WO2013027214A2 - Dialyse d'article à base de nanoparticules - Google Patents

Dialyse d'article à base de nanoparticules Download PDF

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Publication number
WO2013027214A2
WO2013027214A2 PCT/IL2012/050317 IL2012050317W WO2013027214A2 WO 2013027214 A2 WO2013027214 A2 WO 2013027214A2 IL 2012050317 W IL2012050317 W IL 2012050317W WO 2013027214 A2 WO2013027214 A2 WO 2013027214A2
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WIPO (PCT)
Prior art keywords
blood
patient
target
particles
chamber
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PCT/IL2012/050317
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English (en)
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WO2013027214A3 (fr
Inventor
Rachel POPOVTZER
Yoseph MACHTEY
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Bar-Ilan University
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Publication of WO2013027214A2 publication Critical patent/WO2013027214A2/fr
Publication of WO2013027214A3 publication Critical patent/WO2013027214A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3475—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate with filtrate treatment agent in the same enclosure as the membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3493—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate using treatment agents in suspension
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3576—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver
    • A61M2205/3592—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver using telemetric means, e.g. radio or optical transmission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2209/00—Ancillary equipment
    • A61M2209/08—Supports for equipment
    • A61M2209/088—Supports for equipment on the body

Definitions

  • the present invention in some embodiments thereof, relates to a hemodialysis device and, more particularly, but not exclusively, to a device for selective removal of substances from blood.
  • US Patent No. 4247393 discloses "A hemodialysis assist device including a normally nonflowing aqueous sorbents slurry medium chamber and at least one blood flowthrough passage separated therefrom by a semipermeable membrane... this blood detoxification device can be used also to treat the problems of hyperphosphatemia."
  • Additional background art includes: US Patent No. 6830694, US Patent No. 7943664, US Patent Application No. 2008/0317701, US Patent Application No. 2011/0098623, US Patent Application No. 2011/0110985;
  • An aspect of some embodiments of the invention relates to a device for selectively removing one or more target components from the blood of a patient, without significantly removing non-target components.
  • nanoparticles suspended in a fluid are configured to remove the components.
  • a device configured for selective removal of target substances from a patient's blood, the device comprising:
  • an inlet configured for letting the patient's blood enter the device
  • a membrane positioned so that at least the target substances can move from the blood across the membrane into the chamber, the membrane having pores with a size small enough to prevent the particles from entering the blood, the pores are small enough to prevent cellular components from entering the chamber, the pores are large enough to allow molecules having a size at least over 25000 Dalton to enter the chamber.
  • the particles are adapted to bind to phosphate.
  • the device comprises a predetermined number and/or size distribution of the particles to remove a physiologically necessary target particle in an amount and/or at a rate without causing clinical deficiency of the physiologically necessary target particle.
  • the device comprises a predetermined number and/or size distribution of the particles to remove a physiologically necessary target particle to maintain a serum concentration of the physiologically necessary target particle within a predetermined range.
  • a predetermined amount of the particles comprises particles configured to bind and remove phosphorus at an average rate of about 200-500 mg/day.
  • the pores are small enough to prevent red blood cells from entering the chamber.
  • the device further comprises a fluid circulation system operable to circulate the fluid through the chamber so that a pressure of the fluid is lowered relative to a pressure of the blood.
  • the device further comprises one or more sensors operable to sense and produce one or more signals of one or more parameters associated with a serum or blood concentration of the target substance.
  • the device further comprises one or more access ports configured to allow at least one of removal or insertion of the particles.
  • the device further comprises a blood flow control element adapted to control the amount and/or rate of blood in contact with the membrane.
  • the device further comprises a reservoir in fluid communication with a vasculature of the patient, the reservoir containing the target components, the reservoir adapted to inject the target components into the vasculature to raise a serum concentration of the target components.
  • a volume of the fluid in the chamber is small enough so that disposing of the fluid is not clinically significant and/or is clinically beneficial to the patient.
  • the device further comprises circuitry adapted to control one or more device components to remove an amount of the target substance and/or to remove the target substance at a rate, so that a target serum concentration range of the target substance is obtained and/or maintained without removing too much of the target substance.
  • the device further comprises a memory in electrical communication with the circuitry, the memory indicating a removal amount and/or rate of the target components with settings of one or more device elements.
  • the device further comprises a strap configured to attach the device to a body of the patient.
  • the device further comprises a wireless communication transceiver operable to provide monitoring data and/or allow remote control of the device.
  • the device further comprises one or more storage chambers in fluid communication with the chamber, the one or more storage chamber comprise particles in a densely packed state, the one or more storage chambers comprise one or more gates to allow the particles to exit the storage chamber into the chamber.
  • the device further comprises one or more particle flow control elements adapted to control a rate of flow of unbound particles towards the membrane and a flow of bound particles away from the membrane.
  • the particles are suspended in the fluid in the chamber so that the particles can be displaced within the fluid to reduce or prevent clumping and increase a total surface area to bind the target substances, the particles do not give out toxins to the patient's blood.
  • the particles comprise nanoparticles.
  • a device configured for selective removal of target substances from a patient's blood, the device comprising:
  • an inlet configured for letting the patient's blood enter the device
  • particles disposed in the chamber the particles adapted for selectively binding to the target substances
  • a membrane positioned so that at least the target substances can move from the blood across the membrane into the chamber;
  • At least one agitation element configured to agitate the particles and/or the fluid.
  • the at least one agitation element is configured to maintain at least some particles in motion within the fluid to reduce clumping and/or sinking of the particles.
  • the at least one agitation element is selected from the group comprising: one or more electromagnets, one or more pumps, one or more vibration elements, one or more ultrasound emitters, one or more propellers.
  • a device configured for selective removal of target substances from a patient's blood, the device comprising:
  • an inlet configured for letting the patient's blood enter the device
  • particles disposed in the chamber the particles adapted for selectively binding to the target substances
  • a membrane positioned so that at least the target substances can move from the blood across the membrane into the chamber;
  • a temperature control element configured to control a temperature of an interior of the chamber.
  • the temperature is high enough to increase diffusion of the target substances across the membrane, but not high enough to damage tissue and/or the patient.
  • the temperature is about 25-40 degrees Celsius.
  • a method of removing phosphorus from a patient comprising separately removing phosphorus from the patient without removing too much phosphorus.
  • the method further comprises selecting a safe amount of phosphorus to be removed from the patient.
  • selecting a safe amount of phosphorus to be removed from the patient comprising:
  • the treatment plan comprises removing a selected amount of the one or more target components without significantly removing non-target components
  • selecting an amount and/or size of particles to remove the selected amount according to the treatment plan dialyzing the patient to remove the selected amount according to the treatment plan.
  • the one or more target components comprise phosphate.
  • the treatment plan comprises lowering a serum concentration of the one or more target components to a clinically balanced range and/or maintaining the clinically balanced range.
  • the treatment plan comprises lowering a serum concentration of the one or more target components to a level low enough to cause a rebound.
  • the selected amount is removed at a selected rate and/or over a selected time period.
  • the method further comprises matching the selected amount to a diet of the patient.
  • the method further comprises selecting the amount by taking into consideration an amount removed using other treatment methods.
  • dialyzing comprises dialyzing the patient in addition to or instead of a pre-existing hemodialysis treatment regimen.
  • dialyzing comprises continuously dialyzing during a session lasting less time than a current dialysis treatment session of the patient.
  • the method further comprises monitoring the removal according to the treatment plan.
  • the method further comprises adjusting the treatment plan according to the monitoring to obtain the selected removal amount.
  • the method further comprises controlling a temperature of a fluid containing the particles and/or the blood to increase or decrease removal of the target particles according to the treatment plan.
  • the method further comprises agitating the particles to increase or decrease removal of the target components according to the treatment plan. According to some embodiments of the invention, the method further comprises lowering a pressure of a fluid comprising the particles relative to a pressure of blood being dialyzed.
  • the method further comprises adjusting blood flowing from the patient to a dialysis device to increase or decrease removal of the target components according to the treatment plan.
  • the method further comprises shutting down blood flow from the patient to a dialysis device to prevent excess removal of the target components.
  • the method further comprises administering the target components to the patient to restore at least some of the target components in the blood.
  • the method further comprises monitoring a serum target component concentration of the patient.
  • the method further comprises replenishing the particles.
  • a hemodialysis kit for removing one or more target components from a patient's blood, the kit comprising biocompatible nanoparticles adapted to bind to the one or more target components and to not bind non-target components, the nanoparticles having a selected size and a selected number to remove a predetermined amount of the one or more target components, the nanoparticles are configured to not significantly clump together.
  • the kit is labeled with the amount of the one or more target components removable from blood.
  • the nanoparticles are configured to remove phosphate.
  • all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.
  • methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control.
  • the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
  • Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.
  • a data processor such as a computing platform for executing a plurality of instructions.
  • the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data.
  • a network connection is provided as well.
  • a display and/or a user input device such as a keyboard or mouse are optionally provided as well.
  • FIG. 1 is a block diagram of a selective dialysis system, in accordance with an exemplary embodiment of the invention
  • FIG. 2 is a flowchart of a method of operation of the dialysis device (e.g., of figure 1), in accordance with an exemplary embodiment of the invention
  • FIGs. 3A-3D are schematic illustrations of some embodiments of the dialysis device, in accordance with an exemplary embodiment of the invention.
  • FIG. 4 is a schematic illustration of the selective dialysis device used together with a hemodialysis machine (e.g., as in a dialysis clinic), in accordance with an exemplary embodiment of the invention
  • FIG. 5 is a schematic illustration of a portable version of the dialysis device connected to a hand, in accordance with an exemplary embodiment of the invention
  • FIG. 6 is a schematic illustration of a portable dialysis version of the device connected to a central line, in accordance with an exemplary embodiment of the invention.
  • FIG. 7 is a flow chart of a method of treatment using the dialysis device, in accordance with an exemplary embodiment of the invention.
  • the present invention in some embodiments thereof, relates to a hemodialysis device and, more particularly, but not exclusively, to a device for selective removal of substances from blood.
  • An aspect of some embodiments of the invention relates to a method of performing hemodialysis by selectively removing one or more substances from a patient's blood.
  • the non-selected substances are not removed from the blood.
  • the concentration and/or amount of non-target substances is not substantially affected (e.g., to a clinically significant degree).
  • important molecules e.g., known and/or unidentified are not significantly removed from the blood.
  • the substances selectively removed are physiologically important, for example, used by the body in important processes and/or regulated by mechanisms of the body to be maintained within a physiologically balanced range.
  • the substance is phosphorus (e.g., inorganic phosphate, phosphate salt).
  • the substance is potassium.
  • the substances removed are waste products of the body, for example, do not in themselves serve useful functions, for example, creatinine, organic bases, organic acids, urea and/or middle molecules (e.g., beta-2-microglobulin, advanced glycation end products, oxidation products, complement factor D, cytokines).
  • the substances do not include water, cells and/or platelets.
  • the method comprises removing a preselected amount (e.g., milligrams) of the physiologically important substance.
  • the preselected amount is selected to help obtain and/or maintain target blood concentrations of the substances.
  • the preselected amount is removed over a preselected period of time (e.g., at a preselected rate).
  • no pre-selection is performed.
  • the removing is performed in an open-loop manner.
  • the amount removed is estimated after the removal has been performed.
  • the averaged daily rate of removal of phosphate is, for example, about 200mg- 1500mg per day, or about 500mg-800mg/day, or about 200mg-500mg/day, or about 600mg-750mg/day, or about 400mg-600mg/day, or other smaller, intermediate or larger rates.
  • the total capacity of the device for phosphate removal is for example, about 200mg-10000mg, or about 500mg-5000mg, or about 500mg-3000mg, or about lOOOmg- 1500mg, or about 750mg-1000mg, or other smaller, intermediate or larger capacities.
  • the removal of the substance is matched to the estimated and/or measured amount of excess substance in the blood and/or body.
  • the removal is matched to the intake, for example, to phosphate ingested as part of the diet.
  • the removal is matched to the production of waste phosphate products (e.g., metabolic).
  • the removal is matched to removal by other means, for example, by another dialysis device and/or intestinal binding agents.
  • the matching is, for example, within about +/- 33%, or within about +/- 50%, or within about +/- 100%, or other smaller, intermediate or larger values.
  • the rate of removal to the rate of appearance (e.g., diffusion and/or active transport) of the substance in the blood helps to prevent and/or reduce rebound of the serum concentration, while maintaining the serum concentration of the substance within an acceptable range.
  • the removal of the substance is selected to achieve a clinical balanced phosphate state.
  • excess amounts of the substance are first removed (e.g., due to unbalanced intake until treatment has begun).
  • the removal of the excess amount is performed to achieve a clinically safe level, for example, to obtain an acceptable serum concentration according to clinical practice and/or published guidelines.
  • the clinically safe level is then maintained, for example, by matching the removal to the diet as described herein.
  • a target serum concentration is selected.
  • the serum concentration e.g., of phosphate
  • the serum concentration is reduced to and/or maintained at a clinically safe and/or balanced range, for example, according to clinical guidelines. In some cases, some deviation is allowed. For example, within about l-1.5mmol/Liter, or about 0.8-2.1 mmol/L, or about 1.45-2.1 mmol/L, or about 0.5-2.5 mmol/L, or about 1-4 mmol/L, or about 2-5mmol/L, or about 2-3 mmol/L, or other smaller, intermediate or larger ranges.
  • the serum concentration (e.g., of phosphate) is targeted to be reduced to very levels low levels.
  • very levels low levels For example, about 0-1 mmol/Liter, or about 0.5-1 mmol/L, or about 0.3-0.5 mmol/L, or other smaller, intermediate or larger values.
  • the concentration target e.g., of the very low level or other levels described above
  • the concentration target is reached at least some of the time during the dialysis, for example, during the early stages of the dialysis, for example, for at least 15 minutes, or at least 30 minutes, or at least 60 minutes, or at least 2 hours, or at least 4 hours, or other smaller, intermediate or larger time frames.
  • the level is low enough to cause a 'rebound' release of large amounts phosphate from deep body compartments (e.g., intracellular). In some cases, the movement of phosphate into the bloodstream raises the serum concentration.
  • some important substances e.g., phosphate
  • some important substances are stored outside the vasculature, for example, intracellularly and/or in the extracellular space (but not the intravascular space) and/or in bone.
  • intravascular concentration e.g., by hemodialysis methods
  • the shift can take place over several hours, limited by the rate of diffusion.
  • the concentration in the blood stream can lead to clinical complications (e.g., phosphate retention can lead to hypocalcemia and secondary hyperparathyroidism), so the control over the serum concentration (e.g., over the long term) can be important, for example, avoiding rebounds and/or abnormally high or low levels.
  • the rebound is desirable (e.g., during the dialysis session), for example, to bring the phosphate to the blood where the phosphate can be removed.
  • the total amount of phosphate can lead to clinical complications (e.g., vascular calcification and cardiovascular mortality), so the control over the total amount removed can be important to help maintain a clinical balanced state.
  • An aspect of some embodiments of the invention relates to a hemodialysis device to help control the removal of selective substances from the blood.
  • particles e.g., nanoparticles
  • nanoparticles remove the substances from nearby fluid (e.g., in the chamber housing the nanoparticles) so that the concentration of unbound substances in the blood is close to or zero.
  • the low concentration of unbound substances in blood is maintained, for example, throughout the dialysis session. Potentially, a high concentration gradient of the target substances is maintained between the fluid in the chamber and the blood.
  • the nanoparticles strongly bind the target substances.
  • the bond is strong enough so that the target substances remains bound to the nanoparticles throughout the course of treatment.
  • the bond is strong enough so that replenishing of the nanoparticles by removal of the target substances is not feasible.
  • the spent nanoparticles are not replenished by removing of the target substance, but instead are replaced.
  • the nanoparticles are suspended in a fluid within the device so that the nanoparticles can be displaced relative to one another.
  • the nanoparticles do not significantly adhere to one another (e.g., any inter-nanoparticle bonds are easily broken). Potentially the suspension provides for an increased total surface area of the nanoparticles.
  • the device comprises a membrane permeable to allow diffusion of the selective substances.
  • the pore of the membrane allow some larger substances to diffuse therethrough, even if those larger substances are not selected for removal.
  • the pores of the membrane are much larger than the size of the target substances, for example, about 50%- 1000% larger, or about 200%-800% larger, or about 300%-400%, or other smaller, intermediate or larger sizes.
  • the nanoparticles are selected to have a size large enough to prevent diffusion thereof across the membrane (e.g., into the blood).
  • the nanoparticles size is selected to be small enough to increase the total binding surface area, for example, considering the number of nanoparticles.
  • the device e.g., before being connected to the patient and/or another dialysis device
  • the device does not contain an externally supplied fluid.
  • the chamber housing the nanoparticles does not contain fluid.
  • fluid in the chamber is supplied by the blood of the patient, for example, plasma diffuses across the membrane into the chamber.
  • a potential advantage is that no external fluid source (e.g., dialysate) is required.
  • the rate of removal of substances from the blood is proportional to the molecular size passable by the membrane. Potentially, larger holes increase the rate of diffusion and/or help to obtain lower serum concentrations.
  • the amount of nanoparticles is enough to remove excess amounts of the substance from the blood.
  • the amount of nanoparticles provided does not result in removal of more than the estimated excess of the substance. Potentially, over dialysis (causing deficiency) of the substance is prevented.
  • a temperature regulating element controls the temperature of the fluid containing nanoparticles in the chamber. Inventors discovered a faster diffusion rate of substances across the membrane at about 37 degrees Celsius. Optionally, the temperature is lowered below about 37 degrees to slow down the diffusion rate.
  • an agitation element agitates nanoparticles in the device.
  • agitation of the nanoparticles within the device is performed so that clumping and/or aggregation of the nanoparticles is reduced or prevented.
  • some clumping is selectively allowed, for example, to reduce and/or stop the rate of substance removal.
  • agitation is performed to prevent sinking of the nanoparticles to the bottom of the device. Potentially, the unclumped and/or unsunk nanoparticles have a larger total surface area, which helps to increase the rate of uptake of the substance and/or total amount of substance that can be removed.
  • the agitation element is part of a fluid circulation system, for example a closed loop circulation system.
  • the agitation element is a pump operable to circulate fluid (optionally including the bound and/or unbound nanoparticles) through the device and the fluid circulation system.
  • the circulated fluid has a pressure equal to or lower than the plasma flowing through the device so that the pressure differential helps to draw additional target components through the membrane and into the device.
  • a sensor monitors the blood (e.g., serum) concentration of the substance.
  • the amount (e.g., milligrams) of substance removed is calculated from the concentration.
  • the measured concentration is used in a feedback loop to adjust the rate and/or amount of substances removed, for example, to help achieve the target concentration range.
  • the measured concentration is used to stop the removal of substances, for example, if the concentration is too low and/or too much has been removed.
  • chemical based control is used to help control the amount of substance removed, for example, to prevent removal of too much substances.
  • a first material removes the phosphate relatively fast from the blood, and a second material removes the phosphate at a slower rate.
  • the first material is selected so that too much phosphate cannot be removed (e.g., amount of material is safe).
  • the second material is selected so that there is enough time to stop the dialysis once the selected amount has been removed.
  • blood components removed during the treatment are thrown away (e.g., after the treatment).
  • the blood component particles are non-target components that do not bind to the nanoparticles.
  • the blood components that entered the chamber during treatment are disposed, for example, removed during flushing of the chamber, or disposed together with the chamber.
  • Not necessarily limiting examples include: sodium, potassium, calcium, cells, platelets, antibodies, albumin, hormones, lipids, coagulation factors, glucose and/or other substances found in the blood.
  • the amount of removed blood components is not clinically significant.
  • the remaining blood components are still within clinically acceptable ranges.
  • the reduction in the serum and/or whole blood concentration is, for example, about 0.1%-30%, or about 1%-10%, or about 5%-20%, or other smaller, intermediate or larger values.
  • Figure 1 is a block diagram of an exemplary selective dialysis device 100 and/or dialysis system, in accordance with an exemplary embodiment of the invention.
  • device 100 removes a target blood component 110 from the blood of a patient.
  • non-target components are not substantially removed, for example, no more than about 0.01%, or about 0.1%, or about 1%, or about 3%, or about 5%, or about 10%, or about 20% of non-target components are not removed.
  • a membrane 104 selectively allows diffusion of target component 110 from blood source 102 into fluid 124 in a chamber 106.
  • membrane 104 allows diffusion of components 110 that are up to a predetermined molecular weight.
  • mid range molecules are not allowed to pass (e.g., molecular weights of about 0-4000 Dalton).
  • mid range molecules are allowed to pass, but larger molecules are not (e.g., molecular weights of about 0-12000 Da).
  • some larger molecules are allowed to pass (e.g., molecular weights of about 0-20000 Da, about 0-25000 Da, about 0-40000 Da, about 0- 50000 Da).
  • some larger molecules not allowed to pass through.
  • albumin and larger molecules are not allowed to pass (e.g., molecular weights of about 0-68000 Da).
  • large molecules are allowed to pass, but other structures are prevented from passing, for example, red blood cells, white blood cells, platelets, antibodies.
  • the holes of membrane 104 are selected to prevent nanoparticles from diffusing across (e.g., into the blood). As described above, inventors discovered that larger holes increase the rate of diffusion and/or removal of small molecules. Potentially, selection of holes that are large enough and selection of binding nanoparticles can effectively remove large molecular blood components, for example, beta-2-microglobulin.
  • the pore size of membrane 106 is selected to let molecules pass with weights of 25000-about 68,000 Daltons, or about 30,000-about 70,000 Daltons, or 25000- the size of cellular components, or other intermediate or larger sizes.
  • chamber 106 comprises a small volume of fluid 124 (e.g., biocompatible, sterile).
  • fluid 124 e.g., biocompatible, sterile
  • chamber 106 does not initially comprise any fluid, with fluid 124 being provide by the patient, as plasma filtrate enters chamber 106 through the membrane.
  • the volume of fluid in chamber 106 is not significantly changed (e.g. fixed), for example, during a treatment session fluid 124 is not replaced and/or circulated with an external supply.
  • chamber 106 is sized according to the desired fluid 124 volume.
  • the volume of fluid 124 in chamber 106 is, for example, no more than about 10 mL, or about 50 mL, or about 100 mL, or about 250 mL, or about 300 mL, or about 500 mL, or other smaller, intermediate or larger sizes. Potentially, the volume is selected so that the device is small enough to be portable.
  • the volume of fluid 124 is, for example, about 1000 mL, or about 1500 mL, or about 2 Liters, or about 5 Liters, or about 10 Liters, or other smaller, intermediate or larger values.
  • the larger volumes are selected for larger non-portable devices. Potentially, the larger volume helps to remove more substances at a faster rate.
  • the volume of chamber 106 is selected according to the blood (e.g., plasma) that can be lost by the patient without being clinically significant (e.g., significant change in pulse and/or blood pressure).
  • the volume of the chamber is selected by taking into account the excess water that needs to be removed from the patient as part of the treatment.
  • the volume of chamber is, for example, any volume described above large enough to remove the described fluid volumes.
  • the fixed volume of fluid 124 helps maintain non-target components in the blood, for example, once an equilibrium between fluid 124 and the patient's blood is reached, no more non-target components will be lost.
  • fluid 124 is an artificial fluid containing one or more non-target components in a concentration matched to the concentration of non-target components in the patient's blood. Potentially, matching the concentrations further helps to reduce losses of the non-target components. Potentially, use of the artificial fluid (e.g., instead of using the patient's own blood) helps reduce the amount of patient plasma that needs to be removed as part of the treatment.
  • fluid 124 include; normal saline, commercially available dialysate solution.
  • removal agents 108 e.g., nanoparticles suspended in fluid 124 are adapted to bind to target component 110.
  • nanoparticles 108 are free to individually move around in fluid 124.
  • nanoparticles 108 are adapted so as not to diffuse across membrane 104 and into blood source 102.
  • nanoparticles 108 are made from a non- biocompatible material.
  • nanoparticles 108 do not give out toxins to the blood, for example, substances that are potentially harmful to tissues (e.g., even at low levels) do not escape into the blood stream. Potentially, as the nanoparticles are retained in the chamber and do not enter the patient, biocompatibility is not required.
  • nanoparticles 108 are made from a biocompatible material, potentially to improve safety.
  • the nanoparticles are made from the same material.
  • the core and shell are made from two different materials.
  • the linker (links shell to core) can be selected to have different shapes and/or sizes, for example, to allow the design of different sizes nanoparticles and/or different surface areas.
  • the nanoparticles material absorbs, rather than, or in addition to, binding to the target substance (e.g., phosphate).
  • the target substance e.g., phosphate
  • the shape of nanoparticles 108 is, for example, a sphere, a star, a box, or other shapes. Potentially, shapes are selected to increase the total surface area of nanoparticles 108 able to bind component 110.
  • nanoparticles 108 are larger than the holes in membrane 104.
  • nanoparticles have a size distribution, with at least the smallest nanoparticles unable to escape through the membrane.
  • the average size of a nanoparticle and/or the size distribution of nanoparticles is, for example between about 2-250 nm, or about 100-150 nm, or about 150-250 nm.
  • the size and/or distribution of the nanoparticles is selected to bind the largest amount of target components within the limited space of the chamber.
  • the nanoparticles are selected to be as small as possible (e.g., to increase the total surface area), but large enough to be retained by the membrane.
  • nanoparticles 108 are selected to bind a single target component 110. In other embodiments, nanoparticles 108 are selected to bind a plurality of different target components. Optionally, each type of nanoparticle binds one type of target component. Alternatively, each type of nanoparticle binds a plurality of different target components.
  • nanoparticles 108 are made out of a material that strongly binds to the target components.
  • the material is biocompatible.
  • nanoparticles 108 are coated with a material that binds to the target components.
  • nanoparticles 108 are at least partially made from or coated with ZnO, Zn0 2 , Zr0 2 , and/or other metal oxides.
  • nanoparticles 108 are at least partially made from a magnetic material (details of magnetic control will be described below).
  • one or more agitation elements 118 are adapted to agitate nanoparticles 108 within fluid 124.
  • agitators 118 include; a vibration element adapted to produce vibrations (from inside and/or outside), a propeller to stir fluid 124, a pump to circulate fluid within and/or in and out of chamber 106, an electromagnet (e.g., as will be described below with reference to figure 3B), an ultrasound emitter adapted to produce waves in the fluid.
  • agitating nanoparticles 108 helps prevent clumping and/or sinking of the nanoparticles. Potentially, the total surface area of all the nanoparticles is increased, which can help in increasing the rate of removal and/or the amount removed of the target substance.
  • one or more sensors 112 sense one or more parameters associated with the serum concentration of target blood component 110.
  • sensors 112 are positioned downstream (direction of blood flow) of device 100 to sense the parameter associated with the concentration of target component 110 in the treated blood.
  • sensors 112 are positioned upstream of device 100 to sense the serum concentration before being treated.
  • sensors 112 perform automatic measurements, for example, sending signals to the controller.
  • measurements are manually performed, for example, by a healthcare provider manually taking blood samples and sending the samples to the lab for analysis.
  • one or more temperature control elements 114 provide heat to raise the temperature within chamber 106 (e.g., of fluid 124, nanoparticles 108 and/or membrane 104).
  • temperature control element 114 also acts as a cooling element, to reduce the temperature within chamber 106.
  • An optional thermistor provides a feedback loop to maintain the temperature within a desired range by activating of temperature control element 114.
  • Some examples of possible temperatures include; about 37 degrees Celsius, or about 35 degrees Celsius, or about 39 degrees Celsius, or about 22-39 degrees Celsius, or about 25-38 degrees, or about 30-37 degrees, or about 25-35 degrees, or about 36.5-37.5 degrees Celsius, or about 35-40 degrees, or about 35.5-37.5 degrees, or other smaller, intermediate or larger values.
  • the temperature is not high enough to cause tissue damage (e.g., coagulate blood), for example, below about 42 or 41 degrees Celsius.
  • temperature control elements 114 include; heat pump, peltier element, resistive heating element. Potentially, relatively higher temperatures are used to select relatively higher diffusion rates of target component 110 into chamber 106, potentially increasing the rate of removal thereof.
  • one or more access ports 120 provide for fluid communication with the interior of chamber 106.
  • nanoparticles 108 and/or fluid 124 are replaceable through access ports 120.
  • port 120 is adapted for insertion of a needle to access chamber 106.
  • the needle can be used (e.g., manually by a healthcare provide) to remove the contents of chamber 106 and/or to insert fluid and/or nanoparticles into chamber 106.
  • ports 120 are connected to an automated pumping machine, the machine configured to automatically replace the contents of chamber 106.
  • a blood flow control element 130 e.g., valve, solenoid
  • a blood flow control element 130 is adapted to adjust the flow of the patient's blood coming in contact with membrane 104.
  • blood flow is stopped.
  • blood flow is slowed down or increased.
  • blood flow is bypassed avoiding membrane 104 (e.g., through a parallel tube). Potentially, controlling the blood flow helps in controlling the rate of removal of target component 110 from blood, or preventing removal of additional components 110.
  • a component reservoir 132 is adapted to store concentrated amounts of blood target components 110.
  • reservoir 132 is in fluid communication with blood source 102 (or other connections to the vascular of the patient).
  • reservoir 132 is adapted to provide controlled release of target components 110 back into the circulatory system of the patient.
  • reservoir 132 is a syringe placed in an automated pump (e.g., piston). Potentially, reservoir 132 is used to increase the amount of target components 110 in the patient's blood (e.g., back to clinically stable ranges), for example, due to excess removal by dialysis (e.g., hypokalemia, hypophosphatemia).
  • an output interface 126 (e.g., video screen, speaker) provides one or more type of output, for example, visual output and/or audio output.
  • output interface 126 is adapted to display details of the function of device 100 and/or status of the blood, for example, the concentration of the target component in the blood as sensed by sensor 112, the temperature inside chamber 106, estimated total amount of target component that was removed, patient medical data.
  • an input interface 128 (e.g., touch screen, keypad, mouse) provides for control of the system, for example, to change the temperature maintained by heating element 114, to enter patient data for an electronic medical record, to control the amount of agitation, to set the desired target component uptake rate.
  • a communication link 134 provides wired (e.g., USB port) and/or wireless (e.g., Bluetooth, cellular network) receiving and/or transmitting functions to device 100. Potentially, device 100 can be remotely controlled, for example, by a physician monitoring and/or adjusting functions on device 100 using a smartphone.
  • a controller 116 (e.g., circuitry, software on a computer, logic) is adapted to provide control functions for one or more components of device 100.
  • controller 116 is in electrical communication with one or more of; sensor 112, heater 114, agitator 118, power 122, output 126, input 128, blood flow controller 130, component reservoir 132, communication link 134.
  • controller 116 is in electrical communication with a memory 136 adapted to store data.
  • controller 116 adjusts one or more components of device 100 to obtain a predetermined amount and/or rate of removal of target component 110 from blood.
  • at least some of the removal is performed using a feedback loop, for example, according to measurements of sensor 112.
  • at least some of the removal is performed according to a table stored on the memory, the table indicating one or more component settings with removal rates and/or amounts.
  • a power source 122 provides power to one or more components of device 100.
  • Power 122 is, for example, portable (e.g., batteries) and/or an attachment to a wall socket. In other embodiments, device 100 operates without an external power source 122.
  • excess fluid from the patient is removed, for example, by a water removal unit, for example as described by Alex D. Beltz in US Patent No. 5284470, incorporated herein by reference in its entirety.
  • the water removal unit is in fluid communication with chamber 106, for example, through one or more access ports 120.
  • water removal unit is adapted to remove excess water from the body of the patient, for example, water that would normally be removed by the kidneys. Potentially, the water removal unit helps the patient obtain a balance in the amount of water in the body.
  • Figure 2 is an exemplary method of operation of the dialysis device of figure 1, in accordance with an exemplary embodiment of the invention.
  • the method allows for controlled removal of target substances from the blood.
  • the removal of the target substances is performed according to a treatment plan, for example, removal of a predetermined amount, optionally at a predetermined rate.
  • one or more of the described boxes are automatically performed, for example, by the controller.
  • one or more boxes are manually performed, for example, by a healthcare provider.
  • blood components from the blood of the patient diffuse across the membrane and into the chamber.
  • blood components diffuse at a rate associated with the size of the holes of the membrane.
  • some blood components are prevented from diffusing by the size of the membrane holes.
  • plasma e.g., blood without cellular components diffuses across the membrane and into the chamber.
  • the chamber does not initially contain fluid (e.g., artificial dialysate).
  • the plasma provides the fluid to fill the chamber so that nanoparticles can contact the target components. Potentially, using the patient's own blood as the fluid source also helps to remove excess water from the patient. Potentially, the shelf life of the fluid-less device is increased. Potentially, the fluid-less device has reduced risk of contamination.
  • target components are trapped by the nanoparticles in the chamber.
  • the concentration gradient provides for a continuous removal of the target components from the blood.
  • the concentration gradient is maintained until the desired amount of target components have been removed from the blood.
  • the concentration gradient is maintained until the desired concentration of target components in the blood is achieved.
  • the concentration gradient is maintained to maintain the concentration of target components in blood within a predefined range.
  • a concentration equilibrium of non-target components is established between the patient (e.g., blood) and the device (e.g., fluid in chamber). Potentially, the concentration equilibrium of the non-target components between the blood and the device prevents a net outflow of non-target components from the blood.
  • non-target components do not bind (or weakly bind) to the nanoparticles.
  • Non-target components that can flow from the blood across the membrane into the chamber are able to flow back out from the chamber into the blood.
  • the amount of non-target components lost from the body of the patient corresponds to the amount of non-target components in the chamber.
  • the amount of non-target components in the chamber is not clinically significant.
  • the nanoparticles are agitated, for example, by an agitation element.
  • the agitation is controlled to help obtain a desired amount and/or rate of binding between the nanoparticles and the target components.
  • agitation is increased to prevent and/or reduce clumping of nanoparticles.
  • agitation helps prevent or reduce particles sinking to the bottom of the chamber. Potentially the total surface area of the nanoparticles able to bind the target components is increased. Alternatively, agitation is reduced to allow some clumping of nanoparticles. Potentially, the surface area is reduced, reducing the rate of binding and/or total amount bound.
  • fluid is circulated through a fluid circulation system in fluid communication with the device.
  • the nanoparticles are circulated together with the fluid.
  • the circulation rate is fast enough so that pressure of the nanoparticles containing fluid is equal to or lower than the pressure of the blood in fluid communication with the fluid (e.g., blood flowing through the device).
  • the rate of fluid flow is selected to be, about 10%- 100% faster than the flow rate of blood through the device, or about 50%-150%, or about 30%-70%, or other smaller, intermediate or larger values.
  • the fluid flow rate is selected to be, for example, about 300-500 cc/hour, or about 150-400 cc/hour, or about 250-750 cc/hour, or other smaller, intermediate or larger values. In some embodiments, the flow rate is selected to reduce the fluid pressure relative to the blood pressure to about 30%-80%, or about 50%-70%, or other smaller, intermediate or larger values.
  • the temperature of the fluid inside the chamber is controlled, for example, by a temperature control element.
  • the fluid is heated.
  • the fluid is cooled.
  • the temperature is maintained. Potentially, heating the fluid, nanoparticles and/or membrane help to control the diffusion rate of target components through the membrane and/or the binding of components to the nanoparticles.
  • the rate and/or volume of blood flowing along the surface of the membrane are controlled, for example, by a valve upstream of the device. Potentially, controlling the blood flowing along the membrane helps to control the amount and/or rate of removal. In some cases, the blood flow can be stopped, for example, to prevent removal of additional components from the blood.
  • target components are reintroduced back into the blood, for example, from a reservoir in fluid communication with the circulatory system of the patient. Potentially, reintroducing target components helps to restore the balance of the components in the blood, for example, if too many blood components were removed creating a deficiency.
  • At 216 at least some nanoparticles (e.g., with bound target components) are removed and/or replaced with nanoparticles unbound to target components.
  • most (or all) of the nanoparticles are occasionally replenished.
  • the replenishing of the nanoparticles is performed by a needle and/or pump through the access port.
  • the removal of the target component is monitored.
  • the monitoring is performed by one or more sensors sensing the concentration of the target component in the patient's blood.
  • one sensor is positioned upstream of the device and one sensor positioned downstream of the device with the difference in concentrations associated with the removal of the component by the device.
  • blood samples obtained from the circulation of the patient are used to monitor the overall concentration in the blood.
  • monitoring is not performed, for example, an open loop approach is used.
  • one or more adjustments are made, for example, the agitation amount (e.g., 208), the temperature (e.g., 210), source blood flow (e.g., 214), replenishing of the nanoparticles (e.g. 216).
  • adjustments are made according to the treatment plan, for example, to adhere to the removal of a preselected amount and/or rate of target components from the blood.
  • At least some of the adjustments are made in an open loop manner.
  • the controller makes the adjustments according to a table indicating the amount and/or rate removal of the target blood components with one or more factors such as; temperature, agitation amount, blood source flow, replenishing frequency.
  • at least some of the adjustments are made in a closed loop manner. For example, monitoring the removal (e.g., as in 218), comparing the measured removed amount and/or rate to the desired removed amount and/or rate, and adjusting one or more parameters (e.g., increase or decrease) to obtain the desired removal.
  • the adjustment can be incremental (e.g., adjust, re-measure and adjust again), and/or the adjustment amount can be based on the data table.
  • the system is shut down, for example, blood is prevented from coming in contact with the membrane, for example, by closing the valve.
  • further dialysis is stopped after the total amount (or rate over time) of target components have been removed. Potentially, an imbalance or over removal is prevented.
  • one or more of 202, 204, 206, 208, 210, 212, 214, 216, 218, and/or 220 are repeated.
  • the adjustments are made during the repeat.
  • Figure 3 A is an exemplary design of the dialysis device of figure 1, in accordance with an exemplary embodiment of the invention.
  • Blood dialysis device 318 is shown in a cross sectional view.
  • device 318 comprises an inlet 326 to allow unprocessed blood (e.g., higher concentration of target components 316) to enter device 318.
  • an outlet 328 allows the processed blood (e.g., lower concentration of components 316) to exit device 318 (e.g., back to the patient).
  • inlet 326 also functions as an outlet, for example, blood flow direction is occasionally reversed, for example, if using a single needle access into the patient's vasculature.
  • the patient's blood enters a blood flow compartment 320.
  • Compartment 320 is in fluid communication with a binding agent compartment 322 through a semi-permeable membrane 324 that is permeable at least to the target components.
  • compartment 322 contains at least some nanoparticles 330 for selectively binding to target components 316.
  • nanoparticles 330 do not bind strongly (or do not bind, or repel) targets 316.
  • Arrow 332 schematically depicts a net movement of target components 316 from compartment 320 into compartment 322.
  • nanoparticles 330 are coated with a phosphate binding agent.
  • phosphate binding agents are described, for example, in US Patent Application No. 2008/0317701, incorporated by reference in its entirety.
  • phosphate binding agent nanoparticles 330 can be prepared as follows: Neutravidin (e.g., available from Pierce Ltd.) is conjugated to the magnetic nanoparticles (MNP) having a carboxylic end, for example, using the EDC-NHS method. In some embodiments, two different sized MNP are used, for example, 100 and 200 nm. Biotinylated Phos-tagTM (e.g., a dinuclear zinc (II) complex, available from www.phos-tag.com/) is mixed with the resulting structures and attached to the MNP using the high affinity of biotin to the Neutravidin.
  • Figure 3B illustrates some additional optional features added to the device shown in figure 3A, in accordance with some embodiments of the invention. Potentially, the features help to control the rate of removal of the target substances from the blood.
  • device 318B comprises one or more electromagnets 350.
  • nanoparticles 330 are at least partially magnetic.
  • one or more magnetic stirrers that do not bind substances from the blood
  • electromagnets 350 are turned on and off in a pattern that helps to agitate nanoparticles 330 (directly by attracting nanoparticles 330 and/or indirectly by attracting the magnetic stirrers), for example, by causing fluid flow (e.g., back and forth, in a circle).
  • ports 145 and/or 147 provide access to compartment 322.
  • a needle can be inserted through membrane 360 to replace the contents.
  • tubes can be connected to ports 145 and/or 147, for example, to allow circulation of fluid containing nanoparticles 330.
  • unbound nanoparticles 330 are circulated through compartment 322 at a rate slow enough so as not to cause excessive loss of non-target components.
  • the rate of circulation is fast enough so that unbound nanoparticles 330 are constantly available for uptake of the target substances. Potentially, the circulation helps to ensure a high rate of removal of target components from the blood.
  • Figure 3C is a schematic diagram of another embodiment of the selective dialysis device, in accordance with an exemplary embodiment of the invention.
  • the device is shown in an isometric view, with an optional cover removed for clarity.
  • Device 900 is adapted to control the number and/or concentration of nanoparticles free to bind the target blood components. Potentially, the control increases the total amount of target components that can be removed by device 900. Potentially, the control increases the rate of removal of the target components from the blood.
  • device 900 comprises of a membrane 902 at least permeable to target components 904.
  • blood 906 flows from an inlet port 908 to outlet port 910 (e.g., direction shown by arrow 912), for example, through membrane 902 forming a tube (partial or full circumference).
  • the tube design increases the diffusion surface area for the volume of blood (e.g., relative to a flat design).
  • unbound nanoparticles 914 are selectively placed in near proximity 926 to membrane 902 so that unbound components 904 can bind to nanoparticles 914.
  • nanoparticles 916 bound to component 904 are selectively moved away from proximity location 926.
  • the removal is performed so that an amount and/or concentration of unbound nanoparticles 914 is maintained in near proximity to membrane 902.
  • the ratio of unbound to bound nanoparticles near the membrane is, for example, about 1: 1, or about 3: 1, or about 10: 1, or about 100: 1, or about 1:2, or other smaller, intermediate or larger values.
  • the rate of binding is higher to the unbound nanoparticles, the rate slowing down as more components are bound.
  • maintaining a concentration of bound or unbound nanoparticles in near proximity to membrane increases the rate of removal of the components from blood.
  • the removal is performed by one or more nanoparticles flow control elements, for example, electromagnets 918.
  • electromagnets 918 are positioned at one end relative to membrane 902 so that unbound nanoparticles 914 flow towards membrane 902, bind components 904, and bound nanoparticles 916 flow away from membrane 902 by magnet 918.
  • movement of nanoparticles can be electrically controlled (e.g., charged nanoparticles attracted to cathodes or anodes) and/or mechanically controlled (e.g., pump or propeller causing flow).
  • unbound nanoparticles 914 are stored in one or more compartments 920 so that contact with free components 904 is reduced and/or prevented.
  • nanoparticles 914 are stored in a densely packed state, for example, nanoparticles 914 are mostly in contact with one another and/or close to one another.
  • nanoparticles 914 exit from a gate 922 to arrive in near proximity to membrane 902.
  • the density of nanoparticles 914 near membrane 902 is low enough so that nanoparticles 914 are mostly not in contact with one another and/or are further away from one another.
  • the rate of exit is controlled, for example, by size of gate 922, number of gates 922, opening and closing gate (e.g., by a valve), forcing nanoparticles 914 out (pulling by using a magnet, pushing by using a pump).
  • bound nanoparticles 916 are collected in one or more storage compartments 930 so that bound nanoparticles 916 are removed from position next to membrane 902.
  • bound nanoparticles 916 are stored in a densely packed state.
  • different chambers 932 house nanoparticles 934 adapted to bind to different blood components.
  • the chamber houses nanoparticles adapted to bind a plurality of different blood components
  • storing the bound and/or unbound nanoparticles and releasing and/or collecting when needed provides for a larger number of nanoparticles to be used, as nanoparticles can be aggregated close together in the stored state.
  • storing nanoparticles in the densely packed state allows for more nanoparticles to be contained within the device.
  • Figure 3D is a schematic of the device of figure 3A with an optional fluid circulation system 802, in accordance with some embodiments of the invention.
  • system 802 is closed loop, for example, not in fluid communication with other external fluid sources.
  • system 802 comprises one or more tubes 804 in fluid communication with compartment 322 through one or more ports 806A-B.
  • filters 808A-B prevent nanoparticles from flowing through tubes 804.
  • no filters are used so that nanoparticles can flow through tubes 804.
  • one or more pumps 810 are operable to cause the fluid to flow through tubes 804.
  • pumps 810 are operable to cause fluid to flow through compartment 322.
  • Dark arrows e.g., 812 help to illustrate flow of the fluid through compartment 322 and/or tubes 804.
  • the direction of fluid flow is approximately opposite to that of flow of serum through the device. Potentially, the counter fluid flow helps to create larger pressure and/or concentration differences to increase the rate of diffusion of the target components.
  • Figure 7 is a flowchart of an exemplary method of treatment, in accordance with an exemplary embodiment of the invention.
  • the dialysis device provides for selective dialysis of specific target components and/or control of the removal of the target component to obtain blood concentrations within predetermined ranges.
  • a patient e.g., human, mammal
  • the selection can be performed manually by the physician, and/or automatically by a software programmed to select patients according to entered patient data.
  • patients are selected for chronic dialysis treatment.
  • patients with end stage renal disease are selected for chronic dialysis treatment.
  • patients are selected for temporary acute dialysis treatment. These patients can have normally working kidneys, but require immediately removal of excess substances, faster than their kidneys can clear them, or substances the kidneys cannot remove.
  • patients with acute poisoning e.g., salicylic acid, lithium, isopropanol, magnesium containing laxatives, ethylene glycol
  • acute onset of hyperkalemia e.g., secondary to chemotherapy to treat cancer.
  • a treatment plan is selected for the patient.
  • the treatment plan comprises selecting the time duration per treatment.
  • the treatment duration is about 2 hours, or about 4 hours, or about 5 hours, or about 10 hours, or about 12 hours, or about 16 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 5-24 hours, or about 1-3 days, or about 2-4 hours, or about 5-10 hours, or about 1-7 days, or other smaller, intermediate or larger time periods.
  • the device can be used for extended periods of time, for example, before requiring replacement of the nanoparticles.
  • the treatment plan comprises selecting the type of target component (one or more types) to remove from the blood.
  • the target component is physiologically significant to the body, for example, phosphate, potassium.
  • the target component is a waste product (e.g., produced by the body), for example, beta-2-microglobulin.
  • the target component is a poison (e.g., foreign to the body), for example, salicylic acid.
  • the treatment plan comprises selecting the total amount of target component to remove from the body (e.g., in milligrams). Alternatively or additionally, the average rate of removal from the body is selected (e.g., mg/hour). Alternatively or additionally, the serum concentration range of the target component to reach and/or maintain is selected (e.g., mmol/liter).
  • the amount and/or rate and/or target concentration are matched to the estimated rate of formation.
  • the removal of phosphate is matched to the estimated intake of phosphate.
  • the amount and/or rate are matched to the estimated total amount in the patient's body that needs to be removed. For example, the estimated amount of poison the patient injected.
  • the treatment plan comprises taking into account removal of the substance by other methods, for example, by other hemodialysis machines, by use of intestinal binding agents, or other methods.
  • the treatment plan comprises of using the dialysis device in combination with existing hemodialysis treatment (e.g., clinic based).
  • the hospital based hemodialysis is estimated to remove an average of about 300 mg/day of phosphate (e.g., based on 3 treatment days X 4 hours per treatment).
  • the total daily intake due to diet is estimated at 500-800 mg/day (about 50% intestinal absorption).
  • the treatment plan comprises removing an extra of about 200-500 mg/day of phosphate.
  • the treatment plan comprises obtaining and/or maintaining a serum phosphate concentration of about 1-1.5 mmol/L (e.g., clinically safe range).
  • a potential advantage of the treatment plan using the device is that dialysis can be performed for long periods of time without risk of removing too much of the target component. For example, without removing too much phosphate to cause hypophosphatemia, or too much potassium to cause hypokalemia.
  • Another potential advantage of the treatment plan is that dialysis can be performed for long periods of time without removing too many of the non-target components, or other complications of long term hemodialysis. For example, removal of salicylic acid from the blood can be performed for many hours to remove all of the toxic substance without significant disturbance in other blood components.
  • the type of dialysis device is selected. Selecting can be performed by the patient (e.g., based on convenience, cost, personal preference, portability), by the physician, and/or automatically by software.
  • the dialysis device is used alone, for example, for patients undergoing dialysis for poisoning.
  • the dialysis device is used at least part of the time in combination with other dialysis machines, for example, patients with ESRD that are not fully dialyzed by other machines.
  • several devices are used together, for example, connected in series, for example, each device removing a different blood component.
  • the connection of the device to the patient is selected (e.g., to an arm fistula, to a central line, to a temporary access site, surgically implantable). Additional details of some exemplary portable devices as described below.
  • one or more device parameters are selected.
  • the device parameters are selected to obtain treatment according to the selected treatment plan. Selection can be performed, for example, manually by the physician based on experience, manually by the physician using a chart relating treatment parameters to device parameters, and/or automatically by the device itself (e.g., physician programs the device with the treatment and the device automatically selects the parameters, for example, using the look-up table in memory and/or by a set of equations). Data for charts and/or the look-up table and/or the equations can be obtained, for example, from experiments performed in patients (e.g., as part of clinical trials and/or device surveillance), from previous treatments on the patient themselves, and/or from mathematical models.
  • parameters include; hole size of the membrane, amount of nanoparticles, size of nanoparticles, coating of nanoparticles, amount of agitation, temperature, blood flow rate, nanoparticle replenish rate.
  • the patient is connected to the device and undergoes dialysis.
  • the patient connects him/herself to the device.
  • the patient needs to be connected to the device by a healthcare provider but can be mobile.
  • the treatment by the device is monitored. Monitoring can occur during treatment and/or after treatment. In some embodiments, the monitoring comprises comparing the blood levels of the components after treatment with the desired blood levels. Alternatively, the behavior of the patient is monitored, for example, checking compliance of the patient with treatment.
  • monitoring is performed remotely, for example, by the patient using a smartphone to remotely connect to the dialysis device.
  • the treatment is adjusted and optionally repeated.
  • the treatment is adjusted based on the monitoring. For example, the treatment can be increased if the patient is eating more food with phosphate (to remove the excess phosphate). For example, the treatment can be stopped early, for example, if the target concentration is met.
  • phosphate removal treatments are adjusted.
  • the adjustment is performed according to the selected treatment and/or monitoring. For example, the amount of phosphate binders is adjusted (e.g., reduced), and/or the diet of the patient is adjusted (e.g., intake of phosphate containing foods are increased).
  • the treatment plan comprises of first removing the excess amount of substances from the blood to obtain a clinically safe level, for example, at a steady state.
  • the treatment plan then is adjusted to maintain the steady state, for example, by matching to the diet.
  • periodic adjustments can be made, for example, if the patient's diet has changed, to remove the excess amount and then maintain the new steady state.
  • FIG 4 is a simplified schematic showing a dialysis device 418 (e.g., of figures 1 and/or 3) connected to a dialysis machine 450 to dialyze blood from a patient 440, in accordance with an exemplary embodiment of the invention.
  • dialysis device 418 is connected downstream from dialysis machine 450. Potentially in this setup, device 418 helps to remove extra components that machine 450 did not remove.
  • dialysis device 418 is connected upstream from machine 450. Potentially in this setup, device 418 removes high levels of target components to help machine 450 function more efficiently.
  • one or more dialysis devices 418 are connected both upstream and downstream of machine 450.
  • connection of device 418 to dialysis machine 450 allows for removal of higher amounts of target substances than could be removed by machine 450 alone.
  • relatively lower blood concentrations of relatively low molecular weight target blood components, such as phosphate can be obtained after dialysis with device 418 as compared to dialysis apparatus 450 alone.
  • blood from patient 440 flows through a tube 442 connected to an artery to a conventional dialyzer 464.
  • an arterial pressure monitor 52 measures the pressure of the blood as it exits the patient.
  • a pump 454 helps to circulate the blood.
  • an anticoagulant pump 456 supplies heparin to prevent the blood from clotting as it is being treated.
  • a blood inflow pressure monitor 458 measures blood pressure before the blood enters dialyzer 464.
  • dialyzer 464 contains circulation of dialysate, optionally controlled by a dialysate inflow valve 462.
  • a dialysate inflow valve 462 counter-current flow of dialysate and blood is used.
  • spent dialysate leaves dialyser 464 via a dialysate outflow valve 460.
  • the blood after blood has been treated by dialyzer 450, the blood enters device 418. Blood flows into optional blood flow compartment 420 via optional blood inlet 426. Target blood component 416 diffuses through semi-permeable membrane 424 into an optional binding agent compartment 422. Target blood component 416 is bound by binding agent 430, potentially maintaining a concentration gradient of target blood component. Optionally, blood having lower concentration of the target blood component than before entering blood inlet 426 flows out of the blood flow compartment 420 via blood outlet 428.
  • one or more sensors 470 sense one or more parameters associated with the concentration of target blood component in blood, for example, as described with reference to figure 1.
  • blood pressure is monitored by a venous pressure monitor 466.
  • Figure 5 is a simplified schematic (cross sectional view) of a portable blood dialysis device 518, in accordance with an exemplary embodiment of the invention.
  • device 518 is attachable to the arm of a patient in need of dialysis, for example, the patient themselves can attach the device at home.
  • the patient previously underwent an operation to form a fistula 506 between artery 506 and vein 504 of arm 500.
  • one or more needles 532/528 are inserted into the arm of the patient to obtain access. Blood flows through needle 532 into optional tube 534 and into device 518. Optionally, blood returns from device 518 into patient through optional tube 526 and needle 528. Operation of device 518 has been described herein.
  • device 518 is secured in position against arm 500 by a strap 530.
  • an optional septum 540 provide access to compartment 522, for example by piercing of a needle.
  • the needle is used to introduce and/or remove the binding agents.
  • septum 540 is used to remove excess body fluid (e.g., water) during the treatment session.
  • a suitable fluid removal device is attached to septum 540 to remove the excess body fluid.
  • a potential advantage of portable device 518 is that the patient can undergo dialysis for longer periods of time. Potentially, the longer dialysis times help to control phosphate levels and reduce the risk of hyperphosphatemia.
  • Another potential advantage is that less fluid is used, being more environmentally friendly and reducing biological waste.
  • Figure 6 is a simplified schematic of a portable dialysis device 618 attached to a central line connection of a patient, in accordance with an exemplary embodiment of the invention.
  • device 618 can be used to dialyze patients that do not have chronic kidney failure, but that may require occasional dialysis. These patients may not have a fistula in their arm, but may have central line access.
  • device 618 is attached to an optional tube 600, which is connected to an optional port 601.
  • port 601 is in fluid communication with a major artery or vein through a catheter tunneled under the skin.
  • blood is returned to the patient through an outflow tube 602 connected to an optional access port 603, which is optionally connected to the vasculature (e.g., artery or vein).
  • a belt 604 attaches device 618 to the body of the patient.
  • the patient can be mobile while undergoing dialysis.
  • the dialysis device is implantable in the patient, for example, subcutaneously.
  • the device is surgically connected to blood vessels, for example, sutured thereto.
  • the nanoparticles are replenished by insertion of a needle though the skin and through the access port.
  • the device and/or associated components are sold as a kit.
  • the kit is sold pre-sterilized.
  • the kit comprises a device which comprises; a membrane, and a chamber.
  • nanoparticles (and optional fluid) are preloaded in the chamber.
  • the chamber comprises an access port, and nanoparticles (and optional fluid) are loaded into the chamber (e.g., by the user).
  • the kit comprises of a plurality of disposable devices for single time use. For example, a month's supply of the devices in one box.
  • the kit comprises nanoparticles that are packaged separately from the device.
  • the nanoparticles arrive suspended in the fluid (e.g., biocompatible fluid).
  • the nanoparticles and fluid are sold separately, for example, to be mixed upon insertion into the chamber.
  • Nanoparticles can be prepacked, for example, by type of component removed (one or more different types), by total amount of component to remove, by rate of component to remove.
  • the amount of nanoparticles sold in a package is enough to last the entire dialysis treatment period.
  • the packaging is labeled with the removal ability.
  • devices with nanoparticles to remove a single type of component are sold separately.
  • a plurality of devices, each one removing a different type of target component can be connected in series to obtain the desired removal.
  • the kit comprises batteries to power the device.
  • the kit comprises a cable (e.g., USB cable) to connect to a computer.
  • the kit comprises the device (with membrane, chamber and optional nanoparticles), along with one or more attachable (external or internal) components, for example; the agitator, the heating element, the blood flow control element, the sensor, the communication link, and/or the component reservoir.
  • the components and the device can be interconnected to form a system.
  • dialysis device is intended to include all such new technologies a priori.
  • the term "about” refers to ⁇ 10 %
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition

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  • Animal Behavior & Ethology (AREA)
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Abstract

Selon un aspect, certains modes de réalisation de la présente invention concernent un dispositif configuré pour le retrait sélectif de substances cibles à partir du sang d'un patient, le dispositif comprenant : un orifice d'entrée configuré pour laisser le sang du patient entrer dans le dispositif ; un orifice de sortie configuré pour laisser le sang du patient sortir du dispositif ; une chambre conçue pour contenir un fluide ; des particules disposées dans la chambre, les particules étant conçues pour se lier de manière sélective aux substances cibles ; et une membrane positionnée de telle sorte qu'au moins les substances cibles peuvent se déplacer à partir du sang à travers la membrane dans la chambre, la membrane ayant des pores ayant une dimension assez petite pour empêcher les particules d'entrer dans le sang, les pores étant assez petits pour empêcher des composants cellulaires d'entrer dans la chambre, les pores étant assez grands pour permettre à des molécules ayant une dimension au moins supérieure à 25 000 Daltons d'entrer dans la chambre.
PCT/IL2012/050317 2011-08-22 2012-08-19 Dialyse d'article à base de nanoparticules WO2013027214A2 (fr)

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