U.S. patent application number 13/863123 was filed with the patent office on 2014-10-23 for serviceable bioreactor.
The applicant listed for this patent is United Arab Emirates University. Invention is credited to Ali Abdullah Hilal-Alnaqbi, Abdel-Hamid Ismail Mourad.
Application Number | 20140310932 13/863123 |
Document ID | / |
Family ID | 46641018 |
Filed Date | 2014-10-23 |
United States Patent
Application |
20140310932 |
Kind Code |
A2 |
Hilal-Alnaqbi; Ali Abdullah ;
et al. |
October 23, 2014 |
SERVICEABLE BIOREACTOR
Abstract
The invention resides in an apparatus for treatment of a
substance. The apparatus has a substance tube for enabling a
substance to be treated to pass in to the substance tube via the
substance-inlet and out of the substance tube through the
substance-outlet. The apparatus also has a cleaning chamber,
wherein the substance tube is configured in fluid communication
with the cleaning chamber to enable a substance to diffuse the
permeable membrane between the substance tube and the cleaning
chamber such that a substance can be substantially cleaned by a
cleaner, the substance comprising blood or plasma and the cleaner
comprising a cell culture. The substance tube is removably
connectable with the cleaning chamber for inter-changeability or
serviceability. The apparatus can further comprise a support
compartment configured to connect to, or enclosing, the cleaning
chamber, which functions to carry a fluid to substantially maintain
the functionality of the cleaner.
Inventors: |
Hilal-Alnaqbi; Ali Abdullah;
(Al-Ain, Abu Dhabi, AE) ; Mourad; Abdel-Hamid Ismail;
(Al-Ain, Abu Dhabi, AE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
United Arab Emirates University |
Al-Ain, Abu Dhabi |
|
AE |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130333178 A1 |
December 19, 2013 |
|
|
Family ID: |
46641018 |
Appl. No.: |
13/863123 |
Filed: |
April 15, 2013 |
Current U.S.
Class: |
29/402.04;
210/321.69 |
Current CPC
Class: |
B01D 69/082 20130101;
A61M 1/34 20130101; B01D 67/00 20130101; A61M 2205/3331 20130101;
A61M 1/3489 20140204; A61M 1/3403 20140204; B01D 65/02 20130101;
B01D 63/00 20130101; Y10T 29/49723 20150115; B01D 63/02 20130101;
A61M 1/3475 20140204; B01D 61/28 20130101; A61M 1/3496
20130101 |
Class at
Publication: |
29/402.04;
210/321.69 |
International
Class: |
B01D 65/02 20060101
B01D065/02; B01D 67/00 20060101 B01D067/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2012 |
GB |
1210685.2 |
Claims
1. An apparatus for treatment of a substance, the apparatus having:
a substance tube configured to enable a substance to be treated to
pass in and out of the substance tube; a cleaning chamber connected
to the substance tube through a permeable membrane, the cleaning
chamber configured to enable a cleaner to pass in and out of the
cleaning chamber, wherein the substance tube is configured in fluid
communication with the cleaning chamber via the permeable membrane
to enable a substance to perfuse the permeable membrane between the
substance tube and the cleaning chamber such that the substance can
be substantially cleaned by the cleaner, the substance consisting
of blood or plasma and the cleaner comprising a cell culture, and
wherein the substance tube is removably connectable with the
cleaning chamber for inter-changeability or serviceability.
2. The apparatus according to claim 1, the apparatus further
comprising a support compartment configured to be connected to, or
enclosing, the cleaning chamber, the support compartment configured
to enable a biological support fluid to pass in and out of the
compartment, wherein the cleaning chamber is configured in fluid
communication with the support compartment via a permeable membrane
to enable a biological support fluid to perfuse the connection
between the cleaning chamber and the support compartment such that
the biological support fluid can substantially maintain the
functionality of the cleaner.
3. The apparatus according to claim 2, wherein the substance tube
is removably connectable to the support compartment.
4. The apparatus according to claim 3, wherein the cleaning chamber
is removably connectable to the support compartment.
5. The apparatus according to claim 4, wherein the coupling between
the or each connection is an interference-fit for inhibiting liquid
or fluid leakage from the apparatus.
6. The apparatus according to claim 5, wherein the apparatus has a
substance store at each end of the substance tube, wherein the
substance store functions to collect a substance received from the
substance inlet/outlet before said substance passes in/out of the
tube.
7. The apparatus according to claim 6, wherein the substance tube
has a web configured to form the substance store at each end of
said tube, said tube is mounted on said web such that a portion of
the substance tube passes through the web at the mounting point,
and wherein substance tube is removably connected to at least one
web.
8. The apparatus according to claim 7, wherein the apparatus has a
plurality of substance tubes, and a web is configured at each the
end of plurality of said substance tubes.
9. The apparatus according to claim 8, wherein the connection
between the substance tube and the web is a push-fit.
10. The apparatus according to claim 9, wherein the web is
configured to separate the substance store from the cleaning
chamber when the substance tube is connected thereto.
11. The apparatus according to claim 10, wherein the cleaning
chamber is configured to surround or enclose the substance
tube.
12. The apparatus according to claim 11, wherein the cleaning
chamber is configured to surround or enclose the support
compartment.
13. The apparatus according to claim 12, wherein the substance tube
is substantially circular in cross section.
14. The apparatus according to claim 12, wherein the substance
tube, in cross-section has at least two faces.
15. The apparatus according to claim 13 or 14, wherein the cleaning
chamber is substantially circular in cross section.
16. The apparatus according to claim 13 or 14, wherein the cleaning
chamber, in cross-section, has at least two faces.
17. The apparatus according to any one of claims 13 to 16, wherein
the support compartment is substantially circular in cross
section.
18. The apparatus according to any one of claims 13 to 16, wherein
the support compartment, in cross-section, has at least three
faces.
19. Apparatus for culturing cell types, comprising an apparatus
according to claim 1.
20. A method of servicing an apparatus for treatment of a
substance, the method including: disassembling the apparatus
including: a substance tube configured to enable a substance to be
treated to pass in and out of the substance tube; and a cleaning
chamber connected to the substance tube through a permeable
membrane, the cleaning chamber configured to enable a cleaner to
pass in and out of the cleaning chamber, wherein the substance tube
is configured in fluid communication with the cleaning chamber via
a permeable membrane to enable a substance to perfuse the permeable
membrane between the substance tube and the cleaning chamber such
that the substance can be substantially cleaned by the cleaner, the
substance comprising blood or plasma, and the cleaner consisting of
a cell culture; cleaning the substance tube and/or the service
tube; and reassembling the substance tube with the cleaning
chamber.
21. The method of claim 20, wherein the method further includes:
disassembling the substance tube and the cleaning chamber from a
support compartment, wherein the support compartment is configured
to be connected to, or enclosing, the cleaning chamber, the support
compartment configured to enable a biological support fluid to pass
in and out of the compartment, wherein the cleaning chamber is
configured in fluid communication with the support compartment to
enable a biological support fluid to perfuse the connection between
the cleaning chamber and the support compartment such that the
biological support fluid can substantially maintain the
functionality of the cleaner; and reassembling the substance tube
with the cleaning chamber with the support compartment.
Description
[0001] This application claims priority from United Kingdom Patent
Application No. 1210685.2, filed Jun. 15, 2012, entitled
Serviceable Bioreactor, which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The invention relates to a bioreactor and a method of
assembling or servicing a bioreactor. The invention also relates to
bioreactors in the field of biomedicine and biotechnology and, in
particular, cell-based devices such as bioartificial organs that
are configured to develop cell culture e.g. for a bioartificial
liver device, such as a fiber in fiber (FIF) bioartificial liver
(BAL) device.
BACKGROUND OF THE INVENTION
[0003] Fiber in fiber (FIF) bioartificial liver (BAL) devices are
known. An example of which is described and discussed in a paper
titled "Fiber in Fiber (FIF) bioartificial liver device: initial
design and prototyping" by Hilal-Alnaqbi Ali, Basem Yousuf and
Gaylor J. D. S. [Computer-Aided Design & Applications, 8 (1),
2011, 99-109]. Devices are also known from and described in U.S.
Pat. No. 6,582,955B and CN101199436.
[0004] Known designs consist of a conventional hollow fiber
cartridge, which functions as a cell culture system, and a second
hollow fiber placed in the lumen of the cartridge. Three zones or
spaces are created. Known devices use guide plates to arrange the
fibers the bioreactors. Unfortunately, the assembly of the
bioreactor is complex. The assembly requires a body to be clamped
vertically and a guide plate, having holes therein, placed in the
recess in the upper end of the body. Hollow fibers are then
threaded through the holes in the plate and kept static. A flowable
silicone rubber elastomer is injected onto the plate and around the
fiber walls to secure the fibers. Known bioreactors are, therefore,
complex devices requiring delicate assembly techniques and are
expensive to fabricate. Further, they are for one-time use because
of nature of the assembly and the risk contamination.
SUMMARY OF THE INVENTION
[0005] It is against this background that the present invention has
been made. This invention results from efforts to overcome the
problems of known bioreactors. Other aims of the invention will be
apparent from the following description.
[0006] The invention generally resides in an apparatus for
culturing cell types. The apparatus is configured for treatment of
a substance such as a cell culture (animal, human, plant, insect)
e.g. human blood plasma, using a cleaner, such as a cell culture, a
culture medium, blood or plasma e.g. bovine plasma, the apparatus
having a tube through which a substance can flow, and a chamber in
fluid communication the tube through which a cleaner can flow such
that the substance can be substantially cleaned, and wherein the
tube is removably connectable with the chamber for serviceability.
The apparatus can have a compartment in fluid communication with
the chamber through which a fluid, such as oxygen, can flow such
that the functionality of the cleaner is substantially
maintained.
[0007] Overall the invention can provide a serviceable
bioartificial organ (e.g., liver, kidney, pancreas, thyroid,
parathyroid, adrenal, etc.), such as a FIF bioreactor having a
section for cells, perfusate and nutrient phases. Two or more
separate sections can be provided for the cells and/or perfusate.
The nutrient phases can be configured to pass adjacent to and/or
through the perfusate. The blood or plasma to be treated passes
adjacent a membrane in the apparatus, said membrane providing an
interface that enables the blood or plasma to react to a material
in an adjacent section of the apparatus. The perfusing function can
be comparable to that provided by a natural organ.
[0008] The apparatus can have modules, or subcomponents that are
serviceable to improve survivability and/or to adjust the capacity
of the apparatus. The apparatus can function to provide cell
therapy and oxygenation, cell therapy and blood/plasma dialysis,
ultrafiltration or diafiltration. Other treatments are possible,
such as the application of pharmacological agents.
[0009] The invention resides in a serviceable bioreactor in which a
tube or channel for containing a substance to be cleaned is
removably connected to a cleaning chamber. The tube and the chamber
are in fluid communication via a membrane. The tube, chamber and/or
compartment are can be connected and disconnected from each one
another such that the apparatus can be taken apart and reassembled.
In this way, one of the tube, chamber or compartment can be
replaced or cleaned, thus avoiding waste, improving recycling and
reducing cost. In one aspect, the invention resides in an apparatus
for treatment of a substance, the apparatus having: a substance
channel or tube configured to enable a substance to be treated to
pass in to and out of the substance tube; a cleaning chamber
connected to the substance tube, the cleaning chamber configured to
enable a cleaner to pass in to and out of the cleaning chamber,
wherein the substance tube is configured in fluid communication via
a membrane with the cleaning chamber to enable a substance to
diffuse or perfuse or permeate the connection between the substance
tube and the cleaning chamber such that a substance can be
substantially cleaned, or cleaned in part, by a cleaner, and
wherein the substance tube is removable connectable with the
cleaning chamber for inter-changeability or serviceability.
[0010] The substance channel or tube can have a substance-inlet and
a substance-outlet in fluid communication with the substance tube
for enabling a substance to be treated to pass in to the substance
tube via the substance-inlet and out of the substance tube through
the substance-outlet. The cleaning chamber connected to the
substance tube can have a cleaner-inlet and a cleaner-outlet in
fluid communication with the cleaning chamber for enabling a
cleaner to pass in to the cleaning chamber via the cleaner-inlet
and out of the cleaning chamber through the cleaner-outlet.
[0011] The tube can be shaped to increase the area of interface
with the chamber and, by way of example, can have a helical shape
along its axial length. The overall shape of the tube can be
configured to maximise the surface are of the tube exposed to the
interior of the cleaning chamber. The tube can also be configured
to maximise the interaction between the substance passing through
the tube and the cleaner in the cleaning chamber e.g. to maximise
the flow across the surface of the tube.
[0012] The apparatus can further comprise a support compartment
configured to connect to, or enclose, the cleaning chamber, the
support compartment configured for enabling a support fluid to pass
in and out of the support compartment, wherein the cleaning chamber
is configured in fluid communication via a membrane with the
support compartment to enable a fluid to diffuse, perfuse or
permeate the connection between the cleaning chamber and a support
compartment such that the fluid can substantially maintain the
functionality of the cleaner.
[0013] The support compartment can have a support-inlet and a
support-outlet in fluid communication with the support compartment
for enabling a fluid to pass in to the support compartment via the
support-inlet and out of the support compartment through the
support-outlet.
[0014] By way of example, the cleaner passing through the cleaning
chamber may be oxygen dependent, such as a cell culture, blood or
plasma. Depending on the configuration of the apparatus, some of
the cells of the cell culture, blood or plasma may die without
support as they pass through the cleaning chamber. The support
chamber, therefore, is in fluid communication via a membrane with
the cleaning chamber to supply a support fluid, such as oxygen,
directly to the cleaner. Preferably, the support fluid is a
biological support fluid.
[0015] The substance tube and/or the cleaning chamber can be
removably connectable, or coupleable to the support
compartment.
[0016] The connection, or coupling, between the or each components
part of the serviceable BAL can be an interference-fit for
inhibiting liquid or fluid leakage from the apparatus. Said
coupling is a serviceable connection or joint between the
components of the apparatus and can be a screw-fit, compression
fit, pressure-fit, snap fit or bayonet-fit. Additional components,
such as a mechanical compression band, or clip, that can be
tightened around the perimeter of the units, can be used to
compliment the connection. One or more sealing elements, such as a
washer or grommet, can be used to provide or improve the
connection.
[0017] The apparatus can have a manifold, or substance store, at an
end of the substance tube, or at both ends. The manifold functions
to collect a substance received from the substance inlet/outlet
before said substance passes in/out of the tube. A manifold can
connect to a plurality of tubes, chambers or compartments. A
manifold can make several connections within the same assembly or
service action. The manifold can simplify the serviceability of the
apparatus by reducing the number of connections or couplings
required between the different components of the apparatus.
[0018] The substance tube can have a web configured to form the
substance store at each end of said tube. Said tube can be mounted
on said web such that a portion of the substance tube passes
through the web at the mounting point, and wherein substance tube
is removably connected to at least one web. The web can be formed
of a disk-like structure having a plurality of holes, with a
substance tube passing through, or in to, each hole.
[0019] The apparatus can have a plurality of substance tubes. A web
can be configured at each end of the plurality of said substance
tubes. The connection between the substance tube and the web can be
a push-fit. The web can be configured to separate the substance
store from the cleaning chamber when the substance tube is
connected thereto.
[0020] The apparatus can have a manifold, or cleaner store, at an
end of the cleaner chamber, or at both ends. The manifold functions
to collect a cleaner received from the substance inlet/outlet
before said cleaner passes in/out of the chamber. The cleaner
chamber can have a web configured to form the cleaner store at each
end of said tube. Said chamber can be mounted on said web such that
a portion of the cleaner chamber through the web at the mounting
point, and wherein cleaner chamber can be removably connected to at
least one web. The cleaner store can be configured in fluid
communication with a plurality of cleaner chambers.
[0021] Alternative arrangements of the apparatus can have different
interfaces or connections between the tube and the chamber. By way
of example there can be two or more surfaces of the tube, chamber
or compartment. The number of surfaces, and their configuration,
can be optimised to maximise the fluid connectivity between the
tube, chamber and compartment.
[0022] The invention can additionally or alternatively be
implemented in alternative configurations that are more robust. By
being more robust, and less delicate, the handling and
serviceability can be improved. Further, the life of the
serviceable apparatus can be increased. The increase in robustness
can be achieved by the configuration of the tube, chamber and
compartment
[0023] The cleaning chamber can be configured to surround or
enclose the substance tube and/or the support compartment. Where
the cleaning chamber encloses the support compartment the walls of
the support compartment has, at least in part, a membrane and the
surface are of the support compartment is configured to support the
cleaner material. The support compartment can be coiled and/or have
a helical form in an axial direction.
[0024] The substance tube can be substantially circular in cross
section. The substance tube, in cross-section, can have two faces,
or three or more faces. If the substance tube has two faces it can,
by way of example, have a cross-sectional profile comparable to
that of an optical lens having two convex faces. If the substance
tube has three faces it can, by way of example, have a
cross-sectional profile comparable to a triangle, such as an
equilateral triangle.
[0025] The cleaning chamber can be substantially circular in cross
section. The cleaning chamber, in cross-section, can have two, or
three or more faces. The support compartment can be substantially
circular in cross section. The support compartment, in
cross-section, can have two, or three or more faces. The
interfacing surfaces between the tube, chamber and compartments,
whether directly connected or in fluid communication, are
configured to maximise the surface area therebetween. At least a
portion of the cross-section profile of the wall of the support
tube and/or cleaning chamber can be substantially wave-shaped. The
wave shape can be sinusoidal, triangular or square.
[0026] The cleaning chamber, in cross-section, can have one face
configured to engage with a reciprocal face of the substance tube,
and another face configured to have a maximum interface.
[0027] The shape of tube, chamber or compartment can take on a
variety of forms such that the cross-sectional profile can be
irregular, asymmetrical, or symmetrical. By way of example, the
cross-sectional profile can be hexagonally shaped.
[0028] Similarly, the shape of the tube, chamber or compartment can
take on a variety of forms along the longitudinal length to be
irregular, or regular. By way of example, the tube, chamber or
compartment can have a wave-shaped profile, such as a sinusoidal
profile, along its length. The tube, chamber or compartment can
have a helical form. A convective flow configuration can be used.
Alternative flow configurations can be implemented and the flow
direction in one tube or chamber can be in the opposite direction
from an adjacent tube or chamber. To be clear, the flow
configuration can be the same, or different between the tubes, and
the flow can be a convective flow or a dead-end-flow. By way of
example, the flow in the tube 10 and the chamber can be convective,
and in the same direction, while the compartment has a dead-end
flow. Note that the arrangement of the invention is not limited to
the arrangement and functionality described above i.e. that the
tube carries a substance, the chamber carries a cleaner and the
compartment carries a support material. The apparatus of the
invention is flexibly configurable such that any one of the tube,
chamber or compartment can perform the function of the other. By
way of example, the apparatus can be configured such that the
substance to be treated can pass in to the support compartment, the
cleaner can be configured to pass in to the cleaning chamber (as
originally intended) and the support fluid can pass in to the
substance tube.
[0029] Not only is the apparatus serviceable, but it is configured
to achieve acceptable cell viability and functions. The mass
transport (by diffusion or convection) from a nutrient or gas
supply source to the cells is important and the invention aims to
improve the mass transport within the apparatus. Oxygen is
important for cell viability and function and the invention
provides an improved configuration to overcome the limitation of
mass transport (i.e. oxygen) which occurs in known devices. In view
of these and other variants within the inventive concept, reference
should be made to the appended claims rather than the foregoing
specific description in determining the inventive concept.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In order that the invention may be more readily understood,
reference will now be made, by way of example, to the drawings in
which:
[0031] FIG. 1 is a cross-section of a mid-section of known fiber in
fiber (FIF) bioartificial liver (BAL) device, having a number of
tubular fibers, each arranged within a larger fibrous tube, which
are located in a larger tube;
[0032] FIG. 2 is a longitudinal cross-sectional view of an
apparatus according to one aspect of the invention showing the
structure of the apparatus having inlet and outlet ports to three
discrete compartments, wherein each compartment is removable
connectable from the other;
[0033] FIG. 3 shows an end portion of an apparatus according to the
invention indicating, by way of example, the connection points,
coupling points or interfaces between the compartments;
[0034] FIGS. 4a and 4b show, in cross-section, alternative
configurations of the compartments according to the invention;
[0035] FIGS. 5a and 5b show, in cross-section, alternative
configurations of the compartments shown in FIG. 2 according to the
invention;
[0036] FIGS. 6a to 6b show, in cross-section, alternative
configurations of the compartments shown in FIG. 4 according to the
invention; and
[0037] FIG. 7 shows, in cross-section, an alternative configuration
of the compartments according to the invention.
[0038] Although the invention relates to a bioreactor and, in
particular a serviceable bioreactor and a method of servicing a
bioreactor the invention will be described, by way of example, in
relation to a fiber in fiber (FIF) bioartificial liver (BAL)
device.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0039] A FIF BAL device is configured to support acceptable cell
viability and cell functionality. The mass transport (by diffusion
or convection) from a nutrient or gas supply source to the cells is
important and one of the aims of the invention is to improve the
mass transport within the apparatus. Oxygen is important for cell
viability and function and the invention provides an improved
configuration to overcome the limitation of mass transport (i.e.
oxygen) which occurs with known devices.
[0040] The FIF device can comprise a hollow fibre inside another
hollow fibre bioreactor to accommodate liver cells (hepatocytes).
The configuration mimics the liver acinus since it can supply
oxygen at physiological partials pressures. In this configuration,
the hepatocytes reside in the cleaning chamber.
[0041] Referring to FIG. 1, a first compartment 2 is located,
coaxially, within a second compartment 4 to provide a fibre in
fibre (FIF) unit 6. A number of FIF tubes 6 are arranged within a
third compartment 8. The first compartment 2, second compartment 4
and third compartment 8 are cylindrical. The walls of the FIF unit
6 comprise a membrane 9.
[0042] The first compartment 2, second compartment 4 and third
compartment 8 of FIG. 1 are analogous, respectively, with a
substance tube 10, a cleaning chamber 20 and a support compartment
30 as shown in FIG. 2. The or each wall of the tube 10 or chamber
20 can be formed, at least in part, by the membrane 9. The
properties of the membrane on the or each wall can differ.
[0043] In use, a patient's blood would be introduced into the tube
10 of the apparatus of FIG. 2 and a chemical species transported
through the membrane into the chamber 20, either by diffusion or
convection, which carried bovine plasma. There are at least two
ways to use chamber 20, as follows: [0044] (1) If the membrane
excludes all species (mid cells) of a molecular weight (MW)
>70000, then the membrane acts as immunological barrier between
the cells cultured in the chamber 20 and the blood in the tube 10.
Hepatic failure toxins which are not protein bound would diffuse
into the chamber 20 for detoxification. Transformed species may
diffuse back into the tube 10. [0045] (2) If the membrane is
configured as a plasmapheresis membrane, plasma separated from
whole blood in the tube 10 will be convected into the chamber 20.
Assuming cells are present in the chamber 20, protein-bound toxins
will be detoxified and returned by back convection of plasma into
the tube 10 together with synthesised products. Plasma is reunited
with the primary blood flow in the tube 10 and whole blood exits
the tube.
[0046] The membrane between the cell culture and the patient's
perfusate can be configured to 1) maximise the function of the
cells by increasing the density of cultured cells, 2) promote
effective exchange of substances, 3) provide cell anchorage, 4)
reduce immunological hazards and 5) exhibit sieving properties.
[0047] Using the second way described above may compromise the
oxygen requirements of the cells passing through the chamber 20.
While the oxygen requirement of the cells can be met more easily
with blood, plasma perfusion would require oxygenation and a very
high flow rate. These requirements make the procedure more
complicated. A further consideration is the duration over which
plasma separation can be effectively achieved before concentration
polarisation renders the membrane ineffective. Thus, the treatment
time might be dictated by membrane fouling.
[0048] The support compartment 30 can solve the problem of oxygen
delivery requirements to the cells in the chamber 20 if it is
configured as a pure gas supply space with the membrane of the
chamber 20 configured as a gas permeable hydrophobic membrane.
Preferably, the tube 10 should not be more than 200 .mu.m in radius
in order to provide better nutrient and oxygen transport. A
convective flow configuration can be used.
[0049] The walls of the tube 10 or chamber 20 can have
reinforcement to inhibit movement or collision between the membrane
wall of the tube and the membrane wall of the chamber 20. This
could affect the growth, life or even the function of the cells.
Additionally or alternatively, the position and separation of the
tubes and chambers is controlled along the length of the
tube/chamber to maintain uniform separation. The shape of the tube
and/or chamber can be used to inhibit movement.
[0050] If hepatocytes (cells of the liver) were embedded with a
gel/nutrient medium they could be circulated inside the chamber 20
to nourish and maintain the hepatocytes in culture. It can be
circulated counter current to the patients' perfusate. Thus, the
toxins and metabolites produced during liver disease could diffuse
out of the highly permeable hollow fibre along a concentration
gradient. The metabolic end products would then be excreted into
the chamber 20 along the concentration gradient and be removed by
the circulating nutrient medium. Concurrently, essential proteins
and factors produced by the hepatocytes in the chamber 20 would
diffuse along a concentration gradient through the membrane wall of
the tube 10 and enter the patient's perfusate in tube 10.
[0051] The semi-permeable hollow fibre membrane of the tube 10 can
protect the cultured hepatocytes from the body's immune system and
can protect the patients' blood from the toxins coming from
xenogenic cells if such cells were selected. Cell to cell contact
would be addressed for long-term stability of hepatic functions.
The apparatus can be configured to increase the removal of ammonia
and albumin synthesis, as well as sufficient oxygen transfer.
[0052] The compartment 30 is formed by a jacket housing the tube 10
and chamber 20 assembly and allows a fluid (i.e., liquid or gas)
culture medium to pass therethrough to assist in maintaining the
hepatocytes, keeping them alive and functioning for longer within
chamber 20.
[0053] The compartment 30 can be used as receiver of lower
molecular weight substances, which have been produced by the cell
metabolism. These substances will be transported by diffusion from
the chamber 20 into the compartment 30 through a low molecular
weight cut off membrane. The removal of these low molecular weight
substances from the compartment 30 could be supported by transport
of soluble nutrients in a cell culture medium introduced into
compartment 30.
[0054] Alternatively, the compartment 30 can be used for
circulating a gas mixture (containing O2, N2 and CO2). Using the
compartment 30 in this manner would solve the oxygen-limiting
problem suffered by known bioartificial liver devices in that it
provides a parallel pathway for O2 and CO2 removal from the chamber
20. This integral oxygenation can inhibit the axial gradients and
oxygenate the media in the chamber 20 to the levels similar to
those found in the periportal region of the liver i.e. 70 mm
Hg.
[0055] If the compartment 30 is used as a gas supply, the membrane
wall of chamber 20 should have the characteristics of gas-permeable
membranes, such as microporous and non-microporous membranes as
oxygenation membranes.
[0056] Each tube 10 located in a chamber 20 forms a Fibre in Fibre
unit 6, 40. In practice a FIF BAL contains a plurality of units 40,
each unit having a single tube 10 within a chamber 20.
[0057] Note that the support compartment is optional, depending on
the application. If required, a support compartment 30 can be
configured to be connected to a cleaning chamber 20. Additionally
or alternatively a support compartment 30 can be configured to
enclose and/or pass through a cleaning chamber 20. An apparatus
having a tube 10 and chamber 20 can, alternatively, be placed in a
suitable environment such that a dedicated compartment is not
required, for example an oxygenated room.
[0058] Returning back to FIG. 2, apparatus 100 has a
substance-inlet 104 and a substance-outlet 102 configured in fluid
communication with the substance tube 10 for enabling a substance
to be treated to pass in to the substance tube via the
substance-inlet and out of the substance tube through the
substance-outlet. A cleaner-inlet 106 and a cleaner-outlet 108 are
configured in fluid communication with the cleaning chamber 20 for
enabling a cleaner to pass in to the cleaning chamber via the
cleaner-inlet and out of the cleaning chamber through the
cleaner-outlet. A portion of the wall of the substance tube 10 is
configured in fluid communication via a membrane with the cleaning
chamber to enable a substance to diffuse, perfuse or generally pass
through to a controlled degree the connection between the substance
tube and the cleaning chamber such that a substance can be
substantially cleaned by a cleaner.
[0059] As described above, the apparatus can have a support
compartment 30 having a support-inlet 110 and a support-outlet 112
in fluid communication with the support compartment 30 for enabling
a fluid to pass in to the support compartment via the support-inlet
and out of the support compartment through the support-outlet. The
cleaning chamber is configured in fluid communication via a
membrane with the support compartment to enable a fluid to diffuse,
perfuse or generally pass through to a controlled degree between
the cleaning chamber 20 and the support compartment 30 such that
the fluid can substantially maintain the functionality of the
cleaner.
[0060] The apparatus 100 of the invention can be configured such
that each of the substance tube 10, cleaning chamber 20 and support
compartment 30 has a single inlet and a single outlet. Practically,
however, the inlet of the tube 10 and/or the chamber 20 can be
connected to a plurality of tubes or chambers. This connection can
be achieved by using a manifold. The configuration of the apparatus
as shown in FIG. 2 is one example of a single inlet providing
connection to a plurality of tubes or chambers.
[0061] The substance-outlet 102, feeds into a substance store 114
such that a substance can be centrally collected and distributed
between the substance tubes 10. As a substance passes out of the
substance tubes 10 it passes into another substance store at the
opposite end of the tube before passing out of the
substance-outlet. Similarly, there is a cleaner store 116 at each
end of the cleaning chamber. The stores 114, 116 function as
manifolds. The manifolds can be integral with the apparatus.
[0062] The substance tubes 10 are held at each end by a web 118
configured to form the substance store 114. The web forms a barrier
between the substance store and the cleaner store 116. Similarly,
the cleaning chambers are held in a web 120 to separate the
substance store from the cleaning chamber when the substance tube
is connected thereto. When the Fibre in Fibre unit 40 passes
through a support compartment 30 the web 120 separates the cleaner
store 116 from the support compartment 30.
[0063] Detail X of FIG. 2 shows a chamber 20 passing through a web
120, in which it is mounted, which separates the store 116 from the
compartment 30. Tubes 10 are shown passing through the chamber
20.
[0064] Known FIF BAL devices are disposable, and for one-time-use
only. The apparatus of the invention, however, is serviceable. The
substance tube 10 is removably connectable to the cleaning chamber
20 such that a soiled or contaminated tube 10 can be replaced.
Similarly, the chamber 20 can be removably connected with the
support compartment 40.
[0065] The apparatus of FIG. 2 demonstrates an embodiment of the
invention and like components are referred to with like reference
numerals in FIG. 3 that, by way of example, is used to describe the
structural elements of the device that enable the apparatus 100 to
be serviced.
[0066] The illustration of FIG. 3 shows the end portion of three
units, namely: a substance unit 122, having a substance inlet and
outlet 104,1042, a substance store 114 forming a manifold defined
by an upper, lower and a lateral wall, as viewed, of the unit and a
web 118, and a substance tube 10 connected to and passing through
the web 118; a cleaning unit 124, having a cleaner inlet and outlet
106, 108, a cleaner store 116 forming a manifold defined by an
upper and lower wall as viewed, a web 120 and a cleaning chamber 20
connected to and passing through the web 120; and a support unit
126 forming a support compartment 30 in the form of a tube having
open ends, and a support inlet and outlet 110,112. The ends of the
apparatus shown in FIG. 3 are, by way of example, a mirror image of
the opposite end of the apparatus.
[0067] Note that the cleaning unit 124 would, as a stand-alone
component, be open on one side to create a recess that is
configured to be closed off by the substance unit 122 to provide
the store or manifold 116 and, by way of example in FIG. 3, it is
the web that functions to close it off. Similarly, the web 120 of
the cleaning unit is configured to close the ends of the support
compartment 30 the cleaning unit.
[0068] The web 118 and walls of the substance unit 122 provide a
socket area, or recess 128. The socket 128 is configured to receive
the walls of the open end of the cleaning unit 124 and create an
enclosed cleaner store 116. Similarly, the web 120 and walls of the
cleaner unit 124 provide a socket area, or recess 128. The socket
128 of the cleaner unit is configured to receive the walls of the
open end of the support compartment 30. The socket enables the
component of the apparatus to be assembled, and taken apart again
for servicing.
[0069] The sockets shown in FIG. 3 are configured, by way of
example, such that the wall of the support unit 126 has an
interference-fit within the socket 128 configured to inhibiting
liquid or fluid leakage from the apparatus from the support
compartment 30. This type of connection is not permanent and
enables the device to be serviceable.
[0070] The serviceable connection or joint between the substance
unit 122, cleaning unit 124 and support unit 126 can be configured
to inhibit or prevent liquid or fluid leakage from the joints
between the apparatus in a number of ways using: screw-fit, where
the units are screwed together; compression fit, where an
intermediate components functions, upon applied pressure, to form a
seal; bayonet-fit; a mechanical band that can be tightened around
the perimeter of the units; snap-fit; or a combination thereof. One
or more seals can be used in forming the connection.
[0071] The or each web 118, 120 can be rotatably mounted within the
units 122, 124 to allow to walls of the enclosure and socket 128 to
be moved independently of the web and the tube 10 and chamber 20.
To be clear, the tubes 10 and chambers 20 can be movable
independently of the manifolds and/or walls of the units 122, 124,
126.
[0072] Assembling the apparatus can be achieved in number of ways
depending on the type of connection between the units and whether
sub-assemblies are used. By way of example, the assembly of a
complete apparatus (only one end of which is shown in FIG. 3) will
be described as follows.
[0073] A web 120 is positioned in the main body of one end of a
cleaning unit 124, having a port 108, and located at one end of the
apparatus. In this example, the apparatus is substantially
cylindrical and the web is disc-like with a port located therein
for receiving the end of a cleaning chamber 20. At one end the
cleaning chamber 20 is secured in the port of the web 120. The
other end of the chamber 20 is secured in the port of a web 120
located in the body of another cleaning unit 124 located at the
other end of the apparatus.
[0074] If the apparatus is configured with a support compartment
30, the chamber 20 is first fed through the body of the support
unit 126 and connected to the web 120 located in the body of
another cleaning unit 124 located at the other end of the
apparatus. By way of example, the chamber 20 can be connected to
the port of the web 120 using a push-fit. Assembled, the cleaning
chamber 20 is secured between cleaning units 124 at either end of
the apparatus. If a support compartment 30 is used then the chamber
20 passes through the core of the support unit 126 and the ends of
the unit 126 are secured in the sockets 128 located on the cleaning
unit at either end of the apparatus.
[0075] A web 118 is positioned in the main body of one end of a
substance unit 122, having a port 104, and located at one end of
the apparatus. The web is disc-like with a port located therein for
receiving the end of a substance tube 10. At one end the tube 10 is
secured in the port of the web 118. The other end of the tube 10 is
fed through the chamber 20 and secured to the web 118 located in
the port of a web 118 located in the body of the other end of the
substance unit 122 located at the other end of the apparatus. By
way of example, the tube 10 can be connected to the port of the web
118 using a push-fit.
[0076] The connection between the chamber 20 or tube 10 and the web
can be a push-fit. The chamber 20 or tube 10 can, at least in part,
have reinforcement to ease the assembly process and/or connection
with a web, and to inhibit bending or flexing of the chamber 20 or
tube 10. The apparatus can be provided with a number of
intermediate webs positioned between the ends of the apparatus to
control the cross-sectional position of the chamber along the
length of the apparatus.
[0077] Servicing the apparatus requires reversing the
above-mentioned steps.
[0078] In the above example, a single substance tube 10 is
coaxially aligned to pass through a cleaning chamber 20, which is
in turn arranged to pass through a support compartment 30. Other
arrangements of the tube 10, chamber 20 and compartment 30 are
possible using the assembly techniques applied herein. The
apparatus can have a plurality of chambers 20, with each chamber 20
having a single tube passing coaxially therethrough. Alternatively,
the or each chamber 20 can have a plurality of tubes passing
therethrough. Additionally or alternatively, the support
compartment 30 can be configured to pass through the cleaning
chamber 20.
[0079] In one aspect of the invention the tube, chamber and
compartment are coaxial and a single tube or plasmapheresis hollow
fibre is configured within a single chamber or oxygenation hollow
fibre to provide a functional element of the FIF bioreactor.
[0080] The tubes of the apparatus are not, however, limited to
being cylindrical. The cross-sectional profile of the substance
tube 10, cleaning chamber 20 and support compartment can be
quadrilateral in shape, and can be rectangular, in cross-section,
as shown in FIGS. 4a and 4b. To be clear, the tube, chamber and
compartment can be cuboid, or box-shaped. FIG. 4a shows an
apparatus having a tube 10 connected to a chamber 20. The chamber
20 is connected to a compartment 30. A membrane 9 separates is
configured between the tube and chamber, and the chamber and the
compartment such that there is fluid communication therebetween
such that apparatus functions in the same manner, by way of
example, as described above for FIG. 2. The apparatus of FIG. 4a is
serviceable. The tube 10 can be replaceably removed from the
chamber 20. Similarly, the compartment 30 can be replaceably
removed from the chamber 20. By way of example, the connection
therebetween is a sliding bayonet connection.
[0081] FIG. 4a can be described as a flat-plate configuration. In
other words, the tube, chamber and compartment are substantially
planar. The planes of the tube, chamber and compartment can be
substantially parallel to each other.
[0082] FIG. 4b shows, by way of example, in cross-section, a
square-shaped tube 10 having chamber 20 connected on each of its
four sides, having a membrane 9 therebetween. The tube-chamber
assembly is optionally located within a compartment 30.
[0083] The invention is not limited to a fiber-in-fiber arrangement
and the communication between the tube, chamber and compartment can
achieved through alternative arrangements. All, or at least a part,
of the wall between the tube 10 and the chamber 20, and between the
chamber 20 and the compartment 30, has a membrane 9.
[0084] The tube, chamber and compartment are aligned coaxially.
Multiple tubes and/or chambers can be arranged multicoaxially. The
inlets and outlets can be configured on the ends of the apparatus,
and manifolds can be provided for the inlets and outlets.
[0085] The shapes of the tube 10, chamber 20 and compartment 30 can
be a combination of shapes according to the application of the
apparatus. Differing shapes can be configured to increase strength
to inhibit flexing along the axial length of the apparatus. Some
shapes can increase the surface area of the tube 10 or chamber 20
for a given volume. Some shapes can also be advantageous for
serviceability requirements by improving the ease at which one
component can be removably connected to another. By way of example,
in cross section, a portion or section of the connection between
the tube 10, chamber 20 and compartment 30 can have a wave-shaped
profile to increase the surface area therebetween.
[0086] Different configurations of apparatus allow for different
membrane types to be used. By way of example, high permeability
membranes allow faster diffusion of molecules and, consequently, a
better alimentation of the cells in nutrients. To avoid the
deterioration of the cells by the immunological system of the
patient's perfusate, a limitation of the membrane pore size needs
to be observed. As the molecular weight of the plasma proteins
increase it becomes more difficult for them to travel through the
membrane. The apparatus can be configured to inhibit membrane
fouling (concentration polarisation) by plasma proteins. The degree
of fouling is influenced by the flow conditions (i.e. shear rate)
and configuration (i.e. cross flow) within the device. Baffles can
be used to stimulate movement or flow within the apparatus.
[0087] Further, the solute mass transfer in a membrane-based
bioreactor depends on a number of factors including the membrane
type, the bioreactor geometry and the location of the compartments.
Internally, the phenomenon responsible for mass transport is
diffusion, convection, or a combination thereof.
[0088] Different shape combinations are explained, by way of
example, using the cross-sectional profiles of the apparatus. FIGS.
5a and 5b show arrangements wherein the walls of the tube 10 and
the chamber 20 are in fluid communication, but not connected, along
the axial length of the apparatus. The tube 10 described above has
been described as being cylindrical and having a single wall. In
the configuration of FIG. 5a, the tube 10 has 3 sides while the
chamber 20 and compartment 30, in cross-section, is circular and
has one side. The tube can have two or more sides. The chamber 20
too has been described above as being cylindrical and having a
single wall and in the configuration of FIG. 5b, both the tube 10
and the chamber 20 has two or more sides and are shown having
triangular structures in cross-section, while the compartment is
circular. By having two or more sides along at least a portion of
the axial length flexing of the tube and/or the chamber can be
inhibited.
[0089] FIGS. 6a and 6b show cross-sectional arrangements wherein
the tube 10 and the chamber 20 are connected along one axial face
along at least a portion of the axial length of the apparatus. In
the configuration of FIG. 6a, the tube 10 has a triangular
structure and there are three chambers 20, each having two
sides--one side engages with, and is in fluid communication with
the tube 10 via a membrane while the other is hemispherical and in
fluid communication with the compartment 30. In FIG. 6b the tube
has three sides and a chamber is connected to each side--one side
engages with the tube 10 while the other two form the triangular
shape of the chamber.
[0090] FIG. 7 shows an alternative arrangement of FIG. 4a, wherein
a number of support compartments 30, that are circular in
cross-section, pass through the cleaning chamber 20 rather than
being configured to pass adjacent the chamber 20.
[0091] The configurations of FIGS. 4a to 7 can be adapted to have a
plurality of tubes 10 and/or chambers 20. Connections can be made
to the tubes or chambers directly, or via a manifold or substance
store 114 and/or a cleaner store 116.
[0092] The terms tube, chamber and compartment have been used
throughout this application. Respectively, they can alternatively
be named as the first chamber (tube), second chamber (chamber) and
third chamber (compartment). In the above examples a convective
flow configuration can be used. Alternative flow configurations can
be implemented and movement of the substances in the apparatus can
be optimised with baffles.
[0093] In view of these and other variants within the inventive
concept, reference should be made to the appended claims rather
than the foregoing specific description in determining the
inventive concept. The present invention is not to be limited in
scope by the specific aspects and embodiments described herein.
Indeed, various modifications of the invention in addition to those
described herein will become apparent to those skilled in the art
from the foregoing description and accompanying figures. Moreover,
all aspects and embodiments described herein are considered to be
broadly applicable and combinable with any and all other consistent
aspects and embodiments, as appropriate.
[0094] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties.
* * * * *