Patent Application
20230108155
The disclosure relates generally to fluid processing systems and methods for renal therapy, and more particularly to systems and methods including a portable and wearable device for delivering a drug to a patient.
More than 2.5 million patients worldwide utilize some form of dialysis such as hemodialysis (HD) or peritoneal dialysis (PD) as a life-saving treatment. Current dialysis modalities, however, still have many deficiencies in their use as a replacement of the function of normal kidneys. The most important deficiency of current methods of HD is its intermittent nature, resulting in large fluctuations in the internal electrolyte environment and the fluid volume of the patient compared to the regulation achieved by the normal kidney function. PD provides more continuous dialysis, but the clearance of uremic toxins is relatively low compared to HD. Failure of the PD method for patients is frequent over a longer term mostly due to damage caused to the peritoneal membrane by peritonitis infection and the use of high intraperitoneal glucose concentrations that are required for the osmotic fluid removal.
The total effect of the deficiencies of existing renal therapies means that long term survival is much less for these patients compared to the general population. Extended and more frequent treatments can improve survival as well as improve the quality of life of these patients. The use of existing renal therapy technologies in home settings in order to allow for longer and more frequent treatments has had some success at improving outcomes as compared to in-center HD treatment but has been limited by economic factors, logistics issues and limitations of space in patient homes such that only a relatively small percentage of patients are treated with home HD. Another disadvantage of existing home HD treatments is that patients are connected to large medical devices and water treatment systems for extended periods of time, severely affecting mobility. The weight of conventional HD modules is upwards of 60 kg. Also, purification of approximately 120 liters of water per session by additional equipment in a fixed location is needed. This equipment cannot be readily moved to other locations and so limits the home HD patients daily mobility and ability to travel.
The disclosure herein is directed to the use of at least one sorption substance or sorption material in a device for the removal of toxic substances and excess water from blood or other biofluids from a patient, and methods of renal therapy involving removing toxic substances from blood and other biofluids using the sorption substance or sorption material suitable for use in said device and in other hemodialysis and peritoneal dialysis systems. The patient can be a human or an animal.
In an aspect, the disclosure describes a sorbent cartridge for use in a portable wearable renal therapy system. The sorbent cartridge comprises: a inlet and an outlet, the inlet configured to receive process fluid from the renal therapy system and the outlet configured to discharge treated process fluid; and a hydrogel configured to absorb and adsorb a toxin from the process fluid without use of a dialysate to purify the process fluid. The inlet and the outlet are each configured to releasably couple to the renal therapy device for removing the sorbent cartridge.
In another aspect, the disclosure describes a sorbent cartridge for use in a renal therapy system. The sorbent cartridge comprises a hydrogel configured to absorb or adsorb a toxin from a process fluid and the sorbent cartridge is configured to be releasably coupled to the renal therapy system for ease of removability.
In an embodiment, the hydrogel is configured to release to the process fluid at least one of an electrolyte, a buffer, a mineral, a vitamin, or an anti-coagulant. In an embodiment, the buffer is sodium bicarbonate. In an embodiment, the anti-coagulant is at least one of heparin and citrate.
In an embodiment, the hydrogel is formed as a plurality of beads, the plurality of beads positioned in a reservoir of the sorbent cartridge configured to receive process fluid flowing through the sorbent cartridge, the sorbent cartridge comprising a filter to prevent passage of the plurality of beads into circulation of the process fluid.
In an embodiment, the sorbent cartridge is configured such that the hydrogel is in direct contact with the process fluid.
In an embodiment, the sorbent cartridge is configured such that the hydrogel is in indirect communication with the process fluid across a membrane.
In an embodiment, the hydrogel is configured to absorb toxins from the process fluid into the hydrogel without altering electrolyte levels outside of a physiological range that would cause harm to a user of the renal therapy system.
In an embodiment, the hydrogel is configured to absorb 1 gram to 100 grams of urea in 24 hours from the process fluid without altering electrolyte levels outside of a physiological range that would cause harm a user of the renal therapy system.
In an embodiment, the hydrogel is configured to absorb electrolytes into the hydrogel to reduce specific electrolyte levels of the process fluid.
In an embodiment, the sorbent cartridge is configured to be releasably coupled to a renal therapy system, where the renal therapy system is a portable wearable system.
In an embodiment, the sorbent cartridge comprises a first compartment and a second compartment, the first compartment comprising a membrane configured to remove water from the process fluid, and the second compartment comprising the membrane configured for toxin removal.
In an embodiment, the hydrogel is cast in place over the membrane in said sorption cartridge, and wherein the membrane is a hollow fiber membrane.
In an embodiment, the sorbent cartridge comprises a temperature sensor, and at least one of a heating element and/or a cooling element, the temperature sensor configured to send a temperature signal to a controller, and the at least one of a heating element and/or a cooling element configured to receive a output signal from a controller.
In an embodiment, the sorbent cartridge comprises a conductive member configured to couple with a cooling element to create a temperature gradient along a distance between the conductive member and the membrane.
In an embodiment, the sorbent cartridge comprises a vibration element configured to vibrate the hydrogel.
In an embodiment, the hydrogel forms a hydrogel layer having a thickness of greater than or equal to about 1 mm.
In an embodiment, the hydrogel forms a hydrogel layer having a thickness of between 1 mm and 3 mm.
In an embodiment, the hydrogel forms a hydrogel layer having a thickness of greater than or equal to 3 mm.
Embodiments may include combinations of the above features.
In another aspect, the disclosure describes a renal therapy system comprising the sorbent cartridge of any one of the embodiments of the sorbent cartridges described above. The renal therapy system is at least one of a hemodialysis system, a peritoneal dialysis system, a hemoperfusion system, a hemofiltration system, or a hemodiafiltration system.
In an embodiment, the system is a portable wearable system.
In an embodiment, the renal therapy system comprises a cooling element to create a temperature gradient along a length of the hydrogel.
In an embodiment, the renal therapy system comprises a vibration element configured to vibrate the hydrogel.
Embodiments may include combinations of the above features.
In another aspect, the disclosure describes a use of the sorbent cartridge of any one of the sorbent cartridges described above for renal therapy of a user.
In another aspect, the disclosure describes a method for removing toxic substances from process fluid. The method comprises: providing a sorbent cartridge comprising a hydrogel; moving process fluid through the sorbent cartridge in communication with the hydrogel, the process fluid comprising toxins; and absorbing or adsorbing the toxins from the process fluid into the hydrogel to provide treated process fluid.
In an embodiment, the method comprises heating the process fluid to about 37° C.
In an embodiment, the method comprises absorbing water from the process fluid into the hydrogel.
In an embodiment, the method comprises releasing at least one of an electrolyte, a buffer, a mineral, a vitamin, or anti-coagulant from the hydrogel to the process fluid.
In an embodiment, the method comprises moving process fluid through a hollow fiber membrane, the process fluid in indirect communication with the hydrogel through the hollow fiber membrane.
In an embodiment, the method comprises vibrating the hydrogel.
In an embodiment, the method comprises cooling the hydrogel to create a temperature gradient along a length of the hydrogel.
Embodiments may include combinations of the above features.
In a further aspect, the disclosure describes a use of a hydrogel in a renal therapy system, the hydrogel comprising an interpenetrating network of polymer chains, the monomers of the polymer chains having hydrophilic functional groups.
In an embodiment, the monomers comprise at least one of polyacrylamide, acrylic acid, alginate, or chitosan.
In an embodiment, the hydrogel is formed as a plurality of beads having a specific surface area of at least 0.1 m2/m3.
In an embodiment, the hydrogel is cast around hollow filtration fibers.
In an embodiment, the hollow filtration fibres have an inner surface area of between 0.1 to 1.0 m2/m3.
In an embodiment, the hydrogel is a colloidal gel in which water is the dispersion medium.
In an embodiment, the polymer chains are functionalized with chemicals or biological elements to promote sorption of water and toxins in the hydrogel.
Embodiments may include combinations of the above features.
In another aspect, the disclosure describes a portable and wearable renal therapy system comprising: a purification device configured to remove toxins from process fluid and deliver a therapeutic substance to the process fluid; a drug delivery device coupled to the purification device, the drug delivery device comprising: a reservoir for a fluid comprising the therapeutic substance; and a fluid connection coupling the drug delivery device with the purification device, the fluid connection configured for fluidly communicating the reservoir with the process fluid.
In an embodiment, the system comprises a pump configured for moving the fluid to the process fluid.
In an embodiment, the system comprises a control valve for metering a flow rate of the fluid to the process fluid.
In an embodiment, the therapeutic substance is at least one of insulin, Erythropoietin (EPO), erythropoietin stimulating agents, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) specific antibody, a granulocyte colony-stimulating factor (G-CSF), a sclerostin antibody, a calcitonin gene-related peptide (CGRP) antibody; an electrolyte, a buffer, a mineral, and/or a vitamin. In an embodiment, the system the mineral is iron. In an embodiment, the vitamin is at least one of vitamin B12 and/or folate.
In an embodiment, the system comprises a power connection coupling the purification device with the drug delivery device in electrical communication to power the drug delivery device. The power connection may comprise a releasable coupling for reversibly coupling the drug delivery device with the purification device.
In an embodiment, the fluid connection comprises a releasable coupling for reversible coupling the drug delivery device with the purification device.
In an embodiment, the purification device is configured to release at least one of electrolytes and buffer solutions into the process fluid.
In an embodiment, the purification device is configured to remove water from the process fluid.
In an embodiment, the purification device is at least one of a hemodialysis system, a peritoneal dialysis system, a hemoperfusion system, a hemofiltration system, or a hemodiafiltration system.
Embodiments may include combinations of the above features.
In another aspect, the disclosure describes a portable and wearable renal therapy system comprising: a purification device configured to remove toxins from process fluid and deliver a therapeutic substance to the process fluid; the purification device comprising an interface configured to couple to a drug delivery device, the drug delivery device comprising: a reservoir for a fluid comprising a therapeutic substance; and a fluid connection to couple with the purification device at the interface, the fluid connection configured for fluidly communicating the reservoir with the process fluid.
In an embodiment, the interface comprises a power connection for powering the drug delivery device.
In an embodiment, the interface is configured to reversibly couple to the drug delivery device.
In an embodiment, the system comprises a controller configured to deliver at least one of insulin, Erythropoietin (EPO), erythropoietin stimulating agents, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) specific antibody, a granulocyte colony-stimulating factor (G-CSF), a sclerostin antibody, a calcitonin gene-related peptide (CGRP) antibody, an electrolyte, a buffer, a mineral, and/or a vitamin to the process fluid.
In an embodiment, the purification system comprises a sorbent cartridge comprising: a inlet and an outlet, the inlet configured to receive process fluid from the renal therapy system and the outlet configured to discharge treated process fluid; and a hydrogel configured to absorb and adsorb a toxin from the process fluid without use of a dialysate to purify the process fluid; wherein the inlet and the outlet are each configured to releasably couple to the renal therapy system for removing the sorbent cartridge. In an embodiment, the fluid connection is configured to connect to the sorbent cartridge to replenish therapeutic substance in the hydrogel for release to the process fluid.
Embodiments may include combinations of the above features.
In another aspect, the disclosure describes a drug delivery device comprising: a reservoir for a fluid comprising a therapeutic substance; and an interface for coupling to a purification device of a portable and wearable renal therapy system, the interface comprising: a fluid connection configured for fluidly communicating the reservoir with a process fluid in the purification device.
In an embodiment, the interface comprises a power connection for powering the drug delivery device.
In an embodiment, the interface is configured to reversibly couple to the purification device.
Embodiments may include combinations of the above features.
Further details of these and other aspects of the subject matter of this application will be apparent from the detailed description included below and the drawings.
Reference is now made to the accompanying drawings, in which:
The disclosure herein describes systems and methods of using hydrogel as a sorbent to act as a detoxifier of blood in communication directly or indirectly through a membrane as in hemoperfusion or to clear toxins from ultrafiltrate fluids and dialysate fluids used in hemofiltration, hemodialysis or peritoneal dialysis so that these fluids can be regenerated and reused.
Although terms such as “maximize”, “minimize” and “optimize” may be used in the present disclosure, it should be understood that such term may be used to refer to improvements, tuning and refinements that may not be strictly limited to maximal, minimal or optimal.
The term “connected” or “coupled to” may include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements).
The term “substantially” as used herein may be applied to modify any quantitative representation which could permissibly vary without resulting in a change in the basic function to which it is related.
The term “sorption” as used herein, refers to both adsorption and absorption. Adsorption is a process that occurs when a gas or liquid or solute (called adsorbate) accumulates on the surface of a solid or more rarely a liquid (adsorbent), forming a molecular or atomic film (adsorbate). It is different from absorption, where a substance diffuses into a liquid or solid to form a “solution”. The term sorption encompasses both processes, while desorption is the reverse process.
The term “small-sized molecules”, as used herein, refers to molecules with a molecular weight lower than 500 Da, such as uric acid, urea, guanidine, ADMA, creatinine.
The term “middle-sized molecules”, as used herein, refers to molecules with a molecular weight between 500 Da and 5000 Da, such as end products from peptides and lipids, amines, amino acids, protein-bound compounds, cytokines, leptins, microglobulins, and some hormones.
The term “ionic solutes”, as used herein, refers to components such as phosphates, sulphates, carbon hydrates, chlorides, ammonia, potassium, calcium, sodium.
The term “process fluid”, as used herein, refers to dialysate fluid, blood, or blood plasma.
“Nano-sized” as used herein, refers to a size of approximately 1-1000 nm, more preferably 1-100 nm.
“Electrolytes” are substances that produce an electrically conductive solution when dissolved in, for example, water, by separation into positive and negative ions. For example, Sodium Chloride (salt) separates into sodium ions and chloride ions. Other electrolytes are bicarbonate, potassium, and phosphate.
“Buffer” solutions are those which resist changes in pH from additions of acidic or basic substances. The resistance to pH change is conferred by an equilibrium between a weak acid and its' conjugate base. Bicarbonate is an example of a buffering substance. Bicarbonate is in 2 equilibrium reactions with carbonate ion and carbonic acid.
The implementation of a wearable renal therapy device that combines continuous or daily blood purification while maintaining a high efficiency for removal of uremic toxins may provide an improvement in the treatment of patients with renal disease, including end-stage renal disease.
While the more continuous and efficient removal of uremic solutes, as well as water and control of electrolytes, is a great advantage of wearable devices, one of the major challenges is the removal of urea. A relatively large amount of urea of up to 24 g needs to be removed daily. Urea has been shown to be difficult to remove with existing sorption methods. Existing wearable renal therapy devices based on sorbent and enzyme technology to allow for the regeneration of dialysis fluid have been used in some prototypes, but they have had some issues with safety, control, size, weight, and cost of expendable components. Electro-oxidation methods have also been used. The problem with electro-oxidation is with the oxidation of chloride leading to the formation of reactive chlorine species, such as chloramines.
Wearable devices utilizing effective sorbent systems can also be used to enhance the efficacy of PD by continuously regenerating the peritoneal dialysate in order to maintain a larger plasma—dialysate concentration gradient. This reduces the amount of time spent by the patient doing exchanges, while still improving toxin clearance. Reduced exposure of the PD catheter to the environment in such a wearable PD device could also prolong the PD technique survival by reducing the risk of bacterial contamination, and so, lower the risk of peritonitis. Continuous glucose infusion by a wearable PD device can reduce functional deterioration of the peritoneal membrane by reducing somewhat the peak level of glucose concentrations that are needed for osmotic fluid removal in conventional intermittent infusion PD. Further, providing portable dialysis devices or artificial kidneys allow patients to engage in normal daily activities while receiving an extended length blood purification treatment without having frequent interruptions or limitations to what they may do.
Portable dialysis devices may be enabled by a system that is able to clear most of the toxins from the blood using no dialysate or as little dialysate as possible. The features of using no dialysate or as little dialysate as possible may require that a substance or substances be used that have an ability to absorb and retain the toxins that need to be removed as well as controlling the electrolyte levels and restoring the buffer solution. There have been other attempts in the past to find such a material. It has been found that activated carbon is able to efficiently remove most of organic uremic organic toxins, middle MW molecules, uric acid, creatinine, and heavy metals with the notable exception of efficient removal of urea. Activated carbon also has minimal effects on electrolyte levels and has no ability to modify or restore buffer levels. Other methods to regenerate dialysate for reuse have used urease enzymes to convert the urea in the fluid to ammonium carbonate, which was then removed using zirconium compounds. These zirconium compounds also convert the ammonium carbonate to bicarbonate and remove electrolytes. Electrolyte and buffer levels are then restored to the desired level before being passed through the dialyser again with a calibrated infusion of an electrolyte containing fluid. This process (known as the REDY system) is effective and was used from 1973 to 1993 in a recirculating home hemodialysis system using 6 liters of dialysate, proving that a sorbent-based system can provide adequate therapy. This process is no longer used for home hemodialysis due mainly to higher total treatment costs than single pass systems that use larger volumes of water. There were also lingering concerns of possible negative impacts to patients if the system ever failed to convert all of the ammonia or if some of the chemicals in the zirconium compounds leached into the dialysate if the conversion capacity of these compounds was ever exceeded. This urease, plus zirconium compound and activated carbon system has also been used in trials for a wearable hemodialysis system. A wearable system requires that the dialysate volume be much smaller. This smaller volume of dialysate also makes it more difficult to remove any bubbles that may contain ammonia in the fluid. The total size of the multiple sorbent cartridges required make for a heavier and bulkier system and the high cost of the constituent materials may inhibit widespread adoption.
Hydrogel sorbent (also referred to herein as “hydrogel”) may comprise material with an ability to adsorb large quantities of urea that can also be infused with electrolytes and buffers so that when it is used in a wearable or portable renal therapy system, it can provide all of the sorbent capacity, electrolyte management, and buffer replacement functions required. When hydrogel is used as a sorbent to regenerate dialysate for hemodialysis or peritoneal dialysis, the dialysate volume can be kept very low. Hydrogel sorbent can also adsorb toxins and modify electrolyte and buffer concentrations directly in contact with dialysate or indirectly across a membrane without the use of dialysate to purify hemofiltrate for reinfusion in a hemofiltration system. Hydrogel can also adsorb toxins and modify electrolyte and buffer concentrations of blood directly across a membrane without the use of dialysate in a hemoperfusion system. Hydrogel can be manufactured from low-cost common materials and can be made in such a form that no toxic materials can leach from it.
Hydrogel has been used in other biomedical applications to absorb exudate from wounds, slow release of drugs and other compounds, and as a structural material. Hydrogel has been used in industrial applications to adsorb nitrates, phosphorus, and metals from wastewater. Hydrogel has been used in agriculture to absorb and release water as well as fertilizers such as urea, phosphorus, and other electrolytes into the soil. Hydrogel has not been used as a sorbent for urea and other toxins or to modify electrolytes and buffer levels in biomedical applications.
The hydrogel material can be cast in place directly on a membrane structure or be in a separate chamber in which dialysing fluids are pumped through in order to regenerate the dialysate or reinfusion fluid. The hydrogel may also be in the form of smaller spheres or chopped in order to reduce the flow restriction through the chamber and increase the exposed surface area of the hydrogel material.
In an aspect, an artificial kidney consists of extracting urea and other molecules from blood by dialysis and regeneration of the dialysate fluid when the latter is to be recycled into the dialyser. Regeneration is accomplished by means of adsorbent cartridges, previously this has been enabled by incorporating activated carbon. Activated carbon has the capability to adsorb many uremic toxins including urea. U.S. Pat. No. 3,463,728, which is hereby incorporated herein by reference in its entirety, describes a method of using an activated carbon slurry to augment the capacity of dialysate in a recirculating dialysate system. Activated carbon, however, is not an efficient adsorber of urea and to adsorb the amount of urea for effective clearance in hemodialysis would require upwards of 20 kg of activated carbon per day. A specific method of using urease to clear the dialysate of urea in addition to using carbon and zeolites to manage other electrolytes is described in U.S. Pat. No. 4,581,141, which is hereby incorporated herein by reference in its entirety. Further improvements to these methods are described in U.S. Patent Publication No. 2010/0078387, which is hereby incorporated herein by reference in its entirety, utilizing Zirconium phosphate (ZrP) particles and hydrous zirconium oxide (HZO) particles to also help in managing bicarbonate levels. Urease is expensive and has some issues with the risk of passage of ammonia and bubbles generated in the dialysing fluid. U.S. Pat. No. 9,682,184, which is hereby incorporated herein by reference in its entirety, describes a sorbent cartridge using non-enzymatic urea-binding materials in place of urease. U.S. Patent Publication No. 20110171713, which is hereby incorporated herein by reference in its entirety, describes another sorbent comprising a layer of immobilized uremic toxin-treating enzyme particles intermixed with cation exchange particles. European Patent Publication No. EP1935441A1 (Published on Jun. 25, 2008), which is hereby incorporated herein by reference in its entirety, describes yet another alternative sorbing material utilizing a smectite, nanoclay, a layered double hydroxide, and a modified biopolymer.
In an aspect, the principle of the artificial kidney may be based on ultrafiltration or hemofiltration of the plasma portion of the blood. During hemofiltration, the patient's blood is passed through a set of tubing (a filtration circuit) via a machine to a semipermeable membrane (the filter) where waste products and water are removed. Replacement fluid is added and the blood is returned to the patient. In a similar fashion to dialysis, hemofiltration involves the movement of solutes across a semipermeable membrane. However, the membrane used in hemofiltration is more porous to fluid than that used in most hemodialysis treatments, and no dialysate is used, instead, a positive hydrostatic pressure drives water and solutes across the filter membrane where they are drained away as filtrate. An isotonic replacement fluid is added to the resultant filtered blood to replace fluid volume and valuable electrolytes. This blood and replacement fluid is then returned to the patient. Thus, in the case of recycling fluid for replacement in hemofiltration, a key aspect resides in separating the urea and other toxins from the other components in the ultrafiltrate such as salts which have also passed through the membrane but which must be re-incorporated into the blood in order to maintain the electrolyte composition thereof substantially constant. U.S. Pat. No. 5,211,850, which is hereby incorporated herein by reference in its entirety, describes such a sorbent system to purify plasma ultrafiltered from blood so that it can be returned to the replacement solution. A combination of the two systems described above has also been proposed. U.S. Pat. No. 8,029,454, which is hereby incorporated herein by reference in its entirety, describes such a hemodiafiltration system using sorbents for fluid regeneration for both the hemodialysis aspect and the hemofiltration aspect.
Direct hemoperfusion systems, or systems that perform no ultrafiltration, yet which adsorb toxic substances directly from the blood have also been proposed. U.S. Pat. No. 4,169,051, which is hereby incorporated herein by reference in its entirety, describes carbon sorbent spheres coated with a membrane material in order to reduce coagulation of the blood it is in contact. Others have used different adsorbent materials coated in a membrane. In general, hemoperfusion systems are not widely used for artificial kidney systems due to higher costs and the inherent lower efficiency of urea removal. In general hemoperfusion systems target specific toxins not generally removed well by regular hemodialysis or hemofiltration. These are usually meant not for renal replacement therapies but as an adjunct to another renal replacement therapy in order to improve the clearance of targeted molecules. U.S. Pat. No. 6,878,269, which is hereby incorporated herein by reference in its entirety, describes a sorbent column containing spherical hydrogel particles of a cellulose acetate used to remove J32-microglobulin and chemokines. As noted above, the adsorbent for regenerating the dialysate or ultrafiltrate is usually activated carbon. However other adsorbents have been proposed for the removal of substances from dialysis fluids or ultrafiltrate. U.S. Pat. No. 3,874,907, which is hereby incorporated herein by reference in its entirety, describes microcapsules consisting of a crosslinked polymer containing sulphonic acid groups and coated with a polymer containing quaternary ammonium groups, for use in regenerating the dialysate. Examples of the sulphonated polymer include sulphonated styrene/divinyl benzene copolymer and examples of the coating polymer include those obtained by polymerization of for instance vinyldimethylamine monomers.
The disclosures noted above are directed to both dialysing, ultrafiltration and hemoperfusion devices, wherein various substances may be used as sorbents. The disclosures also includes patents granted for the use of specific sorbent materials for use in renal therapy devices. However, a problem with the systems of the disclosures above, that they are still too large due to limited sorption capacity of the materials, have the risk of eluting toxic chemicals such as ammonia or chlorine or not efficient, or all of the above in order to allow small, desktop-sized or wearable dialysing and ultrafiltration systems. The raw materials cost for these systems is also high. This limits their ability to be a lower cost solution to the expensive existing methods of renal therapy.
An object of the present invention is to overcome the problems associated with the devices of the prior art and to provide a compact and efficient sorption system for use in hemodialysis and peritoneal dialysis systems portable renal therapy systems and in a wearable renal therapy system.
Aspects of various embodiments are described through reference to the drawings.
Sorption cartridge 100 may comprise a membrane configured to remove water and waste material (e.g. small-molecules and medium-molecules) from a process fluid. The membrane may be shaped as a hollow fiber, generally flat, generally corrugated, or other suitable shape to separate water and waste material from process fluid. The membrane may define a flow path through the sorbent cartridge, e.g. a hollow fiber membrane may be configured to convey process fluid through the cartridge which may include defining a flow path through the hydrogel within the cartridge. Example flat membranes may include Spectrum™ Spectra/Por™ 1-4 Standard RC Dialysis Membrane in Flat Sheets, having manufacturing nos. SML132677, SML132686, SML132723, SML132712 respectively. Examples of hollow fiber dialysis membranes include Elisio™-H membrane (e.g. models: ELISIOV11H or ELISIOV15H) provided by Nipro Corporation, Polynephron™ membrane provided by Nipro Corporation, Asymmetric Tri-Acetate (ATA) Membrane provided by Nipro Corporation, Membrana™ Purema™ H capillary membrane provided by 3M Company, and Membrana™ Diapes™ capillary membrane provided by 3M Company. In an embodiment, the hollow fibers of the hollow fiber membrane have a thickness of less than 0.5 mm. In another embodiment, the hollow fibers of the hollow fiber membrane have a thickness of less than 200 microns.
In an embodiment, a sorption cartridge according the disclosure herein may comprise one more compartments. In an example, a sorption cartridge may have two compartments. A first compartment may be configured for water removal and a second compartment may be configured for removal of middle-sized molecules and/or small-sized molecules such as uremic toxins. The first compartment configured for water removal may comprise a membrane, as described above, that may remove water and other solutes (e.g. waste material) from a process fluid by ultrafiltration across the membrane to an ultrafiltrate. The second compartment configured for toxin removal (e.g. urea) may comprise the membrane, described above, which may be embedded in hydrogel sorbent.
In an embodiment, hydrogel according to the disclosure herein, may be configured to release supplemental ingredients such as electrolytes, buffer, minerals, vitamins, and/or other substances to the process fluid. For example, hydrogel may also comprise sodium bicarbonate for bicarbonate ion control and/or anti-coagulant (e.g. heparin or citrate) to aid in anti-coagulation, each of which may be released from the hydrogel to the process fluid. The hydrogel of the sorbent cartridge may be pre-loaded with supplemental ingredients such that the supplemental ingredients are desorbed to the process fluid when in use.
In an embodiment, the membrane-hydrogel interface may be functionalized by to promote water and/or toxins to move from the process fluid across the membrane to absorb into, or adsorb onto, the hydrogel. In an example, the molecular structure of the monomers of the polymer chains, which make up the polymeric structure of the hydrogel, may have hydrophilic functional groups that confer hydrophilicity to the hydrogel to promote absorption of water by the hydrogel through the membrane. In another example, chemicals and/or biological elements may be added to the hydrogel to attract toxins in the process fluid. The membrane may also be modified by chemicals to promote toxins to cross the membrane-hydrogel interface into the hydrogel.
Hydrogels described herein, may be cast onto a membrane, and/or may have a membrane embed within the hydrogel, such that the hydrogel has a layer having a thickness. The thickness of the hydrogel may be configured to provide a concentration gradient to absorb toxins from process fluid. In an embodiment, the hydrogel layer has a thickness of greater than or equal to about 1 mm. In another embodiment, the hydrogel layer has a thickness between 1 mm and 3 mm. In another embodiment, the hydrogel layer has a thickness of greater than or equal to 3 mm.
In another embodiment, reservoir (29) of sorption cartridge 100 may comprise hydrogel sorbent in the form of a plurality of hydrogel beads. Process fluid, e.g. blood, plasma, or dialysate fluid may be configured to be direct contact with the bead shaped hydrogel sorbent as it flows through the sorbent cartridge. In an example, each hydrogel bead may have a diameter of greater than or equal to about 1 mm. In another embodiment, the hydrogel beads each have a diameter between 1 mm and 3 mm. In another embodiment, the hydrogel beads have a diameter of 3 mm to 10 mm.
The sorption cartridge of the present disclosure is distinguished from the prior art devices in that it makes use of a hydrogel with a high capacity to sorb urea in order to allow small dimensions for wearability. The sorption system (i.e. the ability of the hydrogel to adsorb and/or absorb), and optional release system (i.e. the ability of the hydrogel to release electrolytes, buffer, minerals, vitamins or other substances to the blood, plasma or dialysis fluid), of the sorption cartridge(s) described herein may have a temporary use until it reaches its maximum sorption capacity. The content of the hydrogel sorbent can be customized to the individual patient needs. A sorbent cartridge according to the present disclosure may form a disposable and replacement part of the renal therapy system, and can be replaced by a fresh sorbent cartridge, for instance when it has been saturated with toxic substances, or if one or more of the components supplemented to the plasma have run out.
The sorption cartridge of the present disclosure may be used for filtering or purification of the blood of patients with a (developing) renal failure. In an embodiment, the sorption cartridge may be used in a wearable artificial kidney device, but can also be embodied in desktop sized equipment or in adapted hemodialysis or peritoneal dialysis equipment.
The sorption cartridge of the present disclosure may be combined with suitable equipment to expose it to toxins in the blood in order to adsorb those toxins is able to perform some of the functions which normally will be done by a properly functioning human or animal kidney, in particular, filtering of blood and regulation and control of the content of substances in the blood. The sorption cartridge of the present disclosure comprise a sorption system for capturing toxic substances from the blood and optionally a release system for releasing minerals, vitamins or other substances to the blood, a filter for separating blood cells from blood plasma on the basis of hemofilter.
A sorption cartridge according to the present disclosure may be configured to remove urea and other toxic material from blood, plasma or dialysis fluid. Although urea is only toxic in the body at high concentrations (above 15 g/kg) and is neither acidic nor alkaline when dissolved in water, the body generates large volumes each day as part of protein metabolism (greater than 1800 mg per day), which should be removed or the concentration of urea would build-up. Urea is highly soluble in water having a solubility in water of about 1079 g/L at 20° C. Urea, being a molecular substance, does not dissociate into ions but will solvate with water by forming hydrogen bonds which may occur in two ways: hydrogen atoms bonded to water will align to the partially electronegative area of the amine group; and/or oxygen of the carbonyl and the hydrogen bonded to the amine group may be attracted and associated to the oxygen end of a water molecule.
Because urea is soluble in water (solubility of ˜1000 g/L depending upon the temperature) allows urea to be readily diffused across a membrane in standard hemodialysis. However, standard hemodialysis is unable to take advantage of the ability of water to dissolve very high concentrations of urea because the concentration of urea in the dialysate must always be kept lower than the concentration of urea in the blood in order to maintain a concentration gradient for removal of urea from the blood.
A hydrogel sorbent comprises a three-dimensional network of cross-linked polymer chains. The hydrogel sorbent may have a high water content, and may be able to swell and shrink as it absorbs or releases water. A hydrogel sorbent may comprise of a network of polymer chains that may be hydrophilic. The molecular structure of the monomers of polymer chains, which make up the polymeric structure of the hydrogel, may have hydrophilic functional groups that confer hydrophilicity to the hydrogel. The ability of a hydrogel to expand/swell is a function of the density and cross-linking of the gel. In an embodiment, the hydrogel sorbent may be a colloidal gel in which water is the dispersion medium. In another embodiment, a hydrogel sorbent may comprise a three-dimensional solid resulting from hydrophilic polymer chains being held together by cross-links. Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. As a result of the high water concentration, hydrogels are able to absorb large quantities of water-soluble substances such as urea. Hydrogels can also provide absorption by adsorbing electrolytes and uremic toxins into the gel matrix pore structure so that the concentration of the fluids in contact with the membranes that also contact the blood can be kept at a lower concentration than in the blood and so maintain a concentration gradient that will continue to clear urea from the blood. The reaction for toxins to adsorb onto the hydrogel polymeric structure may comprise physisorption, which is a physical entrapment of the toxin molecules within the solid pore structure. The sorbing materials may be functionalized, such as to exhibit improved sorbing properties of toxic substances such as urea as compared to the non-functionalized material. In an embodiment, the sorbing materials are hydrogels with a high water absorbing capacity and an interpenetrating network of pores in order to create a large specific surface area. The hydrogel may enable very high sorption efficiency and therefore enable a small-sized, lightweight and wearable device.
Hydrogels can be prepared in different ways from various materials. Examples of suitable hydrogel materials include polyacrylamide, acrylic acid such as polyacrylic acid, alginate, and chitosan. To enhance the available surface area for adsorption hydrogels may have an interpenetrating network. Increasing surface area may increase the rate and capacity of toxin removal. Hydrogel may be formed as small hydrogel beads, which, in an embodiment, have the specific surface area of at least 0.1 m2/m3. As described herein, hydrogel may be disposed to surround hollow filtration fibres, such as those used in ultrafiltration. In an embodiment, the hollow fibre inner surface area is between 0.1 to 1.0 m2/m3.
Other hydrogel properties that influence toxin removal and/or water removal include pore size, water capacity, and monomer concentration.
The following are examples of methods of manufacturing ahydrogel:
a. To synthesize PEG-functionalized PAAm hydrogels, APS (0.056M) and TEMED (0.32M) are used as redox initiator system.
b. AAm (1.0g) APS (1 mL) and MBAAm (0.05g) were added to 50 mL reactor flask and 5 mLof distilled water is added to it.
c. Then PEG (concentrations between 4.8-20 wt %) was dissolved in the monomer solution, the solution is purged with nitrogen gas for 10 minutes to remove any oxygen present that can react with the initiator.
d. To the above solution add 0.2 mL of TEMED and under a nitrogen environment, transfer the solution into a polypropylene Petri dish.
e. Based on the targeted pore size to be formed on the hydrogel, PEG wt. % and the PEG molecular weight is changed. PEG can be found in many sizes, ranging from <100,000 Da to >1 Million Da. Hydrogels created according to the present disclosure typically use PEG sizes under 100,000 Da. Other porogens can be used as an alternative to PEG, including various molecular weight Polyvinyl alcohol (PVA). In this example, PEG may comprise 4.8 wt % using PEG 4000 (PEGs generally do not react with any other components of the reaction).
f. Leave the Petri dish for 24 hours for the polymerization to continue by maintaining the temperature between 20-27° C.
g. Upon completion of the reaction, the hydrogels are cut into specified shape and size as required and are placed in a large excess amount of water for at least 72 hours with regular water changes at least three times a day to wash away any excess reagents that are unreacted and the pore forming agent.
h. Samples are then dried under room temperature to the constant weight required or swollen as per requirement using water/buffer solution.
a. Preparation of Acidifying agent:
To prepare acidifying agent, follow the formula provided below:
To the above solution add citric acid at the required concentration to induce the anti-coagulant effect. The concentration of citric acid should be between 0.1-2.5mEq/L to induce the anticoagulant effect. The addition of citric acid increases the pH markedly. Hence, the pH may be adjusted after the addition of an alkalizing agent.
b. Preparation of Alkalizing agent:
Add above quantity of NaHCO3 to 100 mL of pure water this is added to the above prepared acidifying agent at a weight ratio of 1:1.26:32.74
Then citric acid is added to adjust the pH between 7.25-7.45 (physiological pH) anything below 7.25 causes acidosis and above 7.45 causes alkalosis.
After 2 hours, the obtained hydrogel is now swollen using the dialysate buffer instead of water. The hydrogel is cut into the required shape and then it is placed in the beaker containing dialysate and is swollen up to 72 hrs. The dialysate buffer is changed at least twice a day to replenish the dialysate buffer and to remove any unreacted components leftover after synthesis of the hydrogel.
The buffer mentioned above can also be directly used in place of deionized water in the synthesis of the hydrogel, this will allow the hydrogel to initially form at the pH required for a dialysate. Once the hydrogel is fully swollen, it can be either cut into the required shape to fit into the diffusion chamber and the diffusion of toxin molecules is monitored.
Properties of hydrogel such as their large water absorption capacity and the porosity formed on the hydrogel allows them to have high levels of saturation for the water-soluble compounds. This porosity allows the compounds diffused into the hydrogel through the semi permeable filter to diffuse slowly into deeper layers of hydrogel, therefore creating a layer with less concentration in and around the semi-permeable membrane leading to the continuous influx of the toxin molecules.
Diffusion of uremic toxins from the high-temperature area to low-temperature area (Soret effect) may improve the ability of hydrogel to absorb toxins. Using the principles of soret effect in the diffusion of uremic toxins through hydrogel creates an unsaturated area around the semi-permeable membrane and on the top layers of the hydrogel. The differential temperature in the hydrogel compartment keeps one part of the hydrogel at one specific temperature while the other half is at a different temperature. This kind of differential temperature arrangement creates thermophoretic mobility in the molecular compounds in the solution/hydrogel leading to their diffusion/movement from higher temperature area to lower temperature area. The thermodiffusion response of a solute is quantified by the Soret coefficient, ST, which is proportional to the concentration gradient that builds as a response to a thermal gradient. A positive Soret coefficient indicates that the solute accumulates on the cold side (thermophobic), while a negative sign denotes drift towards the warm side (thermophilic). As discussed in D. Niether, S. Di Lecce, F. Bresme and S. Wiegand, Phys. Chem. Chem. Phys., 2017, DOI: 10.1039/C7CP05843H, the disclosure of which is incorporated herein by reference in its entirety, urea solutions are thermophobic for the concentrations of 0.1 M and 0.05 M (which are equivalent of 2 g/L and 1 g/L urea solutions, respectively, which are physiologically relevant for dialysis).
As disclosed herein, the soret effect was found to improve the ability of a hydrogel absorb uremic toxin. In an example, maintaining a temperature gradient of ˜20° C. across a small thickness (3 mm) of hydrogel using a peltier cooling device demonstrated improved removal of urea from a urea solution. If the temperature gradient is maintained, the Soret effect drove diffusion of urea from the fibres towards the cooler part of the gel, and utilization of the Soret effect increased the removal capacity of our gel fibre devices when compared to a control experiment.
Continuing the example above, during the experiment, over the 30 minute duration, the experiment utilizing the Soret effect was 1.5× as effective as the control experiment, with mostly the same parameters. The only different parameter was the initial volume, which was greater in the control and normally favor greater diffusion in the control. The results imply that using the Soret effect is at least 1.5× more effective, if not slightly more.
As disclosed herein, vibration may increase the rate of sorption of solutes, such as uremic toxins, into a hydrogel. The transfer of uremic toxins, e.g. urea, from a process fluid may be rapid initially as urea adsorbs onto the surface of the hydrogel, then slows as it must penetrate into the pores to be adsorbed by inner surfaces. In an example, vibration was demonstrated to increase the rate of sorption or urea into a hydrogel. Equivalent amounts of urea solution (with the equivalent of 2.5 grams of urea per 1 liter of water) was placed onto two trays of a hydrogel, each having the same formulation, the hydrogel having a surface area of 124 mm by 55 mm (0.007 m2 surface area) with the thickness of 10 mm. Four 5 volt 11000 RPM vibration motors (DigiKey number is 1528-1177-ND) were installed on one tray to vibrate at frequency of 183 Hz, while no vibration motors were connected to the control tray. Table 3, below, illustrates the increased removal of urea due to vibration
In an embodiment, a vibration element 807 may be provided to vibrate a sorption cartridge according the disclosure herein. As shown in
A sorption cartridge according to the present disclosure may be placed in a dialysis fluid system of a hemodialysis or peritoneal dialysis system enabling the removal of toxins consisting of small-sized molecules, middle-sized molecules, and ionic solutes from the dialysis fluid, such as those illustrated in
A sorption cartridge according to the present disclosure may also form part of a wearable peritoneal dialysis system wherein the sorption cartridge package is placed in the flow path of a wearable peritoneal dialysis system. Due to the continuous removal of toxins by the sorption cartridge, the volume of dialysate fluid can be reduced. The wearable peritoneal dialysis system, such as the system illustrated in
A sorption cartridge according to the present disclosure may also form part of a wearable hemodialysis system wherein the sorption cartridge package is placed in a wearable hemodialysis system. Continuous filtering by the sorption cartridge may permit the volume of dialysate fluid to be reduced to typically 1-2 litres. As described below with reference to
A sorption cartridge according to the present disclosure may also form part of an existing Continuous Renal Replacement Therapy (CRRT) device such that solutions from the bags containing ultrafiltrate or used dialysis solutions could be circulated through a purification cartridge utilizing this technology so that the solutions could be continuously reused.
A sorption cartridge according to the present disclosure may also form part of an existing portable dialysis machine such that solutions from the bags containing ultrafiltrate or used dialysis solutions could be circulated through such a purification cartridge utilizing this technology so that the solutions could be continuously reused so that much less solution is required to complete a treatment. The use of such a system may further reduce the constraints on fluid use in a portable system so that higher dialysate flow rates may be used to improve clearance rates and reduce required dialysis times or reduce the need for higher blood flow rates.
A sorption cartridge according to the present disclosure may also form part of an existing hemodialysis machines in such a way that the used dialysis solution could be circulated through such a purification cartridge utilizing this technology and back to the dialyser so that the solution could be continuously reused so that much less solution is required to complete a treatment. Used in this way a continuous supply of purified water is not required. Some of the existing fluid management mechanisms of the dialysis machine such as pressure sensors, blood leak detectors and ultrafiltration pumps and metering systems may continue to be used in this mode. This may allow the flexibility to use a regular dialysis machine in situations such as hospital rooms and home therapies where it is difficult or costly to provide a reliable supply of purified water. This capability may also allow dialysis clinics to continue to provide treatment in cases where safe water supply is interrupted such as floods, earthquakes or other natural disasters. The use of existing machines in such situations would enable the staff that work in that clinic to continue to provide the treatment with minimal additional training.
A sorption cartridge according to the present disclosure may, in any embodiment, further comprise means for supplementing the (purified) blood plasma or dialysate fluid with at least one substance selected from the group consisting of minerals such as calcium, sodium, and potassium; anticoagulants; antimicrobial agents and other medicaments.
A sorption cartridge according to the present disclosure may, in any embodiment, further comprise means for selective sorption of middle molecules, vitamins, and minerals such as calcium, sodium, and potassium. The hydrogel may therefore be loaded with a certain amount of minerals, vitamins, or electrolytes and can only absorb a designated amount.
Optionally, a sorption cartridge according to the present disclosure may incorporate other ion exchange systems.
In another aspect, the present invention provides a method for removing toxic substances from the blood using a sorption cartridge according to the present disclosure.
The sorption cartridge of the present disclosure may take the form of a commercially available hollow fiber dialyser where the dialysate compartment is filled with the sorption material described herein.
In an embodiment, other suitable sorbing materials as small particles may be interspersed within the whole or part of hydrogel in order to enhance the sorbing or electrolyte control of the cartridge. Examples of other suitable sorbing materials may be but are not limited to activated carbon particles, nanoclay particles, graphene-based nanostructured particles, zirconium phosphate particles, and hydrous zirconium oxide particles. Additional sorbent elements can be incorporated at any stage in the device, but preferably it is incorporated in the sorption cartridge system.
Renal therapy, e.g. dialysis, may replace the blood purification function of kidneys. However, the kidney is also responsible for production of Erythropoietin (EPO). EPO is a hormone produced by the kidney that promotes the formation of red blood cells by the bone marrow. Renal anemia is predominantly due to relative EPO deficiency. Many dialysis patients use renal therapy, e.g. hemodialysis machines 3 times per week, for 4 hours at a time. In total such patients would be using dialysis for 12 hours per week. However, a wearable and portable renal therapy system may be connected to the patients with kidney failure more frequently. In some examples, such machines are connected to the patient on a daily basis or even continuously. Therefore, such renal therapy systems are in contact with the blood stream of the patient for a few hours per day to up to 24 hours per day. A wearable or portable renal therapy system may provide an opportunity to perform blood purification more frequently than the existing thrice per week intermittent dialysis. If a drug delivery device, e.g. device (902), is coupled to or integrated with such a wearable/portable renal therapy system, it may provide (EPO) or Erythropoietin Stimulating Agents to be administered as frequently as the renal therapy system is used and for the duration of blood purification or as long as the drug delivery device is in fluid communication with blood.
In the embodiments illustrated in
Drug delivery device (902) may be configured to deliver at least one therapeutic substance to a process fluid. In an embodiment, the therapeutic substance is EPO or Erythropoietin Stimulating Agents. In another embodiment, the therapeutic substance is insulin. In another embodiment, the therapeutic substance is a drug including at least one of a PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) specific antibody, a granulocyte colony-stimulating factor (G-CSF), a sclerostin antibody, or a calcitonin gene-related peptide (CGRP) antibody. In another embodiment, the therapeutic substance is at least one of mineral(s), e.g. iron; and a vitamins(s), e.g. vitamin B12 and/or folate.
Purification device (901) may comprise an interface for coupling with drug delivery device (902). In an example, drug delivery device (902) may be releasably couplable to the interface of purification device (901). Drug delivery device (902) may be coupled to the interface of purification device (901) through power connection (904) and fluid connection (905a). Power connection (904) and fluid connection (905a) may provide power and fluid flow connections between the drug delivery device (902) and the purification device (901) respectively. Power connection (904) may be a male/female electrical power connection to allow for releasable coupling with a power source (not shown) for purification device (901). Fluid connection (905a) may comprise a releasable coupling to allow fluid communication to a process fluid in purification device (901). In an example, fluid connection (905a) may be connected to blood line (25) or dialysate line (27) of systems (200), (300), (400), (500) described herein and illustrated in
The drug delivery device (902) is in fluid communication with a vascular access (903) through blood tubes (906a) and (906b), which are used to flow the blood into and out of renal therapy system (900) from patient P. Blood tubes (906a) and (906b) may be an arterial line having inlet (19a) and outlet (19b) as illustrated in
The above description is meant to be exemplary only, and one skilled in the relevant arts will recognize that changes may be made to the embodiments described without departing from the scope of the invention disclosed. The present disclosure may be embodied in other specific forms without departing from the subject matter of the claims. The present disclosure is intended to cover and embrace all suitable changes in technology. Modifications which fall within the scope of the present invention will be apparent to those skilled in the art, in light of a review of this disclosure, and such modifications are intended to fall within the appended claims. Also, the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
The disclosure of the above references are each hereby incorporated herein by reference their entirety.
The present application claims priority to U.S. Provisional Patent Application No. 62/978,813 filed on Feb. 19, 2020, the entire contents of which are hereby incorporated by reference, and to International Application No. PCT/US2020/026716 filed on Apr. 3, 2020, the entire contents of which are hereby incorporated by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/018867 | 2/19/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62978813 | Feb 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2020/026716 | Apr 2020 | US |
| Child | 17904662 | US |
