also include a thermocouple and/or a
resistance temperature detector for sensing a temperature of the
contents inside the container 18. The thermocouple may be
operatively connected to the temperature controller/heat exchanger
to control temperature of the contents in the container 18.
Optionally, as described herein, a thermally-conductive material
may be associated with a surface of the container 18, for example,
to provide a heat transfer surface 104, 104A in FIG. 2, to overcome
the insulating effect of the material used to form portions of the
container 18.
[0056] In some cases, sensors 108 and/or probes may be connected to
a sensor electronics module 132, the output of which can be sent to
a terminal board 130 and/or a relay box 128. Various sensors and/or
probes for controlling and/or monitoring one or more process
parameters inside the container such as, for example, temperature,
pressure, pH, dissolved oxygen (DO), dissolved carbon dioxide
(DCO.sub.2), mixing rate, and gas flow rate, can be used. The
results of the sensing operations may be input into a computer or
computer-implemented control system 115 for calculation and control
of various parameters such as temperature and weight/volume
measurements, and for display and user interface. Such a control
system 115 may also include a combination of electronic,
mechanical, and/or pneumatic systems to control heat, air, or
liquid delivered to or withdrawn from the container 18 as required
to stabilize or control the environmental parameters of the process
operation. It should be appreciated that the control system 115 may
perform other functions and is not limited to having any particular
function or set of functions.
[0057] The one or more control systems 115 can be implemented in
numerous ways, such as with dedicated hardware and/or firmware,
using a processor that is programmed using microcode or software to
perform the functions recited above or any suitable combination of
the foregoing. A control system 115 may control one or more
operations of a single reactor for a biological or chemical
reaction, or of multiple reactors that are separate or
interconnected. The embodiment depicted in FIG. 2 depicts a drive
control system 110 comprising a drive motor 112 for the
agitator/impeller system, the controller 114 for controlling drive,
and the drive 116 for controlling the motor 112.
[0058] Each embodiment of a system described herein, for example,
with reference to FIG. 2, and components thereof, may be
implemented using any of a variety of technologies, including
software, for example, C, C#, C++, Java, or a combination thereof;
hardware, for example, one or more application-specific integrated
circuits; firmware, for example, electrically-programmed memory; or
any combination of the foregoing.
[0059] Various embodiments described herein may be implemented on
one or more computer systems. These computer systems, may be, for
example, general-purpose computers such as, for example, those
based on INTEL.RTM.) processors such as PENTIUM.RTM. or XSCALE.RTM.
(INTEL Corporation, Inc.). It should be appreciated that one or
more of any type of computer system may be used to implement
various embodiments described herein. The computer system may
include specially-programmed, special-purpose hardware, for
example, an application-specific integrated circuit (ASIC). Various
components may be implemented in software, hardware or firmware, or
any combination thereof. Further, such methods, acts, systems,
system elements and components thereof may be implemented as part
of the computer system described above or as an independent
component.
[0060] In one embodiment, a control system 115 operatively
associated with a vessel described herein is portable, and may
require a significantly shorter time period for set-up than do
conventional fluid manipulation control systems. The control system
115 may include, for example, all or many of the necessary controls
and functions required in a bioreactor system to perform a fluidic
manipulation such as temperature control, mixing, and carrying out
a reaction. The control system 115 may include a support and wheels
for facilitating transport of the vessel. Advantageously, such a
portable control system can be programmed with set instructions,
and if desired, transported separately or with the vessel, and
hooked up to a vessel, ready to perform a fluid manipulation.
[0061] A vessel may also be connected to one or more sources of
gases 118, 124 such as air, oxygen, carbon dioxide, nitrogen,
ammonia, or mixtures thereof, in some embodiments. The gases may be
compressed or may be pumped, for example. Such gases may be used,
for example, to provide suitable growth or reaction conditions for
producing a product inside the container 18. The gases may also be
used to provide sparging to the contents inside the container, for
mixing, or for other purposes. For instance, in certain embodiments
employing spargers, bubble size and distribution can be controlled
by passing an inlet gas stream through a porous surface prior to
being added to the container. Additionally, the sparging surface
may be used as a cell separation device by alternating
pressurization and depressurization, for example, by application of
vacuum on the exterior surface of the porous surface, or by any
other suitable method.
[0062] In FIG. 2, the inlet gases from sources of gases 118 and 124
may optionally pass through filter 120 and/or a flow meter and/or
valve 122, which may be controlled by controller system 115, prior
to entering the container 18. Valve 122 may be a pneumatic
actuator, actuated by, for example, compressed air, carbon dioxide,
or other gas 124, which may be controlled by a solenoid valve 126.
These solenoid valves 126 may be controlled by a relay 128
connected to terminal board 130, which is connected to the
controller system 115. The terminal board may comprise, for
example, a PCI terminal board, or a USB/parallel, or fire port
terminal board of connection. In other embodiments, flush closing
valves can be used for addition ports, harvest and sampling valves.
Progressive tubing pinch valves that are able to meter flow
accurately can also be used. In some cases, for example, for inlet
ports, outlet ports, and sampling ports, the valves may be flush
closing valves. The inlet gases may be connected to any suitable
inlet of the vessel. In one embodiment, the inlet gases are
associated with one or more spargers which can be controlled
independently, as described in more detail below.
[0063] As shown in the exemplary embodiment illustrated in FIG. 2,
the container 18 and support structure 14 illustrated in FIG. 1 can
be operatively associated with a variety of components as part of
an overall bioreactor system 100. Accordingly, in FIG. 2, the
container 18 and/or support structure 102 may include several
fittings to facilitate connection to functional component such as
filters, sensors, and mixers, as well as connections to lines for
providing reagents such as liquid media, gases, and the like. The
container 18 and the fittings may be sterilized prior to use so as
to provide a "sterile envelope" protecting the contents inside the
container 18 from airborne contaminants outside. In some
embodiments, the contents inside the container 18 do not contact
the reusable support structure 102 and, therefore, the reusable
support structure 102 can be reused after carrying out a particular
chemical or biological reaction without being sterilized, while the
container 18 and/or fittings connected to the container 18 can be
discarded. In other embodiments, the container, fittings, and/or
reusable support structure 102 may be reused (for example, after
cleaning and sterilization).
Temperature Controlling Surface
[0064] As used herein, the term "temperature-controlling surface"
has the same meaning as "heat transfer surface." A
temperature-controlling surface may be in contact with one or more
exterior or interior surface portions of a collapsible bag. A
temperature-controlling surface may comprise a thermally-conductive
material, a plurality of particles embedded in a surface of the
bag, a plate comprising channels for allowing fluid to flow
therethrough, channels for allowing fluid to flow therethrough
wherein the channels are not associated with a plate, and
combinations of the foregoing.
[0065] The temperature of the fluid flowing in the collapsible bag
18 can be changed, in one embodiment, by associating one or more
surfaces of the collapsible bag with a heat transfer surface, for
the purpose of promoting transfer of heat to and/or from the
collapsible bag 18. In some embodiments, a system of the invention
includes a heat exchanger in fluid communication with another
vessel that can hold or store the heated or cooled fluid. The
vessel may be positioned adjacent a thermally-conductive material
to help maintain the temperature of the fluid inside the vessel.
Optionally, the vessel may include an impeller or agitator to
uniformly distribute heat throughout the interior of the vessel.
Advantageously, the embodiments described herein may be sterile and
configured for a single use or a single series of uses, after which
the components can be discarded.
[0066] Another aspect of the invention includes a heat exchanger
that can be used to control the temperature of a fluid from
container 18 of FIG. 1, or a fluid from any other suitable fluid
source. Accordingly, the heat exchanger may be in the form of a
container, for example, a collapsible bag, that is constructed and
arranged to receive a fluid. By flowing a fluid through the
collapsible bag, heat can be transferred from the fluid to an
environment exterior to the bag or from an exterior environment to
the fluid via the bag. This process can allow the fluid to be
heated or cooled to a particular temperature before it exits the
collapsible bag into another vessel.
[0067] To enhance heat conduction, one or more surfaces of the
collapsible bag may be associated with a heat transfer surface, for
example, a thermally-conductive material. For instance, in one
embodiment, the material used to form the collapsible bag may have
thermally-conductive particles embedded therein. In another
embodiment, an exterior surface portion of the collapsible bag is
in contact with a temperature-controlling surface, such as a
heating or cooling surface. These and other thermally-conductive
materials/systems are described in more detail below.
[0068] In one embodiment of the invention, the collapsible bag may
include one or more welds connecting a first interior surface
portion to a second interior surface portion of the bag so as to
form a channel between the first and second interior surface
portions. Compared to a bag without welds or channels, the presence
of a channel within the bag can result in a longer path for bulk
fluid flow permitting fluid to be cooled or heated uniformly for a
longer period of time. A channel can also prevent or reduce "dead
zones" that may lead, for example, to non-uniform heating or
cooling of fluid.
[0069] As shown in a side view of the embodiment illustrated in
FIG. 3A, heat exchanger 200 is in the form of a collapsible bag 202
and has a width 204 and a length 206. As illustrated, fluid can be
introduced into the collapsible bag 202 via inlet 220; the fluid
may flow in the direction of arrows 236 in channel 211, and in each
of the channel segments 212 until it reaches outlet 222.
[0070] In this particular embodiment, the width is the maximum
dimension 219 across the perimeter 208 of the collapsible bag 202.
The width can be measured while the collapsible bag 202 is fully
expanded, or fully collapsed. Heat exchanger 200 also includes a
plurality of welds 210 connecting a first interior surface portion
to a second interior surface portion of the collapsible bag 202.
The welds 210 can be positioned at various interior portions of the
collapsible bag 202 so as to form a channel 211 between the first
and second interior surface portions. As illustrated, channel 211
includes a plurality of channel segments 212 having a width
216.
[0071] Channel 211 defines a bulk fluid flow pathway through the
collapsible bag 202; that is, a fluid flowing from a first portion
to a second portion of the bag may flow in a predetermined
orientation and/or at a predetermined flow rate by applying a
pressure differential between the first and second portions. This
and other configurations comprising channels can reduce the amount
of random or non-directed fluid flow, for example, turbulence,
eddies, and so forth, in the collapsible bag 202.
[0072] Typically, the channel 211 comprises from about 4 channel
segments to about 10 channel segments. The presence of the channel
segments 212 allows a directed and longer fluid flow pathway than a
bag of a similar shape and volume which does not include the welds
210 and channel segments 212. For example, the selected bulk fluid
flow pathway length may be from about 2 times to about 12 times the
maximum dimension 219 across the collapsible bag 202 outer
perimeter 208, or from about 3 times to about 8 times the maximum
dimension across the collapsible bag 202 outer perimeter 208.
Because the fluid pathway is lengthened by the presence of the
channel 211, the fluid can flow in the collapsible bag 202 for a
longer period of time and can allow the fluid to be heated or
cooled for a longer period of time than the flow period and heating
or cooling period for a bag without channel segments 212. Such a
configuration can also prevent or reduce "dead zones" that may
lead, for example, to non-uniform heating or cooling of fluid.
[0073] As depicted in FIG. 3C, in some embodiments, the welds 210
results in the formation of channel 211 with a plurality of channel
segments 212, each having a maximum cross-sectional dimension 216,
which is smaller than a maximum dimension 219 across a perimeter
208 of the collapsible bag 202 at full expansion of the collapsible
bag 202. FIG. 3B shows a cross-sectional view of a collapsible bag
202 that does not include welds 210, and which has a perimeter 208
and a maximum dimension 219 across the perimeter. As illustrated in
the cross-sectional view of FIG. 3C, the same collapsible bag 202
as the one shown in FIG. 3B, but with welds 210, also has a maximum
dimension 219 across perimeter 208 of the bag. The presence of the
welds 210 provides a longer flow path for reaction, or for heating
and cooling
[0074] In one embodiment, the average cross-sectional dimension of
the channel 211 at full expansion of the collapsible bag 202 is
from about one tenth to about one fourth of the maximum dimension
219 of the collapsible bag 202. The maximum cross-sectional
dimension 221 of a channel segment 212 may be, for example, from
about 1/2 to about 1/20 of the maximum dimension 219 across a
perimeter 208 of the collapsible bag 202, or from about 1/3 to
about 1/8 of the maximum dimension 219 across a perimeter 208 of
the collapsible bag 202, measured at full expansion or full
collapse of the collapsible bag 202.
[0075] The cross-sectional dimension of the channel may be designed
to allow a particular flow rate, internal pressure, and/or length
of time of fluid flow inside the bag. These parameters, in turn,
may be chosen depending on, for example, the particular fluid to be
flowed in the bag, the volume of the collapsible bag 202, the
desired temperature change, and the like. Accordingly, depending on
these and other factors, a channel 211 of the collapsible bag 202,
at full expansion, or full collapse, of the collapsible bag 202,
may have, for example, a maximum cross-sectional dimension 221
taken perpendicular to the centerline of the channel 211 of from
about 1 centimeter to about 20 centimeters. In some embodiments,
the maximum cross-sectional dimension 221 of a channel 211 portion
is from about 5 centimeters to about 10 centimeters. Furthermore, a
container may include any suitable number of channel segments 212,
for example from about 2 to about 20, or from about 4 to about 10
channel segments. Typically, a greater number of channel segments
212 results in channels 211 having smaller cross-sectional
dimensions compared to a container of the same volume and shape
having a smaller number of channel segments 212. A greater number
of channel segments 212 may be suitable for applications involving
relatively slower fluid flow, lower internal pressures, and/or for
applications where it is desirable to maintain fluid flow in the
collapsible bag 202 for a longer period of time.
[0076] The volume of the collapsible bag 202 may depend on the
volume of fluid to be heated or cooled, as well as the volume of a
container that may be in fluid communication with the collapsible
bag 202, as described in more detail below.
[0077] As stated above, a collapsible bag 202 may optionally
include one or more sensors, such as temperature sensors, for
determining a component or a condition within the collapsible bag
202. For example, a temperature sensor may be used to determine the
temperature of a fluid inside the collapsible bag 202. A pressure
sensor may be used to determine the amount of pressure inside the
collapsible bag 202, for example, during the flow of fluid in the
collapsible bag 202. A flow rate sensor may determine the flow rate
of a fluid flowing in the collapsible bag 202, for example, so that
a particular flow rate can be maintained. Sensors for determining
components, for example, reactants and products, of a fluid may
also be incorporated into the collapsible bag 202. The sensor may
be positioned at any suitable location such as inside the
collapsible bag 202, within a wall of the collapsible bag 202; or
it may be embedded in a wall of the collapsible bag 202.
Furthermore, a collapsible bag may include more than one sensor.
For example, FIG. 3A shows a first sensor 215 positioned near inlet
220 and a second sensor 217 near outlet 222. Sensors 215 and 217
can be used to measure the difference in temperature between the
fluid flowing into and out of the collapsible bag 202.
[0078] It should be understood that welds 210 may be formed by any
suitable process and, in some cases, may depend on the particular
materials used to form the container. Accordingly, a weld 210 may
include any suitable joining of two or more wall portions, for
example, two or more interior surface portions of a container, and
may be achieved by methods such as welding, including, for example,
heat welding and ultrasonic welding, use of the adhesive, clamping,
fastening, or other attaching techniques.
[0079] In some cases, a plurality of welds 210 are present in a
container to form a channel 211 having a non-linear configuration.
For example, as illustrated in FIG. 3A, channel 211 may be in the
form of a serpentine configuration. A second serpentine
configuration is shown in a side view of the embodiment illustrated
in FIG. 4A. Other configurations of channels 211 and welds 210 are
shown in FIGS. 4B and 4C. As illustrated in the side view of a
container 242 shown in FIG. 4B, a single, continuous weld 210 may
be used to form channel 211 in the form of a spiral configuration.
FIG. 4C shows a side view of a container 244 in yet another
configuration that can allow formation of a fluid pathway that can
allow uniform heating or cooling of a fluid. These and other
configurations can allow inlet 220 and outlet 222 to be positioned
at different locations within the container.
[0080] FIG. 4D shows a cross section of a channel segment according
to one embodiment of the invention. Channel 211 includes interior
surface portions 252 and exterior surface portions 254. The channel
is formed by welds 210 that connect two interior surface portions
of the bag. FIG. 4D shows channel 211 upon full expansion of the
bag. As illustrated in this exemplary embodiment, channel 211
includes a perimeter 209 having a maximum cross section 258, as
described above, therethrough. The maximum cross section, in some
embodiments, can be varied by changing the distance between welds
210. For instance, as shown in the embodiment illustrated in FIG.
4E, a closer distance between welds 210 may result in a smaller
maximum cross section 258, a smaller cross-sectional area, and a
different shape of the channel.
[0081] As shown in the embodiments illustrated in FIGS. 4F and 4G,
a collapsible bag may be positioned between two surfaces 260 in
some embodiments. One or both of surfaces 260 may be a heat
transfer surface or temperature-controlling surface; that is, the
temperature of all or a portion of the surface may be varied,
controlled and/or set to a particular temperature or range of
temperatures. Temperature-controlling surfaces may comprise a
thermally-conductive material and can be used to locally heat or
cool a container positioned adjacent the surface. Examples of
temperature-controlling surfaces are provided below.
[0082] In some embodiments, surfaces 260 may be positioned so as to
inhibit full expansion of the bag and channel 211. FIG. 4F shows a
relatively small separation distance 264 between surfaces 260 that
can promote greater inhibition of full expansion of channel 211
compared to that shown in FIG. 4G, which shows a greater separation
distance 266 between surfaces 260. The configuration shown in FIG.
4F can allow, in some embodiments, a greater amount of exterior
surface portion 254 to be in contact with surface 260. This
configuration may be advantageous for certain applications, for
example, when surface 260 is a thermally-conductive surface that
can promote heat transfer into and out of a fluid in channel 211.
As shown in FIG. 4G, the positioning of surfaces 260 which allows
greater expansion of channel 211 can result in less surface area of
contact between surfaces 260 and exterior surface portions 254 of
the bag.
[0083] Accordingly, any suitable separation distance may be
maintained between surfaces 260. For example, the average minimum
separation distance between the two surfaces may be from about 1
centimeter to about 30 centimeters, or from about 5 centimeters to
about 20 centimeters, or from about 7 centimeters to about 10
centimeters. As described herein, the separation distance may
depend on the size and volume of the container positioned between
the surfaces, the number of channel segments, the flow rate to be
used with the system, the internal pressure in the container, etc.
In some embodiments, the separation distance is chosen to inhibit
full expansion of a collapsible bag during use.
[0084] Surfaces 260 may also be used to contain and support a
collapsible bag. For instance, the surface may form at least one
wall of a reusable support structure for supporting and containing
the collapsible bag. The reusable support structure may simply
include two plates separated by a distance to allow support of a
collapsible bag, or it may be part of a larger structure that
additionally includes support for a second collapsible bag, which
may hold a fluid. The plates may allow variation of the separation
distance. As one or more surfaces 260 may be thermally-conductive,
the heat exchanger may be used to heat or cool fluids at various
steps in a chemical or biological reaction process, as described in
more detail below. In some embodiments, the reusable support
structure is portable and can include wheels 324 or other
components to facilitate transport of the system.
[0085] A collapsible bag or other container can be maintained
between two surfaces by any suitable method such as by friction,
pressure (for example, pressure exerted on the surfaces upon
expansion of the collapsible bag), gravity, fastening with screws,
pegs, clamps, or the like, and use of adhesives. In some
embodiments, the two surfaces are a part of a single component that
acts as a reservoir for containing the collapsible bag. The
component may have a shape that is complementary to the shape of
the collapsible bag.
Heat Exchanger in the Form of a Collapsible Bag
[0086] Another aspect of the invention includes a heat exchange
system in fluid communication with a container for holding and/or
storing a fluid. As shown in the system 300 illustrated in FIG. 5,
a heat exchanger may be in the form of a collapsible bag 302. The
heat exchanger collapsible bag 302 may optionally include one or
more thermally-conductive materials, which may be, for example,
embedded in a wall of the collapsible bag 302. In the configuration
depicted in FIG. 5, the collapsible bag 302 is contained in and
supported by two heat transfer surfaces 306. A heat transfer
surface such as 306 and 320 may comprise a thermally-conductive
material for temperature control, including cooling or heating.
Collapsible bag 302 may be in fluid communication with a container
308, which may be in the form of a second collapsible bag or a
rigid container, via tubing 310, for example. As illustrated, an
impeller 316 may be associated with container 308 and can be used
to agitate or mix a fluid and/or to maintain a particular
temperature of a fluid inside the container. Impellers are
described in more detail below.
[0087] A heat transfer surface 320 for conducting heat either to or
away from container 308 may be in contact with one or more surfaces
of container 308. Additionally or alternatively, a heat transfer
surface 306 can also be used to control a temperature of a fluid in
container 308 by positioning container 308 adjacent heat transfer
surface 306.
[0088] As illustrated, system 300 may include wheels 324 or any
other suitable means, such as rails, rollers, and the like, for
transporting system 300. System 300 also comprises two horizontal
support bands 312, which support the sidewalls of container 308. In
one embodiment, support bands 312 are plastic-encased stainless
angle-iron, and are connected throughout the circumference of the
tank.
[0089] FIG. 6 shows a perspective view of system 300, including
support bands 312, the container 308 adjacent one of the heat
transfer surfaces 306, and the heat exchanger collapsible bag 302
sandwiched in between the two heat transfer surfaces 306.
[0090] FIG. 7 shows another example of a heat exchange system 330.
As illustrated in this exemplary embodiment, a collapsible bag may
be a heat exchanger bag 332 positioned adjacent a second
collapsible bag 334 which can contain and/or store a fluid. An
inlet 338 is arranged for introducing a fluid into the heat
exchanger bag 332. An outlet 340 of heat exchanger bag 332 may be
connected to an inlet 342 of second collapsible bag 334 via tubing
346. In some embodiments, a fluid is transferred from a first
container, for example, a bioreactor, to heat exchanger bag 332,
where the fluid is heated or cooled. Without storing any fluid in
collapsible bag 332, the fluid may be immediately transferred to
the second collapsible bag 334 where it is stored. After the fluid
is transferred into heat exchanger bag 332, inlet 338 may be closed
off by one or more valves to maintain a sterile environment inside
the heat exchanger bag 332. The fluid pathway between heat
exchanger bag 332 and the second collapsible bag 334 may also be
closed off by a valve after transferring the fluid.
[0091] As shown in the embodiment illustrated in FIG. 7, heat
exchanger bag 332 may be positioned between two heat transfer
surfaces 350, which may be in the form of plates. The plates may be
positioned relative to the bag so as to inhibit the full expansion
of the bag and channels during use. One of the two heat transfer
surfaces 350 may also be in contact with a side portion of the
second collapsible bag 334, so as to maintain a temperature of a
fluid transferred to the second collapsible bag 334.
[0092] Any suitable temperature-controlling surface may be used to
control the temperature of a fluid. In one embodiment, a
temperature-controlling surface, for example, heat transfer surface
350, includes one or more fluid channels for flowing a cooling or
heating fluid therethrough. For instance, a cooling or a heating
fluid may be flowed into inlet 354, through the channels of the
thermally-conductive surface, and may exit the channels via outlet
356. The fluid can then be re-circulated if desired. The
temperature of heat transfer surface 350 may be controlled by the
temperature of the cooling fluid flowing in one or more channels of
the thermally-conductive surface. Optionally, heat transfer
surfaces 350 may include one or more sensors. The sensors may
include a temperature sensor for determining the temperature of the
fluid circulating in the channels of heat transfer surface 350.
[0093] In another embodiment, a heat transfer surface 350 includes
a single sheet of thermally-conductive material that is operatively
associated with a heating or cooling source. Various heating and
cooling sources are known to those of ordinary skill in the art and
can be combined with heat exchange systems described herein. A heat
transfer surface 350 may be configured so as to vary and regulate
temperature of the surface and/or a fluid in a container adjacent
the surface within, for example, plus or minus 0.1.degree. Celsius
(.degree. C.), 0.2.degree. C., 0.5.degree. C., 1.0.degree. C., or
2.0.degree. C. of the desired temperature.
[0094] Also illustrated in FIG. 7 is a reusable support structure
360 that may contain and support the second collapsible bag 334. As
shown in this exemplary embodiment, the reusable support structure
360 may also contain and support heat exchanger bag 332 and heat
transfer surface surfaces 350.
[0095] The second collapsible bag 334 may include additional ports
370 for transferring a fluid into and/or out of second collapsible
bag 334. For instance, in one embodiment, second collapsible bag
334 is used to store and/or mix one or more fluids prior to
transferring the fluids into a chemical or biological reactor
system. The fluid in second collapsible bag 334 can be maintained
at a particular temperature which can facilitate the next process
to be performed with the fluid. The fluid can then be transferred
out of the second collapsible bag 334 via ports 370. In another
embodiment, second collapsible bag 334 is used to perform a
chemical, biological, or pharmaceutical reaction, and ports 370 can
be used to introduce and remove fluids or reagents from the second
collapsible bag 334.
[0096] FIG. 8 depicts a container 308 for holding a fluid
comprising, for example, reactants or products of a chemical or
biological process, the container 308 having at least one heat
transfer surface 380 that includes channels 382 for flowing a
heating or cooling fluid therethrough. The heating or cooling fluid
can be introduced into the channel 382 via inlet 386 and may exit
the channel 382 via outlet 388. The heat transfer surface 380 may
optionally include an opening 390 for positioning therethrough an
impeller to allow agitation or mixing inside the container 308,
which may be a collapsible bag. The heat transfer surface 380 may
also include another opening 391, which may be for draining a fluid
from the container.
[0097] As shown in the embodiment illustrated in FIG. 9, a heat
exchanger system 390 includes one or more containers 308 positioned
in series to allow simultaneous temperature control of fluids. For
example, a heat exchanger in the form of a collapsible bag heat
exchanger 302 may be positioned between two containers 308 for
storing and/or holding fluid. A plurality of heat transfer surfaces
306 may be positioned adjacent the containers 308. The heat
exchanger bag 302 and containers 308 may be in the form of
independent, interchangeable modules 392, 394 and 396. Accordingly,
as shown if FIG. 9, in one embodiment of the invention, the system
may comprise a collapsible heat exchanger bag positioned in contact
with the first or the second exterior surface portion of the first
collapsible bag and in contact with the first or the second
exterior surface portion of the second collapsible bag. After
completion of a fluid manipulation process, the modules 392, 394,
396 can be separated and rearranged into a different configuration
to allow the performance of a second fluid manipulation process.
Containers 308 and heat exchanger bag 302 can be removed after the
first manipulation process, and replaced with new containers and/or
collapsible bags so as to maintain the sterile environment for the
second process without the need for washing any components of the
system.
[0098] Specific examples of the use and rearrangement of modules
are described in International Patent Application No.
PCT/US2005/002985, filed Feb. 3, 2005, entitled "System and Method
for Manufacturing," by G. Hodge, et al., published as WO
2005/076093 on Aug. 18, 2005 and U.S. application Ser. No.
11/879,033, filed Jul. 13, 2007, entitled "Environmental
Containment Systems", which are incorporated herein by
reference.
[0099] The heat exchangers described herein may be used to change
the temperature of a fluid to varying degrees. For instance, the
temperature of a fluid may be varied by at least 2.degree. C., at
least 5.degree. C., at least 10.degree. C., at least 15.degree. C.,
at least 20.degree. C., or at least 30.degree. C. In some cases,
the temperature change is measured using one or more sensors, as
described in more detail below.
[0100] One particular method of operating a heat exchanger may
include, for example, flowing a reaction fluid from a chemical,
biological, or pharmaceutical reactor into a collapsible bag which
is in fluid communication with the reactor, the reaction fluid
having a first temperature,. The collapsible bag can include a
channel that may be formed by one or more welds connecting first
and second interior surface portions of the bag. While the reaction
fluid is flowing in the collapsible bag, the temperature of the
reaction fluid may be changed by one of the temperatures mentioned
above, for example, at least 5.degree. C. The reaction fluid can
then be flowed from the collapsible bag into a container in fluid
communication with the collapsible bag. In some cases, the reaction
fluid can be re-circulated between the heat exchanger and another
container. The reaction fluid may be maintained at a temperature
different than that of the reaction fluid prior to being flowed in
the heat exchanger.
[0101] As described herein, in some embodiments a container is
associated with a thermally-conductive material in order to
facilitate heat exchange between a fluid inside the container and
an environment exterior to the container. In some cases, the rate
of heat exchange is limited below desirable or optimal levels by
the material used to form the container. For instance, systems
involving the use of disposable liners in the form of collapsible
bags are generally made of low thermally-conductive materials such
as polyethylene, polytetrafluoroethylene (PTFE), or ethylene vinyl
acetate. To address this problem, containers described herein, such
as collapsible bags or rigid containers, may include in certain
embodiments one or more thermally-conductive material(s) associated
therewith. In one embodiment, the container comprises a
thermally-conductive material embedded in at least a portion of a
wall of the container. Additionally or alternatively, the
thermally-conductive material may line a wall of the container. For
instance, the thermally-conductive material and the wall of the
container may form a laminate structure.
[0102] Advantageously, the container may be formed and configured
such that the thermally-conductive material is adapted to conduct
heat away from an interior of the container to an environment
outside of the container, or to conduct heat into the container
from an environment outside of the container. In embodiments in
which the container is supported by a reusable support structure,
for example, thermally-conductive plates or a stainless steel tank,
heat conduction away from or into the container can be facilitated
by the support structure. For instance, heat from the contents
inside the container can be dissipated, via the
thermally-conductive material of the container, to the support
structure which may also be thermally-conductive. The support
structure may optionally be cooled using a suitable cooling system,
such as the system shown in FIG. 9, to enhance the rate of heat
exchange.
[0103] In some embodiments, the thermally-conductive material is in
the form of a plurality of particles. The particles may be in the
form of nanoparticles, microparticles, powders, and the like. The
thermally-conductive material may also be in the form of nanotubes,
nanowires, nanorods, fibers, meshes, or other entities. The
thermally-conductive material can be embedded in the material used
to form the container, for example, such that all or a portion of
each entity is enveloped or enclosed by the material used to form
the container.
[0104] In some embodiments, an embedded thermally-conductive
material is substantially uniformly dispersed throughout a bulk
portion of a material used to form a container. "Substantially
uniformly dispersed," in this context, means that, upon viewing a
cross-sectional portion of any such material, where the
cross-section comprises the average makeup of a number of random
cross-sectional positions of the material, investigation of the
material at a size specificity, for example, on the order of
grains, or atoms, reveals essentially uniform dispersion of the
thermally-conductive material in the bulk material. A
photomicrograph, scanning electron micrograph, or other similar
microscale or nanoscale investigative process may reveal
essentially uniform distribution.
[0105] It should be understood that in other embodiments, a
thermally-conductive material is not substantially uniformly
dispersed throughout a bulk portion of the material used to form a
container. For example, a gradient of particles may be formed
across a cross-section of the container. For example, the
thermally-conductive material may be configured such that one
portion of the container includes a thermally-conducive material
and another, adjacent portion of the container also comprises the
thermally-conductive material. Alternatively, the
thermally-conductive material may be present as strips, wires, or
may have other configurations such that one portion of the
container includes a thermally-conducive material and another,
adjacent portion of the container does not comprise a
thermally-conductive material.
[0106] The thermally-conductive material may in certain embodiments
be encapsulated between two polymeric sheets. Alternating layers of
thermally-conductive material and polymeric layers are also
possible. Alternatively, in some embodiments, an outer surface of
the container may include a layer of thermally-conductive material,
while an inner surface of the container does not include the
thermally-conductive material. This configuration may allow heat to
be conducted away from (or into) the contents of the container,
while avoiding or limiting any reactivity between the contents of
the container and the thermally-conductive material. For example,
silver has a high thermal conductivity and may be used as a
thermally-conductive material, but is known to have antimicrobial
effects. By positioning the silver at an outer surface of the
container (or embedded between two polymer layers), but not in
contact with any contents inside the container, heat conduction of
the container may be enhanced without adversely affecting the
contents inside the container (for example, cells, proteins,
etc.).
[0107] The thermally-conductive material may have any suitable size
or dimension. The size of the thermally-conductive entities may be
chosen, for example, to achieve a certain dispersion, for example,
a gradient or a substantially uniformly dispersion, within the bulk
material used to form the container, to prevent protrusion of the
entity through a portion of the container, or to have a certain
surface area or thermally conductive material to container volume
ratio. For example, the thermally-conductive material may have at
least one cross-sectional dimension less than 500 microns, or in
another embodiment less than 1 nanometer.
[0108] Any suitable thermally conducting material can be used as a
thermally-conductive material in an embodiment of the invention.
The thermally-conductive material may be chosen based on factors
such as its thermal conductivity, particle size, magnetic
properties, compatibility with certain processing techniques, for
example, ability to be deposited by certain deposition techniques,
compatibility with the bulk material used to form the container,
compatibility with any materials contained in the container,
compatibility with any treatments or pre-treatments associated with
performing a reaction inside the container, as well as other
factors.
[0109] In one set of embodiments, the thermally-conductive material
comprises a metal. In other cases, the thermally-conductive
material comprises a semiconductor. Materials potentially suitable
for use as thermally-conductive materials include, for example, an
element in any of Groups 1-17 of the Periodic Table. Typical
examples include a Group 2-14 element, or a Group 2, 10, 11, 12,
13, 14, 15 element. Non-limiting examples of potentially suitable
elements from Group 2 of the Periodic Table include magnesium and
barium; from Group 10 include nickel, palladium, or platinum; from
Group 11 include copper, silver, or gold; from Group 12 include
zinc; from Group 13 include boron, aluminum, and gallium; from
Group 14 include carbon, silicon, germanium, tin, or lead. In some
cases, the thermally-conductive material is aluminum, copper, iron,
or tin.
[0110] The thermally-conductive material may comprise one or more
metals. Similarly, where the thermally-conductive material
comprises a semiconductor, one or more semiconducting materials can
be used. Additionally, alloys can be used, and a mixture of metals
and semiconductors can be used. That is, the thermally-conductive
material can be a single metal, a single semiconductor, or one or
more metals or one or more semiconductors mixed. Non-limiting
examples of suitable metals are listed above, and suitable
components of semiconductors are listed above. Those of ordinary
skill in the art are well aware of semiconductors that can be
formed from one or more of the elements listed above, or other
elements.
[0111] In certain cases, the thermally-conductive material is a
nonmetal. For example, the thermally-conductive material may
comprise carbon. The thermally-conductive material may be in the
form of a conductive polymer, for instance. Non-limiting examples
of conductive polymers include polypyrroles, polyanilines,
polyphenylenes, polythiophenes, and polyacetylenes.
[0112] Those of ordinary skill in the art can easily select,
without undue burden or undue experimentation, from materials
described above or other materials known in the field, suitable
metals, semiconductors, and/or nonmetals. The teachings described
herein also enable those of skill in the relevant art to screen
materials for suitable use in connection with embodiments described
herein. Optionally, thermally-conductive materials may be coated or
treated to enhance certain chemical or physical properties of the
materials. For example, the surfaces of the thermally-conductive
materials may be treated with a surfactant, an oxide or any other
suitable material, to make the materials more hydrophilic, more
hydrophobic, less reactive, have a certain pH, and so forth. These
and other processes can allow the thermally-conductive materials to
be more compatible with the material used to form the container
and/or with certain processing techniques. For example, treatment
of the thermally-conductive material may allow it to adhere to the
material used to form the container to a desired degree, be more
soluble in a particular solvent, or be more dispersible.
[0113] Containers comprising a thermally-conductive material may be
formed by any suitable method. In one embodiment, a
thermally-conductive material is physically mixed with a material
used to form the container, optionally with other components such
as reactants, solvents, gases, and surfactants. The
thermally-conductive material may be injected into the bulk
material, for example. The resulting mixture may be in the form of
a solution, emulsion, or suspension.
[0114] The mixture may be shaped into a container, or a precursor
of a container, by a method such as blow molding, injection
molding, spin cast molding, and extrusion, for instance, as
described above and/or by methods known to those of ordinary skill
in the art. For example, in one embodiment, the
thermally-conductive material and material used to form the
container may be co-extruded at a sufficiently high temperature at
which the materials are pliable. The materials can then be shaped
into a container or a precursor to the container such as a sheet.
Containers including thermally-conductive materials may be seamless
or may include seams that are welded together to form the
container. In some cases, more controlled welding can be achieved
by heating the thermally-conductive material by an energy source
such as a microwave source or a laser.
[0115] In some embodiments, the thermally-conductive material is
applied to all or a portion of a material used to form a container
by methods such as physical deposition methods, chemical vapor
deposition methods, plasma enhanced chemical vapor deposition
techniques, thermal evaporation, for example, resistive, inductive,
radiation, and electron beam heating, sputtering, for example,
diode, DC magnetron, RF, and reactive sputtering, jet vapor
deposition, electrophoretic deposition, magnetophorectic
deposition, spin coating, dip coating, spraying, brushing, screen
printing, ink-jet printing, toner printing, sintering, laser
ablation, electroplating, ion plating, cathodic arc, and
combinations thereof. Such methods can be carried out in a vacuum
or inert atmosphere.
[0116] The thermally-conductive material may optionally be aligned,
especially in embodiments in which the materials are embedded in a
bulk material, using magnetic interactions, electrostatic
interactions, and the like. The container or any other article
described herein may include any suitable amount of
thermally-conductive material. The container may comprise, for
example, from about 0.1 wt percent to about 50 wt percent of
thermally-conductive material, based on the total weight of the
container. In some cases, these percentages are based on the total
weight of the flexible portions, for example, the wall portions, of
the container.
[0117] The amount and type of thermally-conductive material(s), the
material used to form the container, the arrangement of the
thermally-conductive material with respect to the material used to
form the container, and the thickness of the container can be
chosen such that the container achieves a certain overall level of
thermal conductivity. The overall thermal conductivity of the
container may be, for example, from about 0.1 Wattsm.sup.-1K.sup.-1
to about 15 Wattsm.sup.-1K.sup.-1. In some cases, the thermal
conductivity of a container including a thermally-conductive
material is from about 1.5 times to about 50 times greater than a
container without a thermally-conductive material. The thermal
conductivity can be measured by those of ordinary skill in the art
by determining the quantity of heat transmitted, during a period of
time, through a thickness of the container in a direction normal to
a surface area of the container, wherein the quantity of heat
transmitted is due to a temperature difference under steady state
conditions and when the heat transfer is dependent only on the
temperature gradient.
[0118] In addition to the benefits of enhanced heat conduction
using containers comprising thermally-conductive materials, such
articles may also have enhanced sensing capabilities. For instance,
the containers may be use to determine temperature, conductance,
impedance, as well as dissipation and control of static charge. In
some embodiments, the containers can be used to detect any leakage
of materials from the interior to the outside of the container.
Such measurements can be performed, for example, by determining a
change in the thermal and/or electrical conductivity of one or more
portions of the container.
[0119] One embodiment of the disclosed system for use in a
chemical, biological, or pharmaceutical process comprises: a first
collapsible bag having a perimeter and a maximum dimension
thereacross measured at full expansion of the first collapsible
bag; a first interior surface portion; a second interior surface
portion; one or more welds connecting the first and second interior
surface portions of the first collapsible bag so as to form a
channel between the first and second interior surface portions, an
inlet connected to a first portion of the channel; an outlet
connected to a second portion of the channel, the channel defining
a bulk fluid flow pathway through the first collapsible bag from
the inlet to the outlet; a first temperature-controlling surface in
contact with a first exterior surface portion of the first
collapsible bag; and a second temperature-controlling surface in
contact with a second exterior surface portion of the first
collapsible bag. The disclosed system may be configured and
arranged to allow variation of the distance between the first and
second temperature-controlling surfaces. The system may further
include a component associated with the first collapsible bag that
inhibits full expansion of the first collapsible bag during
use.
[0120] The component that inhibits full expansion of the first
collapsible bag during use may include the first and second
temperature-controlling surfaces maintained at a separation
distance from one another that does not allow full expansion of the
first collapsible bag. The system may further include a second
collapsible bag having a first exterior surface portion and a
second exterior surface portion, the second collapsible bag
comprising an impeller in fluid communication with the first
collapsible bag. The system may be configured such that the first
temperature-controlling surface is in contact with the first
exterior surface portion of the second collapsible bag, in addition
to being in contact with a first exterior surface portion of the
first collapsible bag.
[0121] The system may further include a second
temperature-controlling surface in contact with the second exterior
surface portion of the first collapsible bag. The system may
further include a third temperature-controlling surface in contact
with the second exterior surface portion of the second collapsible
bag. The system may be configured and arranged to allow
recirculation of fluid between the first and second collapsible
bags.
The Support Structure
[0122] A support structure that may be used to support a
collapsible bag may have any suitable shape able to surround and/or
contain the bag. In some cases, the support structure is reusable.
The support structure may be formed of a substantially rigid
material. Non-limiting examples of materials that can be used to
form the support structure include stainless steel, aluminum,
glass, resin-impregnated fiberglass or carbon fiber, polymers such
as high-density polyethylene, polyacrylate, polycarbonate,
polystyrene, nylon or other polyamides, polyesters, phenolic
polymers, and combinations thereof. The materials may be certified
for use in the environment in which it is used. For example,
non-shedding materials may be used in environments where minimal
particulate generation is required. In addition, the support
structure may include other components, such as channels, for
flowing a fluid and/or containing a material to modify the
properties of the support structure.
[0123] A reusable support structure may have any suitable volume
and, in some instances, has a volume substantially similar to that
of the container contained in the support structure. The reusable
support structure may have a volume between, for example, of from
about 5 liters to about 5,000 liters. Volumes greater than 10,000
liters are also possible.
[0124] In other embodiments, however, a vessel does not include a
separate container, for example, a collapsible bag and support
structure, but instead comprises a self-supporting disposable
container. For example, a container that may be used to hold and/or
store fluids may be in the form of a plastic vessel and may
optionally include an agitation system integrally or releasably
attached thereto. The agitation system may be disposable along with
the container. In one particular embodiment, such a system includes
an impeller welded or bolted to a polymeric container. In another
embodiment, a container that is used as a heat exchanger is in the
form of a rigid container. It should therefore be understood that
many of the aspects and features of the vessels described herein
with reference to a container and a support structure are also
applicable to a self-supporting disposable container.
[0125] As described herein a vessel such as a collapsible bag may
include a mixing system for mixing contents of the vessel. In some
cases, more than one agitator or impeller may be used to increase
mixing power, and the impellers may be the same or different. In
some cases, the agitator may be one in which the height can be
adjusted, for example, such that the drive shaft allows raising of
an impeller above the bottom of the tank and/or allows for multiple
impellers to be used. A mixing system of a vessel may be disposable
or intended for a single use, along with the container in some
cases. Various methods for mixing fluids can be implemented in the
container. For instance, impellers based on magnetic actuation,
sparging, and/or air-lift can be used. Direct shaft-drive mixers
that are sealed and not magnetically coupled can also be used.
Additionally or alternatively, a mixing system may include an
impeller with varying impeller blade configurations.
[0126] In certain embodiments, a magnetic impeller is used. A
magnetic impeller may use magnets such as fixed, permanent, or
electromagnets to rotate or otherwise move the impeller. In some
cases, the magnets within the magnetic impeller are stationary and
can be turned on or activated in sequence to accelerate or
decelerate the impeller, for example, via an inner magnetic
impeller hub. As there is no penetration of the container by a
shaft, there may be no need to maintain the impeller in a sterile
condition.
Equivalents
[0127] While several embodiments of the present invention have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present invention. Those skilled in the art will
readily appreciate that all parameters, dimensions, materials, and
configurations described herein are meant to be exemplary and that
the actual parameters, dimensions, materials, or configurations
will depend upon the specific application for which the teachings
of the present invention are used. Those skilled in the art will
recognize, or be able to ascertain using no more than routine
experimentation, many equivalents to the specific embodiments of
the invention described herein. It is, therefore, to be understood
that the foregoing embodiments are presented by way of example only
and that, within the scope of the appended claims and equivalents
thereto, the invention may be practiced otherwise than as
specifically described and claimed. The present invention is
directed to each individual feature, system, article, material,
kit, and/or method described herein, and to any combination of the
foregoing.
[0128] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one." Throughout
the description and claims of this specification, the words
"comprise," "contain," "include," "having," "composed of," and
variations of them mean "including but not limited to", and they
are not intended to (and do not) exclude other moieties, additives,
components, integers or steps. Throughout the description and
claims of this specification, the singular encompasses the plural
unless the context otherwise requires. In particular, where the
indefinite article is used, the specification is to be understood
as contemplating plurality as well as singularity, unless the
context requires otherwise.
[0129] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0130] Features groups described in conjunction with a particular
aspect of the invention are to be understood to be applicable to
any other aspect described herein unless incompatible therewith.
All of the features disclosed in the specification, and claims,
abstract and drawings, and/or all of the steps of any method or
process disclosed, may be combined in any combination, except
combinations where at least some of such features or steps are
mutually exclusive. The invention is not restricted to the details
of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
* * * * *