Title: Pump for low flow rates
Abstract: The present invention concerns a pump for flow rates from about 1 to 1000 nl/min in which liquid transport takes place by evaporation of a transport liquid through a wettable membrane. The pumps according to the invention are particularly suitable for applications in the field of medical diagnostics such as microdialysis or ultrafiltration.
Patent Number: 6,860,993 Issued on 03/01/2005 to Effenhauser, et al.
| Inventors:
|
Effenhauser; Carlo (Weinheim, DE);
Harttig; Herbert (Altrip, DE);
Kraemer; Peter (Deidesheim, DE)
|
| Assignee:
|
Roche Diagnostics Corporation (Indianapolis, IN)
|
| Appl. No.:
|
884879 |
| Filed:
|
June 19, 2001 |
Foreign Application Priority Data
| Jun 21, 2000[DE] | 100 29 453 |
| Current U.S. Class: |
210/321.6; 210/321.72; 210/321.9; 210/266; 210/283; 210/502.1; 96/4; 95/45; 600/347 |
| Intern'l Class: |
B01D 063//00 |
| Field of Search: |
210/640,321.6,321.72,321.75,263,264,266,283,321.9,502.1
95/45,52
96/4
600/347
|
References Cited [Referenced By]
U.S. Patent Documents
| 4636307 | Jan., 1987 | Inoue et al. | 210/188.
|
| 4832034 | May., 1989 | Pizziconi et al. | 128/632.
|
| 4976866 | Dec., 1990 | Grinstead et al. | 210/638.
|
| 5045207 | Sep., 1991 | Fecondini et al. | 210/645.
|
| 5552046 | Sep., 1996 | Johnston et al. | 210/266.
|
| 5693230 | Dec., 1997 | Asher | 210/650.
|
| 5938928 | Aug., 1999 | Michaels | 210/634.
|
| 6039792 | Mar., 2000 | Calamur et al. | 95/45.
|
| 6136189 | Oct., 2000 | Smith et al. | 210/266.
|
| 6660165 | Dec., 2003 | Hirabayashi et al. | 210/640.
|
| Foreign Patent Documents |
| 0 722 288 | Jul., 1996 | EP.
| |
| 2 208 324 | Mar., 1989 | GB.
| |
| WO 95/10221 | Apr., 1995 | WO.
| |
Other References
Stanley Abramowitz, "DNA Analysis in Microfabricated Formats" Journal of
Biomedical Microdevices 1:2, 107-112, 1999, 1999 Kluwer Publishers.
|
Primary Examiner: Fortuna; Ana
Attorney, Agent or Firm: Woodburn; Jill L
Claims
What is claimed is:
1. Pump for low flow rates comprising
a channel which is at least partially filled with a transport liquid (3)
a membrane (4, 12) at one opening of the channel that can be wetted by the
transport liquid,
a gas space having an essentially constant vapour pressure of evaporated
transport liquid located at the side of the membrane opposite to the
transport liquid, wherein a continuous and constant loss of vapour results
in a vapour pressure below a saturation vapour pressure, thus leading to
an essentialy constant flow rate through the membrane.
2. Pump as claimed in claim 1, in which the space contains a sorbent (6,
15) which sorbs evaporated transport liquid.
3. Pump as claimed in claim 1, in which the space and the transport liquid
are separated from one another by the membrane.
4. Pump as claimed in claim 2, in which the sorbent has no direct contact
with the membrane.
5. Pump as claimed in claim 2, in which the sorbent is located in the
housing having an opening, wherein the opening is closed by the membrane.
6. Pump as claimed in claim 3, in which the space contains a sorbent and in
which the sorbent is located in a housing having an opening, wherein the
opening is closed by the membrane.
7. Pump as claimed in claim 6, in which the sorbent has no direct contact
with the membrane.
8. Pump as claimed in claim 1, in which the space is formed by a housing
(7') which exchanges evaporated transport liquid with the outer space.
9. Pump as claimed in claim 1, in which the membrane is hydrophilic.
10. Ultrafiltration device comprising a pump as claimed in claim 1 and an
ultrafiltration membrane through which a body fluid is drawn into the
channel.
11. Pump for low flow rates comprising
a channel which is at least partially filled with a transtport liquid (3)
a membrane (4, 12) at one opening of the channel that can be wetted by the
transport liquid, and
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid, in which the space contains a sorbent (6, 15) which sorbs
evaporated transport liquid, wherein
the membrane has a hydrophilic region facing the transport liquid and a
hydrophobic region which faces the sorbent.
12. Pump as claimed in claim 11, in which the sorbent is in contact with
the hydrophobic region of the membrane.
13. Pump for low flow rates comprising
a channel which is at least partially filled with a transport liquid (3)
a membrane (4, 12) at one opening of the channel that can be wetted by the
transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid, and
at least one non-wettable membrane (5) which is located on a side of the
wettable membrane facing away from the transport liquid.
14. Pump for low flow rates comprising
a channel which is at least partially filled with a transport liquid (3)
a membrane (4, 12) at one opening of the channel that can be wetted by the
transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid, wherein
the channel contains a working liquid that is segmented from the transport
liquid.
15. Pump for low flow rates comprising
a channel which is at least partially filled with a transport liquid (3)
a membrane (4, 12) at one opening of the channel that channel wetted by the
transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid, wherein the membrane is formed by an array of capillary channels.
16. Pump as claimed in claim 15, in which the capillary channels are
located in a body in which the channel conveying the transport liquid is
also located.
17. Pump as claimed in claim 16, in which the capillary channels are
manufactured by microtechnology using etching processes, laser machining,
or by stamping injection moulding or moulding processes.
18. Pump as claimed in claim 15, in which the capillary channels are
manufactured by microtechnology using etching processes, laser machining,
or by stamping, injection moulding or moulding processes.
19. Pump as claimed in claim 15, in which the array comprises 3 to 100
capillary channels.
20. Pump as claimed in claim 15, in which the capillary channels of the
array have a diameter of the individual channels in the range of 10 nm to
100 .mu.m.
21. Microdialysis system comprising
a pump having
a channel which is at least partially filled with a transport liquid (3)
a membrane which (4, 12) at one opening of the channel that can be wetted
by the transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid, and
a microdialysis membrane, wherein the transport liquid or a working liquid
is transported through the microdialysis membrane by the pump.
22. Microdialysis system as claimed in claim 21 containing a sensor located
downstream of the microdialysis membrane for the detection of one or
several analytes in the transport or working liquid.
23. Ultrafiltration device comprising
a pump having
a channel which is at least partially filled with a transport liquid (3)
a membrane which (4, 12) at one opening the channel that can be wetted by
the transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid,
an ultrafiltration membrane through which a body fluid is drawn into the
channel, and
a sensor located downstream of the ultrafiltration membrane for the
detection of one or several analytes in the body fluid.
24. System for pumping a working liquid at a low flow rate, wherein at
least one dilution reservoir (22) containing a liquid which is essentially
free of substances that cannot evaporate at the membrane is located
between a fluid system in which the working liquid is located and a pump
including
a channel which is at least partially filled with a transport liquid (3)
a membrane (4, 12) at one opening of the channel that can be wetted by the
transport liquid,
a space having an essentially constant vapour pressure of the transport
liquid located at the side of the membrane opposite to the transport
liquid.
25. System as claimed in claim 24, in which two or more reservoirs that are
connected to one another (22.sup.1, 22.sup.2, 22.sup.3, 22.sup.4,
22.sup.5, 22.sup.6, 22.sup.7, 22.sup.8) which form a dilution cascade are
arranged between the fluid system containing the working liquid and the
pump.
26. A pump comprising:
a housing defining a gas space and including a channel, the channel being
at least partially filled with a transport liquid, and
a membrane positioned in the housing, the membrane including a first side
facing toward the liquid and a second side facing the gas space, wherein
the gas space has an essentially constant vapour pressure of evaporated
transport liquid, wherein a continuous and constant loss of vapour results
in a vapour pressure below a saturation vapour pressure, thus leading to
an essentially constant flow rate through the membrane.
27. The pump of claim 26 further comprising a sorbent positioned in the
space.
28. The pump of claim 27 wherein the sorbent is spaced apart from the
membrane.
29. The pump of claim 27 wherein the membrane separates the transport
liquid and the space from one another.
30. The pump of claim 26 wherein the membrane separates the transport
liquid and the space from one another.
31. The pump of claim 26 wherein the housing comprises a means for
exchanging evaporated transport liquid with a space outside the housing.
32. The pump of claim 26 wherein the membrane is hydrophilic.
33. A pump comprising:
a housing defining a space and including a channel, the channel being at
least partially filled with a transport liquid, and
a membrane positioned in the housing, the membrane including a first side
facing toward the liquid and a second side facing the space, wherein the
space has an essentially constant vapour pressure of the transport liquid,
wherein the membrane has a hydrophilic region facing the transport liquid
and a hydrophobic region facing the space.
34. A pump comprising:
a housing defining a space and including a channel, the channel being at
least partially filled with a transport liquid, and
a membrane positioned in the housing, the membrane including a first side
facing toward the liquid and a second side facing the space, wherein the
space has an essentially constant vapour pressure of the transport liquid,
and
at least one non-wettable membrane positioned in the space.
35. A pump comprising:
a housing defining a space and including a channel, the channel being at
least partially filled with a transport liquid, and
a membrane positioned in the housing, the membrane including a first side
facing toward the liquid and a second side facing the space, wherein the
space has an essentially constant vapour pressure of the transport liquid,
and
a working liquid positioned in the channel that is segmented from the
transport liquid.
36. A pump comprising:
a housing defining a space and including a channel, the channel being at
least partially filled with a transport liquid, and
a membrane positioned in the housing, the membrane including a first side
facing toward the liquid and a second side facing the space, wherein the
space has an essentially constant vapour pressure of the transport liquid,
the membrane is formed to include capillary channels.
37. The pump of claim 36 wherein the membrane includes 3 to 100 capillary
channels.
38. The pump of claim 37 wherein the membrane includes 5 to 25 capillary
channels.
39. The pump of claim 36 wherein the capillary channels each have a
diameter of 10 nm to 100 .mu.m.
40. The pump of claim 36 wherein the housing includes a base plate and a
cover and the channel is formed in the base plate.
41. The pump of claim 40 wherein the membrane is disposed between the base
plate and the cover.
42. The pump of claim 40 wherein the space is formed in the cover.
43. The pump of claim 36 wherein the housing is formed to include openings
in communication with the space.
Description
BACKGROUND AND SUMMARY OF THE INVENTION
The present invention concerns a pump for flow rates in the range from
about 1 to 1000 nl/mm. The pumps according to the invention are
particularly suitable for applications in the field of medical diagnostics
such as microdialysis or ultrafiltration.
A pump is claimed for low flow rates which having channel which is at least
partially filled with a transport liquid and a membrane that can be wetted
by the transport liquid which closes one opening of the channel and
through which evaporation can take place. There is a space on the opposite
side of the membrane to the transport liquid which has an essentially
constant vapour pressure of the transport liquid. The invention also
encompasses microdialysis and ultrafiltration systems containing such a
pump.
Miniaturized pumps are known in the prior art e.g. peristaltic pumps which
can achieve flow rates as low as about 100 nl/min. The focus of
miniaturized pump development is usually to achieve the highest possible
delivery rate with a minimum pump volume. Furthermore it has turned out
that such pumps do not operate reliably enough in the low pumping range
when used for long-term applications and in particular it is difficult to
avoid large variations in the flow rates. Other arrangements are known in
the field of ultrafiltration and microdialysis in which a negative
pressure reservoir (for example a drawn syringe) is connected to a fluid
system via a constricted capillary path. However, this has the
disadvantage that the pressure time course is non-linear. A further
arrangement for achieving low flow rates is known from the document WO
95/10221. In this arrangement a liquid located in a channel is directly
contacted with a sorbent. Typical flow rates for such a system are in the
range of a few .mu.l/min. The long-term constancy (measured over several
days) of this pump is quite low.
The object of the present invention was to provide a pump for very low flow
rates which operates reliably and has a sufficiently constant flow rate
over a long time period (e.g. several days). A further object of the
present invention was to propose a pump for such low flow rates which is
very simple and cost-effective to manufacture. The pump should also be
mechanically simple to manufacture and be compatible with integrated
microfluidic systems based on planar technologies (e.g. microtechnology).
With a pump according to the invention a transport liquid is located in a
channel which has an opening which is closed by a membrane that can be
wetted by the transport liquid. Transport liquid penetrates the membrane
due to capillary effects and is led away via capillary channels through
the membrane into a gas space having an essentially constant vapour
pressure of the transport liquid or it is physically or chemically bound
(taken up) by a suitable sorbent such that further unhindered evaporation
through the membrane can occur. The constant vapour pressure conditions in
the gas space result in a constant flow rate.
Within the scope of the invention it is possible to generally use transport
liquids which can penetrate into a membrane and evaporate through it.
Aqueous transport liquids are preferred within the scope of the present
invention. In addition to the water component, aqueous transport liquids
can contain substances or mixtures which influence the surface tension
and/or the viscosity in order to adjust the permeation properties of the
transport liquid into the membrane to a desired value. However, the
transport liquids preferably contain no substances that cannot evaporate
at room temperature, e.g. salts, since these could lead to a blockage of
the membrane. Suitable embodiments are described further below for cases
in which it is intended to transport liquids containing substances that
cannot evaporate.
The channel of the pump according to the invention preferably has an area
in the range 1 to 10.sup.5 .mu.m.sup.2 and a length of 1-1000 mm. The
lateral dimension of the cross section is preferably greatly enlarged (1
to 1000 mm.sup.2) in the area of the wettable membrane in order to provide
an adequately large exchange area with the adjoining gas space. The
evaporation process at the membrane removes transport liquid from the
fluid channel and thus generates an underpressure which causes the desired
pump action. The pump can be used to transport the transport liquid itself
when for example this liquid is used as a perfusion liquid for a
microdialysis. In another inventive embodiment the fluid channel contains
a working fluid which for example is used as a perfusate or for other
purposes and is segmented from the transport liquid. In another
application of the pump such as ultrafiltration, evaporation of the
transport liquid generates an underpressure in the channel which conveys a
fluid from the surroundings into the fluid channel. In the field of
ultrafiltration this would be an external fluid (interstitial fluid) which
enters the channel through an ultrafiltration membrane.
The term membrane in the sense of the present invention is intended to
generally encompass structures through which liquid is sucked from the
fluid channel by capillary forces and evaporated. In addition to the
bodies that are referred to as membranes in everyday usage which have a
plurality of usually disordered capillary channels, the term membrane is
also intended to encompass arrays of (possibly only a few) capillary
channels. Such an embodiment is described in more detail in conjunction
with the figures. Such capillary arrays can be manufactured by
microtechnical methods in which very small and constant cross-sections are
achievable. Very low flow rates can be achieved with such capillary-active
membranes that can be adjusted by the manufacturing process via the number
and cross-section of the capillary channels.
The evaporation rate can be additionally controlled by sealing with a
hydrophobic, non-wettable membrane (e.g. Teflon).
In cases were either a direct contact of the liquid to be transported with
the evaporator membrane has to be avoided e.g. when transporting liquids
containing salts where direct evaporation on the membrane would lead to
the formation of a solid salt residue with a concomitant damaging effect
on the constancy of the evaporation rate, or when for example a suitable
sorbent is not available for the liquid to be transported, the indirect
approach of using an additional transport liquid (for example degassed and
deionized water) can ensure the pump operation.
In the case of immiscible liquids (e.g. toluene as the liquid (working
fluid) to be transported, water as the evaporating transport liquid), it
is possible for the two liquids to be present directly in the system with
a common phase boundary without the liquid to be transported coming into
contact with the membrane during pump operation over a long period (e.g.
for several days). This can be achieved by using a stock of transport
liquid in an intermediate buffer which is preferably larger than the total
volume of transport liquid (working fluid) to be conveyed.
In the case of miscible liquids the two liquids (e.g. Ringer's solution and
pure water) can be segmented from one another by an impermeable membrane.
In this case a diffusion barrier can also be preferably used such that in
the above case the Ringer's solution displaces a water volume located in
one or several connected reservoirs (e.g. a dilution cascade) and the
concomitant dilution ensures that the salt concentration at the
evaporation membrane is reduced to an adequate extent. This can prevent or
at least reduce salting-out on the membrane which would otherwise alter
the pump rate. The advantages of this solution are that it avoids moving
parts (e.g. a bending membrane), and is simple to manufacture and
integrate into the pump body.
A further advantage of this solution is that, depending on the geometric
design of the transport path, the reservoirs can act wholly or partially
as bubble traps for gases that may be present in the liquid to be
transported or which may be released during transport and thus can help to
prevent direct contact of gas bubbles with the evaporation membrane.
Another simple method for segmenting the liquid to be transported and the
transport liquid is to introduce a gas bubble which permanently separates
the two liquids. The volume of this gas bubble must be large enough to
guarantee segmentation over all changes in the cross-section of the
transport path and optionally also in the container which serves as a
storage medium for the transport liquid.
An advantage of the solution employing one or several reservoirs to dilute
the liquid to be transported compared to a gas bubble for segmentation is
that the function is still ensured even after strong shaking movements
which in the case of gas bubble segmentation could lead to a mixing of the
liquids. The fact that the gas bubble may dissolve in the liquid shows
that it also has the disadvantage that the flow rate additionally depends
on temperature due to the temperature-dependent expansion/contraction of
the gas buffer.
An important aspect of the present invention is the membrane that can be
wetted by the transport liquid. The pump effect of the membrane is based
on the fact that a liquid can be sucked by surface forces into capillaries
or pores of the membrane. The capillary pressure that is generated by this
means is directly proportional to the surface tension of the liquid and to
the cosine of the angle of contact between the liquid and the membrane
material and is inversely proportional to the radius of the capillaries or
pores. Hence membranes are suitable for the present invention which have a
contact angle with regard to the transport liquid between 0 and 90
degrees. This stated relationship also shows that the capillary pressure
increases when the diameter of the capillaries or pores decreases. Typical
pore diameters of capillaries in the membrane are in the range from 10 nm
to 100 .mu.m. It is important for the present invention that the transport
liquid is in direct contact with the membrane such that a capillary effect
occurs. Consequently it is necessary to ensure that there is no
interruption in the liquid contact between the transport liquid and
membrane which may occur when the pore diameter of the membrane becomes
too large with a concomitant decrease in capillary pressure or it may also
be caused by a defect (hole) in the membrane which would lead to a
pressure equilibration by the return flow of gas.
Furthermore it is advantageous to use membrane systems within the scope of
the invention which, apart from a wettable membrane, have an additional
membrane which is located on the side of the first membrane which faces
away from the transport liquid. Membranes which cannot be penetrated by
liquids with a high surface tension can be used for this second membrane
such as membranes made of PTFE, Cuprophan.RTM. or Gambran.RTM.. The
evaporation rate of the transport liquid can be modulated by means of the
properties of this second membrane. Furthermore it is also possible to use
membranes which have different regions of which one region facing the
transport liquid is wettable and a region facing away is not wettable.
It is also possible to integrate the manufacture of the pump body and
membrane (monolithic) or to use tailor-made membranes of a defined pore
size and pore distribution in a hybrid approach. The integrated
manufacture of such membranes based on silicon is described for example in
T. A. Desai et al., Biomedical Microdevices 2 (1999), 11-41. Another
method is to use a microporous Si membrane having a statistical
distribution of pore sizes (R. W. Tjerkstra et al., Micro Total Analysor
Systems 1998, Kluwer 1998, p. 133-136). Such membranes can for example be
manufactured in polymer substrates using laser ablation, hot-stamping etc.
The pump action of the membrane used is maintained until the partial
pressure of the liquid to be pumped on the side of the membrane facing
away from the liquid (gas side) is less than the saturation vapour
pressure at the respective working temperature. In order to maintain a
constant vapour pressure (and to minimize possible environmental
influences) it is proposed that a gas space be provided which contains a
sorbent which is not in direct contact with the wettable membrane. The
continuous sorption of the evaporating liquid maintains a constant
difference of the vapour pressure over the liquid in the pores and the
saturation vapour pressure.
The term sorbent encompasses adsorbents as well as absorbents. Suitable
sorbents are for example silica gels, molecular sieves, aluminium oxides,
zeolites, clays, active charcoal, sodium sulfate, phosphorous pentoxide
etc.
It is important for the desired pump function that there is no direct
contact between the sorbent and the capillaries/pores of the wettable
membrane to prevent direct transfer of liquid by this means. On the
contrary, in order to achieve low flow rates that remain constant over
long periods it is necessary that firstly evaporation of transport liquid
occurs and that the evaporated transport liquid is taken up from the gas
phase by the sorbent. This can be achieved by spacing apart the wettable
membrane and the sorbent such that there is no direct fluid contact.
Furthermore it is possible to use one (or also several) non-wettable
membrane(s) which are preferably located directly next to the wettable
membrane. With such a membrane the sorbent can also be in direct contact
without generating a fluid short circuit. Such an arrangement also enables
the use of a liquid sorbent such as a highly concentrated or saturated
salt solution. Another method is to modify a region of the wettable
membrane that faces away from the transport liquids or faces the sorbent
in such a manner that the membrane cannot be wetted and thus adopts the
function of a second non-wettable membrane. Such a modification of the
membrane can for example be achieved by a plasma reaction. With
embodiments containing membranes which have a wettable region and a
non-wettable region, the sorbent can directly contact the non-wettable
region without making a fluid short-circuit.
In order to be effective the sorbent should be located in a vessel
(container) which seals it from the outer space and in particular largely
prevents penetration of moisture from the external space. The vessel has
an opening which is closed by the wettable membrane or the non-wettable
membrane. As a result evaporated transport fluid enters the vessel through
the membrane and is taken up there by the sorbent. The sorbent should be
selected such that the equilibrium vapour pressure of the transport liquid
which is less than the saturation vapour pressure of the fluid in the gas
phase remains constant for a long period as a result of the sorbent. This
is important in order to set a defined evaporation rate of the transport
liquid which increases the constancy of the flow rate.
It was surprisingly found that embodiments of the vessel containing the
sorbent having flexible walls did not have an adverse effect on the pump
action but on the contrary variations in the flow caused by pressure
changes in the external space or by temperature changes were considerably
reduced. Foils such as 3E composite aluminium foils of low density and low
buckling strength are especially suitable as flexible walls. Elastic
plastics such as silicons can also be used.
It was surprisingly found that another simplified embodiment which does not
need any sorbent also results in very constant transport rates. In this
embodiment a space is enclosed by walls to form a housing above the side
of the membrane or of the membrane sandwich which faces away from the
transport liquid, the walls having openings which comprise between 0.001%
and 100% of the surface of the walls i.e. the housing is omitted in the
extreme case. The transport rate of liquid vapour into the surrounding gas
phase can be adjusted over a wide range by the geometric dimensions and
number of openings and by the choice of gas permeable membranes.
Embodiments are also possible in which the space on the side of the
membrane opposite to the transport liquid is not surrounded by a housing
belonging to the pump. This is the case when the space per se has an
essentially constant vapour pressure of the transport liquid which is the
case for air-conditioned rooms. In particular designs are also possible in
which the pump according to the invention is used within an
air-conditioned system for example an analyser.
The transport rate depends on a number of factors of which the viscosity of
the liquid and the membrane properties have already been mentioned above.
These influencing variables in turn depend on the temperature. Hence, for
example the evaporation rate and also the diffusion rate in the gas phase
increase with increasing temperature. In contrast a temperature increase
has the opposite effect on the viscosity of the liquid, the surface
tension of the liquid and the interfacial tension between the membrane and
liquid. Hence there is a complex relationship between the transport rate
and the temperature. However, a low temperature dependency can be ensured
by suitable selection of the relevant materials such as the membrane(s)
and the sorbent. The present invention is particularly suitable for
applications under thermostatted conditions. On the one hand it is
possible to have an active temperature control where for example the
temperature in the region surrounding the membrane is adjusted to a
preselected range using a peltier element. A pump according to the
invention can be used particularly advantageously in close contact with
the human body. In this case direct contact of the housing in which the
pump is located with the body surface is advantageous. The temperature
regulation can be additionally supported by thermally insulating the sides
of the pump or microdialysis or ultrafiltration system that are not
adjacent to the body. In addition it is also possible to integrate a
temperature measuring unit into a system containing a pump according to
the invention which reports deviations from a target temperature range or
even takes into account the currently measured temperature when evaluating
analytical measurements.
There is preferably no direct contact between the transport fluid and the
wettable membrane when the pump according to the invention is delivered to
avoid an unnecessary consumption of liquid. When the pump is put into
operation by the user the contact can be made by applying a pressure pulse
to a certain area.
The liquid pumps according to the invention enable the very advantageous
construction of microdialysis and ultrafiltration systems. In the case of
microdialysis the transport liquid can be used directly as the perfusate
which is led through a microdialysis catheter in order to take up the
analyte. Alternatively it is also possible to have a liquid (e.g. Ringer's
solution) which is different from the transport liquid which is
fluidically coupled to the transport liquid.
In the case of ultrafiltration the consumption of transport liquid by the
evaporation process can be used to generate an underpressure in the
channel which draws in body fluid (interstitial fluid) into an
ultrafiltration catheter. In the case of microdialysis as well as
ultrafiltration a sensor may be provided downstream of the microdialysis
membrane or ultrafiltration membrane for the detection of one or several
analytes.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention is elucidated in more detail by figures.
FIG. 1: Cross-section through a first embodiment of a pump containing
sorbent
FIG. 2: Top-view and cross-section through a pump according to a second
embodiment
FIG. 3: Flow rate of a pump according to FIG. 1
FIG. 4: Cross-section through a pump without sorbent
FIG. 5: Top-view and cross-section through a dilution cascade.
FIG. 6: Cross-section through a membrane region containing individual
capillaries.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a cross-section through a pump according to a first
embodiment. The arrangement shown has a channel (2) having a diameter of
100 .mu.m in which a transport liquid is located. Water was chosen as the
transport liquid in the case shown. The channel is closed with a wettable
membrane (4) in a region of the transport channel with an enlarged
cross-section. In the present case a BTS 65 from the Memtec Company (now:
USF Filtration and Separations Group, San Diego, Calif., USA) (PESu
hydrophilized with hydroxypropyl cellulose) was used as the membrane. This
very hydrophilic membrane is asymmetric and has pores in the range from
about 10 .mu.m on one side and 0.1 .mu.m on the other side. The side with
the larger pores faces the liquid. A non-wettable membrane made of
expanded PTFE is located above the wettable membrane (4). The non-wettable
membrane is mounted on the wettable membrane in such a manner that it
completely covers the side of the wettable membrane (4) which faces away
from the transport liquid (3). The figure shows that the arrangement was
selected such that the transport liquid can only evaporate from the
channel system via the wettable membrane (4). The system comprising the
wettable (4) and non-wettable membrane (5) is surrounded by a housing (7)
in such a manner that evaporated transport liquid can only reach the
interior of the of the housing or vessel (7). The interior of the housing
(7) contains a sorbent (6) which is silica gel in the present example
(molecular sieve MS 518, Grace Favison, Baltimore, Md., USA). FIG. 1 also
shows that the sorbent is in direct contact with the non-wettable
membrane. As described above this is possible because the non-wettable
membrane prevents a fluid short-circuit i.e. a direct sorbtion of liquid
from the capillaries of the wettable membrane without a gaseous/vaporous
intermediate phase. The pump shown achieved in experiments a flow rate in
the range of 1 to 1000 nl/min (nanolitres per minute) in the direction of
the arrow (8).
FIG. 2 shows a system which is technically very advantageous to manufacture
and to miniaturize. The pump of FIG. 2 has a base plate (9) with
depressions which form a capillary system (11) in conjunction with a cover
(10). FIG. 2b shows how the base plate and cover are arranged relative to
one another. A wettable membrane (12) is disposed above a channel system
(13) and is located between these two units. The membrane can be attached
by simply clamping it between the base plate and cover. The cover and base
plate can for example be joined together by glueing, pressing or
ultrasonic welding. The channel system (13) can be simply formed by a
recess in the base plate in which additional cross-pieces are located to
prevent the membrane from sagging. In this manner capillary channels are
formed by interaction with the underside of the membrane which ensure that
the channel system is completely filled with transport liquid. Such a
channel system enlarges the surface from which transport liquid passes
into the wettable membrane. FIG. 2b additionally shows that the cover has
a recess (14) which is located above the membrane (12). The relative
arrangement of the channel, membrane and vessel for taking up evaporated
transport liquid ensures that transport liquid can only escape into the
recess (14). The recess (14) which forms the vessel contains a sorbent
(15) which absorbs transport liquid located in the gas space (16). The
embodiment shown in FIG. 2 only requires a single wettable membrane (12).
A non-wettable membrane can be omitted since the membrane and sorbent are
spaced apart and can only exchange via the gas space.
FIG. 3 shows a measurement of flow rates which were achieved with an
apparatus according to FIG. 1 over a period of 6 days. The flow rate was
measured by gravimetric determination of the decrease of liquid in the
storage container. The pump which gave the results shown in FIG. 3 had a
circular exchange surface of the transport liquid with the membrane
(diameter 2 mm). A hydrophilic membrane named BTS 65 (see the above
description) and a non-wettable polytetrafluoroethylene membrane as an
evaporation limiter were used. 8 g silica gel was used as the sorbent for
the transport liquid (water). Apart from the enlarged section of the
channel below the membrane, the channel had a diameter of 100 .mu.m and a
length of 40 cm. FIG. 3 shows that the flow rate only decreased from 100
nl/min to about 80 nl/min during the period of 6 days. Such a change in
flow rate can be tolerated for applications in the field of microdialysis
and ultrafiltration since they do not significantly effect the analytical
result.
FIG. 4 shows a pump according to the invention without a sorbent. The
dimensions as well as the wettable (4) and non-wettable membrane (5) of
this pump correspond to that shown in FIG. 1. A housing (7') is located
above the non-wettable membrane and is arranged such that transport liquid
(3) can only evaporate into the space (16) of this housing. The housing
(7') differs from the housing shown in FIG. 1 in that it has openings (17)
through which the evaporated transport liquid can escape from the space
(16). Membranes can be provided instead of openings which allow diffusion
of gaseous transport liquid. Thus it is for example possible to make the
housing completely of a material that allows adequate diffusion and has no
openings. The said embodiments achieve a diffusion equilibrium between the
inner space (16) and the surroundings which ensures that the vapour
pressure of the transport liquid in the interior space (16) is essentially
constant. Hence an essentially constant evaporation rate and thus also
transport rate is achieved in the channel (2).
FIG. 5 shows a top-view and cross-section of a dilution cascade that can be
used to adequately separate transport liquid from working liquid and thus
prevents a change in the evaporation rate at the membrane due to
components (e.g. salts) in the working fluid that cannot evaporate. The
dilution cascade (20) has a base body (21) which can be for example
manufactured from plastic and, in the case shown, has 8 reservoirs. The
reservoirs are formed by through bores in the base body (21) which are
closed by cover plates (23, 23'). The base body is also provided with
microstructured channels (24) which, after the base body is covered with
the cover plates, allow fluid exchange between the individual reservoirs
and allow liquid to enter and be discharged from the dilution cascade.
The operating principle of the dilution cascade (20) is as follows: The
dilution cascade (20) is connected via its inlet port (26) to a fluid
system in which liquid is to be transported. The dilution cascade is
linked by its outlet port (27) to a pump according to the invention. When
the dilution cascade is put into operation it is filled with an evaporable
liquid which contains no or only very small additions of non-evaporable
components. Liquid contained in the dilution cascade is now drawn out of
the outlet port (27) by the action of a pump according to the invention
and is followed by the liquid to be pumped which flows into the inlet port
(26). The first reservoir (22.sup.1) now contains a mixture of the liquid
to be pumped and the dilution fluid contained in the dilution cascade.
Successive dilutions take place in the subsequent reservoirs (22.sup.2,
22.sup.3, 22.sup.4 . . . ) such that practically only dilution fluid
without substantial amounts of the fluid to be transported emerges at the
outlet port (27). In order to ensure adequate functioning of the dilution
cascade, the total volume pumped by the pump should be less than half,
preferably less than a quarter of the total volume of the dilution liquid
in the dilution cascade.
FIG. 6 shows the membrane region of a pump based on capillary channels
generated by microtechnology. The fluid channel (2) branches into several
capillaries (30) having a defined pore diameter and thus forms a membrane
with a low number of pores. The end of a capillary can be regarded as a
single pore from which evaporation into the gas phase occurs. The
evaporation rate from the menisci in the capillaries can be additionally
regulated by means of a non-wettable hydrophobic membrane.
FIG. 6 shows a hollow space (32) into which evaporation from the
capillaries takes place. The hollow space is closed from the outer space
by means of a membrane (31) in order to ensure an essentially constant
vapour pressure of the fluid in the hollow space.
*
