WO2006042554A2

WO2006042554A2 - Device for micro dialysis integrating pump, probe and perfusion fluid

Info

Publication number: WO2006042554A2
Application number: PCT/DK2005/000680
Authority: WO
Inventors: Holger Dirac; Peter Gravesen
Original assignee: Danfoss A/S
Priority date: 2004-10-21
Filing date: 2005-10-20
Publication date: 2006-04-27

Abstract

A replaceable device for an analysis system, comprising a sampling probe in fluid connection with a fluid inlet connected to a feed tube and a fluid outlet connected to a return tube, pressurizing means, said pressurizing means pressurizing a fluid, said fluid being in fluid connection with said fluid inlet, where, prior to use said pressurizing means, said fluid connections, said probe and said fluid is contained in a sterile package.

Description

Device for micro dialysis integrating pump, probe and perfusion fluid

This invention relates to a micro dialysis device for sensing the level of a constituent in a medium, or a fluid, particularly body fluids, and the sensed species may be such as glucose, oxygen, antibiotics, enzymes, hormones, tumour markers, fatty acids, or amino acid levels. The device comprises a probe to be placed in connection with the medium, a perfusion fluid to col¬ lect the species as they cross the membrane of the probe, a constant pressure pumping system (CP-pump) for driving the perfusion fluid, and a flow regulating element to control the flow rate of the perfusion fluid. Capil¬ lary tubes connect the parts of the device.

Background Millions of people, especially in the Western world, have diagnosed diabe¬ tes and further millions are estimated to have it undiagnosed. The disease is a chronic metabolic disorder characterized by an abnormal metabolism of carbohydrates, proteins and fats in the body. In a healthy body carbo¬ hydrates are digested to glucose in the gut, and the glucose is absorbed into the circulatory system and carried to most cells of the body as the principal source of nutrition.

In one form of diabetes, the glucose cannot enter the liver, muscle and fat cells in normal amounts for storage or energy use and as a consequence builds up in the blood and urine. Abnormally high blood glucose levels may lead to the accumulation of toxic ketone metabolites often leading to coma and death.

Currently a large proportion of diabetics monitor their own glucose level by finger pricking, but at least for clinical purposes, it is also common to moni¬ tor by dialysis, where subsequent chemical and biological analysis of tiny samples of body fluid in human or veterinary medicine is taken and ana- lysed. Sampling is normally effected by inserting into the body a very fine, hollow probe containing a suitable membrane in communication with the body fluid or tissue, and pumping perfusion liquid therethrough to fetch out the diffused solute therein.

Since then, the method of sampling by dialysis has found its use in a vari¬ ety of fields where an analysis of species in a medium is to be performed. This may range as wide as contamination or nutrition in water-systems, manufacturing industries where unpolluted fluids are necessary, or it may be used for monitoring cell damage in patients in intensive care, in the brain or other tissues, where there may be some not visible injury.

Dialysis probes can take a number of different physical forms. An earlier type of probe was essentially a sleeve-like tube a few millimetres in diame- ter and made of some impermeable material with the first end being closed by a suitable semi-permeable membrane. Smaller tubes are seal- ingly inserted at the second end of the sleeve-like tube, to allow perfusion fluid to be fed to and withdrawn from the interior (the lumen) of the sleeve. In use, the first end of such a probe is inserted into a suitable tissue, for example, a vein or an artery, and perfusion fluid is pumped in through and out of the sleeve, taking with it any materials that have diffused from the body through the first-end membrane into the sleeve's lumen.

To perform the dialysis, the perfusion fluid needs to be driven in the flow- system, and a typical choice is a syringe pump, where a syringe contain¬ ing the perfusion fluid is loaded into the pump. The pump then performs a steady and accurate forward movement of the syringe-piston by predeter¬ mined speed, producing a constant rate of flow into the attached probe- system of tubes and membrane. The typical syringe pump is electric, needing some power-supply like a battery or wire-connection to electricity. There is also the need for connecting the probe to the syringe, as well as placing the syringe into the pump, Currently, a widely used method of measuring for the glucose levels in the blood is to take a sample of fresh, whole blood (typically 20-40 μl) and place it on an ethyl cellulose-coated reagent pad containing an enzyme system having glucose oxidase and peroxidase activity. The enzyme sys¬ tem reacts with glucose and releases hydrogen peroxide. The pad also contains an indicator, which reacts with the hydrogen peroxide in the presence of peroxidase to give a colour proportional in intensity to the sample's glucose level.

Another popular blood glucose test method employs similar chemistry, but in place of the ethyl cellulose-coated pad employs a water-resistant film, through which the enzymes and the indicator are dispersed. In both cases the evaluation is made either by comparing the colour generated with a colour chart or by placing the pad or film in a diffuse reflectance instrument to read a colour intensity value.

It is known art to have a single replaceable device comprising a pumping system, like US 5,84,894, where an infuser is divided into two parts, a re- usable device and a disposable device comprising a reservoir with the in¬ fusion liquid and a communication tube connected to a needle for the infu¬ sion. To drive the infusion flow, the disposable device also comprises a single-use pumping system and its energy reservoir, where the pump preferably isan electric pump and the energy reservoir is a battery. US 5,984,894 describes an infusion system having a reusable and a re¬ placeable device. The self-contained replaceable device contains a reser¬ voir with a liquid to be infused, an infusion line communicating with the reservoir, a pump for pumping the liquid from the reservoir out through the infusion line and an energy reservoir for operating the pump. The infusion line ends in a needle to be inserted into body tissue. A similar system is found in US 6,589,229, describing a wearable, self contained drug infusion device with a two-part construction, the first with the more expensive elec- tronics and a second disposable part with the fluid delivery components. The disposable part comprises a housing containing a reservoir with a liq¬ uid and a Bellville spring element for pressurizing the liquid. The dispos¬ able part further comprises a delivery needle and a fluid-communication channel.

Another example of a disposable pump is US 2004/0073175 disclosing a disposable medical line-set comprising a length of tubing with a first end and a fluid extraction spike connected to the first end of the tubing. The system further contains a MEMS pump (MEMS = micro-electromechanical system) housed within the fluid extraction spike and operatively connected to the tubing. The spike may be used in conjunction with other elements of a medical line-set to pump fluids from a rigid or flexible container or reser¬ voir. Insertion of the spike into a bag, container or reservoir provides a complete, closed infusion system that may be discarded after use.

In US 6,572,566 a micro dialysis probe is in one embodiment connected to a constant pressure system, of the kind where a thin flexible wall sepa¬ rates a pressurized gas from a liquid. The pressurized gas exerts at pres- sure on the flexible wall pushing it against the liquid and hereby squeezing it into a channel system in fluid connection with the probe at a constant rate. The whole system is built as a single device, where channels and reservoirs are defined by grooves and holes into members joined together.

The object of this invention is to create a dialysis device on the same prin¬ ciple as in US 6,572,566, where there are no electronics or motors in¬ volved in making the perfusion flow, and where the flows are of micro¬ scopic dimension with flows less than one micro-litre per minute, and where the system may come in a ready-to-use sterile package, but with the big difference that, when exhausted, the device is easily replaced in a quick and safe manner without having to replace the whole analysing de- vice too, and where, in principle, it may be connected to any system for analysing a micro-fluidic sample.

This is achieved by: A replaceable device for an analysis system, comprising a sampling probe in fluid connection with a fluid inlet connected to a feed tube and a fluid outlet connected to a return tube, pressurizing means, said pressurizing means pressurizing a fluid, said fluid being in fluid connection with said fluid inlet, where, prior to use said pressurizing means, said fluid connections, said probe and said fluid is contained in a sterile package.

Figure 1 : A schematic drawing of the dialyzing device prior to activation.

Figure 2: A schematic drawing of the dialyzing device when activated for sampling.

Figure 3: A schematic drawing of an alternative constant pressure pump- ing system.

Figure 4: A schematic drawing of an alternative design embodiment of the constant pressure pumping system.

Figure 5: A schematic drawing of the dialyzing device attached directly to the analysing apparatus.

Figure 6: A schematic drawing of the dialyzing device with a valve initially blocking the fluid-access.

Figure 7: A schematic drawing of an alternative embodiment of the dialyz¬ ing device. Figure 8: A schematic drawing of one embodiment of the dialysing device comprising a priming arrangement.

Detailed description of the invention

A first preferred embodiment of the invention is illustrated in Fig. 1 where the dialyzing device 1 comprises a constant-pressure pumping system (CP-pump) 2, capable of delivering at substantially constant flow. The CP- pump 2 in the preferred example comprises a syringe 6 having a hollow piston 7, an elastomer bladder 8 and a flow-restricting element 9. The elastomer bladder 8 is placed inside the hollow of the piston 7 and at¬ tached to its endplate 15.

Prior to activation of the dialyzing device 1 , the hollow piston is positioned in a first position as seen in Fig. 1 , with the chamber 11 enclosed between the endplate 12 and the end-wall 15 of the syringe and filled with a perfu¬ sion fluid 13. The elastomer bladder 8 is empty and floppy. The endplate 12 is pierced by a fluid communication 14 providing access from the chamber 11 to the inside of the elastomer bladder. This fluid communica¬ tion 14 may initially be closed by some pressure activated valve or mem¬ brane, or by some other removable means blocking the fluid communica¬ tion, preventing the perfusion fluid 13 from entering the elastomer bladder 8.

In front of the syringe 6 is located a protective casing 14 containing a flow restricting element 9 connecting the interior of the syringe to the external flow system of tubes 3 and 4 and the probe 5. The flow restricting element regulates flow rates in the flow system. A natural choice for the flow re¬ stricting element would be a portion of a capillary tube, the capillary tube having the property that for any given pressure difference the flow rate may be fixed at a desired value by choosing a capillary of suitable length and diameter.

The inlet tube 3 is a fluid connection between the flow-restricting element 9 and the probe 5, and the outlet tube 4 forms a fluid connection between the probe 5 and the fluid exit 15 of the outlet tube 4. At the exit 15, the out¬ let tube 4 is equipped with a holder 19 to grab a collection vial for collect¬ ing fluids of samples.

The whole of the dialyzing device 1 is to be wrapped in a sterile package and delivered in a ready-to-use manner, containing the perfusion fluid for some predetermined operation time of the device. This is not shown in the figure.

Fig. 2 shows the system when it is activated and inserted for performing the sampling process. The dialysing device 1 has been removed from its sterile packaging, and the probe 5 is inserted into the fluid medium 17, for example, body tissue, to be analysed. The exit 15 of the outlet tube 4 is inserted into a collection vial 18, the collection vial 18 being connected to the vial holder 19.

To start the sampling process, the hollow piston is pressed from the first position of Fig. 1 to a second position as seen in Fig. 2, so that the end- plate 12 is pushed forward reducing the volume of the chamber 11 and in consequence squeezing most of the perfusion fluid 13 into the inside of the elastomer bladder 8 via the fluid communication 14, where the fluid communication has opened for fluid access. This inflates the elastomer bladder 8 and accumulates a compressive force in its elastic walls.

Close to the endplate 15 is a small bulge 20 protruding into the internal of the chamber 11. This is to fixate the hollow piston when it is pushed to the second position. The bulge is small enough for the piston to pass it with a little squeeze, but large enough for the piston to be fixated when in the second position. The rubber O-ring 21 ensures that there is no substantial leak when the ring passes the bulge. Any other method of fixating the hol¬ low piston may be used instead.

This ensures that when fluid access is allowed to the fluid system of tubes 3 and 4 and the probe 5, the accumulated force in the elastic walls of the elastomer bladder 8 starts to squeeze out the perfusion fluid at a substan¬ tially constant flow rate, into the flow restricting element 9 of a length and internal diameter chosen to ensure a determined flow rate of the perfusion fluid. From the flow restricting element the perfusion fluid is communicated to the probe 5 by the inlet tube 3. Passing the probe, it is enriched with species from the medium 17 to be analysed, as they cross the membrane covering the probe and separating the perfusion fluid from the medium. This enriched perfusion fluid is now communicated from the probe to the collection vial 18 by the outlet tube 4.

The collection vial 18 is most likely a relatively small microvial only with the storing capacity in the order of micro-litres in order to minimize evaporation of the sampled fluid, but any sizes of the collection vials may be used. As the collection vials are filled with the enriched perfusion fluid, they are ex¬ changed and moved to an analysing apparatus for further processing. De¬ pending on the sizes of the collection vials and on the rates of flow of the perfusion fluid, the collection vial may be exchanged after a few minutes of sampling or it may take hours, and when, for example, microvials are used, a fast measurement of the concentration of species, like glucose, in the tissue is achieved.

In the above example, the CP-pump is made of an elastomer bladder be- ing inflated by the perfusion fluid when activated, but the invention is not limited to this structure, any kind of variable volume chamber system may be considered, like illustrated in Fig. 3, where the chamber 30 has a wall 31 movable in a fluid-tight manner. When the chamber 30 is filled with a fluid, it expands as the movable wall squeezes the spring 32, storing en¬ ergy in the spring, to push back the movable wall when released, hereby squeezing out the fluid in the same manner the elastomer bladder.

In another embodiment of the invention, the hollow piston is replaced by the clamping construction as illustrated in Fig. 7. The perfusion fluid 13 is stored in the bellows-shaped flexible container 70 that is attached to at lid 71 , and the lid is itself attached to the container 72 at the pivot element 73, so that it is able to move around 73. The flexible container 70 is in fluid connection 74 with the elastomer bladder 8. When the system is activated for use, the lid 71 is pressed against the container 72 around the pivot element 73, whereby the perfusion fluid 13 inside the flexible container 70 is squeezed into the elastomer bladder 8, filling it with the perfusion fluid, thereby inflating it.

In another design embodiment of the CP-pump 1 , Fig. 4, the positioning of the flow-restricting element 9 is moved to a direct fluid communication with the elastomer bladder 8. The restricting element 9 is fixed by embedding it into a plug 40 positioned inside the hollow piston 7. This eliminates the need for the protective casing in front of the syringe, since the hollow pis¬ ton takes on the additional task of protecting the restricting element.

In another embodiment of the invention, connecting the outlet tube 4 di- rectly to the analysing apparatus 50, Fig. 5, eliminates the need for collect¬ ing the enriched perfusion fluid. The sample fluid could then be analysed almost in real-time, since there would no longer be any operator to ex¬ change sample vials and manually convey them for analysis. The delays in the system would then relate to the flow rate and the length of the tube system from the probe to the communication port in the analysing appara¬ tus, and to the analysing processes inside the respective analysing appa¬ ratus. The CP-pumping system may be external as Fig. 5 illustrates, or it may be inserted into the analysing apparatus and perhaps activated when a lid is closed when inserted.

A potential problem in the dialyzing device is air trapped inside, especially in the elastomer bladder, before activation. This could lead to problems with the stability and predictability of the device, as bubbles may enter the flow system. To keep air from being trapped inside the elastomer bladder when it fills with perfusion fluid, one or more among a plurality of different strategies may be employed. A first strategy could be initially to have the elastomer bladder 8 free of air by keeping it totally flat, possible by gluing the inside walls together in some very light way. A way of doing this is to moisten the inside of the elastomer bladder with perfusion fluid and keep the system under vacuum. Then the surface tension of the moist would keep the internal walls together. When the dialyzing device is taken from its sterile vacuum package, and the hollow piston is pressed, the walls would easily split when the perfusion starts entering the inside of the elas¬ tomer bladder.

Another strategy is to have an open fluid connection between the perfu- sion fluid and the inside of the elastomer bladder, and letting the bladder be filled with just so much perfusion fluid that it is totally filled without stretching. A third strategy is to incorporate some filter into the system, of the kind where air may freely leave from the inside to the outside, whereby air in the bladder is squeezed out as it fills with perfusion fluid.

As long as the dialyzing device is stored in a sterile package, or just not deemed for activation yet, there needs to be some obstruction to keep the perfusion fluid from the chamber 11 , Fig. 6, from entering the flow restrict¬ ing element 9 and the tube system composed by the inlet tube 3, the outlet tube 4 and probe 5. A natural choice is to insert some kind of valve 60 downstream of the CP-pump, closing for flow until it is opened, either manually or as a integrated part of the activation of the system, when the hollow piston is compressed to fill the elastomer bladder with the perfusion fluid, part of the compression energy goes to open the valve.

In a related embodiment, the valve or plug is placed relatively close to the exit 15 of the outlet tube 4, so that the flow system of inlet tube 3, probe 5 and most of the outlet tube 4 is filled with perfusion fluid from the begin¬ ning, thereby limiting the time before the analysis process begins, and preventing bubbles from clogging the tubular system.

Another embodiment of the invention comprises a priming arrangement to fill the tube-probe system, 3, 4, 5 with perfusion fluid before the analysis begins. This is done both to flush the system minimizing the risk of bub¬ bles, and to make it ready for sampling as the communication to the spe¬ cies has been started when the elastomer bladder starts to squeeze the perfusion fluid into the system, thereby minimizing delays in the system. One possible embodiment is seen in Fig. 8, where the chamber containing the perfusion fluid is split into two sub-chambers 80 and 81 , where the wall 82 separating the sub-chambers is movable in a forward direction. When the piston 7 is pushed to let the perfusion fluid 13 fill the elastomer bladder 8, the perfusion fluid inside sub-chamber 80 also pushes at the movable wall 82, moving it forwards, whereby the perfusion fluid inside sub- chamber 81 is squeezed into the probe-system 3, 4 ,5, ensuring it to be ready for action, when the elastomer bladder is released to operate. In the movable wall is a fluid connection between the sub-chambers, possibly some hydrophobic membrane impenetrable to the perfusion fluid beneath some pressure threshold, and when the piston is pushed, the membrane blocks the fluid connection just long enough for the sub-chamber 81 to be emptied.

Claims

Claim 1

A replaceable device for an analysis system, comprising a sampling probe in fluid connection with a fluid inlet connected to a feed tube and a fluid outlet connected to a return tube, pressurizing means, said pressurizing means pressurizing a fluid, said fluid being in fluid connection with said fluid inlet, where, prior to use, said pressurizing means, said fluid connec¬ tions, said probe and said fluid are contained in a sterile package.

Claim 2

A replaceable device for an analysis system, comprising a syringe with a hollow piston, pressurizing means placed inside said hollow piston, said syringe being in fluid connection with a sampling probe through a fluid inlet connected to a feed tube and a fluid outlet connected to a return tube, and where

- a chamber containing a fluid is disclosed inside the syringe when said hollow piston is in a first position, and

- Where said fluid is pressed to the inside of said hollow piston when the hollow piston is moved to a second position, thereby pressurizing said pressurizing means.

Claim 3

A device according to claim 2, where, prior to use, said device is contained in a sterile package.

Claim 4 A device according to claim 1 or 2, where at least one flow-restricting means is inserted downstream of said fluid. Claim 5

A device according to claim 4, where said flow-restricting means is con¬ tained inside a protective casing in front of said syringe.

Claim 6

A device according to claim 4 , where said pressurizing means is an elas¬ tomer bladder.

Claim 7 A device according to claim 4 , where said pressurizing means comprises a spring and a movable wall.

Claim 8

A device according to claim 1 or 2, further comprising a second chamber containing a fluid, when said hollow piston is in the first position, the fluid in the second chamber being expelled into said fluid communication means, as the hollow piston is pushed from the first position to the second position.

Claim 9

A device according to any of the preceding claims, where squeezing a fluid between two solid parts pressurizes the pressurizing means, said solid parts being connected by a pivot element.

Claim 10

A device according to any of the preceding claims, where said probe is a micro-dialysis probe.