AN IMPLANTABLE RENAL REPLACEMENT THERAPY SYSTEM

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent Provisional Application No.

62/262,915, filed December 4, 201 5, titled "AN IMPLANTABLE RENAL REPLACEMENT THERAPY," which is herein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

FIELD

[0003] The present invention is in the technical field of medical devices and renal replacement therapies.

BACKGROUND

[0004] There are nearly three million patients with kidney failure (end-stage renal disease) around the world. Patients' survival depend on dialysis, a thrice a week renal replacement therapy that they undergo until they receive a kidney transplant. The mortality rate of patients under dialysis is more than 60% in five years. On average, a year of dialysis of each patient costs upwards of $82,000 in the United States. Patients have to use dialysis for five to seven years on average before they find a kidney donated for transplantation. Thrice a week dialysis imposes lifestyle restrictions on patients and they endure a lot more hardships from complications due to dialysis treatment.

[0005] An implantable renal replacement therapy can provide access to treatment continuously and automatically 24/7 and removes the hardship of going to the dialysis clinics. In general, it can provide a more normal life for kidney patients and it can be a temporary solution for the patients in need of a kidney transplant until they find a kidney donated for transplantation.

[0006] Kidneys receive 25% of cardiac output. The total blood volume passes through kidneys every 4-5 minutes. Kidneys produce 180 liters of fluid per day and reabsorbs 178.5 liters of it, generating 1.5 liter of acidic (pH~6) urine per day which also contains uremic toxins. SUMMARY OF THE DISCLOSURE

[0007] This invention describes a medical device which is an implantable renal replacement therapy for patients with end stage renal disease.

[0008] Blood is diverted from iliac artery (or another artery) into a filtration system which removes uremic toxins and excess water from blood. Blood is passed back into iliac vein (or another vein) and the uremic toxins and excess water go to the bladder.

[0009] The device has (i) a filtration system which blocks passage of blood proteins such as albumin but removes uremic toxins and excess water and (ii) a re-absorption system to re-claim some salt and water back into the blood from the filtrate of the filtration system. The device is connected to a control unit outside the body of the patient through a percutaneous driveline. The percutaneous driveline has (i) wires to electronics inside the body of the patient and (ii) at least one tube to transfer washing fluid to clean the filters and open the pores in case of clogging. Patient also carries batteries to power the device.

[0010] In general, in one embodiment, a renal replacement therapy system, including (1) a filtration system having a feed side, a filtrate side and a non-silicon ceramic filter separating the feed side and the filtrate side; (2) a re-absorption system having a feed side, a filtrate side and a non-silicon ceramic filter separating the feed side and the filtrate side; (3) a valveless blood flow circuit in communication with an arterial graft, an inlet to the filtration system feed side, an outlet to the filtration system feed side, an inlet to the re-absorption system filtrate side, an outlet to the re-absorption system filtrate side and a venous graft; (4) a percutaneous drive line including a fluid supply channel, a fluid return channel, a power cable, and a data

communications cable; (5) a filtration system inlet valve in communication with the fluid supply channel and an inlet to the filtration system filtrate side; (6) a re-absorption system first outlet valve in communication with the re-absorption system feed side and the fluid return channel; (7) a re-absorption system second outlet valve in communication with the re-absorption system feed side and a graft in communication with a bladder or a urine collection bag ; (8) a filtrate pump with an inlet in communication with the filtration system filtrate side and an outlet in communication with the re-absorption system feed side; and (9) an implantable housing containing the filtration system, the re-absorption system, and the filtrate pump.

[0011] The implantable housing can be completely sealed except for four openings.

[0012] The four openings can be positioned to provide communication to an interior portion of the implantable housing for the percutaneous drive line, the blood flow circuit inlet to the filtration system feed side; the blood flow circuit outlet to the re-absorption system filtrate side and an opening in communication with the re-absorption system second outlet valve.

[0013] The implantable housing can be completely sealed except for five openings. [0014] The five openings can be positioned to provide communication to an interior portion of the implantable housing for a fluid supply line, a fluid return line, the blood flow circuit inlet to the filtration system feed side; the blood flow circuit outlet to the re-absorption system filtrate side and an opening in communication with the re-absorption system second outlet valve.

[0015] The filtration system non-silicon ceramic filter can be selected to filter blood components less than 66,500 Daltons into the filtration system filtrate side.

[0016] The re-absorption system non-silicon ceramic filter can be sized to pass components within the filtrate feed side having a molecular weight of less than 500 Daltons into the re- absorption system filtrate side and into the valveless blood flow circuit.

[0017] The filtration system non-silicon ceramic filter can be selected to maintain substantially all albumin within the blood flowing within the valveless blood flow circuit flowing from the inlet to the filtration system feed side through the outlet to the filtration system feed side while passing through to the filtration system filtrate side molecular weight fluids having a molecular weight below 65,000 Dalton.

[0018] The filtration system non-silicon ceramic filter can contain one or more of aluminum oxide, zinc oxide, titanium oxide, and pyrolytic carbon.

[0019] The filtration system filter can contain one or more of the materials and structures with fracture toughness IC values of higher than 1.00 (MPa . ml/2)

[0020] The re-absorption system non-silicon ceramic filter can contain one or more of aluminum oxide, zinc oxide, titanium oxide, and pyrolytic carbon.

[0021] The filtration system can include the fluid supply channel, the fluid return channel, the power cable, and the data communications cable of the percutaneous drive line are enclosed within a single biocompatible sheath.

[0022] The filtration system can include one or more of a sensor to measure a pressure within the filtration system; a sensor to measure a flow within the filtration system; a sensor to measure a pressure within the re-absorption system; or a sensor to measure a flow within the re- absorption system.

[0023] The filtration system can include one or more of a sensor to measure a quantity of a blood protein, a sensor to measure a quantity of a blood glucose, a sensor to measure a quantity of a blood urea or a sensor to measure a quantity of a blood creatinine within the filtration system.

[0024] The filtration system can include one or more of a sensor to measure a quantity of a blood protein, a sensor to measure a quantity of a blood glucose, a sensor to measure a quantity of a blood urea or a sensor to measure a quantity of a blood creatinine within the re-absorption system. [0025] The system can include a sensor to indicate fouling or fracture of the non-silicon ceramic filter in the filtration system or a sensor to indicate fouling or fracture of the non-silicon ceramic filter in the re-absorption system.

[0026] In general, in one embodiment, the system can further include a control unit with an electronic display and a computer controller in electronic communication with the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve and the filtrate pump.

[0027] The computer controller can be in electronic communication with one or more of the sensors.

[0028] The system can further include a blood pump with an inlet in communication with the arterial graft and an outlet in communication with the inlet to the filtration system feed side.

[0029] The system can include the computer controller which can further include a computer readable instruction for operating the system in a preselected functioning mode selected from a filtration mode, a re-absorption mode, a filter cleaning mode and a urine flushing mode.

[0030] The pre-selected functioning mode can be the filtration mode with the computer readable instruction for operating the system which can further include instructions to close the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate from the filtration system to the re-absorption system.

[0031] The pre-selected functioning mode can be the re-absorption mode with the computer readable instruction for operating the system which can further include instructions to close the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate through the re-absorption system non-silicon ceramic filter.

[0032] The pre-selected functioning mode can be the filter cleaning mode with the computer readable instruction for operating the system which can further include instructions to open the filtration system inlet valve, open the re-absorption system first outlet valve, close the re- absorption system second outlet valve while controlling the operation of the filtrate pump to pump a cleaning fluid.

[0033] The pre-selected functioning mode can be the urine flushing mode with the computer readable instruction for operating the system which can further include instructions to close the filtration system inlet valve, close the re-absorption system first outlet valve, open the re- absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate from the re-absorption system to the and the graft in communication with the bladder or a urine collection bag. [0034] The pre-selected functioning mode can be the service mode with the computer readable instruction for operating the system and van further include instructions to open or close the filtration system inlet valve, open or close the re-absorption system first outlet valve, open or close the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump or not to pump the filtrate from the re-absorption system to the and the graft in communication with the bladder.

[0035] The system can include the computer readable instruction for operating the system which can further include controlling operation of the blood pump during a pre-selected functioning mode.

[0036] The system can further include at least one battery pack connected to the control unit.

[0037] The controller display can further include a touch screen selecting one of the preselected functioning modes.

[0038] In general, in one embodiment, a method of performing a renal replacement filtration therapy includes (1) flowing blood from a patient arterial graft into a valveless blood flow circuit that flows through an inlet to a filtration system feed side, an outlet to a filtration system feed side, an inlet to a re-absorption system filtrate side, an outlet to a re-absorption system filtrate side and a venous graft; (2) filtering a portion of the components in the flowing blood in the filtration system feed side through a first non-silicon ceramic filter to provide a filtrate into a filtration system filtrate side; (3) pumping a portion of the filtrate from the filtration system filtrate side to a feed side of a re-absorption system; and (4) filtering a portion of the filtrate in the feed side of the re-absorption system through a second non-silicon ceramic filter to provide a portion of the filtrate components into the re-absorption system filtrate side in communication with the blood flow circuit.

[0039] The method can further include (1 ) performing one or more of the flowing, filtering, pumping and filtering steps by operating a filtration system inlet valve in communication with a fluid supply channel of a percutaneous drive line and an inlet to the filtration system filtrate side, (2) a re-absorption system first outlet valve in communication with the re-absorption system feed side and a fluid return channel of the percutaneous drive line, (3) a re-absorption system second outlet valve in communication with the re-absorption system feed side and a graft in

communication with a bladder, and (4) a filtrate pump with an inlet in communication with the filtration system filtrate side and an outlet in communication with the re-absorption system feed side using a computer controller in electronic communication with the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve and the filtrate pump. [0040] The computer controller can be in wireless electronic communication with the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve and the filtrate pump.

[0041] The computer controller can be in electronic communication with the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve and the filtrate pump using a wired connection within the percutaneous drive line.

[0042] The method can further include executing a computer readable instruction in the computer controller for operating the therapy system in a preselected functioning mode selected from a filtration mode, a re-absorption mode, a filter cleaning mode and a urine flushing mode.

[0043] The pre-selected functioning mode can be the filtration mode and executing the computer readable instruction for operating the system for closing the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve while controlling the operation of the filtrate pump for pumping filtrate from the filtration system to the re-absorption system.

[0044] The pre-selected functioning mode can be the re-absorption mode and executing the computer readable instruction for operating the system for closing the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve while controlling the operation of the filtrate pump for pumping filtrate through the second non- silicon ceramic filter.

[0045] The pre-selected functioning mode can be the filter cleaning mode and executing the computer readable instruction for operating the system for opening the filtration system inlet valve and the re-absorption system first outlet valve and closing the re-absorption system second outlet valve while controlling the operation of the filtrate pump for pumping a cleaning fluid.

[0046] The pre-selected functioning mode can be the urine flushing mode and executing the computer readable instruction for operating the system for closing the filtration system inlet valve and the re-absorption system first outlet valve and opening the re-absorption system second outlet valve while controlling the operation of the filtrate pump for pumping filtrate from the re-absorption system to the and the graft in communication with the bladder.

[0047] The method can include the flowing blood from a patient step which can further include executing a computer readable instruction for controlling operation of a blood pump during a pre-selected functioning mode.

[0048] The filtering step using the first non-silicon ceramic filter can provide a filtrate of blood components less than 66,500 Daltons into the filtration system filtrate side. [0049] The filtering step using the second non-silicon ceramic filter can provide a filtrate with components within the filtrate feed side having a molecular weight of less than 500 Daltons into the re-absorption system filtrate side and into the valveless blood flow circuit.

[0050] The first non-silicon ceramic filter can be selected to maintain substantially all albumin within the blood flowing within the valveless blood flow circuit flowing from the inlet to the filtration system feed side through the outlet to the filtration system feed side while passing through to the filtration system filtrate side molecular weight fluids having a molecular weight below 65,000 Dalton.

[0051] The filtering steps through the first non-silicon ceramic filter and the second non- silicon ceramic filter can include filtering pathways formed in one or more of aluminum oxide, zinc oxide, titanium oxide, and pyrolytic carbon.

[0052] The method can further include (1 ) one or more of communicating a pressure reading from a sensor measuring a pressure within the filtration system to the controller using the data communication channel of the percutaneous drive line; (2) communicating a pressure reading from a sensor measuring a flow within the filtration system to the controller using the data communication channel of the percutaneous drive line; (3) communicating a pressure reading from a sensor measuring a pressure within the re-absorption system to the controller using the data communication channel of the percutaneous drive line; (4) or communicating a pressure reading from a sensor measuring a flow within the re-absorption system to the controller using the data communication channel of the percutaneous drive line.

[0053] The method can further include communicating an output of one or more of a sensor to measure a quantity of a blood protein, a sensor to measure a quantity of a blood glucose, a sensor to measure a quantity of a blood urea or a sensor to measure a quantity of a blood creatinine within the filtration system to the controller using the data communication channel of the percutaneous drive line.

[0054] The method can further include communicating an output of one or more of a sensor to indicate fouling or fracture of the non-silicon ceramic filter in the filtration system or a sensor to indicate fouling or fracture of the non-silicon ceramic filter in the re-absorption system to the controller using the data communication channel of the percutaneous drive line.

[0055] The method can further include executing computer readable instructions in the computer controller for operating the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve and the filtrate pump in response to one or more communicating steps. [0056] The implantable housing containing the components of the filtration system and the re-absorption system can be percutaneously implanted adjacent to one of an artery, a vein or a bladder.

[0057] The implantable housing containing the components of the filtration system and the re-absorption system can be subcutaneously implanted to be adjacent to a skin of the patient receiving the therapy.

[0058] The controller and a housing containing the components of the filtration system and the re-absorption system can be external to the patient and connected percutaneously to the artery graft, the vein graft and the graft connected to the bladder.

[0059] Components of the filtration system and re-absorption system can be subcutaneously- implanted with appropriate percutaneous access or subcutaneous access to a left side vein, a left side artery and a bladder or a urine collection bag or to a right side vein, a right side artery and a bladder or a urine collection bag.

[0060] The filtration and re-absorption system or associated method can provide processed filtrate or double processed filtrate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0061] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative

embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0062] FIG. 1 shows the implantable renal replacement therapy device 100.

[0063] FIG. 2 is a schematic side view diagram 200 of the implanted filtration system 1 10.

[0064] FIG. 3 is a schematic diagram 300 of the implanted filtration system 1 10 with a blood pump 255.

[0065] FIG. 4 is a view 400 of the implanted filtration system 1 10 as in FIG. 2 configured to operate in a urine flushing mode.

[0066] FIG. 5 is a view 425 of the implanted filtration system 1 10 as in FIG. 2 configured to operate in a filter cleaning mode.

[0067] FIG. 6 is a schematic view 450 of the implanted filtration system 1 10 as in FIG. 3 configured to operate in a urine flushing mode.

[0068] FIG. 7 is a schematic view 475 of the implanted filtration system 1 10 as in FIG. 3 configured to operate in a filter cleaning mode. [0069] FIG. 8 is a view of a filtration system as in FIG. 1 implanted at an appropriate left side implantation site as described above.

[0070] FIG. 9 is a therapy method 500 which describes the blood cleaning methods, techniques and mechanisms which are used in the implantable renal replacement therapy system of FIGs. 1, 2 or 3 and other configurations such as external (extracorporeal) and subcutaneously- implanted versions of the embodiments of the device.

[0071] FIG. 10 is a therapy method 600 which describes a more general form of method 500 of FIG. 9 for applications beyond renal replacement therapy.

DETAILED DESCRIPTION

[0072] The present invention relates to renal replacement therapies, and particularly to an implantable medical device to remove uremic toxins and excess water from blood of patients with end stage renal disease and to excrete some of them through bladder. This invention also describes how to re-absorb some molecules with molecular weight <500 Da such as some salts and water back into the blood from what was filtered from blood.

[0073] The various alternative embodiments of the implantable system for renal replacement therapy may include a wide variety of different configurations providing many advantages over conventional systems. In one of more different embodiments of the inventive system may include, in any combination one of more of the following advantageous capabilities:

[0074] The use of non-silicon ceramic filter materials including a filtration system having a feed side, a filtrate side and a non-silicon ceramic filter separating the feed side and the filtrate side along with or optionally a re-absorption system having a feed side, a filtrate side and a non- silicon ceramic filter separating the feed side and the filter side. The filtration system non-silicon ceramic filter and the re-absorption system non-silicon ceramic filter may contain filtration flow paths formed from one or more of aluminum oxide, zinc oxide, titanium oxide, and pyrolytic carbon in any configuration.

[0075] At least one filter to block passage of albumin (MW=66.5 kDa ) from blood under defined pressure, while letting blood components and fluids with molecular weights smaller than 66.5 kDa pass though;

[0076] At least one filter to re-absorb some molecules with molecular weight MW < 500 Da back into the blood from the filtrate of the filter(s) described in (a), while blocking the passage of some other molecules with molecular weight MW < 500 Da;

[0077] At least one pump to create and maintain defined pressure on at least one of the filters. [0078] At least one cleaning mechanism to open pores and clean the surface of filters in case of fouling;

[0079] At least one optional sensor measuring quantities such as pressure, membrane fouling, membrane fracture, blood protein, blood glucose, blood urea, blood creatinine, the sensor may be placed directly in contact with body fluids or positioned for measuring the values indirectly without contact with the body fluids;

[0080] At least a power source which is a battery or a wired connection or a wireless method of transferring electric power to the device or combination of at least two of these methods;

[0081] At least one control unit;

[0082] A wired or wireless communication system to establish a line of communication between the device inside the body of the patient and a control unit outside the body of the patient, to send and receive data and to control the function of different components of the device. These features and others are better appreciated with reference to FIGs. 1 -10 and the description that follows.

[0083] In some embodiments, a protein-free or substantially free ultrafiltrate generated by embodiments of the present invention may be in itself valuable and useful for ends other than the removal of toxins in blood filtering applications. For example, in various embodiments of the ultrafiltration devices of the present invention also find use in diagnostic applications. For example, the devices provides a means for selectively screening out undesired molecules (e.g., proteins) within fluids, such that a particular analyte to be analyzed (e.g., small molecules such as glucose, lactic acid, electrolytes, ions, including, but not limited to, potassium, sodium, calcium, chloride, oxygen, and carbon dioxide) in the absence of interfering molecules. Present electrochemical sensors for glucose measurement are severely hampered by protein fouling of the sensor, and great effort is devoted to the invention of fouling retardants to prolong sensor life. An ultrafiltrate substantially free of proteins, but still containing smaller constituents of blood, including but not limited to sodium, potassium, chloride, glucose, provides a solution to assay for glucose concentration without protein fouling. Thus, various embodiments of the present invention further provide systems for use in the analysis of small molecule, including, but not limited to those listed above. Furthermore, as the intracellular aqueous milieu differs from extracellular fluid, the separate testing of whole blood and a protein and cell-free ultrafiltrate for electrolyte compositions, magnetic susceptance, optical, infrared, or magnetic resonance spectroscopy, and other physical properties of matter, provides detailed information regarding the cellular composition of the blood.

[0084] Furthermore, in still another aspect a protein and cell free ultrafiltrate of blood so generated may be in itself valuable and useful for ends other than the removal of toxins and the measurement of the constituents of blood. The constituents of blood necessary for at least temporary support of a metabolically active cell are small in molecular size (including but not limited to oxygen, glucose, insulin, triiodothyronine, and retinoic acid, for example) while those immune mediators responsible for rejection of an allograft or xenograft are large in molecular size, such as antibodies, or components of the complement cascade, or reside in cell membranes, such as the major histocompatibility complexes. Thus a stream of ultrafiltrate of blood may be used to supply nutrients and carry away wastes by an efficient convective transport process, rather than by less efficient diffusive transport. As a result, various embodiments of the systems described herein may be directly applicable to any generalized cell population considered for transplantation, including but not limited to islet cell transplantation, liver cell transplantation, kidney cell transplantation, and in general transplant of any alio- or xeno- geneic cell type.

[0085] As used herein, the term "free of refers to fluids of mixtures that have had one or more components (e.g., protein components) removed. "Substantially free of fluids or mixtures are at least 50% free, preferably at least 75% free, and more preferably at least 90% free from a component with which they are otherwise naturally associated. For example, a fluid that is

"substantially free of protein" is a fluid that has at least 50% or less of the protein content of an unfiltered or unpurified fluid.

[0086] As used herein, the term "dialysis" refers to a form of filtration, or a process of selective diffusion through a membrane; it is typically used to separate low-molecular weight solutes that diffuse through the membrane from the colloidal and high-molecular weight solutes which do not. In some embodiments, a feed of fluid is passed over a semipermeable membrane, and a feed of dialysate is passed over the other side of that membrane; the membrane is wetted by one or both solvents, and then there is diffusive transport of dissolved solutes between the fluids. The composition of one fluid, the dialysate, is used to deplete the composition of the other fluid, the feed fluid, of some molecule or molecules.

[0087] As used herein, the term "filtration" refers to a process of separating particulate matter from a fluid, such as air or a liquid, by passing the fluid carrier through a medium that will not pass the particulates.

[0088] As used herein, the term "ultrafiltration" refers to subjecting a fluid to filtration, where the filtered material is very small; typically, the fluid comprises colloidal, dissolved solutes or very fine solid materials, and the filter is a microporous, nanoporous, or semipermeable medium. A typical medium is a membrane. The fluid to be filtered is referred to as the "feed fluid." During ultrafiltration, the feed fluid is separated into a "permeate" or "filtrate" or "ultrafiltrate," which has been filtered through the medium, and a "retentate," which is that part of the feed fluid which did not get filtered through the medium, or which is retained by the medium.

[0089] FIG. 1 shows the implantable renal replacement therapy device 100.

[0090] The implanted filtration system 1 10 is connected to the control unit 160 through percutaneous driveline 150.

[0091] The implanted filtration system 1 10 is connected to an artery (such as iliac artery) 102 through the tube 120. The implanted filtration system 1 10 is connected to iliac vein 101 (or any other vein) through the tube 130.

[0092] The implanted filtration system 1 10 is connected to bladder 103 through the tube 140.

[0093] The tubes 120, 130 and 140 can be medical grade polymer grafts.

[0094] The implanted filtration system 1 10 has at least one filtration system to remove some blood components smaller than 65,000 Da in molecular weight (such as uremic toxins, salts and water) from blood.

[0095] The implanted filtration system 1 10 may have at least one re-absorption system to return some blood components with molecular weight smaller than 500 Daltons (such as some salt and water) back into the blood from the filtrate generated by the filtration system.

[0096] The percutaneous driveline 1 0 contains power cords and fluid transfer tubes and data transfer lines and connects the control unit 160 to the implanted filtration system 1 10. The control unit 160 is connected to the batteries 180 through power cords 170. The batteries can be placed in hangers 181 . Additionally, the control unit 160 is attached to the belt 190.

[0097] The control unit 160 includes an electronic display (i.e., an LCD or a touch screen) and a computer controller in electronic communication with the components of the filtration system and the re-absorption system. The control unit 160 is configured to operate or control, for example, the filtration system inlet valve, the re-absorption system first outlet valve, the re- absorption system second outlet valve and the filtrate pump as in FIG. 2 as well as a blood pump when included as in FIG. 3. Tables 1 and 2 below provide exemplary configurations of these valves for operating the filtration and re-absorption system in a preselected functioning mode. By way of illustration and not limitation, the pre-selected functioning modes may be selected from a filtration mode, a re-absorption mode, a filter cleaning mode, a urine flushing mode and a service mode.

[0098] The fluid transfer tubes in the percutaneous driveline 150 are mainly used to transfer fluids into and out of the implanted filtration system 1 10 to wash the filters and to open the clogged pores of the filters. The washing solution can be at least one of intravenous (IV) fluid, saline solution, dialysate or replacement fluid used in renal replacement therapy or any other fluid that is safe to blood if it passes through the filters into the blood. [0099] At least one bag of washing solution can be attached to the control unit 160. The control unit 160 can pump the washing solution into the implanted filtration system 1 10 through the percutaneous driveline 150. The control unit 160 can collect the used washing solution in the same or another bag from the implanted filtration system 1 10 through the percutaneous driveline

150.

[0100] The tubes 120, 130 and 140 are manufactured from bio-compatible materials such as medical grade Dacron or medical grade Polytetrafluoroethylene (PTFE).

[0101] FIG. 2 is a schematic side view diagram 200 of the implanted filtration system 1 10.

[0102] Blood is diverted from an artery through the connection 120 into the filtration system

210.

[0103] In one embodiment, the blood flow rate at the device inlet is up to 200 ml/min which is set by the size of the graft 120.

[0104] Blood is passed across the feed side 21 1 of at least one filter 230 in the filtration system 210. The filtration system 210 has at least one filter to remove some blood components smaller than 65,000 Da in molecular weight (such as uremic toxins, salts and water) from blood. The filtrate is collected at the filtrate side 212 of the filter 230 and is pumped into the feed side 222 of the re-absorption system 220 using a micro-pump 250 when the valves 260, 270 and 280 are closed. The micro-pump 250 creates a pressure on one side 222 of the filter 240 which is higher than the pressure at the other side 221 of the filter 240. Blood is passed across one side 221 of at least one filter 240 in the re-absorption system 220. The re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 500 Daltons (mainly some salt and water) back into the blood from the filtrate generated by the filtration system 210.

[0105] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 66,500 Daltons back into the blood from the filtrate generated by the filtration system 210.

[0106] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 70,000 Daltons back into the blood from the filtrate generated by the filtration system 210.

[0107] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 200,000 Daltons back into the blood from the filtrate generated by the filtration system 210. In other embodiments, the pore size or filtration capacity of the filtration system and the pore size or filtration capacity of the re- absorption system many vary depending upon desired operating characteristics. In some aspects, one or more different or additional filters or other additional processing components may be included within the implantable filtration unit 1 10, the control unit 160, an embodiment of a filtration system or an embodiment of a re-absorption system or as part of a configuration within one or both of the filtration system or the re-absorption system to provide "processed filtrate" or "double processed filtrate" capabilities as described herein.

[0108] In another embodiment, one of or the combination of filtrate side 212, feed side 222, micro-pump 250 and re-absorption system 220 produce(s) at least one of "processed filtrate" and "double processed filtrate" as described below in method 500 (FIG. 9).

[0109] In another embodiment, one of or the combination of filtrate side 212, feed side 222, micro-pump 250 and re-absorption system 220 produce(s) at least one of "processed filtrate" and "double processed filtrate" as described below in method 600 (FIG. 10).

[0110] Tube 215 connects filtration system 210 to the re-absorption system 220.

[0111] Blood from the filtration system 210 goes into the re-absorption system 220 through the connection tube 215.

[0112] Tube 130 connects the re-absorption system 220 to the vein.

[0113] Blood from the re-absorption system 220 is passed into the vein 101 through the tube 130.

[0114] Blood flows from the tube 120 to the tube 130 due to the higher blood pressure in the artery 102 in comparison to the blood pressure in the vein 101.

[0115] FIG. 4 is a view 400 of the implanted filtration system 1 10 as in FIG. 2 configured to operate in a urine flushing mode.

[0116] When valve 260 and valve 270 are closed and valve 280 is open, the micro-pump 250 can be used to transfer fluids from the 212 side of the filtration system 210 and the 222 side of the re-absorption system 220 to bladder 103 through the tube 140.

[0117] FIG. 5 is a view 425 of the implanted filtration system 1 10 as in FIG. 2 configured to operate in a filter cleaning mode.

[0118] When valve 280 is closed and valve 260 and valve 270 are open, at least one washing solution can be pumped from percutaneous driveline into and out of the implanted filtration system 1 10 through the connection tubes 151 and 152. The washing solution can minimize the membrane fouling and pore clogging in the filters 230 and 240.

[0119] FIG. 3 is a schematic diagram 300 of the implanted filtration system 1 10 with a blood pump 255.

[0120] Blood is diverted from an artery through the connection 120 and is pumped into the filtration system 210. In one embodiment, the blood flow rate at the device inlet is up to 200 ml/min which is set by the blood pump 255. In another embodiment, blood flow > 500 ml /min, preferably > 800 ml/min. [0121] Blood is passed across the feed side 21 1 of at least one filter 230 in the filtration system 210. The filtration system 210 has at least one filter to remove some blood components smaller than 65,000 Da in molecular weight (such as uremic toxins, salts and water) from blood. The filtrate is collected at the filtrate side 212 of the filter 230 and is pumped into the feed side 222 of the re-absorption system 220 using a micro-pump 250 when the valves 260, 270 and 280 are closed. The micro-pump 250 creates a pressure on one side 222 of the filter 240 which is higher than the pressure at the other side 221 of the filter 240. Blood is passed across one side 221 of at least one filter 240 in the re-absorption system 220. The re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 500 Daltons (mainly some salt and water) back into the blood from the filtrate generated by the filtration system 210.

[0122] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 66,500 Daltons back into the blood from the filtrate generated by the filtration system 210.

[0123]

[0124] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 70,000 Daltons back into the blood from the filtrate generated by the filtration system 210.

[0125] In another embodiment, the re-absorption system 220 has at least one filter to return some blood components with molecular weight smaller than 200,000 Daltons back into the blood from the filtrate generated by the filtration system 210.

[0126] In another embodiment, one of or the combination of filtrate side 212, feed side 222, micro-pump 250 and re-absorption system 220 produce(s) at least one of "processed filtrate" and "double processed filtrate" as described in schematic 500.

[0127] In another embodiment, one of or the combination of filtrate side 212, feed side 222, micro-pump 250 and re-absorption system 220 produce(s) at least one of "processed filtrate" and "double processed filtrate" as described in schematic 600.

[0128] Tube 215 connects filtration system 210 to the re-absorption system 220.

[0129] Tube 130 connects the re-absorption system 220 to the vein.

[0130] Blood from the re-absorption system 220 is passed into the vein 101 through the tube 130.

[0131] Blood flows from the tube 120 to the tube 130 due to the pressure created by the blood pump 255 and higher blood pressure in the artery 102 in comparison to the blood pressure in the vein 101. [0132] The pressure created by the blood pump 255 pushes the blood from the filtration system 210 into the re-absorption system 220 through the connection tube 215.

[0133] FIG. 6 is a schematic view 450 of the implanted filtration system 1 10 as in FIG. 3 configured to operate in a urine flushing mode.

[0134] When valve 260 and valve 270 are closed and valve 280 is open, the micro-pump 250 can be used to transfer fluids from the 212 side of the filtration system 210 and the 222 side of the re-absorption system 220 to bladder 103 through the tube 140.

[0135] FIG. 7 is a schematic view 475 of the implanted filtration system 1 10 as in FIG. 3 configured to operate in a filter cleaning mode.

[0136] When valve 280 is closed and valve 260 and valve 270 are open, at least one washing solution can be pumped from percutaneous driveline into and out of the implanted filtration system 1 10 through the connection tubes 151 and 152. The washing solution can minimize the membrane fouling and pore clogging in the filters 230 and 240.

[0137] Table 1 describes various functioning modes and corresponding state of the device 200 of FIG. 2 which is set by the controller 160.

Valve 260 Valve 270 Valve 280 Micro-pump 250

Filtration mode closed closed closed off/on

Re-absorption closed closed closed on

mode

Filter cleaning open open closed on

mode

Urine flushing closed closed open on

mode

Table 1 [0138] Table 2 describes various functioning modes and corresponding state of the device 300 of FIG. 3 which is set by the controller 160.

Table 2 [0139] In some embodiments, a pump operating within the implantable filtration unit 1 10, a filtration system or a re-absorption system may be operated in a forward or reverse direction depending upon desired operations and fluid movement. As such, Table 1 and Table 2 may also indicate "on" but also direction (forward or reverse) as well as stead state, pulsed, increasing speed or decreasing speed based on operational mode and control systems and instructions within the control unit. Moreover, while some embodiments of the filtration system have been illustrated and described as having an external controller with implanted filtration systems 200,

300, other configurations are possible.

[0140] In one additional embodiment, the control unit 160 and single pump filtration system 200 (the system of FIGs. 1 and 2) be outside of the body with appropriate percutaneous access or subcutaneous access to a left side vein, a left side artery and a urine collection bag or to a right side vein, a right side artery and a urine collection bag.

[0141] In still another additional embodiment, the control unit 160 and dual pump filtration system 300 (the system of FIGs. 1 and 3) be outside of the body with appropriate percutaneous access or subcutaneous access to a left side vein, a left side artery and a urine collection bag or to a right side vein, a right side artery and a urine collection bag.

[0142] In still another additional embodiment, the control unit 160 be outside of the body with single pump filtration system 200 (the system of FIG. 2) subcutaneously-implanted with appropriate percutaneous access or subcutaneous access to a left side vein, a left side artery and a bladder or urine collection bag or to a right side vein, a right side artery and a bladder or a urine collection bag.

[0143] In still another additional embodiment, the control unit 160 be outside of the body with dual pump filtration system 300 (the system of FIG. 3) subcutaneously-implanted with appropriate percutaneous access or subcutaneous access to a left side vein, a left side artery and a bladder or a urine collection bag or to a right side vein, a right side artery and a bladder or a urine collection bag. FIG. 8 is a view of a filtration system as in FIG. 1 implanted at an appropriate left side implantation site as described above.

[0144] In combination and with modifications according to the various configurations above, in one aspect, the computer controller includes a computer readable instruction for operating the system in a preselected functioning mode selected from a filtration mode, a re-absorption mode, a filter cleaning mode, a urine flushing mode and a service mode.

[0145] In one specific embodiment, the pre-selected functioning mode is the filtration mode with the computer readable instruction for operating the system further comprising instructions to close the filtration system inlet valve, the re-absorption system first outlet valve, the re- absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate from the filtration system to the re-absorption system.

[0146] In one specific embodiment, the pre-selected functioning mode is the re-absorption mode with the computer readable instruction for operating the system further comprising instructions to close the filtration system inlet valve, the re-absorption system first outlet valve, the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate through the re-absorption system non-silicon ceramic filter. [0147] In one specific embodiment, the pre-selected functioning mode is the filter cleaning mode with the computer readable instruction for operating the system further comprising instructions to open the filtration system inlet valve, open the re-absorption system first outlet valve, close the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump a cleaning fluid.

[0148] In one specific embodiment, the pre-selected functioning mode is the urine flushing mode with the computer readable instruction for operating the system further comprising instructions to close the filtration system inlet valve, close the re-absorption system first outlet valve, open the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump filtrate from the re-absorption system to the and the graft in

communication with the bladder.

[0149] In one specific embodiment, the pre-selected functioning mode is the service mode with the computer readable instruction for operating the system further comprising instructions to open or close the filtration system inlet valve, open or close the re-absorption system first outlet valve, open or close the re-absorption system second outlet valve while controlling the operation of the filtrate pump to pump or not to pump the filtrate from the re-absorption system to the and the graft in communication with the bladder.

[0150] In still another embodiment in conjunction with any of the above modes the computer readable instruction for operating the system also includes controlling operation of the blood pump during a pre-selected functioning mode for systems configured as in FIG. 3.

[0151] It is to be appreciated that the various embodiments of the systems described herein may be provided in a number of different configurations to provide numerous advantageous results. In one such aspect, FIG. 9 is a therapy method 500 which describes the blood cleaning methods, techniques and mechanisms which are used in the implantable renal replacement therapy system of FIGs. 1 , 2 or 3 and other configurations such as external (extracorporeal) and subcutaneously-implanted versions of the embodiments of the device.

[0152] (i) Separation of filtrate from blood

[0153] In the first step 505 blood flows into the filtration system, some blood components are separated from blood in the form of a fluid called the filtrate (step 510). The operating characteristics of the filtration system are selected such that filtrate does not contain any platelets or is substantially free of platelets. Coagulation and thrombosis are primarily a function of endothelial cells, platelets, and soluble coagulation factors, therefore in the absence of platelets, the filtrate does not clot, even if the soluble coagulation factor would be present. This advantage allows us to further process the filtrate without the risk of coagulation and thrombosis. [0154] In one embodiment, the filtrate is substantially free of proteins (such as albumin) and cellular elements (such as red blood cells, white blood cells and platelets).

[0155] In one additional embodiment, the filtrate may still have substantial amount of proteins (such as albumin), but is substantially free of cellular elements (such as red blood cells, white blood cells and platelets).

[0156] (ii) Filtrate processing stage 1

[0157] The collected filtrate is processed in this step.

[0158] For renal replacement therapy application, uremic toxins, excess fluid and excess solutes are separated from the filtrate at step 515. The combination of the removed uremic toxins, excess fluid and excess solutes makes urine (step 535). "Processed filtrate" in step 520 refers to the filtrate remains after removal of uremic toxins, excess fluid and excess solutes. In one embodiment, the "processed filtrate" is substantially free of at least one of water soluble uremic toxins, protein bound uremic toxins, proteins (such as albumin), excess fluids, excess solutes. In another embodiment, this step can be done using at least one of filter 230 in device 200. In still another embodiment, this step can be done using filter 230 in device 300.

[0159] (iii) Filtrate processing stage 2

[0160] "Processed filtrate" is processed again at step 525 to make it chemically, biologically and physically suitable and safe to be returned to the blood. Processed filtrate that undergoes such additional processing is "double processed filtrate".

[0161] For example, in one embodiment, one or all of the temperature, osmolality and pH of the "processed filtrate" are adjusted according to requirements set for the patient.

[0162] (iv) Urine removal:

[0163] Urine is removed from the system and is collected in a bag or in bladder as in step 540.

[0164] (v) re-absorption process.

[0165] The "double processed filtrate" is returned to the blood safely as in step 530.

[0166] In one embodiment, up to 99.5 % of the filtrate collected in stage (i) may be returned back to the blood in this stage.

[0167] (vi) Blood is circulated in the body of the patient and the steps (i) to (vi) (steps 505 through 530) are repeated until the set outcome is achieved.

[0168] In still further alternatives are appreciated with reference to FIG. 10. FIG. 10 is a therapy method 600 which describes a more general form of method 500 of FIG. 9 for applications beyond renal replacement therapy.

[0169] (i) Separation of filtrate from blood [0170] In the first step 605, some blood components entering the filtration system are separated from blood in the form of a fluid called the filtrate (step 610). The operating characteristics of the filtration system as selected such that filtrate does not contain any platelets or is substantially free of platelets. Coagulation and thrombosis are primarily a function of endothelial cells, platelets, and soluble coagulation factors, therefore in the absence of platelets, the filtrate does not clot, even if the soluble coagulation factor would be present. This advantage allows us to further process the filtrate without the risk of coagulation and thrombosis.

[0171] In one embodiment, the filtrate is substantially free of proteins (such as albumin) and cellular elements (such as red blood cells, white blood cells and platelets).

[0172] In an additional embodiment, the filtrate may still have substantial amount of proteins (such as albumin), but is substantially free of cellular elements.

[0173] In an additional embodiment, the filtrate may still have substantial amount of proteins (such as albumin) , but is substantially free of at least one of red blood cells, white blood cells and platelets.

[0174] (ii) Filtrate processing stage 1

[0175] The collected filtrate from step 610 is processed in this step. Targeted blood components, molecules or cells or what is circulating in the blood stream are separated in the separation process of step 615.

[0176] In one embodiment circulating tumor cells are separated from the collected filtrate.

[0177] In another embodiment pathogens such as bacteria and viruses can be separated from the collected filtrate.

[0178] (iii) Filtrate processing stage 2

[0179] "Processed filtrate" from step 620 is processed again to make it chemically, biologically and physically suitable and safe to be returned to the blood. We call the result in step 625 the "double processed filtrate".

[0180] For example, in one embodiment, one or all of the temperature, osmolality and pH of the "processed filtrate" are adjusted according to requirements set for the patient.

[0181] (iv) Removal of separated fluid and molecules and cells:

[0182] At least one of the fluid and molecules and cells which were separated in stage (ii) step 635 are collected in a container at step 640.

[0183] (v) re-absorption process.

[0184] The "double processed filtrate" from step 625 is returned to the blood safely at step 630.

[0185] (vi) Blood is circulated in the body of the patient and the steps (i) to (vi) are repeated until the set outcome is achieved. [0186] Additional details for various additional alternative or additional embodiments may be appreciated by reference to US Patent Application Publication US 2012/0289881 , US Patent

Application Publication US 2016/03321 19, US Patent 8682431 , US Patent 9452249, US Patent

Application US201600641 17, US Patent Application US20160181730 US Patent 8827890, US Patent 7998054, US Patent Application US20120022645, US Patent Application

US20150290377 WIPO Patent Application WO2015134871, US Patent Application

US20150290378, US Patent Application US20150290374 , US Patent Application

US20150294550 and US Patent Application US20160175502 each one of which is incorporated herein by reference in its entirety.

[0187] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0188] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as "/".

[0189] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0190] Although the terms "first" and "second" may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one

feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.

[0191] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising" means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term "comprising" will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0192] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or "approximately," even if the term does not expressly appear. The phrase "about" or

"approximately" may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/- 0.1 % of the stated value (or range of values), +/- 1 % of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 1 1 , 12, 13, and 14 are also disclosed.

[0193] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others.

Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0194] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.