CN117120117A - Priming of forward osmosis units - Google Patents
Priming of forward osmosis units Download PDFInfo
- Publication number
- CN117120117A CN117120117A CN202280027552.4A CN202280027552A CN117120117A CN 117120117 A CN117120117 A CN 117120117A CN 202280027552 A CN202280027552 A CN 202280027552A CN 117120117 A CN117120117 A CN 117120117A
- Authority
- CN
- China
- Prior art keywords
- fluid
- gas collection
- collection chamber
- perfusion fluid
- path
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000037452 priming Effects 0.000 title claims abstract description 89
- 238000009292 forward osmosis Methods 0.000 title claims abstract description 13
- 239000012530 fluid Substances 0.000 claims abstract description 429
- 230000010412 perfusion Effects 0.000 claims abstract description 227
- 239000012141 concentrate Substances 0.000 claims abstract description 128
- 238000000034 method Methods 0.000 claims abstract description 116
- 239000000385 dialysis solution Substances 0.000 claims abstract description 84
- 238000000502 dialysis Methods 0.000 claims abstract description 46
- 239000012528 membrane Substances 0.000 claims abstract description 33
- 238000007865 diluting Methods 0.000 claims abstract description 14
- 238000011282 treatment Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 30
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 238000004590 computer program Methods 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 5
- 239000007789 gas Substances 0.000 description 266
- 210000004379 membrane Anatomy 0.000 description 30
- 239000007788 liquid Substances 0.000 description 27
- 230000008569 process Effects 0.000 description 13
- 238000005086 pumping Methods 0.000 description 13
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 239000002699 waste material Substances 0.000 description 10
- 239000000835 fiber Substances 0.000 description 7
- 230000003204 osmotic effect Effects 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 239000003053 toxin Substances 0.000 description 7
- 231100000765 toxin Toxicity 0.000 description 7
- 108700012359 toxins Proteins 0.000 description 7
- 239000012510 hollow fiber Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 210000003200 peritoneal cavity Anatomy 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 208000001647 Renal Insufficiency Diseases 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000004891 communication Methods 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 201000006370 kidney failure Diseases 0.000 description 5
- 230000015654 memory Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000007872 degassing Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002262 irrigation Effects 0.000 description 4
- 238000003973 irrigation Methods 0.000 description 4
- 238000003809 water extraction Methods 0.000 description 4
- 230000001351 cycling effect Effects 0.000 description 3
- 239000008151 electrolyte solution Substances 0.000 description 3
- 239000012527 feed solution Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000013022 venting Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 102000010637 Aquaporins Human genes 0.000 description 1
- 108010063290 Aquaporins Proteins 0.000 description 1
- 101100174424 Arabidopsis thaliana FTSH1 gene Proteins 0.000 description 1
- 229920006310 Asahi-Kasei Polymers 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 101150054895 ftsH gene Proteins 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002615 hemofiltration Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000003134 recirculating effect Effects 0.000 description 1
- 238000012959 renal replacement therapy Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
Landscapes
- External Artificial Organs (AREA)
Abstract
Apparatus (1) for producing a dialysis fluid, comprising: a forward osmosis unit (2) for diluting a dialysis concentrate for producing a dialysis fluid, the FO unit (2) comprising a FO membrane (2 c) separating a first side (2 a) from a second side (2 b). The device (1) comprises: a first flow path (3) comprising a first side (2 a); -control means (60) for providing perfusion fluid from a source (19) to the first flow path (3); a return path (8) connecting the inlet port (E) of the first side (2 a) in ) An outlet port (E) fluidly connected to the first side (2 a) out ) To allow flow from the outlet port (E out ) Is circulated to the inlet port (E) via the return path (8) in ) The method comprises the steps of carrying out a first treatment on the surface of the And a gas collection chamber (5) arranged in the first flow path (3) between the first side (2 a) and the return path (8), wherein the gas collection chamber (5) removes gas from the first flow path (3). The disclosure also relates to a method for priming a FO unit (2).
Description
Priority claiming
U.S. provisional application No. 63/172,850 entitled "Priming, method and System for Forward Osmosis Unit (forward osmosis unit Priming, method and System)" filed on month 4 and 9 of 2021 and swedish patent application No. 2151562-2 entitled "Priming of a Forward Osmosis Unit (forward osmosis unit Priming)" filed on month 12 and 21 of 2021, the disclosures of which are incorporated herein by reference in their entireties, are hereby claimed.
Technical Field
The present invention relates to the field of priming, and in particular to priming of a forward osmosis unit arranged for producing a dialysis fluid.
Background
Renal failure occurs when the kidneys lose sufficient capacity to filter waste products in the patient's blood. Waste accumulates in the body and over time, the toxins in the body become overloaded. Renal failure can be life threatening if left untreated. Reduced renal function, particularly renal failure, can be treated by dialysis. Dialysis removes waste, toxins and excess water from the normal functioning kidneys in the body.
One type of renal failure therapy is hemodialysis ("HD"), which generally uses diffusion to remove waste from the patient's blood. A diffusion gradient occurs on the semi-permeable dialyzer between the blood and the electrolyte solution, called the dialysis fluid, to cause diffusion. HD fluid is typically produced by a dialysis machine by mixing concentrate and clean water.
Hemofiltration ("HF") is an alternative renal replacement therapy that relies on convective transport of toxins from the patient's blood. HF is achieved by adding replacement or substitution fluids to the extracorporeal circuit during treatment. During HF treatment, ultrafiltration of the fluids displaced and accumulated by the patient during treatment provides a convective transport mechanism particularly advantageous for removal of medium and macromolecules.
Hemodiafiltration ("HDF") is a therapeutic approach that combines convective clearance and diffusive clearance. HDF uses a dialysis fluid flowing through a dialyzer, similar to standard hemodialysis, to provide diffusion clearance. In addition, the replacement solution is delivered directly to the extracorporeal circuit, providing convective clearance. Here, more fluid than the patient's excess fluid is removed from the patient, resulting in increased convective transport of waste from the patient. The removed additional fluid is replaced by a replacement fluid or replacement fluid.
Another type of renal failure therapy is peritoneal dialysis ("PD") which infuses a dialysis solution (also referred to as a dialysis fluid) into the peritoneal cavity of a patient via a catheter. The dialysis fluid contacts the peritoneum located in the patient's peritoneal cavity. Waste, toxins and excess moisture pass from the patient's blood stream through capillaries in the peritoneum and into the dialysis fluid due to diffusion and osmosis, i.e. there is an osmotic gradient across the membrane. The osmotic agent in the PD dialysis fluid provides an osmotic gradient. The spent or spent dialysis fluid is removed from the patient, removing waste, toxins and excess moisture from the patient. The cycle is repeated, for example, a plurality of times. PD fluids are typically prepared at the factory and shipped in ready-to-use bags to the patient's home.
There are various types of peritoneal dialysis therapies, including continuous ambulatory peritoneal dialysis ("CAPD"), automated peritoneal dialysis ("APD"), tidal current dialysis, and continuous flow peritoneal dialysis ("CFPD"). CAPD is a manual dialysis treatment in which fluid delivery is driven by gravity. If the patient is initially filled with spent dialysis fluid, the patient manually connects the implant catheter to the drain to allow the used or spent dialysis fluid to drain from the patient's peritoneal cavity. The patient then switches fluid communication such that the patient conduit communicates with the bag of fresh dialysis fluid to allow fresh dialysis fluid to pass through the conduit and infuse into the patient. The patient disconnects the catheter from the fresh dialysis fluid bag and allows the dialysis fluid to reside within the peritoneal cavity, wherein transfer of waste, toxins and excess moisture occurs. After the dwell period, the patient repeats the manual dialysis procedure, for example, four times per day. If the patient is not initially filled with spent dialysis fluid, the sequence is patient fill, dwell, and drain. Manual peritoneal dialysis requires a significant amount of time and effort from the patient, leaving sufficient room for improvement.
Automated peritoneal dialysis ("APD") is similar to CAPD in that dialysis treatment includes drain, fill, and dwell cycles. However, APD machines typically automatically perform a cycle while the patient is asleep. APD machines eliminate the need for the patient to manually perform a treatment cycle and the need to deliver supplies during the day. The APD machine is fluidly connected to the patient's implanted catheter, a source or bag of fresh dialysis fluid, and a fluid drain via a patient line. The APD machine pumps fresh dialysis fluid from a fresh dialysis fluid source through a catheter into the peritoneal cavity of the patient. APD machines also allow dialysis fluid to reside within the patient's peritoneal cavity and allow transfer of waste, toxins and excess moisture to occur. The source may comprise a multi-liter dialysis fluid, including several solution bags.
Dialysis treatment can be performed at a clinic or remotely (e.g., in a patient's home). The delivery of dialysis fluid increases the cost of treatment and has a negative impact on the environment. The storage of dialysis fluid requires space and requires the user to handle a large number of bags of dialysis fluid. Thus, there is a need for a method of reducing or eliminating the amount of dialysis fluid delivered to a patient's home.
Disclosure of Invention
To reduce the above negative consequences of delivering the dialysis fluid to the patient's home, the dialysis fluid may be produced from a concentrate at the point of care. In the apparatus and methods of the present disclosure, forward osmosis ("FO") may be used to dilute the dialysis concentrate with water to provide a diluted dialysis concentrate (which may be referred to as a dialysis solution). The dialysis solution can thereafter be mixed with other concentrates to provide a final dialysis fluid, which can be used in a dialysis treatment to treat a patient. The final dialysis fluid may be a dialysis fluid for PD, a dialysis fluid for HD or HDF, or a replacement fluid or substitution fluid for HF or HDF. FO utilizes an osmotic pressure gradient between a feed fluid and concentrate as draw fluid, the feed fluid and concentrate being separated by a FO membrane. The osmotic pressure gradient acts as an energy source for migration of water from the feed fluid to the draw fluid, making FO an attractive low energy alternative. FO membranes are semipermeable membranes, typically having a hollow fiber geometry. Hollow fiber type FO membranes have thousands of hollow fibers packaged together in bundles and arranged in FO units. One of the feed and draw fluids passes inside the fiber lumen (lumen side) while the other fluid passes outside the lumen (housing side). The feed fluid is for example water or spent (used) dialysis fluid. If spent dialysis fluid is used as the feed fluid, the amount of fresh water used in the process can be greatly reduced. Alternative FO membrane types are for example flat sheet membranes or spiral wound membranes.
During the test, the dilution performance was found to be different due to the presence of air in the FO unit. Some of the fibers of the FO membrane may then remain unused, thereby reducing the effective area of the FO membrane. There is therefore a need for a method of effectively removing air present in FO units.
It is an object of the present disclosure to mitigate at least some of the drawbacks of the prior art. Another object is to provide a method for effectively removing air present in a FO unit. It is a further object to provide a method for automatically removing air present in a FO unit.
These and other objects are at least partly achieved by means of a device and a method according to the independent claims and by embodiments according to the dependent claims.
According to one aspect, which may be combined in whole or in part with any other aspect or part of any other aspect, the present disclosure relates to an apparatus for producing a fluid for dialysis. The apparatus includes a forward osmosis FO unit configured for diluting the dialysis concentrate during production of the dialysis fluid. The FO unit includes a FO membrane separating a first side from a second side of the FO unit. The apparatus further comprises a first flow path comprising a first side and a control device configured to provide perfusion fluid from a perfusion fluid source to the first flow path. The apparatus further includes a return path fluidly connecting the inlet port of the first side of the FO unit to the outlet port of the first side of the FO unit to allow perfusion fluid discharged from the outlet port to circulate to the inlet port via the return path. The apparatus further includes a gas collection chamber disposed in the first flow path between the first side and the return path, wherein the gas collection chamber is configured to receive gas removed from the first flow path.
The apparatus achieves efficient priming of the first side by providing a return path where the priming fluid residing on the first side may be circulated to the gas collection chamber and where the gas may accumulate and drain. As the priming fluid may be circulated back to the inlet port, the fluid will contain less and less gas with each pass through the gas collection chamber, as opposed to being primed continuously with fresh priming fluid, which is easier to remove from the priming fluid. Furthermore, the perfusion fluid may be reused during perfusion, thereby reducing wastage of the perfusion fluid.
According to some embodiments, the control device is configured to monitor the level of the perfusion fluid in the gas collection chamber and to provide the perfusion fluid to the gas collection chamber until the level of the perfusion fluid in the gas collection chamber has reached a predetermined level. Thus, gas may accumulate in the gas collection chamber while the gas collection chamber contains sufficient perfusion fluid to provide a flow of perfusion fluid out of the gas collection chamber.
According to some embodiments, the apparatus is positioned and arranged to expel gas from the gas collection chamber while providing perfusion fluid to the gas collection chamber. Thereby, gas can be removed from the first flow path.
According to some embodiments, the gas collection chamber comprises a gas outlet port for exhausting gas from the gas collection chamber. Thereby, gas can be exhausted from the gas collection chamber.
According to some embodiments, the apparatus comprises a gas collection path fluidly connecting the gas outlet port of the gas collection chamber to the drain. Thereby, gas can be transported from the gas collection chamber to the discharge.
According to some embodiments, the control device is configured to provide priming fluid from the priming fluid source to the first side of the FO unit via the first flow path and the gas collection chamber to fill the first side with priming fluid. Thereby, the first side may be filled with a gas-removed perfusion fluid, thereby supporting the resulting degassing of the first side.
According to some embodiments, the control device is configured to provide the priming fluid from the priming fluid source to the first side of the FO unit via the first flow path and the gas collection chamber when the level of the priming fluid in the gas collection chamber reaches a predetermined level. Thus, there is a sufficient volume of perfusion fluid in the gas collection chamber such that the flow of perfusion fluid can pass through the gas collection chamber while gas accumulates in the gas collection chamber.
According to some embodiments, the control device is configured to stop the flow via the return path when the perfusion fluid is provided to the first flow path from the perfusion fluid source. Thus, the filling of the gas collection chamber and/or the first side may be more easily controlled.
According to some embodiments, the control device is configured to circulate perfusion fluid provided to the first side in a first direction in a recirculation path comprising the first side, a return path and the gas collection chamber. Thereby, the bubbles at the first side can be removed and collected in the gas collection chamber.
According to some embodiments, the control device is configured to circulate the perfusion fluid in the recirculation path in the second direction. Thus, even more gas bubbles at the first side may be collected in the gas collection chamber, as flow in the other direction may cause other gas bubbles to loosen from the first side than flow in the first direction. In addition, if the first direction is from the uppermost portion (inlet port) to the lowermost portion (outlet port) of the first side, the second direction may be from the lowermost portion (outlet port) to the uppermost portion (inlet port), such that flow in the first direction may remove bubbles from the first side, while flow in the second direction may deliver bubbles trapped at the inlet of the first side to the gas collection chamber.
According to some embodiments, the control device is configured to repeat the circulation of the perfusion fluid in the recirculation path in the first direction and the circulation of the perfusion fluid in the recirculation path in the second direction at least once until one or more predetermined perfusion criteria are met. Thereby, more bubbles are loosened and transported to the gas collection chamber, as repeated changes of direction result in a change of direction of the shearing force at the first side, which results in more bubbles being loosened.
According to some embodiments, the apparatus comprises a second flow path comprising a second side for providing fluid to the second side, wherein the control device is configured to provide fluid from the solution source to an inlet port of the second side via the second flow path, the inlet port being arranged below an outlet port of the second side, when one or more predetermined perfusion criteria are met. Thus, the second side is also primed. The second side may be primed before, during and/or after the first side is primed.
According to some embodiments, the control device is configured to circulate the perfusion fluid in a first direction at a first flow rate and to circulate the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate. Thus, different magnitudes of shear forces can be achieved at the first side. The flow rates may also be different in that they are intended to do different things, e.g. a first flow rate may be intended to loosen bubbles from the first side, while a second flow rate may be intended to convey loosened bubbles to the gas collection chamber.
According to some embodiments, the first flow rate is greater than the second flow rate. For example, in the second direction, if the purpose of the second flow is to merely deliver bubbles to the gas collection chamber, it may be sufficient to have a slower flow. The larger first flow creates a larger shear force at the first side that more easily removes bubbles.
According to some embodiments, the control device is configured to circulate the perfusion fluid in the recirculation path in a first direction for a predetermined first period of time and to circulate the perfusion fluid in the recirculation path in a second direction for a second period of time, wherein the first period of time and the second period of time have different lengths. Hereby, the perfusion can be optimized in terms of time, as the effect achieved by the flow in either direction may be different and thus require more or less time to achieve.
According to some embodiments, the first period of time is greater than the second period of time. Thereby, a longer transport of perfusion fluid from the first side to the gas collection chamber may be achieved during the first period of time than during the second period of time.
According to some embodiments, the control device comprises at least one pump. Thereby, the provision of perfusion fluid and/or circulating perfusion fluid may be achieved by means of one or more pumps.
According to some embodiments, the at least one pump comprises a first pump arranged to provide perfusion fluid from a source of perfusion fluid to the first path.
According to some embodiments, the at least one pump comprises a second pump arranged to circulate the perfusion fluid in the recirculation path.
According to some embodiments, the gas collection chamber comprises at least two fluid ports, and wherein perfusion fluid is allowed to enter and exit via any of the at least two ports. Thereby, perfusion fluid may be transported through the gas collection chamber in two opposite directions.
According to some embodiments, the priming fluid is the same fluid used to dilute the dialysis concentrate during production, and wherein the priming fluid is water or a used dialysis solution. Thus, handling of the device during priming may be facilitated, as no different way is needed to prepare the device than when used for producing dialysis fluid.
According to a second aspect, which may be combined in whole or in part with any other aspect or part of any other aspect, the present disclosure relates to a method for priming a forward osmosis FO unit configured for diluting a dialysis concentrate during production of a dialysis fluid. The FO unit includes a FO membrane separating a first side from a second side of the FO unit. The method comprises the following steps: the perfusion fluid is provided to a first flow path that includes a first side and a gas collection chamber configured to receive gas removed from the first flow path. The method further comprises the steps of: the provided perfusion fluid is circulated in a recirculation path comprising a first side, a return path and a gas collection chamber. The return path fluidly connects the inlet port of the first side of the FO unit to the outlet port of the first side of the FO unit.
According to some embodiments, there is provided a method comprising: the level of the perfusion fluid in the gas collection chamber is monitored and the perfusion fluid is provided to the gas collection chamber until the level of the perfusion fluid in the gas collection chamber has reached a predetermined level.
According to some embodiments, a method comprises: the gas is exhausted from the gas collection chamber while the perfusion fluid is provided to the gas collection chamber.
According to some embodiments, a method comprises: the gas is exhausted from the gas collection chamber to the exhaust via a gas collection path fluidly connecting a gas outlet port of the gas collection chamber to the exhaust.
According to some embodiments, a method comprises: a priming fluid is provided from a priming fluid source to the first side of the FO unit via the first flow path and the gas collection chamber to fill the first side with the priming fluid.
According to some embodiments, a method comprises: when the level of the priming fluid in the gas collection chamber reaches a predetermined level, the priming fluid is provided from the priming fluid source to the first side of the FO unit via the first flow path and the gas collection chamber.
According to some embodiments, there is provided a method comprising: flow through the return path is stopped when irrigation fluid is provided to the first flow path from the irrigation fluid source.
According to some embodiments, a method comprises: the perfusion fluid provided to the first side is circulated in a recirculation path in a first direction.
According to some embodiments, a method comprises: the perfusion fluid is circulated in the recirculation path in a second direction.
According to some embodiments, a method comprises: the circulating of the perfusion fluid in the first direction in the recirculation path and the circulating of the perfusion fluid in the second direction in the recirculation path are repeated at least once until one or more predetermined perfusion criteria are met.
According to some embodiments, when the one or more predetermined perfusion criteria are met, the method comprises: fluid is provided from the solution source via a second flow path to an inlet port of the second side, the inlet port being arranged below an outlet port of the second side.
According to some embodiments, a method comprises: circulating the perfusion fluid in a first direction at a first flow rate and circulating the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate.
According to some embodiments, the first flow rate is greater than the second flow rate.
According to some embodiments, a method comprises: circulating the perfusion fluid in the recirculation path in a first direction for a predetermined first period of time and circulating the perfusion fluid in the recirculation path in a second direction for a second period of time, wherein the first period of time and the second period of time have different lengths.
According to some embodiments, the first period of time is greater than the second period of time.
According to a third aspect, which may be combined in whole or in part with any other aspect or part of any other aspect, the present disclosure relates to a computer program comprising instructions to cause an apparatus according to any of the embodiments or aspects described herein to perform a method according to any of the embodiments or aspects described herein.
According to a fourth aspect, which may be combined in whole or in part with any other aspect or part of any other aspect, the present disclosure relates to a computer readable medium having stored thereon a computer program according to the third aspect.
Drawings
Fig. 1 illustrates a portion of an apparatus for producing a dialysis solution that includes a FO unit according to some embodiments of the present disclosure.
Fig. 2 schematically illustrates a gas collection chamber according to some embodiments of the present disclosure.
Fig. 3 is a flowchart illustrating method steps for performing a perfusion procedure, according to some embodiments of the present disclosure.
Fig. 4A-4E illustrate priming sequences for priming the FO unit in fig. 1 and 5, according to some embodiments of the present disclosure.
Fig. 5 illustrates an apparatus for producing a dialysis solution according to some embodiments of the present disclosure.
Detailed Description
In order to produce accurate dialysis solutions in a timely manner, it is important to extract water continuously and efficiently from the feed solution. The volumes available for the feed solution and draw solution are typically limited, so care should be taken to use them effectively. The FO process can also be operated in a single pass mode, so that the high efficiency of the FO process is important to make full use of the osmotic pressure gradient. If some of the hollow fibers of the hollow fiber FO membrane are not available due to the presence of gas (e.g., air), resulting in a stop of solution flow within the lumen, the effective area of the FO membrane will decrease and the FO process will be less effective. This may be especially a problem at one of the first side and the second side, where the fluid during production is introduced from the uppermost part of the side and discharged from the lowermost part of the side. Here, some of the excess gas in the FO unit will not follow the fluid flow, either because it will be trapped at the inlet (uppermost) due to lighter weight than the fluid, or because it will be trapped inside the lumen due to the narrowing of the lumen. The gas will instead remain in the FO unit. There is a risk that the concentrate solution will not be diluted sufficiently and that the final dialysis solution will not be produced correctly. The term "gas" herein includes air or any other gas present in the apparatus from the beginning, any air or other gas supplied to the FO unit, or any air or other gas produced by degassing a fluid present in the apparatus. Alternative FO membrane types useful in the present disclosure are, for example, flat sheet membranes or spiral wound membranes.
In order to avoid the above, a device for producing a fluid for dialysis is proposed, which device is arranged for effectively priming its FO unit. Furthermore, a method for efficient priming is disclosed, which may be performed automatically by the device. The apparatus includes a gas collection chamber and a return path. The gas collection chamber enables gas to be collected and removed from the first side of the FO unit. The return path connects the outlet of a first side of the FO unit with the inlet of the same first side of the FO unit. The FO unit is arranged such that during production fluid will be introduced from the uppermost part of the first side (inlet port) and discharged from the lowermost part of the first side (outlet port). The return path is external to the FO unit. The return path enables recirculation of the perfusion fluid in a recirculation path comprising the first side of the FO unit, the return path and the gas collection chamber. The gas may then be delivered by circulating the perfusion fluid and released in the gas collection chamber. In some embodiments, the priming fluid is pumped sequentially in the opposite direction to more effectively remove gas trapped inside the FO unit (i.e., at the first side). The perfusion fluid may then be pumped at a high flow rate in a first direction (the same direction as the fluid during production) to remove bubbles from the lumen, and at a lower flow rate in a second direction (opposite the direction of the fluid during production) to deliver the removed bubbles trapped at the uppermost portion of the first side from the first side to the gas collection chamber. Thus, the present invention removes gas from the FO unit, thereby increasing the effective area of the FO membrane. Thus, water extraction efficiency may be improved and, in some embodiments, maximized even by making the entire FO membrane surface area available for water extraction.
The same reference numerals may not be used throughout the figures to describe every embodiment but all structures, functions, and alternatives described are still included for every embodiment.
Fig. 1 shows a section 50 of a device 1 for producing a fluid for dialysis. Portion 50 includes components that enable efficient priming of FO unit 2. But first explain how the section 50 operates in the context of producing a fluid for dialysis. Portion 50 includes FO unit 2, first flow path 3 and second flow path 4. The FO unit 2 comprises a FO membrane 2c separating a first side 2a from a second side 2b of the FO unit 2. A "side" of the unit 2 may also be referred to herein as a "compartment" or "chamber". The FO unit 2 typically comprises a cartridge enclosing a first side 2a, a second side 2b and a FO membrane 2c. The first flow path 3 is arranged to supply the first fluid to the first side 2a of the FO unit 2 and to remove the first fluid output from the first side 2a. The second flow path 4 is arranged to supply the second fluid to the second side 2b of the FO unit 2 and to remove the second fluid from the second side 2b. Depending on the composition of the fluids, one fluid may be referred to as a feed fluid and the other fluid may be referred to as a draw fluid. In the FO process, the feed fluid discharges water to the draw fluid due to the osmotic pressure gradient. In some embodiments, during production, a feed fluid, such as water or spent dialysis fluid, is delivered to the first side 2a. The first fluid is a feed fluid and the first side 2a may be referred to as the feed side. Spent dialysis fluid may also be referred to herein as spent dialysis fluid or effluent. A draw fluid, such as a dialysis concentrate, is transferred to the second side 2b. The second fluid is the drawing fluid and the second side 2b may be referred to as the drawing side. In the FO unit 2, water from the feed solution passes through the FO membrane 2c to the dialysis concentrate, thereby diluting the dialysis concentrate into a diluted dialysis concentrate solution. The solution may thereafter be mixed with one or more other concentrates to provide a final dialysis fluid. The FO unit 2 is thus configured for diluting the dialysis concentrate during the production of the dialysis fluid. The dewatered feed fluid is typically directed to a discharge.
In the embodiment shown in fig. 1, FO unit 2 has an inlet port E in And an outlet port E out Inlet port E in In fluid communication with the first side 2a and through the inlet port E in Is transferred into the first side 2a, outlet port E out In fluid communication with the first side 2a, a first fluid passes through the outlet port E out Is conveyed out from the first side 2 a. Inlet port E in Arranged at the outlet port E out Above. FO unit 2 also has an inlet port L in And an outlet port L out Inlet port L in In fluid communication with the second side 2b, a second solution passes through the inlet port L in Is transferred into the second side 2b, the outlet port L out In fluid communication with the second side 2b, a second solution passes through the outlet port L out Is transferred out from the second side 2 b. Outlet port L out Arranged at the inlet port L in Above. In order to achieve an efficient filling, the first flow path 3 further comprises a gas collection chamber 5. The gas collection chamber 5 is configured to receive the gas removed from the first flow path 3, and the function of the gas collection chamber 5 is explained in more detail below with reference to priming.
The first flow path 3 comprises a first side input line 3a, the first side input line 3a being arranged between a point P1 connected to the first fluid source and an inlet port 5a (fig. 2) of the gas collection chamber 5. The first side input line 3a fluidly connects point P1 and inlet port 5a. The first side inlet line valve 20b is arranged to operate with the first side inlet line 3a to regulate the flow in the first side inlet line 3a. The first flow path 3 further comprises a container line 3b arranged between the container 19 and the point P1, which connects the container 19 and the point P1. The first pump 6 is arranged to operate with the container line 3b to provide a flow in the container line 3b. The container valve 20p is connected to the container line 3b. The direct current line 3e is arranged between the container line 3b and the first side input line 3a. Thus, the direct current line 3e fluidly connects the vessel line 3b and the first side input line 3a. The direct line 3e is connected to the container line 3b between the container valve 20p and the first pump 6. The direct-current line valve 20s is connected to the direct-current line 3e. The direct line 3e is connected to the first side input line 3a between the first side input valve 20b and the gas collection chamber 5. The container 19 is a first fluid source and here comprises a first fluid (e.g. spent dialysis fluid). For example, spent dialysis fluid has been previously pumped from the patient connected at point P1 to the reservoir 19 using the first pump 6. Alternatively, point P1 is connected to a water source (e.g., a faucet). The first pump 6 may then pump water to the container 19 and store it for later use. In some embodiments, the first pump 6 pumps spent dialysis fluid from the reservoir 19 to the first side input line 3a, the gas collection chamber 5, etc., by opening the reservoir valve 20p and the first side input line valve 20b, closing the direct line valve 20s and pumping (in a rearward direction) with the first pump 6. Thus, in some embodiments, the first pump 6 is a bi-directional pump. Spent dialysis fluid or water is then pumped from the reservoir 19 via reservoir line 3b into the first side input line 3a. The first pump 6 may instead be advanced by utilizing the first pump 6 Line pumping (in the forward direction), opening the direct line valve 20s and closing the container valve 20P and the first side input line valve 20b pumps spent dialysis fluid directly from the patient or other source connected to point P1, or pumps water from a tap connected to point P1. The spent dialysis fluid or water is then pumped via the container line 3b and the direct line 3e into the first side input line 3 a. The first pump 6 is for example a volumetric pump such as a piston pump, which is operated in an open loop manner (a specific voltage or frequency command from the control device 50 to provide a specific flow). Alternatively, the first pump 6 is a non-volumetric pump that operates to achieve a specific flow rate using feedback from the flow sensor 43. As shown in fig. 1, the flow sensor 43 is connected to the tank line 3b between the first pump 6 and the point P1, but may be connected to the tank line 3b at any side of the first pump 6, except for being connected to the tank line 3b between the tank 19 and the connection point of the direct current line 3e and the tank line 3b. The first flow path 3 further comprises an outlet port 5b (fig. 2) and an inlet port E arranged in the gas collection chamber 5 in A connecting line 3c therebetween. Thus, the connecting line 3c fluidly connects the outlet port 5b and the inlet port E of the gas collection chamber 5 in . The first pump 6 is arranged to pump fluid from the container 19 or other source at point P1 in the first fluid line 3a and to provide the first fluid to the first side 2a via the gas collection chamber 5. The first flow path 3 further comprises a first side 2a. The first flow path 3 further comprises a discharge line 3d. The discharge line 3d is arranged at the outlet port E out Between the discharge point P4, the waste first fluid may be conveyed from the discharge line 3d to a discharge (reference numeral 31 in fig. 5). Thus, the discharge line 3d is fluidly connected to the outlet port E out And a discharge portion. The second pump 7 is arranged to operate with the discharge line 3d to provide a fluid flow in the discharge line 3d. The discharge valve 20i is arranged to regulate the flow in the discharge line 3d. The discharge valve 20i is arranged to operate with the discharge line 3d between the connection point of the return path 8 with the discharge line 3d and the connection point of the gas collecting path 9 with the discharge line 3d.
The second flow path 4 comprises a second side input line 4b. A second fluid source and inlet port L with a second side input line 4b arranged at point P3 in And fluidly connects the second fluid source and the inlet port L in . In some embodiments, point P3 is an outlet port to main line 4f (fig. 5), which main line 4f is capable of directly mixing concentrate in concentrate container 15. The second side fluid path 4 further comprises a concentrate line 4d, the concentrate line 4d being arranged between the concentrate container 15 and the point P3 to connect the concentrate container 15 and the point P3. The concentrate pump 10 is arranged to operate with the concentrate line 4d to provide a flow in the concentrate line 4 d. The concentrate container 15 comprises, for example, a fluid dialysis concentrate. The concentrate pump 10 is positioned and arranged to pump fluid from the concentrate container 15 or other source at point P3 in the second side input line 4b and to provide a second fluid, concentrate fluid, to the second side 2b. The second flow path 4 further comprises a second side 2b. The second flow path 4 further comprises a second side output line 4c. The second side output line 4c is arranged at the output port L out From the second side output line 4c, the second fluid is transferred to, for example, a dilution fluid container (see fig. 5, reference numeral 16) or directly for further mixing, between point P2. Thus, the second side output line 4c is fluidly connected to the output port L out And a collection vessel, or directly providing the diluted concentrate for further mixing. The concentrate pump 10 is positioned and arranged to provide a flow from a second fluid source (e.g., concentrate container 15) to the second side 2b and further through the second side 2b and the second side output line 4c to the dilution fluid container. In fig. 1, the first flow path 3 is arranged to convey a first fluid via the first side 2a, while the second flow path 4 is arranged to convey a second fluid via the second side 2 b. In some embodiments, the flow sensor 45 is positioned and arranged to sense the flow of diluted concentrated fluid output from the second side 2 b. The flow sensor 45 is connected to the second side output line 4c.
Here, the FO membrane 2c has a geometry of hollow fiber. The FO membrane 2c is a water permeable membrane. The FO membrane 2c is designed to be more or less exclusively selective for permeate water molecules, which enables the FO membrane 2c to separate water from all other contaminants. FO membranes 2c typically have pore sizes in the nanometer (nm) range, e.g., 0.5 to 5nm or less, depending on the solute that is intended to be blocked. Combination for FO unit 2 Suitable FO units can be made up of, for example, aquaporin TM 、AsahiKASEI TM 、Berghof TM 、CSM TM 、FTSH 2 O TM 、Koch Membrane Systems TM 、Porifera TM 、Toyobo TM And Toray TM Providing.
The control means 60 is arranged to control the device 1 to execute a plurality of programs. The control device 60 comprises a control unit 30, valve means 20 (20 a-20 p) and at least one pump 6, 7, 10. The valve means 20 are positioned and arranged to configure a plurality of different flow paths of the device 1. In some embodiments, the control means 60 is configured to control the device 1 to perform a procedure or steps of a procedure for diluting the dialysis concentrate and producing the dialysis fluid. The control unit 30 may include at least one memory and at least one processor. The at least one memory includes computer instructions for performing a program or steps of a program for diluting a dialysis concentrate and producing a dialysis fluid. The control unit 30, when executed on at least one processor, controls at least one pump and/or one or more valves 20 of the apparatus 1 to perform one or more programs as described herein.
The device 1 is further arranged to perform one or more priming procedures on the FO unit 2. The apparatus 1 thus comprises a return path 8 and a gas collection chamber 5. The priming fluid for the one or more priming procedures is a fluid provided at point P1, for example, water or spent dialysis fluid from the reservoir 19, or a fluid otherwise provided at point P1. Thus, the priming fluid may be the same as the feed fluid used to dilute the dialysis concentrate during production. The control means 60 are further arranged to control the device 1 to perform one or more perfusion procedures, which will be explained in detail herein. The return path 8 is arranged between the discharge line 3d and the first side input line 3a. Thus, the return path 8 fluidly connects the drain line 3d and the first side input line 3a. The return path 8 may comprise one or more lines. The return path 8 is connected to the discharge line 3d between the second pump 7 and the discharge valve 20 i. The return path 8 is also connected to the first side input line 3a at a point between the connection point of the direct current line 3e to the first side input line 3a and the inlet port 5a of the gas collection chamber 5. Because of The apparatus 1 comprises here an inlet port E to the first side 2a of the FO unit 2 in An outlet port E fluidly connected to the first side 2a of the FO unit 2 out Is provided for the return path 8 of (c). A return path valve 20c is connected to the return path 8 to regulate flow in the FO unit 2. When the device 1 is producing diluted dialysis concentrate, the return path valve 20c is closed, and thus the return path 8 is not used. In some embodiments, a bubble sensor 44 is connected to the return path 8 to detect the presence of bubbles, such as air bubbles, in the return path 8. Further, a gas collection chamber 5 is arranged in the first flow path 3 between the first side 2a and the return path 8. In some embodiments, the apparatus 1 comprises a gas collection path 9 for removing gas from the gas collection chamber 5. The gas collection path 9 is arranged between the gas outlet port 5c of the gas collection chamber 5 and the discharge line 3d. Thus, the gas collection path 9 fluidly connects the gas outlet port 5c and the discharge line 3d. The gas collecting path 9 is connected to the discharge line 3d downstream of the second pump 7 and downstream of the connection point of the return path 8 with the discharge line 3d. Thus, the apparatus 1 comprises a gas collection path 9 fluidly connecting the gas outlet port 5c of the gas collection chamber 5 to the drain 31 (fig. 5). The gas collection path valve 20n is connected to the gas collection path 9 to regulate the flow in the gas collection path 9.
Return path 8 allows flow from outlet port E out The expelled priming fluid circulates via a return path 8 to an inlet port E in . Thus, the return path 8, the gas collection chamber 5 and the first side 2a are all comprised in the recirculation path 12. The recirculation path 12 further comprises a connection line 3c, a portion of the first side input line 3a and a portion of the discharge line 3 d. By closing the discharge valve 20i, the gas collection path valve 20n, the direct line valve 20s and the first side input line valve 20b, opening the return path valve 20c and operating the second pump 7, the perfusion fluid present in the recirculation path 12 is recirculated in the recirculation path 12. In some embodiments, the second pump 7 is configured to operate in two directions, namely a first direction (here forward) and a second direction (here backward). The second pump 7 is then arranged to provide a flow in the opposite direction in the recirculation path 12. The second pump 7 can be arranged two by two, for exampleEither a volumetric pump or a non-volumetric pump operated in one direction, the second pump 7 is therefore bi-directional. In case the second pump 7 is a volumetric pump, it may be operated in an open loop manner (a specific voltage or frequency command from the control device 50 to provide a specific flow). In the case of a non-positive displacement pump, the second pump may be operated to achieve a specific flow rate using feedback from a flow sensor 41 (in fig. 1, the flow sensor 41 is connected to the return path 8, but may be connected anywhere to the recirculation path 12), or to achieve a specific pressure using feedback from one or more pressure sensors 42a, 42b, at least one of which is connected to the recirculation path 8, such that the sensor is able to sense the pressure of the fluid input to the first side 2 a. In fig. 1, the first pressure sensor 42a is located between the second pump 7 and the inlet port E in Is connected to the recirculation path 8 to sense the pressure when pumping fluid in the first direction, while the second pressure sensor 42b is connected between the second pump 7 and the outlet port E out Is connected to the recirculation path 8 to sense the pressure when pumping fluid in the second direction.
Fig. 2 illustrates a schematic view of the gas collection chamber 5 of fig. 1, according to some embodiments of the present disclosure. The gas collection chamber 5 is for example a degassing chamber, a drip chamber or an air trap. The gas collection chamber 5 comprises a wall section 5d enclosing a volume 55. The wall section 55 has, for example, a cylindrical shape with a top and a bottom (e.g., like a can). The wall section 5d is provided with an inlet port 5a, an outlet port 5b and a gas outlet port 5c. In one embodiment, these ports are the only connection between the volume 55 and the outside of the gas collection chamber 5. When connected within the device 1, these ports are connected to fluid paths or lines, as previously explained. The inlet port 5a is typically arranged at a higher level than the outlet port 5b to facilitate the release of gas from the perfusion fluid in the gas collection chamber 5 before the perfusion fluid is conveyed out of the outlet port 5 b. However, the perfusion fluid may instead be input into the gas collection chamber 5 via the outlet port 5b and output via the inlet port 5a, while the gas in the fluid is still released in the gas collection chamber 5. The inlet port 5a and the outlet port 5b are typically arranged at opposite sides of the wall section 5d of the gas collection chamber 5. One or both of the ports 5a, 5b may be arranged tangentially in the wall section 5d. The fluid introduced via the tangentially arranged ports creates a vortex flow which promotes the separation of the gas from the fluid by keeping the fluid close to the wall section 5d and keeping the gas in the central region of the gas collection chamber 5. The vortex also keeps the fluid close to the fluid ports 5a, 5b to ensure that there is fluid at the port where the fluid will be discharged from the gas collection chamber 5. The gas collection chamber 5 thus comprises at least two fluid ports 5a, 5b, wherein the perfusion fluid is allowed to enter and exit via any of the at least two ports. The gas outlet port 5c is arranged to exhaust gas from the gas collection chamber 5. The gas outlet port 5c is typically arranged in an uppermost portion, e.g. in a top portion, of the wall section 55. In some embodiments, the gas collection path 9 fluidly connects the gas outlet port 5c of the gas collection chamber 5 to the drain. Thereby, the gas is accumulated in the gas collection chamber 5, and the gas can be easily removed from the gas collection chamber 5. The level sensor means 22 is positioned and arranged to measure the level 35 of the fluid in the gas collection chamber 5. In one embodiment, the level sensor arrangement 22 comprises two sensors, an upper sensor being arranged above a lower sensor. The two sensors indicate whether they sense fluid. The fluid level 35 should typically be located between the two sensors, so if no sensor indicates that fluid is sensed, the level is too low. If the lower sensor senses fluid but the upper sensor does not sense fluid, the fluid level 35 is appropriate. If both sensors indicate that fluid is detected, the fluid level is too high. The liquid level sensor device 22 is configured to send a sensed value or output to the control unit 30 of the control device 60, the control unit 30 being configured to receive the sensed value or output and monitor the liquid level based thereon. Based on the monitoring result, the gas collection chamber 5 may be automatically filled so that the fluid level becomes appropriate.
At least one memory of the control unit 30 stores computer instructions to perform one or more perfusion programs. When the at least one processor of the control unit 30 executes instructions, the at least one pump 6, 7, 10 and the valve arrangement 20 are controlled to perform one or more priming processes. For example, the control unit 30 may be configured to send one or more control signals or control data to the at least one pump 6, 7, 10 and the valve of the valve arrangement 20. The pump may be controlled to a particular speed corresponding to a particular flow rate. In general, the valve connected to the pipeline or path may be an on/off valve. When the valve is open, fluid flow in the line or path is allowed, and when the valve is closed, fluid flow in the line or path is stopped. Alternatively, the valve may be a control valve that can be controlled to allow a specific flow between zero flow and unimpeded flow.
To perform one or more programs, the control device 60 is configured to perform a plurality of measurements. For example, the control device 60 is configured to perform a method as explained in the flowchart of fig. 3, which is explained as follows. In some embodiments, the control device 60 is configured to perform one or more of the following:
providing perfusion fluid from a perfusion fluid source to the first flow path 3. In some embodiments, the first pump 6 is positioned and arranged to provide perfusion fluid from a source of perfusion fluid to the first path 3. The source of perfusion fluid is, for example, a reservoir 19 or other source connected to point P1. The control unit 30 then sends control signals/data to the first pump 6 to have a specific speed providing a specific flow or pressure. Moreover, the control unit 30 controls the appropriate valves to provide the fluid.
Monitoring the level of the perfusion fluid in the gas collection chamber 5 and providing the perfusion fluid to the gas collection chamber 5 until the level of the perfusion fluid in the gas collection chamber 5 has reached a predetermined level. For example, a sensing signal or output from the liquid level sensing means 22 is sent to the control unit 30 or collected by the control unit 30, the control unit 30 controlling the device 1 based on the sensing signal.
Exhausting gas from the gas collection chamber 5 while providing perfusion fluid to the gas collection chamber 5. The control unit 30 opens the gas collection path valve 20n, for example, to discharge the gas along the gas collection path 9.
A priming fluid is provided from a priming fluid source via the first flow path 3 and the gas collection chamber 5 to the first side 2a of the FO unit 2 to fill the first side 2a with priming fluid. Then, the control unit 30 closes the gas collection path valve 20n, for example.
When the level of the priming fluid in the gas collection chamber 5 reaches a predetermined level, the priming fluid is provided from the priming fluid source to the first side 2a of the FO unit 2.
When the priming fluid is supplied from the reservoir 19 (here the priming fluid source) to the first flow path 3,
the flow through the return path 8 is stopped. Then, the control unit 30 closes the return path valve 20c. Circulating the perfusion fluid provided to the first side 2a in the recirculation path 12 in a first direction. In some embodiments, the recirculation path 12 is defined to include the first side 2a, the return path 8, and the gas collection chamber 5. In some embodiments, the second pump 7 is positioned and arranged to circulate the perfusion fluid in the recirculation path 12. The control unit 30 then opens the return path valve 20c, closes the first side input line valve 20b, the direct line valve 20s and the discharge valve 20i, and controls the second pump 7 to a specific speed to provide a specific flow rate or pressure.
Circulating the perfusion fluid in the recirculation path 12 in the second direction. The control unit 30 then controls the second pump 7 to a certain speed in the second direction to provide a certain flow or pressure.
Repeating (i) circulating the perfusion fluid in the recirculation path 12 in the first direction and (ii) circulating the perfusion fluid in the recirculation path in the second direction, e.g., at least once, until one or more predetermined perfusion criteria are met.
When one or more predetermined filling criteria are met, fluid is provided from the solution source 15 via a second flow path to an inlet port L leading to the second side 2b in . In some embodiments, the inlet port L in An outlet port L arranged at the second side 2b out And below. The control unit 30 then controls the concentrate pump 10 to a specific speed to provide a specific flow or pressure.
-circulating the perfusion fluid in a first direction at a first flow rate and circulating the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate. In some embodiments, the first flow is greater than the second flow.
Circulating the perfusion fluid in the recirculation path 12 in a first direction for a predetermined first period of time and circulating the perfusion fluid in the recirculation path 12 in a second direction for a second period of time, wherein the first period of time and the second period of time have different lengths. In some embodiments, the first period of time is greater than the second period of time.
A method for priming the FO unit 2 will now be explained with reference to the flow chart of fig. 3 and fig. 4A to 4E, which show different steps of priming. According to the legend shown in the figures, the open valve is shown as a black filled valve, while the closed valve is unfilled to help identify the current flow path. In fig. 4A-4E, some reference numerals have been removed to clarify the steps, but still include all of the structures, functions, and alternatives discussed in connection with fig. 1 and 5. In addition, certain components (e.g., pressure sensor, flow sensor, and bubble detector) in fig. 1 are omitted from fig. 4A-4E and 5 to make these figures clearer, but it should be understood that each such omitted component may also be provided in fig. 4A-4E and 5, including all of the structures, functions, and alternatives discussed in connection with fig. 1. The method is typically stored as a computer program on a computer readable medium, e.g. one or more memories of the control unit 30 of the device 1. The computer program comprises instructions that cause the apparatus 1 to operate as described according to any of the embodiments herein to perform a method according to any of the embodiments described herein. When the instructions are executed by one or more processors of the control unit 30 of the device 1, one or more processes for priming the FO unit 2 are performed.
FO unit 2 is for example the FO unit in any other figure. As shown, the FO unit 2 remains in the same position during priming, as when performing the process of diluting the dialysis concentrate as explained previously. In this position, the first fluid is at the inlet port E of the first side 2a when the process of diluting the dialysis concentrate is performed in Introduced at the outlet port E ou At t, the second fluid is discharged at the inlet port L of the second side 2b in Introduced at the outlet port L out And is discharged.
The proposed method may be used for removing gas from the first side 2a according to a predetermined routine (e.g. at a predetermined moment in the 24 hour treatment period of the whole cycle). The method is performed, for example, by the explained control device 60 by controlling the valves of the valve device 20, controlling one or more pumps 6, 7, 10, monitoring the liquid level, etc. The control device 60 provides appropriate control signals to the valves and pumps and receives operational data and other data (e.g., fluid level data) to perform the method. The method may be performed before each use of the device 1, and thus before each start of a process of diluting the dialysis concentrate. Alternatively or in combination, evaluating the current perfusion status of the first side 2a may reveal when the method should be performed. For example, the method may be performed when the liquid level in the gas collection chamber 5 is too low. A considerable amount of air may then have been added by the first fluid source, which air may have entered the first side 2a and thereby changed the water extraction properties. Alternatively, the method may be performed when an undesirably high conductivity and/or an undesirably low flow of fluid output from the second side 2b is obtained, taking into account the current operating point and the recent operating history. Thus, the priming may be performed during production as a response to, for example, a decrease in device performance (e.g., an increase in conductivity of the diluted concentrated fluid as measured with the conductivity sensor 11 of fig. 5, or a decrease in flow of the diluted concentrated fluid as measured with the flow sensor 45 connected to the second side output line 4 c). The measured conductivity is compared to a desired conductivity, and in response to the measured conductivity being greater than the desired conductivity, priming is initiated. The desired conductivity may be a conductivity value, a threshold value, or an interval. Alternatively or in combination, the flow rate of the diluted concentrated fluid is compared to a desired flow rate, and in response to the measured flow rate being lower than the desired flow rate, priming is initiated. The expected flow may be a flow value, threshold, or interval. Production must then be temporarily interrupted, but production can be resumed after infusion. Thus, the method may be triggered by various trigger conditions.
The method may comprise connecting the container line 3b to the container 19 or connecting the point P1 to the source of irrigation fluid before the start of the irrigation. Alternatively, the container line 3b may already be connected to the container 19 or to the point P1, the point P1 being connected to the source of perfusion fluid. The method may comprise pumping the perfusion fluid from the source of perfusion fluid to the container 19 using the first pump 6. The container valve 20p is then opened and the first side input line valve 20b and the direct current line valve 20s are closed. The source of perfusion fluid is, for example, spent dialysis fluid from the patient or a tap. The perfusion fluid from the patient is spent dialysis fluid. The priming fluid may be the same fluid used during production.
The method comprises providing S1a perfusion fluid to the first flow path 3. The perfusion fluid is provided from a source of perfusion fluid. As previously explained, the first flow path 3 comprises a gas collection chamber 5 and a first side 2a. Providing S1 the perfusion fluid may be performed by: the first fluid pump 6 is operated (here in the backward direction), the tank valve 20p and the first side input line valve 20b are opened, and the direct current line valve 20s is closed (as shown in fig. 4A). The perfusion fluid is then pumped from the container 19 into the first side inlet line 3a and flows towards the gas collection chamber 5. Alternatively, the perfusion fluid is pumped directly from point P1 by pumping in a forward direction with the first pump 6, opening the direct line valve 20s and closing the container valve 20P and the first side input line 20 b. Thus, providing S1 the perfusion fluid comprises providing the perfusion fluid to the gas collection chamber 5. The direction of the perfusion fluid is indicated in fig. 4A by solid arrows. The perfusion fluid forces any gas present in the first side inlet line 3a to the gas collection chamber 5. In some embodiments, the method includes exhausting gas from the gas collection chamber 5 while providing S1 perfusion fluid to the gas collection chamber 5. While the gas collection chamber 5 is being supplied S1 with the perfusion fluid, the discharge valve 20i and the return path valve 20c are closed to allow the liquid level in the gas collection chamber 5 to rise and discharge the gas present in the gas collection chamber 5. In other words, providing S1 may include stopping flow via the return path 8 when perfusion fluid is provided to the first flow path 3 from the perfusion fluid source. The gas may be discharged to the outside of the gas collection chamber 5 through a check valve (not shown) with leakage protection disposed to the gas outlet port 5c of the gas collection chamber 5. In some embodiments, the method comprises exhausting gas from the gas collection chamber 5 to the exhaust via the gas collection path 9. The gas collection path 9 fluidly connects the gas outlet port 5c of the gas collection chamber 5 to the drain. The direction of the discharged gas from the gas collection chamber 5 to the discharge via the gas collection path 9 and the discharge line 3d is indicated with hatched arrows in fig. 4A. Thus, point P4 is connected to the drain. Here, the gas is discharged to the discharge portion by opening the gas collection path valve 20 n. In some embodiments, providing S1 includes monitoring S1A the level of the perfusion fluid in the gas collection chamber 5 and providing the perfusion fluid to the gas collection chamber 5 until the level of the perfusion fluid in the gas collection chamber 5 has reached a predetermined level. The predetermined liquid level is for example the liquid level between two liquid level sensors. The gas collection chamber 5 is then filled, for example, 50% to 90%. Alternatively, the predetermined liquid level is the liquid level when the gas collection chamber 5 is considered to be completely filled, which occurs when two or at least the uppermost liquid level sensors sense the fluid in the gas collection chamber 5. Thus, as long as the liquid level has not reached or is not at the predetermined liquid level, the method comprises providing a perfusion fluid to the gas collection chamber 5.
In some embodiments, after reaching the predetermined level, the method comprises providing perfusion fluid to the first side 2a via the gas collection chamber 5, as shown in fig. 4B. Thus, in some embodiments, the method comprises providing S1B the priming fluid from the priming fluid source to the first side 2a of the FO unit 2 via the first flow path 3 and the gas collection chamber 5 when the level of the priming fluid in the gas collection chamber 5 reaches a predetermined level. Providing S1B perfusion fluid is performed, for example, by: the first fluid pump 6 is operated (here, in the backward direction) such that the tank valve 20p, the first side input line valve 20b, and the discharge valve 20i are opened, and the direct line valve 20s, the gas collection path valve 20n, and the return path valve 20c are closed. In case the gas collection chamber 5 already comprises a predetermined level of perfusion fluid, providing S1 comprises providing the perfusion fluid directly to the first side 2a via the gas collection chamber 5 without first filling the gas collection chamber 5.
In some embodiments, the pressure at the first side 2a is reduced as the first side 2a is filled and/or shortly thereafter. Reduced pressure refers to a pressure below atmospheric pressure. This reduced pressure causes any bubbles at the first side 2a to increase in size, whereby they are more easily released from the inside of the lumen. The reduced pressure also deaerates the fluid at the first side 2a. The reduced pressure may be achieved in a number of ways. In an alternative, the second pump 7 is a non-positive displacement pump, which allows leakage through the pump. When filling the first side 2a, then the second pump 7 may not be operated or the second pump 7 may be operated to pump towards the discharge. In either case, air/gas and perfusion fluid leak through the non-positive displacement second pump 7. The non-positive displacement second pump 7 may act as a throttle valve. In an embodiment, when the second pump 7 is not operated and the perfusion fluid is pumped with the first pump 6 towards the first side 2a, the pressure at the first side 2a will not change significantly, as the air causes a low flow resistance when passing the second pump 7. When the perfusion fluid reaches the second pump 7, the pressure at the first side 2a will increase as the perfusion fluid is pushed through the second pump 7, leading to a high flow resistance when the perfusion fluid passes the second pump 7. This increase in pressure may be sensed by either the first pressure sensor 42a or the second pressure sensor 42b and indicates when the perfusion fluid reaches the second pump 7. The second pump 7 may then be controlled to start pumping to reduce the pressure at the first side 2a to the desired low pressure. Then, the second pump 7 is operated using pressure feedback from the first pressure sensor 42a or the second pressure sensor 42 b. Thus, the pressure difference can be detected according to whether a gas or a fluid (liquid) passes through the second pump 7. In embodiments where the second pump 7 is operating and pumping perfusion fluid towards the first side 2a with the first pump 6, the pressure at the first side 2a will be lower than if the second pump 7 is not operating. Depending on the speed of the second pump 7, the pressure at the first side 2a will be lower, equal or higher than the atmospheric pressure. Also here, when the perfusion fluid reaches the second pump 7, the pressure at the first side 2a will change compared to when the second pump 7 pumps air, and the change can be detected. Thereafter, a desired low pressure may be established by operating the second pump 7 with pressure feedback from the first pressure sensor 42a or the second pressure sensor 42 b. When the desired low pressure has been established, the second pump 7 is operated to maintain the low pressure at the same value. In an embodiment, when the second pump 7 is a volumetric pump and pumps the perfusion fluid towards the first side 2a with the first pump 6, the second pump 7 is operated, otherwise it will stop the flow, and the first side 2a cannot be filled. In order to establish a low pressure at the first side 2a, the second pump 7 is operated with pressure feedback from the first pressure sensor 42a or the second pressure sensor 42 b. The second pump 7 is typically operated to provide a higher flow than the first pump 6 for a period of time until a low pressure has been established. Thereafter, the second pump 7 is operated to provide approximately the same flow rate as the first pump 6 to maintain the low pressure at the same value. The low pressure is typically maintained by pressure feedback to the second pump 7. When a low pressure has been established, the perfusion fluid may be recirculated in the recirculation path 12 at the low pressure established in the entire recirculation path 12.
In case a low pressure at the first side 2a is not desired and the second pump 7 is a non-volumetric pump, the second pump 7 is controlled to reach a pressure at the first side 2a equal to or higher than the atmospheric pressure when the perfusion fluid reaches the second pump 7 or before or simultaneously with pumping the perfusion fluid towards the first side 2a with the first pump 6. Then, when the perfusion fluid has reached the second pump 7, the second pump 7 may first start pumping, which occurs for example when a predetermined amount of perfusion fluid has been pumped by the first pump 6 after the gas collecting chamber 5 has been filled or when an increased first side 2 pressure has been detected. In the case where the second pump 7 is a volumetric pump, the second pump 7 is controlled to reach a pressure equal to or higher than the atmospheric pressure at the first side 2a while pumping the perfusion fluid toward the first side 2a with the first pump 6. When a pressure equal to or higher than the atmospheric pressure at the first side 2a has been established, the perfusion fluid may be recirculated in the recirculation path 12 at the established atmospheric pressure or higher.
The second pump 7 may pump any expelled perfusion fluid from the first side 2a for expelling. In other words, in some embodiments, the method comprises providing S1B from the priming fluid source to the first side 2a of the FO unit 2 via the first flow path 3 and the gas collection chamber 5, so as to fill the first side 2a with priming fluid.
In some embodiments, after filling the first side 2a, the method comprises providing S1 the perfusion fluid again to the gas collection chamber 5 while venting gas from the gas collection chamber 5 to fill the gas collection chamber 5 to a predetermined liquid level. The measurement may be performed in response to checking the liquid level in the gas collection chamber 5 with the liquid level sensing means 22. When the liquid level is detected to be too low, the method comprises providing S1 a perfusion fluid to the gas collection chamber 5. This sequence is shown in fig. 4A.
When the first side 2a has been filled with a perfusion fluid, the method thus comprises circulating the provided perfusion fluid in the recirculation path 12 when the perfusion fluid has reached the second pump 7 and/or when a predetermined volume of perfusion fluid has been pumped with the first pump 6, and optionally when the first side pressure is at a low pressure and the gas collecting chamber 5 has a predetermined level of perfusion fluid. This is shown in fig. 4C and 4D. For example, the method comprises operating the second pump 7 to circulate the perfusion fluid in the recirculation path 12. In some embodiments, during circulation, no new perfusion fluid enters the recirculation path 12. During recirculation, the gas present in the recirculation path 12, which moves around by the circulating perfusion fluid, is collected in the gas collection chamber 5. During the cycle, the return path valve 20c is open, while the first side input line valve 20b, the direct line valve 20s, the gas collection path valve 20n, and the drain valve 20i are closed. The container valve 20p may also be closed. The method comprises circulating S2 the provided perfusion fluid in a first direction in the recirculation path 12. The second pump 7 is then operated to provide a flow of perfusion fluid in the first direction. In some embodiments, circulating S2 the priming fluid in the first direction means circulating the fluid such that it is at the inlet port E in Is input through the outlet port E of the first side 2a ou t out, thus in the direction indicated by the arrow in fig. 4C. The first direction through the first side 2a corresponds to the direction of the first fluid during production. The circulation S2 generally comprises circulating the provided perfusion fluid in a first direction for a predetermined period of time. The predetermined period of time is, for example, between 10 seconds and 120 seconds. As gas is collected in the gas collection chamber 5, the level of the perfusion fluid in the gas collection chamber 5 decreases. In some embodiments, the flow rate at which the fluid is first circulated is a low flow rate, such as 200-400ml/min. In another embodiment, the flow is higher, for example 400-1500ml/min.However, the flow rate depends on the system component size, FO membrane type, etc., and thus may vary.
In some embodiments, the method includes maintaining a low pressure at the first side 2a during circulation of the perfusion fluid in the recirculation path 12. Thus, the perfusion may become more efficient. The low pressure can be established by operating the first pump 6 and the second pump 7 to achieve different flows before entering the recirculation stage.
In some embodiments, after the first circulating the perfusion fluid, the method comprises providing S1 the perfusion fluid to the gas collection chamber 5 again while evacuating gas from the gas collection chamber 5 to fill the gas collection chamber 5 to a predetermined liquid level. The measurement may be performed in response to checking the liquid level in the gas collection chamber 5 with the liquid level sensing means 22. When the liquid level is too low, the method comprises providing S1 a perfusion fluid to the gas collection chamber 5. As explained, this sequence is shown in fig. 4A.
The recirculation path 12 and thus the first side 2a of the FO unit 2 has now released gas that can be removed relatively easily. However, the first side 2a may still contain trapped gas. In some embodiments, to remove such trapped gases, the method includes circulating the perfusion fluid through the recirculation path 12 at a high flow rate (e.g., 400-1500 ml/min). Further, in some embodiments, the method includes circulating the perfusion fluid through the recirculation path 12 in an opposite direction. Thus, the method may further comprise circulating S3 the perfusion fluid in the recirculation path 12 in the second direction. In some embodiments, circulating S3 the priming fluid in the second direction means circulating the fluid such that the fluid is at the outlet port E out Is input through the inlet port E of the first side 2a in Output, thus in the direction indicated by the arrow in fig. 4D opposite the first direction. The second pump 7 is then operated to provide a flow of perfusion fluid in a second direction. In some embodiments, the method includes circulating the perfusion fluid through the recirculation path 12 in the opposite direction at a high flow rate. In order to provide different flow rates, the second pump 7 is operated at different speeds. In some embodiments, the method includes flowing at a high flow rate (e.g., 400-1500 ml/min) and a low flow rate An amount (e.g., 50-200ml/min or 200-400 ml/min) circulates the perfusion fluid through the recirculation path 12 in different directions. In some embodiments, the method includes circulating S2 the perfusion fluid in a first direction at a first flow rate and circulating S3 the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate. In some embodiments, the first flow is greater than the second flow. The cycles in different directions may follow each other immediately or may not take a long time after each other. In some embodiments, the method includes circulating the perfusion fluid in different directions for different lengths of time. In some embodiments, the method includes circulating S2 the perfusion fluid in the recirculation path 12 in a first direction for a predetermined first period of time, and circulating S3 the perfusion fluid in the recirculation path 12 in a second direction for a second period of time, wherein. The first time period and the second time period have different lengths. The first period of time is, for example, greater than the second period of time. Any of the above steps may be combined and/or repeated one or more times. In some embodiments, the method includes (i) circulating S2 the perfusion fluid in the recirculation path 12 in a first direction and (ii) circulating S3 the perfusion fluid in the recirculation path 12 at least once in a second direction until one or more predetermined perfusion criteria are met. For example, in some embodiments, the method includes circulating the perfusion fluid in a first direction at a high flow rate for a first period of time. The first period of time is for example between 10 seconds and 120 seconds. This step is performed to force any gas present in the fibre lumen at the first side 2a out of the lumen by means of a high pressure drop caused by the high flow. Thus, due to the higher flow resistance on the first side 2a, the high flow results in a high pressure drop from the inlet to the outlet at the first side 2 a. The cycle is then stopped. In an example, the method thereafter includes circulating the perfusion fluid in the second direction at a low flow rate for a second period of time. The purpose of circulating the priming fluid in the second direction is to be present at the inlet port E in The nearby gas is delivered to the gas collection chamber 5. The second period of time should be long enough to allow the gas in the uppermost portion of the first side 2a to be transported with the perfusion fluid from the first side 2a to the gas collection chamber 5. Thus, the second period of time depends on the length of the connecting line 3c and the size of the low flow. For example, at the second timeThe interval is a few seconds, for example 3 to 10 seconds. The first period of time is typically longer than the second period of time because the perfusion fluid at the first side 2a must travel a longer distance to reach the gas collection chamber 5 when circulating in the first direction than when circulating in the second direction. Thus, the length of the first period of time is typically at least the time it takes for the perfusion fluid at the first side 2a to travel to the gas collection chamber 5 via the return path 8. The procedure of circulating the perfusion fluid in the first direction at a high flow rate for a first period of time and then circulating the perfusion fluid in the second direction at a low flow rate for a second period of time may be performed multiple times. For example, the procedure may be repeated 5 to 10 times to ensure that the first side 2a is free of gas. Thus, the criteria for stopping the repetition or cycling may be that the repetition or cycling has been performed a number of times, for example a certain number of times. In some embodiments, the apparatus 1 comprises a bubble sensor 44 connected to the return path 8. The method may then include detecting the presence of bubbles based on, for example, the bubble size and/or number. In response to detecting a bubble meeting one or more low detection criteria, the repetition or cycling may be stopped and the perfusion of the first side is deemed satisfactory. The low detection criteria may include, for example, no bubbles greater than a predetermined size for a predetermined period of time, and/or a predetermined number of bubbles less than a predetermined size during a predetermined period of time.
In some embodiments, in addition to circulating the perfusion fluid in the first direction for a first period of time at a high flow rate, and then circulating the perfusion fluid in the second direction for a second period of time at a low flow rate, the method further includes circulating the perfusion fluid through the first side 2a in the second direction at a high flow rate. More bubbles can be removed from the fibre lumen and collected in the gas collection chamber 5 accordingly. Circulating the perfusion fluid through the first side 2a in the second direction at a high flow rate is performed for a third period of time. The third time period follows the second time period, typically immediately after the second time period. The third time period may have the same length as the second time period, and thus be between 3 and 10 seconds.
The first side 2a has now been primed and is intended to be free of gas, at least larger bubbles. This also means that the first side 2a has fulfilled aOne or more predetermined perfusion criteria. In some embodiments, when one or more predetermined perfusion criteria are met, the method includes providing fluid from the solution source 15 to an inlet port L leading to the second side 2b via a second flow path in Inlet port L in An outlet port L arranged at the second side 2b out And below. Alternatively, the supply of fluid from the solution source 15 to the second side 2b is performed before, during and/or after priming the first side 2a. The fluid from the solution source 15 is typically a concentrate solution to be provided to the second side 2b during dialysis fluid production. Thus, the filling of the second side 2b may also be the start of the process of diluting the concentrate. As shown in fig. 4E, the second side 2b is filled from the bottom up and any gas at the second side 2b is transported to the collection chamber by the diluted concentrate solution (fig. 5, reference numeral 16). Since the second side 2b is located along the outside of the lumen (the shell side), the gas is not trapped at the second side 2b as easily. After the second side 2b is filled, the priming of the FO unit 2 is completed. The FO unit 2 can now effectively produce a diluted dialysis concentrate fluid. In fig. 4E it is shown that the feed fluid flows at the first side 2a and the draw fluid flows at the second side 2 b.
The higher pressure at the first side 2a (compared to the lower pressure at the first side 2a during priming) is typically associated with a water extraction stage (session) that reduces the size of any remaining and possibly flow-impeding bubbles. This stage also reduces the risk of formation of additional gas due to degassing of the fluid.
In some embodiments, in addition to the above-described measurements, flow and/or pressure transients may be used to force bubbles out of the fiber lumen at the first side 2 a. Thus, the method may comprise providing a pulsating flow generating a flow transient that facilitates release of bubbles from the fibre lumen at the first side 2 a. The method may then comprise operating the second pump 7 to provide a pulsating flow or periodic flow pattern in the recirculation path 12, thus simultaneously recirculating the perfusion fluid as shown in fig. 4C or fig. 4D. Alternatively or in combination, the method may include generating an accumulated pressure (build-up pressure) that is periodically released to generate the high flow pulse. This will create a flow transient that will aid in the release of the bubbles from the fiber lumen. For example, the first pump 6 may periodically build up pressure in the gas collection chamber 5 and then release the pressure through the first side 2a of the FO unit 2.
In some embodiments, the priming is enhanced by applying motion to the FO unit 2 by an external device to facilitate air removal, such as mechanically vibrating the FO unit 2.
An example perfusion scenario is now explained with reference to fig. 1 and 4A-4F. In response to a predetermined opportunity (e.g., 1 pm every day), a perfusion sequence is initiated. The priming sequence starts with filling the gas collection chamber 5 with a priming fluid up to a predetermined level while venting gas via the venting path 9, see steps S1-S1A and fig. 4A. Thereafter, the first side 2a is filled by supplying a predetermined amount of perfusion fluid to the first side 2a, see step S1B and fig. 4B. Thereafter, the gas collection chamber 5 is refilled with a perfusion fluid up to a predetermined level while the gas is exhausted via the exhaust path 9, see steps S1-S1A and fig. 4A. Thereafter, the perfusion fluid in the recirculation path 12 is recirculated in the first direction (i.e. forward direction) in the recirculation path 12, see step S2 and fig. 4C. Thereafter, the gas collection chamber 5 is again filled with the perfusion fluid up to a predetermined level, while the gas is discharged via the discharge path 9, see steps S1-S1A and fig. 4A. The priming sequence is now repeatedly performed, including circulating the priming fluid in a first direction for a first period of time at a high flow rate, followed by circulating the priming fluid in a second direction for a second period of time at a low flow rate, see steps S2-S4 and fig. 4C and 4D. This sequence may be repeated, for example, 5-10 times to ensure that the feed side is free of air. Thereafter, the first side 2a is primed, see fig. 4E. The concentrated fluid is now provided to the second side 2b to fill the second side 2b, see step S5. When the second side 2b is filled, the second side 2b is also primed, and the entire FO unit 2 is considered primed. Thus, first the first side 2a is primed and the second side 2b is empty. Thereafter, the second side 2b is primed, whereas the first side 2a has been filled, i.e. primed. Alternatively, the second side 2b is infused before or simultaneously with the first side 2 a.
An example of a device 1 for producing a fluid for dialysis will now be explained with reference to fig. 5. The legend for the open valve and the closed valve is not applicable to fig. 5. The device 1 comprises a portion 50 shown in fig. 1 and 4A to 4E and some additional components omitted from fig. 1. The apparatus 1 thus comprises a FO unit 2, a first flow path 3 and a second flow path 4. The method explained for perfusion is equally applicable to the device 1 in fig. 5.
The first flow path 3 starts at the inlet connector Pi and ends at the discharge 31. The second flow path 4 starts from the concentrate container 15 and ends at the outlet connector Po. The inlet connector Pi may be connected, for example, to a catheter of a PD patient, or to a spent dialysis fluid line of an HD or CRRT device. The outlet connector Po may be connected to a catheter of a PD patient, or a dialysis fluid line of an HD or CRRT device, for example. The first flow path 3 includes a plurality of fluid lines, i.e., a first side input line 3a, a container line 3b, a connection line 3c, and a discharge line 3d. The first side input line 3a is arranged between the input point Pi and an inlet port 5a of a gas collection chamber 5 (e.g. a gas collection chamber 5 as shown in fig. 2). The first side inlet line 3a fluidly connects the inlet point Pi with the inlet port 5a of the gas collection chamber 5. The vessel line 3b is arranged between the connection point P1 of the first side input line 3a and the vessel 19. As shown, the connection point P1 in fig. 1 and fig. 4A to 4E corresponds to the connection point P1 in fig. 5. The vessel line 3b connects the vessel 19 and the first side input line 3a. The connecting line 3c is arranged between the outlet port 5b (fig. 2) of the gas collection chamber 5 and the inlet port E of the first side 2a in Between them. Thus, the connecting line 3c fluidly connects the outlet port 5b and the inlet port E of the gas collection chamber 5 in . The discharge line 3d is arranged at the outlet port E of the first side 2a out And the connection point P4 to the drain 31. Thus, the discharge line 3d is fluidly connected to the outlet port E out And a discharge portion 31. A pressure sensor 26 is connected to the first side input line 3a to sense the pressure of the fluid in the first side input line 3a. The sensed pressure from the pressure sensor 26 is representative of the pressure in the gas collection chamber 5. The first pump 6 is arranged to operate with the container line 3b to provide a flow in the container line 3 b. The first pump 6 is positioned and arranged to pump in a forward directionFluid to fill the container 19 with, for example, spent dialysis fluid. The first pump 6 is further arranged to pump fluid in a backward direction to pump fluid from the container 19 in a direction to the gas collection chamber 5. The input valve 20a is arranged to operate with the first side input line 3a between the inlet connector Pi and the point P1. The first side inlet line valve 20b is arranged to operate with the first side inlet line 3a between the point P1 and the gas collection chamber 5. The second pump 7 is arranged to operate with the discharge line 3d to provide a fluid flow in the discharge line 3d. The discharge valve 20i is arranged to operate with the discharge line 3d between the connection point of the return path 8 with the discharge line 3d and the connection point of the gas collecting path 9 with the discharge line 3d. The return path 8 is arranged between the discharge line 3d and the first side input line 3a. Thus, the return path 8 fluidly connects the drain line 3d and the first side input line 3a. The return path 8 is connected to the discharge line 3d between the second pump 7 and the discharge valve 20 i. The return path 8 is also connected to the first side input line 3a at a point between the connection point of the direct current line 3e to the first side input line 3a and the inlet port 5a of the gas collection chamber 5. The gas collection path 9 is arranged between the outlet port 5c (fig. 2) of the gas collection chamber 5 and the discharge line 3d. Thus, the gas collection path 9 fluidly connects the gas outlet port 5c and the discharge line 3d. The gas collection path 9 is connected to the discharge line 3d between the discharge valve 20i and the discharge portion. Spent dialysis fluid may be collected in the container 19 by: the spent dialysis fluid is pumped to the reservoir 19 by means of the first pump 6, the first inlet valve 20a and the reservoir valve 20p are opened, and the first side inlet line valve 20b and the direct line valve 20s are closed. Thereafter, spent dialysis fluid may be delivered to the first side 2a by: pumping is performed using the first pump 6 and the second pump 7, the first side input line valve 20b, the tank valve 20p, and the discharge valve 20i are opened, and the inlet valve 20a, the direct line valve 20s, the return path valve 20c, and the gas collection path valve 20n are closed. The gas collection chamber 5 may be filled by additionally opening the gas collection path valve 20n and not operating the second pump 7 or operating the second pump 7 at a lower flow rate than the first pump 6. The first side 2a may be filled by additionally closing the gas collection path valve 20n.
Second streamThe dynamic path 4 comprises a plurality of fluid lines, namely a concentrate line 4d, a second side input line 4b, a second side output line 4c, a first dilute concentrate line 4e, a second dilute concentrate line 4a, a main line 4f, a plain water line 4g, a second concentrate line 4h and a drain connection line 4i. The concentrate line 4d is arranged between the concentrate container 15 and the connection point P3 to the main line 4f and the second side input line 4b. Thus, the concentrate line 4d connects the concentrate container 15 to the second side input line 4b (and to the main line 4 f). As shown, the connection point P3 in fig. 1 and fig. 4A to 4E corresponds to the connection point P3 in fig. 5. The concentrate valve 20d is connected to the concentrate line 4d. The second side input line 4b is arranged at the connection point P3 to the concentrate line 4d and at the inlet port L of the second side 2b in Between them. Thus, the second side input line 4b connects the connection point P3 and the inlet port L in . The concentrate pump 10 is positioned and arranged to provide a flow in the concentrate line 4d. The second side input valve 20h is connected to the second side input line 4b. The second side output line 4c is arranged at the outlet port L of the second side 2b out And a junction point P2 on the first dilute concentrate line 4 e. As shown, the connection point P2 in fig. 1 and fig. 4A to 4E corresponds to the connection point P2 in fig. 5. Thus, the second side output line 4c is connected to the outlet port L out And a first dilute concentrate line 4e. The first dilute concentrate line 4e is arranged between the inlet of the dilute fluid container 16 and the connection point P3 at the concentrate line 4 d. Thus, the first dilute concentrate line 4e connects the inlet of the dilute fluid reservoir 16 with the connection point P3 of the concentrate line 4 d. The first dilute concentrate valve 20e is connected to the first dilute concentrate line 4e between the connection point P2 of the second side output line 4c and the first dilute concentrate line 4e and the connection point of the first dilute concentrate line 4e and the concentrate line 4 d. The conductivity sensor 11 is connected to the first dilute concentrate line 4e between point P2 and the inlet of the dilute fluid reservoir 16. The main line 4f is arranged between the connection point P3 to the concentrate line 4d and the outlet connector Po. Thus, the main line 4f connects the connection point P3 and the outlet connector Po. The second dilute concentrate line 4a is arranged between the outlet of the dilute fluid container 16 and the connection point P3 to the main line 4f. Second oneThe dilute concentrate valve 20f is connected to the second dilute concentrate line 4a. Thus, the connection point P3 connects the main line 4f, the concentrate line 4d, the second dilute concentrate line 4a and the second side input line 4b. The second flow path 4 further comprises a plurality of components connected to the main line 4f, namely a main valve 20g, a heating element 65, a temperature sensor 27, a main pump 23, a mixing chamber 24, a conductivity sensor 25 and an outlet valve 20j. The deionized water line 4g is disposed between the deionized water container 17 and the main line 4f. Therefore, the deionized water line 4g connects the deionized water container 17 and the main line 4f. The main valve 20g is connected to the main line 4f between the point P3 and the connection point of the plain water line 4g and the main line 4f. The second concentrate line 4h is arranged between the second concentrate container 18 and the main line 4f. Thus, the second concentrate line 4h connects the second concentrate container 18 and the main line 4f. The second concentrate pump 29 is positioned and arranged to provide a second concentrate stream in the second concentrate line 4 h. The main pump 23 is positioned and arranged to provide flow in the main line 4f downstream of the junction of the plain water line 4g with the main line 4f and downstream of the junction of the second concentrate line 4h with the main line 4f. The temperature sensor 27 is positioned and arranged to sense the temperature of the fluid in the main line 4f upstream of the main pump 23 but downstream of the junction of the second concentrate line 4h with the main line 4f. The mixing chamber 24 is arranged downstream of the main pump 23 and upstream of the main conductivity sensor 25. The vent valve 20m is arranged to operate with a vent line 4j connected between the mixing chamber 24 and the vent line 3 d. The exhaust line 4j delivers the excess gas in the mixing chamber 24 to the exhaust 31.
To dilute the concentrate, the concentrate pump 10 is operated to pump concentrate solution from the concentrate container 15 to the second side 2b. The concentrate valve 20d and the second side input valve 20h are then opened, and the first dilute concentrate valve 20e and the second dilute concentrate valve 20f are closed. At the same time, spent dialysis fluid is provided at the first side 2 a. Then, pure water in the spent dialysis fluid at the first side 2a is extracted to the concentrate solution at the second side 2b by means of an osmotic pressure difference. Thus, the concentrate solution will be diluted to form an intermediate dialysis solution, thus forming a diluted concentrate solution, which is collected in the dilution fluid container 16. This procedure may be referred to as the FO phase. After the diluted concentrate has been collected in the dilution fluid container 16, the diluted concentrate may be circulated in the first dilution concentrate line 4e, the partial concentrate line 4d, the second dilution concentrate line 4a, and the dilution fluid container 16 by pumping with the concentrate pump 10, opening the first dilution concentrate valve 20e and the second dilution concentrate valve 20f, and closing the second side input valve 20h, the concentrate valve 20d, and the main valve 20 g. The conductivity sensor 11 measures the conductivity of the circulating diluted concentrate to monitor when the conductivity is stable and thus the diluted concentrate is homogenous.
To mix the dialysis fluid, the diluted concentrate solution in the dilution fluid container 16 is pumped to the main line 4f by operating the concentrate pump 10, opening the first diluted concentrate valve 20e, the main valve 20g, the outlet valve 20j, and closing the concentrate valve 20d, the second side input valve 20h, the second diluted concentrate valve 20f, and the drain connection valve 20 k. At the same time, a second concentrate solution, such as glucose, is transferred to the main line 4f by operating the second concentrate solution pump 29. Pure water flows from the pure water container 17 to the main line 4f. The main pump 23 provides the desired flow of the resulting dialysis fluid in the main line 4f downstream of the main pump 23. The conductivity sensor 25 measures the conductivity of the resulting dialysis fluid from the main pump 23. The concentrate pump 10 is controlled to a specific speed to achieve a desired predetermined concentration of the resulting dialysis fluid, based on the conductivity of the produced fluid, the conductivity of the diluted concentrate solution, and the flow rate of the produced fluid. The second concentrate solution pump 29 is controlled to a specific speed based on the flow rate of the produced fluid to achieve a specific composition of concentrate in the produced fluid. In the mixing chamber 24, the diluted concentrate solution, the second concentrate solution, and pure water mix to form a dialysis fluid. The mixing chamber 24 is small and can typically only hold 30-100ml of fluid. The dialysis fluid is then delivered to a desired destination (e.g., a storage container or dialysis machine or a catheter connected to the PD patient) at an outlet connector Po. The liquid level sensing means 66 monitors the liquid level in the mixing chamber 24 and if the liquid level becomes too low to responsively convey gas to the drain and thereby raise the liquid level, the vent valve 20m is opened. The main conductivity sensor 25 measures the conductivity of the final dialysis fluid. If the conductivity is not within the predetermined limits, the dialysis fluid is transferred to the drain 31 via the drain connection line 4 i. The drain connection valve 20k is connected to the drain connection line 4i, and the drain connection valve 20k is opened when the dialysis fluid is transferred to the drain portion 31. A pressure sensor 28 is connected to the main line 4f downstream of the output valve 20j to sense the pressure at the outlet connector Po.
Any of the pumps described herein may be, for example, volumetric pumps (e.g., piston pumps) or non-volumetric pumps (e.g., gear pumps) that operate with flow feedback from a flow sensor (not shown). The one or more pumps may be unidirectional or bidirectional. The concentrate container 15 includes an electrolyte solution. For example, the electrolyte solution may include an electrolyte and a buffer, e.g., na, ca, mg, and lactate. The second concentrate container 18 includes, for example, a glucose concentrate. The control device 60 further comprises a control unit 30, the control unit 30 comprising at least one memory and at least one processor. The control device 60 is configured to control the pumps 6, 7, 10, 23 and 29 and the valves 20a-20p of the valve device 20 to perform a number of different processes, such as for example to produce a dialysis fluid or to perform a priming process. The control device 60 is further configured to receive a measurement of the conductivity from the conductivity sensor 11, 25. The control device 60 is further configured to receive measurements of pressure from the pressure sensors 26, 28 and the temperature sensor 27. Thus, the control means 60 is configured to receive or collect any signals or data from the components of the device 1 and control the pump and/or the valve based thereon. The results may be provided to the user via a user interface (not shown).
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims (38)
1. An apparatus (1) for producing a fluid for dialysis, comprising:
a forward osmosis FO unit (2) configured for diluting a dialysis concentrate during production of a dialysis fluid, the FO unit (2) comprising a FO membrane (2 c) separating a first side (2 a) from a second side (2 b) of the FO unit (2);
-a first flow path (3) comprising said first side (2 a);
-a control device (60) configured to provide perfusion fluid from a perfusion fluid source (19) to the first flow path (3);
a return path (8) connecting the inlet port (E) of the first side (2 a) of the FO unit (2) in ) An outlet port (E) fluidly connected to the first side (2 a) of the FO unit (2) out ) To allow flow from the outlet port (E out ) The expelled perfusion fluid is circulated via a return path (8) to an inlet port (E) in ) The method comprises the steps of carrying out a first treatment on the surface of the And
a gas collection chamber (5) arranged in the first flow path (3) between the first side (2 a) and the return path (8), wherein the gas collection chamber (5) is configured to receive gas removed from the first flow path (3).
2. The device (1) according to any one of the preceding claims, wherein the control means (60) is configured to monitor the level of the perfusion fluid in the gas collection chamber (5) and to provide the perfusion fluid to the gas collection chamber (5) until the level of the perfusion fluid in the gas collection chamber (5) has reached a predetermined level.
3. The apparatus according to claim 2, wherein the apparatus is positioned and arranged to exhaust gas from the gas collection chamber (5) while providing perfusion fluid to the gas collection chamber (5).
4. The apparatus according to any one of the preceding claims, wherein the gas collection chamber (5) comprises a gas outlet port (5 c) for exhausting gas from the gas collection chamber (5).
5. The device (1) according to claim 4, comprising a gas collection path (9) fluidly connecting the gas outlet port (5 c) of the gas collection chamber (5) to the drain (31).
6. The device (1) according to any one of the preceding claims, wherein the control means (60) is configured to provide perfusion fluid from the perfusion fluid source (19) to the first side (2 a) of the FO unit (2) via the first flow path (3) and the gas collection chamber (5) to fill the first side (2 a) with the perfusion fluid.
7. The device (1) according to claims 2 and 6, wherein the control means (60) is configured to provide the priming fluid from the priming fluid source (19) to the first side (2 a) of the FO unit (2) via the first flow path (3) and the gas collection chamber (5) when the level of the priming fluid in the gas collection chamber (5) reaches a predetermined level.
8. The device (1) according to any one of the preceding claims, wherein the control means (60) is configured to stop the flow via the return path (8) while providing perfusion fluid from the source of perfusion fluid (19) to the first flow path (3).
9. The device (1) according to claim 6 or 7, wherein the control means (60) is configured to circulate the perfusion fluid provided to the first side (2 a) in a first direction in a recirculation path (12), the recirculation path (12) comprising the first side (2 a), the return path (8) and the gas collection chamber (5).
10. The device (1) according to claim 9, wherein the control means (60) is configured to circulate the perfusion fluid in the recirculation path (12) in the second direction.
11. The apparatus (1) according to claim 10, wherein the control device (60) is configured to repeat (i) the circulation of the perfusion fluid in the recirculation path in the first direction and (ii) the circulation of the perfusion fluid in the recirculation path in the second direction at least once until one or more predetermined perfusion criteria are met.
12. The device (1) according to claim 11, comprising a second flow path (4),the second flow path (4) comprises said second side (2 b) for providing fluid to the second side (2 b), wherein the control means (60) is configured to provide fluid from the solution source (15) to the inlet port (L) of the second side (2 b) via the second flow path when said one or more predetermined perfusion criteria of the first side (2 a) are met in ) The inlet port (L) of the second side (2 b) in ) An outlet port (L) arranged on the second side (2 b) out ) And below.
13. The device (1) according to claim 11 or 12, wherein the control means (60) is configured to circulate the perfusion fluid in a first direction at a first flow rate and to circulate the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate.
14. The device (1) according to claim 13, wherein the first flow rate is greater than the second flow rate.
15. The device (1) according to one of claims 11 to 14, wherein the control means (60) is configured to circulate the perfusion fluid in the recirculation path (12) in a first direction for a predetermined first period of time and to circulate the perfusion fluid in the recirculation path (12) in a second direction for a second period of time, wherein the first period of time and the second period of time have different lengths.
16. The device (1) according to claim 15, wherein the first period of time is greater than the second period of time.
17. Apparatus (1) according to any one of the preceding claims, wherein the control device (60) comprises at least one pump.
18. The device (1) according to claim 17, wherein the at least one pump comprises a first pump (6), the first pump (6) being arranged to provide perfusion fluid from a source of perfusion fluid to the first path (3).
19. The apparatus (1) according to any one of claims 9 to 16 and 17 or 18, wherein the at least one pump comprises a second pump (7), the second pump (7) being arranged to circulate the perfusion fluid in the recirculation path (12).
20. The device (1) according to any one of the preceding claims, wherein the gas collection chamber (5) comprises at least two fluid ports, and wherein the perfusion fluid is allowed to enter and exit via any one of said at least two ports.
21. The device (1) according to any of the preceding claims, wherein the priming fluid is the same fluid as is used for diluting the dialysis concentrate during production, and wherein the priming fluid is water or a used dialysis solution.
22. A method for priming a forward osmosis FO unit (2), the FO unit (2) being configured for diluting a dialysis concentrate during production of a dialysis fluid, the FO unit (2) comprising a FO membrane (2 c) separating a first side (2 a) from a second side (2 b) of the FO unit (2), the method comprising:
-providing (S1) a perfusion fluid to a first flow path (3), the first flow path (3) comprising the first side (2 a) and a gas collection chamber (5), the gas collection chamber (5) being configured to receive gas removed from the first flow path (3); and
-circulating (S2) the provided perfusion fluid in a recirculation path (12), the recirculation path (12) comprising said first side (2 a), a return path (8) and a gas collection chamber (5), wherein the return path (8) connects an inlet port (E) of the first side (2 a) of the FO unit (2) in ) An outlet port (E) fluidly connected to the first side (2 a) of the FO unit (2) out )。
23. The method of claim 22, wherein providing (S1) comprises: monitoring (S1A) the level of the perfusion fluid in the gas collection chamber (5) and providing the perfusion fluid to the gas collection chamber (5) until the level of the perfusion fluid in the gas collection chamber (5) has reached a predetermined level.
24. The method of claim 23, comprising: the gas is exhausted from the gas collection chamber (5) while the perfusion fluid is supplied (S1A) to the gas collection chamber (5).
25. The method of claim 24, comprising: the gas is discharged from the gas collection chamber (5) to the discharge (31) via a gas collection path (9), wherein the gas collection path (9) fluidly connects the gas outlet port (5 c) of the gas collection chamber (5) to the discharge (31).
26. The method of any one of claims 22 to 25, comprising: a priming fluid is provided (S1B) from a priming fluid source (19) to the first side (2 a) of the FO unit (2) via the first flow path (3) and the gas collection chamber (5) to fill the first side (2 a) with the priming fluid.
27. The method according to claims 23 and 26, comprising: when the level of the priming fluid in the gas collection chamber (5) reaches a predetermined level, the priming fluid is provided (S1B) from the priming fluid source (19) to the first side (2 a) of the FO unit (2) via the first flow path (3) and the gas collection chamber (5).
28. The method according to any one of claims 22 to 27, wherein providing (S1) comprises: the flow via the return path (8) is stopped while the perfusion fluid is supplied from the perfusion fluid source (19) to the first flow path (3).
29. The method according to claim 26 or 27, comprising: the perfusion fluid provided to the first side (2 a) is circulated (S2) in a first direction in a recirculation path (12).
30. The method of claim 29, comprising: circulating (S3) the perfusion fluid in a second direction in the recirculation path (12).
31. The method of claim 30, comprising: (i) Circulating (S2) the perfusion fluid in a first direction in the recirculation path (12) and (ii) circulating (S3) the perfusion fluid at least once in a second direction in the recirculation path (12) until one or more predetermined perfusion criteria are met.
32. The method of claim 31, comprising: when the one or more predetermined perfusion criteria are met, fluid is provided from the solution source (15) to the inlet port (E) of the second side (2 b) via the second flow path in ) Wherein the inlet port (E) of the second side (2 b) in ) An outlet port (E) arranged on the second side (2 b) out ) And below.
33. The method of claim 32, comprising: circulating (S2) the perfusion fluid in a first direction at a first flow rate and circulating (S3) the perfusion fluid in a second direction at a second flow rate, wherein the first flow rate is different from the second flow rate.
34. The method of claim 33, wherein the first flow rate is greater than the second flow rate.
35. The method according to one of claims 30 to 34, comprising: circulating (S2) the perfusion fluid in the recirculation path (12) in a first direction for a predetermined first period of time and circulating (S3) the perfusion fluid in the recirculation path (12) in a second direction for a second period of time, wherein the first period of time and the second period of time have different lengths.
36. The method of claim 35, wherein the first period of time is greater than the second period of time.
37. A computer program comprising instructions to cause a device (1) according to any one of claims 1 to 21 to perform the method according to any one of claims 22 to 36.
38. A computer readable medium having stored thereon a computer program according to claim 37.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163172850P | 2021-04-09 | 2021-04-09 | |
US63/172,850 | 2021-04-09 | ||
SE2151562-2 | 2021-12-21 | ||
PCT/EP2022/058923 WO2022214447A1 (en) | 2021-04-09 | 2022-04-05 | Priming of a forward osmosis unit |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117120117A true CN117120117A (en) | 2023-11-24 |
Family
ID=88795267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280027552.4A Pending CN117120117A (en) | 2021-04-09 | 2022-04-05 | Priming of forward osmosis units |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117120117A (en) |
-
2022
- 2022-04-05 CN CN202280027552.4A patent/CN117120117A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9872949B2 (en) | Systems and methods for multifunctional volumetric fluid control | |
EP2950843B1 (en) | Sodium and buffer source cartridges for use in a modular controlled complaint flow path | |
US10940256B2 (en) | Hemodialysis system | |
EP2950834A1 (en) | Degassing module for a controlled compliant flow path | |
WO2014121166A1 (en) | Modular fluid therapy system having jumpered flow paths and systems and methods for cleaning and disinfection | |
US20230069896A1 (en) | A system and method for producing fluid for peritoneal dialysis | |
CN111372620A (en) | Extracorporeal blood treatment apparatus | |
CN111936179B (en) | Blood tube set, open-loop or closed-loop control device, blood treatment apparatus and method for single needle treatment | |
CN117120117A (en) | Priming of forward osmosis units | |
US20240197972A1 (en) | Priming method and system for forward osmosis | |
AU2022286326A1 (en) | Methods and systems for controlling dialysate salt concentration | |
CN111511418B (en) | Dialysis system with carbon dioxide generation and infusion | |
JP7132093B2 (en) | blood purifier | |
US11904078B2 (en) | Hemodialysis system with variable dialysate flow rate | |
US20240238494A1 (en) | Apparatus and methods for efficient production of dialysis fluid using forward osmosis | |
CN117120118A (en) | Apparatus and method for efficient production of dialysis fluid using forward osmosis | |
AU2020211019A1 (en) | Device for an extracorporeal blood treatment | |
JP2023537434A (en) | Dialysis filter device | |
JP2024033781A (en) | Hemodialysis system with variable dialysate flow rate | |
MXPA06005045A (en) | High convection home hemodialysis/hemofiltration and sorbent system |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |