Methods of amelioration of cerebrospinal fluid, and devices and systems therefor

Abstract

To provide cerebrospinal fluid (CSF) and other fluid amelioration systems completely or partially implantable in a mammalian subject, and associated methods.SOLUTION: The cerebrospinal fluid (CSF) and other fluid amelioration systems completely or partially implantable in a mammalian subject and associated methods include a substrate and an agent for amelioration of a toxic biomolecule present in the CSF or fluid, where the agent is disposed on or in the substrate.SELECTED DRAWING: Figure 15A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 832,486, filed April 11, 2019, the entire disclosure of which is incorporated herein by reference in its entirety. This application also claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 960,861, filed January 14, 2020.

[0002] Various embodiments of the present invention provide systems and methods for improving fluid flow within the subarachnoid space, and more specifically, methods and systems in which an improvement agent disposed, placed or located on a structure in fluid communication with the subarachnoid space of a mammalian subject improves the biomolecules contained within the subarachnoid space. [Background technology]

[0003] Many neurodegenerative diseases are related to the accumulation of biomolecules (e.g., toxic proteins) contained in cerebrospinal fluid (CSF) or other fluids (e.g., interstitial fluid) in the subarachnoid space (SAS) of mammalian subjects. The problem is that these (e.g., toxic) biomolecules can be secreted and transported by the CSF to other cells in the body, a process that can occur over many years. For example, dipeptide repeat proteins (DPRs) and / or TDP-43 have been implicated in neuronal cell death in the pathologies of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), Alzheimer's disease (AD), frontotemporal degeneration (FTD), Parkinson's disease (PD), Huntington's disease (HD), and progressive supranuclear palsy (PSP), to name just a few. Thus, research has focused primarily on removing harmful DPRs. Techniques for removing DPR and / or TDP-43 include shunting the CSF from the CSF space, diluting the CSF (e.g., with artificial fluids), administering drugs to the CSF, conditioning the CSF, and / or manipulating CSF flow, however, these conventional techniques often result in complications.

[0004] Summary of the Invention As a result, it is desirable to provide in situ and other systems and methods for the improvement of CSF and other fluids (e.g., interstitial fluid) within the SAS by partially or completely implanting the system or components thereof in vivo (e.g., completely or primarily within the SAS).

[0005] In a first aspect, some embodiments of the present invention relate to a method for treating a mammalian subject suffering from at least one of a pathology, trauma, neurological disease, non-neurological disease, or deficiency characterized by the presence of a toxic biomolecule in the CSF. In some embodiments, the method includes ameliorating the toxic biomolecule in the CSF using an ameliorating agent, ameliorating technique, or a combination thereof (e.g., via enzymatically digesting the toxic biomolecule, and / or by disposing pin1, exosomes, and / or live cells in a cartridge and circulating the CSF through the cartridge). In some variations, enzymatically digesting the toxic biomolecule may include enzymatically digesting the toxic biomolecule using a protease. The amelioration of the toxic biomolecule may occur, at least in part, in the ventricular space of the subject, the subarachnoid space of the subject, and / or the lumbar region of the subject.

[0006] In some embodiments, the method includes the steps of selecting a patient having at least one symptom of a pathology, trauma, neurological disease (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and Parkinson's disease (PD), cancer, intracranial metastatic disease (IMD), diabetes, type 3 diabetes, lupus, poisoning, chronic traumatic encephalopathy (CTE), bacterial meningitis, aneurysm, stroke, cerebral vasospasm, and traumatic brain injury), non-neurological disease, or deficiency, and administering a volume (e.g., about 0.1 mL / min to about 100 mL / min) of the blood to the patient. The method may include removing a volume of CSF (between about 1 mL and about 200 mL at a flow rate of 1 mL to about 200 mL) from a first location (e.g., a location within the lumbar CSF space), processing the volume of CSF with the cartridge to treat (e.g., remove, reduce, modify, sequester, digest, neutralize, or inactivate) disease states such as substances (e.g., tau, cis p-tau, amyloid beta, TDP-43, SOD1, DPR, neurofilaments, and alpha-synuclein), e.g., by enzymatic activity, and returning the processed volume of CSF to the patient at a second location (e.g., a location within the cervical CSF space or the ventricular CSF space). In some applications, method embodiments also include waiting a first length of time after removing the volume of fluid from the patient and / or waiting a second length of time after returning the processed volume of fluid to the patient.

[0007] In some embodiments, the method may also include using a sensor to measure a characteristic of the processed amount of CSF, and returning the processed amount of CSF to the patient at a second location in the patient's cervical CSF space and / or ventricular CSF space. In some variations, due to the bidirectional and / or dual flow nature of the method, in the alternative, a volume of CSF may be removed from a first location in the patient's cervical CSF space and / or ventricular CSF space, and the processed amount of CSF to the patient may be returned to a second location in the patient's lumbar CSF space. Additionally, the CSF may be reversibly flowed through the enzyme cartridge one or more times to increase residence time in the cartridge and enhance the efficacy and effectiveness of the treatment. Preferably, the processed CSF is returned to the patient at substantially the same rate as the volume of CSF is removed. In some embodiments, these steps may occur at least partially simultaneously. Optionally, the method may include filtering the processed CSF with a getter to capture unbound enzymes prior to returning the processed CSF to the patient.

[0008] In some variations, the method also includes updating one or more parameters of the set of process operational parameters based on the measured CSF characteristics meeting or exceeding a predetermined threshold. The operational parameters may be set to maintain a particular pressure and / or a particular volume.

[0009] In some embodiments, the method may include repeating the steps of retrieving, processing, returning, and / or updating parameters of a set of processing operational parameters (e.g., parameters that maintain at least one of a particular pressure, a particular volume change, and a particular flow rate within the patient's CSF space) based on measured fluid characteristics that meet or exceed predetermined thresholds until one or more criteria are met.

[0010] In some variations, the amount of CSF removed is equal to or greater than the amount of processed CSF returned. Preferably, the amount of CSF is returned to the patient at substantially the same rate as the amount of CSF is removed from the patient.

[0011] In a second aspect, some embodiments of the present invention relate to a CSF improvement system for use in fluid communication with a mammalian subject (e.g., implantable (fully or partially) within a mammalian subject). In one embodiment, the system includes a substrate (e.g., a cartridge) and an improvement agent. The improvement agent can be an enzyme disposed on the inner surface of the cartridge and / or an enzyme applied to the inner surface of the cartridge. Alternatively, the improvement agent can include pin1, exosomes, and / or live cells disposed within the cartridge.

[0012] In one embodiment, the ameliorating agent modifies or degrades biomolecules present in the CSF by enzymatic digestion, and in some variations, the enzymes used in the enzymatic digestion are proteases (e.g., trypsin; elastase; cathepsin; clostripain; calpains, including calpain-2; caspases, including caspase-1, caspase-3, caspase-6, caspase-7, and caspase-8; M24 homologs; human airway trypsin-like peptidase; proteinases, such as ribosome-specific endothelial cell line (RICL), ribosome-specific endothelial cell line (RICL), or ribosome-specific endothelial cell line (RICL). The proteinase may be selected from the group consisting of: enzyme K; thermolysin; Asp-N endopeptidase; chymotrypsin; LysC; LysN; glutamyl endopeptidase; staphylococcal peptidase; arg-C proteinase; proline-endopeptidase; thrombin; cathepsin E, S, B, K, L1; tissue type A; heparinase; granzymes including granzyme A; meprin alpha; pepsin; endothiapepcallikrein-6; kallikrein-5, and combinations thereof.

[0013] Exemplary embodiments of the substrate may include a substrate that is foldable and / or flexible to facilitate catheter-based implantation within a subject, a substrate that includes a plurality of cilia (e.g., ciliary projections extending from an outer shell portion, retractable and / or extendable fibers and / or brush fibers from within the substrate), beads (e.g., superparamagnetic beads) disposed within or on the substrate (e.g., a reservoir), a dialysis membrane catheter, a tubular device that includes a biomolecular improvement agent, and / or a plurality of appendages.

[0014] In some applications, the system also includes a subcutaneous port for sampling the CSF, introducing, removing, or replenishing an ameliorant, introducing or removing a substrate, introducing a drug, and / or chronically maintaining a drug. In another application, the system may also include one or more CSF fluid loops with access ports (e.g., a first access port and a second access port) for enhancing CSF flow across the substrate, and one or more of sensors (e.g., temperature sensors, pressure sensors, pH sensors, UV sensors, IR sensors, turbulence sensors, Raman scattering sensors, dynamic light scattering sensors, constituent concentration sensors, flow sensors, and combinations thereof) located in the CSF loop, pumps (e.g., peristaltic pumps, rotary vane pumps, Archimedes screws, air bladders, pneumatic bladders, hydraulic bladders, displacement pumps, electric pumps, passive pumps, automatic pumps, valveless pumps, bidirectional pumps, and combinations thereof), valves (e.g., one-way valves, bicuspid valves, tricuspid valves, ruby ​​valves, and combinations thereof), and / or actuators located in the CSF loop. Preferably, a system controller (e.g., an open loop controller, a closed loop controller, a PID controller, a PID threshold controller, a system identification algorithm, and combinations thereof) may be operatively coupled to one or more of the sensors, pumps, and / or actuators.

[0015] In some variations, the system may also include a stent and / or a pump (e.g., having porous walls) and / or an actuator, such that the biomolecule improvement agent is applied to the inner surface of the pump, and more specifically, the biomolecule improvement agent is retained by the porous walls.

[0016] In some applications, the system also includes one or more of a CSF direction system, a jugular catheter, a timber catheter, or a ventricular catheter, and one or more sensors for measuring or sensing CSF components and / or CSF properties. The control system may maintain the pressure and / or flow of the CSF within the mammalian subject. In some variations, the control system has a programmable memory, a data processing system, and a communication subsystem, while the CSF direction system has a pump, tubing, T-valves, anti-reflux valves, and / or shutoff valves, and an access port and / or a subcutaneous access port.

[0017] In some embodiments, processing the amount of CSF may include filtering the amount of CSF using at least one of size filtration, ion filtration, tangential flow filtration, countercurrent tangential flow filtration, ultrafiltration, notch filtration, serial filtration, or cascade filtration. In other embodiments, processing the amount of CSF may include removing waste products, exposing the amount of CSF to enzymatic digestion, exposing the amount of CSF to a bioaffinity interaction with or without an antibody, exposing the amount of CSF to ultraviolet radiation, exposing the amount of CSF to heat or cold or a temperature change, introducing the amount of CSF to an electromagnetic field, exposing the amount of CSF to a pressure change, exposing the amount of CSF to a pH change, or exposing the amount of CSF to a manipulation agent (e.g., magnetic beads, nanoparticles, optical tweezers, and combinations thereof) alone or in combination with a bioaffinity agent.

[0018] In some applications, the methods may also include maintaining a reduced toxic biomolecule content in the CSF after the initial toxic biomolecule content in the CSF has been reduced, charge or size filtering the CSF to filter out toxic biomolecules, antibody or nanobody treatment of the CSF to filter out toxic biomolecules, a combination of enzymatic and charge or size filtration methods to filter out toxic biomolecules, and / or enhancing the naturally occurring (e.g., focused) flow of the CSF.

[0019] In some embodiments, the ameliorating agent can be introduced into the CSF in the subarachnoid space of the subject. In other embodiments, the ameliorating agent can be disposed on a solid, foldable, or flexible structure that can be implanted into the subject (e.g., by catheter-based implantation). In some variations, the structure includes one or more of a substrate, cilia, cilia extending from a substrate, fibers, fibers extending from a substrate, appendages, appendages extending from a substrate, fenestrations, beads, a plurality of beads, a bi-stable monolithic structure, an exposed appendage, a stent, a catheter, a cartridge, a slurry, and combinations thereof.

[0020] In some embodiments, the structure comprises cilia on a surface (e.g., a hydraulically activatable surface, a pneumatically activatable surface, and / or a shape-memory surface), which in some variations may comprise an outer shell surrounding an inner core. Using such compositions, the method may further comprise expanding the outer shell on which the cilia are formed, expanding the inner core such that CSF located between the inner core and the outer shell passes through the cilia, and collapsing the inner core and the outer shell.

[0021] In other embodiments, the structure may include fibers. Using such compositions, the method may include extending the fibers from within the delivery device into the CSF and storing the fibers within the delivery device.

[0022] In yet another embodiment, the structure includes a monolithic bistable structure with appendages formed thereon. Using such compositions, methods can include expanding the monolithic bistable structure to deploy the appendages into the CSF and expose them from the monolithic bistable structure, and collapsing the monolithic bistable structure to retract the appendages and provide a mixing motion within the CSF.

[0023] In some embodiments of the method, the improvement technique includes introducing an improvement agent outside the subarachnoid space of the subject and allowing circulation of the CSF through the improvement agent (e.g., using an active or passive pump). In some implementations, the embodiment includes returning the treated CSF to the subarachnoid space. In some applications, circulating the CSF and returning the treated CSF may include transporting the CSF (e.g., using a catheter) through multiple catheter insertion locations that access the subarachnoid space, transporting the CSF (e.g., using a multi-lumen catheter arrangement) through a single catheter insertion location that accesses the subarachnoid space, and / or active circulation (e.g., by active or passive pumping) to maintain a controlled fluid flow. In some implementations, circulating the CSF includes disposing the improvement agent in a catheter or cartridge and flowing the CSF through the catheter or cartridge.

[0024] In a third aspect, some embodiments of the present invention relate to a CSF improvement system implantable (e.g., fully or partially) in fluid communication with a mammalian subject. In some embodiments, the system is operable to provide a focused flow of CSF and is configured to include a flow controller, a catheter, a pump, and / or a structure for modifying the flow of fluid. Optionally, the system may also include catheters located at separate fluid access points to the subarachnoid space (e.g., in the lateral ventricle and lumbar sac, in the cisterna magna and lumbar sac, in the cisterna magna and frontal lobe, in the lateral subarachnoid space, and / or in the cervical subarachnoid space and lumbar sac). In some implementations, one or more passive pumps, internal active pumps, and / or passive flow regulators may be implanted substantially within the subarachnoid space.

[0025] In a fourth aspect, some embodiments of the invention relate to a CSF improvement system implantable (e.g., fully or partially) in fluid communication with a mammalian subject. In some embodiments, the system is configured to provide a focused flow of CSF and includes a substrate, an improvement agent disposed on and / or within the substrate, and one or more of a flow controller, a catheter, a pump, and / or a structure for modifying the fluid flow.

[0026] In a fifth aspect, some embodiments of the present invention relate to a method for treating a mammalian subject suffering from at least one of a pathology, trauma, neurological disease, non-neurological disease, or deficiency characterized by the presence of a toxic biomolecule in the CSF. In some embodiments, the method includes ameliorating the toxic biomolecule in the CSF using an ameliorating agent, ameliorating technique, or a combination thereof (e.g., via enzymatically digesting the toxic biomolecule, and / or by disposing pin1, exosomes, and / or live cells in a cartridge and circulating the CSF through the cartridge). In some variations, enzymatically digesting the toxic biomolecule may include enzymatically digesting the toxic biomolecule using a protease. The amelioration of the toxic biomolecule may occur, at least in part, in the ventricular space of the subject, the subarachnoid space of the subject, and / or the lumbar region of the subject. In some applications, the method may include reversibly flowing the CSF through an enzyme cartridge.

[0027] In yet another embodiment of the method, the improvement technique includes circulating the CSF in a flow from a first location in the subarachnoid space to a second location in the subarachnoid space (e.g., actively transporting the CSF using an automated bladder pump). In some variations, the flow remains substantially within the subarachnoid space. In some applications, the method also includes allowing the CSF to circulate outside the subarachnoid space or circulating the CSF at a natural flow rate. The circulation can be from a first location with a low concentration of biomolecules to a location with a high concentration of biomolecules, or from a first location with a high concentration of biomolecules to a location with a low concentration of biomolecules.

[0028] In another embodiment, the method includes increasing the naturally occurring (e.g., focused) flow of CSF (e.g., the phase, direction, and / or amplitude of CSF flow). In some applications, the method may also include circulating an ameliorative agent through the CSF of the subject.

[0029] In yet another embodiment, the method may include the ameliorating agent circulated through the CSF of the subject. In various applications, the ameliorating agent may be circulated through the CSF flowing at natural flow level, the ameliorating agent may be circulated through the CSF outside the subarachnoid space of the subject, and / or the ameliorating agent may be circulated through the CSF substantially within the subarachnoid space of the subject. In some variations, circulating the ameliorating agent through the CSF in the subarachnoid space may include applying the ameliorating agent to a plurality of beads, introducing beads into the CSF in the subarachnoid space (e.g., by containing the beads in a dialysis membrane catheter or a porous bag, by introducing the beads into a slurry, by containing the beads in a tubular device, and / or by containing the beads in a multi-lumen catheter), and imparting motion to the beads. Optionally, a syringe may be used to add or remove beads.

[0030] In some applications, when using a multi-lumen catheter, the method may include introducing beads from a supply reservoir into a first lumen of the multi-lumen catheter, circulating the beads through the first lumen and the second lumen of the multi-lumen catheter, and introducing the beads from the second lumen into a receiving reservoir. Additionally, circulating the ameliorative agent through the CSF outside the subarachnoid space may include applying the ameliorative agent to a plurality of beads, introducing the beads into the CSF outside the subarachnoid space, and circulating the beads. In some variations, the first lumen and the second lumen of the multi-lumen catheter include pores sized to allow CSF biomolecules to pass through the pores while preventing beads from passing through the pores. In other variations, the multi-lumen catheter is operable to allow counterflow.

[0031] In a sixth aspect, some embodiments of the present invention relate to a method of treating a mammalian subject suffering from a neurological or non-neurological condition, neurological or non-neurological trauma, or neurological or non-neurological deficit. In some embodiments, the method comprises circulating CSF in a focused flow in the subject. In some applications, amelioration of toxic biomolecules in the CSF using an amelioration agent, amelioration technique, or a combination thereof. In other embodiments, an amelioration agent is not utilized. In some embodiments, circulating CSF in a focused flow comprises circulating CSF at natural flow levels, allowing CSF flow outside the subarachnoid space, restricting CSF flow only within the subarachnoid space, and / or using a passive pump.

[0032] In a seventh aspect, some embodiments of the present invention relate to a kit for use in improving a fluid taken from a mammalian subject. In some embodiments, the kit includes a ventricular line section removably attachable to a first location of the subject, a lumbar line section removably attachable to a second location of the subject, a circulatory system in fluid communication between the ventricular line section and the lumbar line section, monitoring hardware including a cartridge in operative communication with the circulatory system, the cartridge containing an improving agent for improving the fluid, and a pumping device for taking the fluid, circulating the fluid, and returning the fluid to the subject. In some implementations, the ventricular line section may include a ventricular catheter, a catheter adapter removably attachable to the ventricular catheter, a subcutaneous access port, and a subcutaneous access needle. In some implementations, the lumbar line section may include a lumbar catheter, a catheter adapter removably attachable to the lumbar catheter, a subcutaneous access port, and a subcutaneous access needle. Optionally, the ventricular line section and / or the lumbar line section may include a peritoneal catheter. [Brief description of the drawings]

[0033] Various features and advantages of various embodiments and implementations of aspects of the present invention, as well as the invention itself, can be more fully understood from the following description of various represented embodiments, when read in conjunction with the accompanying schematic drawings. [Figure 1A] FIG. 13 shows a schematic diagram of a passive substrate having multiple cilia with an improvement agent applied thereto after the shell has expanded, according to some embodiments of the present invention. [Figure 1B] FIG. 1B shows a schematic diagram of the passive matrix of FIG. 1A after the inner core has expanded, according to some embodiments of the present invention. [Figure 1C] FIG. 1C shows a schematic diagram of the passive substrate of FIG. 1B after the inner core and outer shell have collapsed, according to some embodiments of the present invention. [Diagram 2] FIG. 2A shows a schematic diagram of a resting (collapsed) state of a monolithic bistable structure having multiple improver-coated cilia formed on multiple appendages, according to some embodiments of the present invention; FIG. 2B shows a schematic diagram of an inset of a gap between a pair of appendages from FIG. 2A, according to some embodiments of the present invention; and FIG. 2C shows a schematic diagram of an expanded state of the monolithic bistable structure of FIG. 2A, according to some embodiments of the present invention. [Diagram 3] 1 shows a schematic diagram of a fenestrated flexible structure with an improvement agent applied thereto, according to some embodiments of the present invention. [Figure 4A] 1 shows a schematic diagram of a tubular structure (e.g., a catheter) including a plurality of contained fibers having an improving agent applied thereto, according to some embodiments of the present invention. [Figure 4B] FIG. 4B shows a schematic diagram of the tubular structure of FIG. 4A with improvement agent-applied fibers extending outwardly into the CSF space, according to some embodiments of the present invention. [Diagram 5] FIG. 1 shows a schematic diagram of a coated stent placed in the aqueduct, according to some embodiments of the present invention. [Figure 6] FIG. 1 shows a schematic diagram of a combined enzyme filter and size filter system according to some embodiments of the present invention. [Figure 7A] FIG. 1 illustrates a schematic diagram of a side view of a hydraulic peristaltic pump, according to some embodiments of the present invention. [Figure 7B] FIG. 7C shows a schematic top view of the peristaltic pump of FIG. 7B. [Figure 8A] FIG. 1 shows a schematic diagram of the first stage of a passive pump for driving fluid through a pump using normal pressure fluctuations of a SAS fluid, according to some embodiments of the present invention. [Figure 8B] FIG. 8B shows a schematic diagram of a second stage of the passive pump of FIG. 8A for driving fluid through the pump using normal pressure fluctuations of the SAS fluid, according to some embodiments of the present invention. [Figure 8C] FIG. 8B shows a schematic diagram of a third stage of the passive pump of FIG. 8A for driving fluid through the pump using normal pressure fluctuations of the SAS fluid, according to some embodiments of the present invention. [Figure 8D] FIG. 1 shows a schematic diagram of a passive pump having a porous partition, according to some embodiments of the present invention. [Figure 8E] 1 shows an image of an open-ended balloon catheter pump, according to some embodiments of the present invention. [Figure 8F] 1 shows an image of a closed end balloon catheter pump, according to some embodiments of the present invention. [Figure 9A] 1A-1D show schematic diagrams of structures for actively pumping fluid from the left bladder to the right bladder, according to some embodiments of the present invention. [Figure 9B] FIG. 9B shows a schematic diagram of the structure of FIG. 9A in a quiescent or intermediate (no flow) state, according to some embodiments of the present invention. [Figure 9C] FIG. 9B shows a schematic diagram of the structure of FIG. 9A for actively pumping fluid from the right bladder towards the left bladder, according to some embodiments of the present invention. [Figure 10A] FIG. 1 shows a schematic diagram of a first improved system having a bulk flow system according to some embodiments of the present invention. [Figure 10B] FIG. 1 shows a schematic diagram of a second improved system having a bulk flow system substantially embedded within a SAS, according to some embodiments of the present invention. [Figure 11]FIG. 1 shows a schematic diagram of a multi-lumen catheter including a plurality of circulating beads having an improving agent applied thereto, according to some embodiments of the present invention. [Figure 12A] FIG. 1 shows a schematic diagram of a system for providing focused flow across the motor cortex, according to some embodiments of the present invention. [Figure 12B] 1 shows a schematic diagram of a first system for providing focused flow from a ventricular region to a lumbar region, according to some embodiments of the present invention. [Figure 12C] FIG. 1 shows a schematic diagram of a second system for providing focused flow from the ventricular region to the lumbar region, according to some embodiments of the present invention. [Figure 12D] FIG. 13 shows a schematic diagram of a third system for providing focused flow from the ventricular region to the lumbar region, according to some embodiments of the present invention. [Figure 13] 1 shows a schematic diagram of a pressurized chamber automated pump with a flexible closed-loop cartridge, according to some embodiments of the present invention. [Figure 14A] FIG. 1 shows a schematic diagram of a pressurized chamber automated pump with a balloon-filled cartridge (at rest), according to some embodiments of the present invention. [Figure 14B] FIG. 14B shows a schematic diagram of the pressurized chamber automated pump of FIG. 14A with the balloon collapsed due to an increase in ambient pressure, according to some embodiments of the present invention. [Figure 14C] FIG. 14B shows a schematic diagram of the pressurized chamber automated pump of FIG. 14A with the balloon inflated due to a reduction in ambient pressure, according to some embodiments of the present invention. [Figure 15A] FIG. 1 shows a schematic diagram of an exemplary system for extracorporeal remediation of fluids (e.g., CSF), according to some embodiments of the present invention. [Figure 15B] 15B shows a schematic diagram of a front and rear view of a control system and a pump system for the system shown in FIG. 15A according to some embodiments of the present invention. [Figure 15C] 15B shows a schematic diagram of a fluid direction system of the system shown in FIG. 15A according to some embodiments of the present invention. [Figure 16]15B shows a flowchart of a method for extracorporeal remediation of CSF using the system shown in FIG. 15A according to some embodiments of the present invention. [Figure 17] FIG. 1 shows a schematic diagram of a three-stage tangential flow filtration subsystem integrated with an enzyme cartridge and subsequent getter, according to some embodiments of the present invention. [Figure 18] 1 shows a schematic diagram of a cartridge, according to some embodiments of the present invention. [Figure 19] 1 shows a block diagram of a remediation kit according to some embodiments of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Although embodiments of the present invention are described primarily with respect to treating neurological disorders in fluids, and more specifically with respect to improving cerebrospinal fluid (CSF) from a mammalian subject, the systems, methods, and techniques described herein are equally applicable to non-neurological diseases and disorders, as well as applications and conditions (e.g., cancer, intracranial metastatic disease (IMD), diabetes, type 3 diabetes, lupus, poisoning, chronic traumatic encephalopathy (CTE), bacterial meningitis, aneurysm, stroke, cerebral vasospasm, traumatic brain injury, rheumatoid arthritis, drug overdose, certain trauma, etc.). Additionally, embodiments of the present invention also apply to conditions and uses in live cells. For example, certain embodiments and applications or implementations of the present invention can provide an access point for delivering live cells or exosomes to fluids (e.g., CSF) and the nervous system. More specifically, live cells or other organisms (e.g., yeast, bacteria, viruses, etc.) can be placed in an external (external) cartridge that provides secreted products that can benefit, for example, the health of the central nervous system. The CSF can be passed through the cartridge containing the live cells.

[0035] definition As used in this specification and the accompanying claims, the following terms are intended to have the meanings indicated unless the context requires or makes clear a different meaning.

[0036] A biomolecule refers to any molecule that can be produced by or resembles a living system (i.e., an organism). By way of example and not limitation, biomolecules can include RNA, DNA, proteins, peptides, lipids, carbohydrates, polysaccharides, nucleic acids, oligonucleotides, antisense oligonucleotides, polynucleotides, amino acids, enzymes, antibodies, nanobodies, molecularly imprinted polymers, primary metabolites, secondary metabolites, and natural products.

[0037] Fluid refers to any fluid biological medium present in the subarachnoid space or elsewhere in a subject, such as fluid media including cerebrospinal fluid (CSF), interstitial fluid (ISF), blood, sweat, tears, semen, lymph, urine, breast milk, and the like.

[0038] The cerebrospinal fluid space refers to the volume within the blood-brain barrier, including the subarachnoid space.

[0039] A subject or patient refers to a mammal (eg, a human or animal) undergoing medical treatment, diagnosis, monitoring, research, or care.

[0040] Extracorporeal refers to occurring outside the mammalian body, and may be used interchangeably herein with the terms extracorporeal and ex vivo.

[0041] In situ refers to occurring within the mammalian body, and may be used interchangeably with the term in vivo.

[0042] improvement Embodiments of the present invention generally provide systems and methods for amelioration of fluid (e.g., cerebrospinal fluid (CSF), interstitial fluid (ISF), blood, etc.) within the subarachnoid space (SAS) of a mammalian subject, referred to herein as CSF unless otherwise distinguished (e.g., simply referred to as CSF). Exemplary systems may be fully or partially implanted within the body of a mammalian subject. Within the body, the system and / or its components may also be fully or partially implanted within the SAS. Methods may include steps that may occur entirely in vivo or may include some steps that occur outside the body.

[0043] Improvement may include, by way of example and not limitation, altering the physical parameters of the fluid, as well as digesting, removing, fixing, reducing, and / or modifying to become more acceptable, and / or inactivating certain entities, including target molecules, proteins, aggregates, viruses, bacteria, cells, couples, enzymes, antibodies, substances, and / or any combination thereof. For example, in some embodiments and applications of the invention, improvement may refer to removing toxic proteins from or adjusting one or more of the blood, interstitial fluid, or lymphatic fluid or other fluids contained therein, and the impact of this removal in treating a disease or condition that affects various bodily functions (i.e., improving the clinical condition of the patient). Further, improvements may be performed by any one of digestion, enzymatic digestion, filtration, size filtration, tangential flow filtration, countercurrent cascade ultrafiltration, centrifugation, separation, magnetic separation (including nanoparticles and the like), electrophysical separation (performed by one or more means of enzymes, antibodies, nanobodies, molecularly imprinted polymers, ligand-receptor complexes, and other charge and / or bioaffinity interactions), photonic methods (including fluorescence activated cell sorting (FACS), ultraviolet (UV) sterilization, and / or optical tweezers), photoacoustic interactions, chemical treatments, thermal methods, and combinations thereof. Advantageously, various embodiments or implementations of the present invention may reduce the level of toxicity and, once reduced, may facilitate maintaining the reduced level over time.

[0044] The degree of improvement, as reflected by the concentration of the target biomolecule, can be detected by various means. These include optical techniques (e.g., Raman, coherent Stokes, and anti-Stokes Raman spectroscopy, surface-enhanced Raman spectroscopy, diamond nitrogen vacancy magnetometry, fluorescence correlation spectroscopy, dynamic light scattering, etc.) and the use of nanostructures such as carbon nanotubes, enzyme-linked immunosorbent assays, surface plasmon resonance, liquid chromatography mass spectrometry, and circular proximity ligation assays.

[0045] The modifications may include treatment systems (eg, UV radiation, IR radiation) as well as the use of materials whose properties make them suitable for modification.

[0046] Improved CSF or improved CSF are terms that may be used interchangeably herein and refer to a processed amount of CSF from which one or more target compounds have been partially, largely, or completely removed. As used herein, the term removed may refer not only to spatial separation, as in the case of removal, but also to effective removal by isolating, fixing, or transforming the molecule (e.g., by shape change, denaturation, digestion, isomerization, or post-translational modification) to make it less toxic, non-toxic, or irrelevant.

[0047] An improvement agent refers to any material or process capable of improving a fluid, including enzymes, antibodies or antibody fragments, nucleic acids, receptors, antibacterial agents, antiviral agents, anti-DNA / RNA, proteins / amino acids, carbohydrates, enzymes, isomerases, compounds with high or low biospecific binding affinity, aptamers, exosomes, ultraviolet light, temperature changes, electric fields, molecularly imprinted polymers, living cells, etc.

[0048] Improvement by enzymatic digestion The improvement of biomolecules in CSF can also be by enzymatic digestion, and thus in some embodiments and applications, the improvement agent modifies or degrades biomolecules in CSF. To that end, enzyme-substrate pairs can be selected by panel and counter panel search. For example, a panel of candidate enzymes for digesting biomolecules can be graded for stability, commercial availability, and related interaction mechanisms, while a counter panel can ensure that the candidate enzyme does not affect substances in CSF that the enzyme should not change. Alternatively, enzymes can be discovered through microbial screening, such as mutant hunts or nitrogen viability assays. In yet another embodiment, enzymes can be selected using biomolecular engineering computational models.

[0049] The improved methods and chemistries are described in International Patent Application Nos. PCT / US2019 / 042880 and PCT / US2019 / 042879, both entitled "Methods of Treating Neurological Disorders," filed July 22, 2019, the disclosures of which are incorporated by reference in their entireties herein.

[0050] In some embodiments, agents for use in the improvement system may include trypsin; elastase; clostripain; calpains, including calpain-2; caspases, including caspase-1, caspase-3, caspase-6, caspase-7, and caspase-8; M24 homolog; human airway trypsin-like peptidase; proteinase K; thermolysin; Asp-N endopeptidase; chymotrypsin; LysC; LysN; glutamyl endopeptidase; staphylococcal peptidase; arg-C proteinase; proline-endopeptidase; thrombin; cathepsins, including cathepsin E, S, B, K, or L1; tissue type A; heparinase; granzymes, including granzyme A; meprin alpha; pepsin; endothiapepsin; kallikrein-6; kallikrein-5, and combinations thereof. In other embodiments, pin1, exosomes, and / or live cells may be used as ameliorative agents.

[0051] Toxic protein modification Various applications of the present invention provide methods for treating neurological disorders or related conditions characterized by the presence of a toxic protein in the CSF, the methods comprising contacting the CSF of a subject in need thereof with an effective amount of a post-translationally modified protein capable of modifying the toxic protein, in situ or otherwise, thereby reducing the concentration of the toxic protein.

[0052] In some embodiments, the substrate, target molecule, or substance is a reactive oxidized species of beta amyloid (any species or form) or tau (or any number of hyperphosphorylated tau isoforms (e.g., tau protein aggregates, tau protein tangles, tau oligomers, hyperphosphorylated tau protein, soluble tau protein, tau dimers, cis p tau) protein, inflammatory mediators (e.g., cytokines including TNF-a, IL-1, IL-2, IL-6, IL-12, interferon-y, etc.), alpha-synuclein, phospholipids ... proteins (including peptides or oligomers), insoluble superoxide dismutase-1 (SODI) (e.g., mutant proteins or misfolded wild-type SOD1 protein), glutamate, neurofilament proteins, and anti-GM1-ganglioside antibodies, anti-AGM1-ganglioside antibodies, and sulfatides, blood cells (e.g., red blood cells), oxyhemoglobin, endothelin, inflammatory mediators, bacterial or viral entities, tumor necrosis factor-α (TNFa) and IgG, C5a, TNF a, IL 2, IL-6, interferon-γ, IgG, and endotoxin, T cells, B cells, anti-myelin antibodies, and inflammatory mediators including, but not limited to, TNF a, IL 2, IL-6, interferon-γ, endothelin, and enolase, DPR, circulating tumor cells. In certain embodiments, the toxic protein is a mutant FUS / TLS protein. In certain embodiments, the toxic protein is a toxic form.

[0053] The microtubule-associated protein tau is a major component of neurofibrillary tangles (NFTs) associated with AD and tauopathies, characterized by tau hyperphosphorylation and aggregation. Tau is an inherently unstructured protein due to its very low hydrophobic content, including the projection region, basic proline-rich region, and assembly region. Tau is known to undergo various post-translational modifications, including acetylation, deamidation, glycation, glycosylation, isomerization, methylation, nitration, phosphorylation, proteolysis, sumoylation, and ubiquitination. Hyperphosphorylation of tau, especially in the assembly region, reduces the affinity of tau to microtubules and impairs its ability to regulate microtubule dynamics and axonal transport. In addition, the basic proline-rich region and part of the pseudorepeats also stabilize microtubules by interacting with its negatively charged surface. Alternative splicing of two N-terminal insert regions and exon 2, exon 3, and exon 10 of tau generates six tau isoforms of different lengths in the CNS. The assembly region in the carboxyl-terminal portion of the protein contains three or four repeats (3R or 4R) of a conserved tubulin-binding motif, depending on alternative splicing of exon 10. Tau 4R isoforms have higher microtubule binding and stabilizing capacity than 3R isoforms. Human adult brains have similar levels of 3R and 4R isoforms, but at fetal stages, only 3R tau is expressed. In tauopathies, mutations that alter the splicing of tau transcripts and the ratio of 3R and 4R tau isoforms are sufficient to cause neurodegenerative disease. In addition to full-length tau protein isoforms, certain tau fragments (e.g., fragments resulting from endogenous protease cleavage) also exhibit a tendency to polymerize or aggregate, an ability to promote the polymerization or aggregation of another tau isoform or fragment, and / or an ability to propagate tau polymerization or aggregation to other cells, thereby resulting in neurotoxicity.Such tau fragments include, but are not limited to, fragments 14-441, 26-230, 1-314, 26-44, 1-44, 1-156, 45-230, 243-441, 256-441, 256-368, 1-368, 1-421, 151-421, 1-391, and X-441, where X is any integer between 182 and 194 (amino acid positions numbered according to the sequence of the 2N4R isoform). In addition to these tau fragments, certain other fragments, such as fragments 124-441 and 1-402 (amino acid positions numbered according to the sequence of the 2N4R isoform), may be useful as biomarkers for diagnosing neurological disorders or for monitoring patient progression or response to treatment. Post-translational modifications of tau, such as phosphorylation and isomerization (cis or trans isomers), also greatly affect the ability of tau to aggregate. For example, hyperphosphorylation of tau at serine and threonine residues preceding proline (pSer / Thr-Pro) results in insolubility and causes neurofibrillary tangles (NFTs). Phosphorylation of tau, particularly at Thr231-Pro, allows the binding of prolyl isomerase Pin1, which catalyzes the conversion between the cis and trans forms. Phosphatases such as PP2A catalyze the dephosphorylation of tau only in the trans form. In view of the above, tau in human brain tissues may exist in a variety of different lengths and forms, with multiple post-translational modifications. As used herein, the term "tau" includes various isoforms and fragments of tau protein in any folded state, with one or more post-translational modifications. As tau progresses from normal to NFTs, the protein passes through a "soluble" state in which it can become hyperphosphorylated, mislocalized, conformationally changed, and / or oligomerized but is not yet fibrillar.

[0054] Post-translationally modified proteins In some embodiments, embodiments of the present invention provide a method for treating a neurological injury or related condition characterized by the presence of a toxic protein in the CSF, the method comprising contacting the CSF of a subject in need thereof with an effective amount of a post-translationally modified protein capable of modifying the toxic protein, thereby reducing the concentration of the toxic protein.

[0055] In some variations, embodiments also provide compositions comprising the CSF of a subject having a neurological disorder or related condition characterized by the presence of a toxic or pre-toxic form of a toxic protein in the CSF, and a post-translationally modified protein capable of modifying the toxic protein, thus reducing the concentration of the toxic protein.

[0056] The selective alteration of toxic or pre-toxic forms of toxic proteins by the post-translationally modified proteins of the embodiments of the present invention is achieved by a combination of substrate selectivity (the post-translationally modified protein preferentially recognizes the toxic or pre-toxic forms of the toxic protein), active site specificity (the post-translationally modified protein has specificity for cleaving peptide bonds of residue motifs encountered in the toxic or pre-toxic forms of the toxic protein), substrate affinity (based on binding kinetics), and enzymatic efficiency (rate of the enzymatic reaction). In certain embodiments of the present invention, the post-translationally modified protein is a mammalian, microbial (e.g., fungal, bacterial, or viral), or plant protein.

[0057] In other aspects and embodiments of the invention, the post-translational modification protein may be a phosphatase, an isomerase, a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), a ubiquitin ligase (E3), a kinase, an acetylase, a deacetylase, a glycosylase, or a deglycosylase.

[0058] Phosphatase Phosphatases are enzymes that remove phosphate groups from phosphorylated amino acid residues of substrate proteins. In certain variations of the present embodiment, the post-translationally modified proteins are PP1, PP2A, PP2B, PP4, PP5, PP6, PP7, PP2C, VHR, DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUSP10, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP17, DUSP18, DUSP19, DUSP20, DUSP21, DUSP22, DUSP23, DUSP24, DUSP25, DUSP26, DUSP27, DUSP28, PHP, PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP2CB , PPP3CA, PPP3CB, PPP3CC, PPP4C, PPP5C, PPP6C, CDC14A, CDC14B, CDC14C, CDKN3, PTEN, SSH1, SSH2, SSH3, CTDP1, CTDSP1, CTDSP2, CTDSPL, DULLARD, EPM2A, ILKAP, MDSP, PGAM5, PHLPP1, PHLPP2, PPEF1, PPEF2, PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPTC7, PTPMT1, SSU72, and UBLCP1.

[0059] Isomerase Isomerases are enzymes that catalyze the conversion of molecules from one isomeric structure to another. Intramolecular bonds are broken and formed during isomerization, resulting in molecules with the same molecular formula but different bond connectivity or spatial arrangement. In certain embodiments of the present invention, the post-translational modification protein is selected from the group consisting of FK506 binding protein 4 (FKBP52), FK506 binding protein 51 (FKBP51, also known as FKBP5), FK506 binding protein (FKBP12), peptidyl prolyl cis / trans isomerase NIMA interacting 1 (Pin1), alanine racemase, methionine racemase, lactate racemase, tartrate epimerase, ribulose phosphate 3-epimerase, UDP-glucose 4-epimerase, methylmalonyl CoA epimerase, hydan maleate isomerase, maleylacetoacetate isomerase, maleylpyruvate isomerase, linoleate isomerase, furylfuramide isomerase, peptidyl prolyl cis / trans isomerase, and the like. Loryl isomerase, Farnesol 2-isomerase, 2-chloro-4-carboxymethylenebut-2-en-1,4-olide isomerase, Zeta-carotene isomerase, Prolycopene isomerase, Beta-carotene isomerase, Triose phosphate isomerase, Ribose-5-phosphate isomerase, Phenylpyruvate tautomerase, Oxaloacetate tautomerase, Steroid delta isomerase, L-dopachrome isomerase, Protein disulfide isomerase, Prostaglandin-D synthase, Allene oxide cyclase, Lysolecithin acyl mutase, Precorrin-8X methylmutase, Phosphoglucomutase, Phosphopentatase, Beta-lysine 5,6-aminomutase, Tyrosine 2,3-Aminomutase, (hydroxyamino)benzenemutase, isochorismate synthase, methylaspartate mutase, chorismate mutase, muconate cycloisomerase, 3-carboxy-cis,cis-muconate cycloisomerase, tetrahydroxypteridine cycloisomerase, inositol-3-phosphate synthase, carboxy-cis,cis-muconate cyclase, chalcone isomerase, chloromuconate cycloisomerase, (+)-bornyl diphosphate synthase, cycloeucalenolate In a particular embodiment, the isomerase is selected from the list comprising: Pin1, alpha-pinene oxide decyclase, dichloromuconic acid cycloisomerase, copalyl diphosphate synthase, Ent-copalyl diphosphate synthase, Syn-copalyl diphosphate synthase, terpene thienyl diphosphate synthase, halimadienyl diphosphate synthase, (S)-beta-macrocarpene epsilon cyclase, lycopene beta cyclase, prosolanapyrone-III cycloisomerase, and D-ribose pyranase. In a particular embodiment, the isomerase is Pin1.

[0060] Ubiquitination enzymes Ubiquitination is a post-translational modification in which a small regulatory protein, ubiquitin, is attached to targeted lysine residues on protein substrates. Ubiquitination involves multiple steps: activation (performed by the ubiquitin-activating enzyme E1), conjugation (performed by the ubiquitin-conjugating enzyme E2), and ligation (performed by the ubiquitin ligase E3).

[0061] In certain applications of various embodiments, the post-translational modification protein is an E1 ubiquitin activating enzyme, e.g., UBA1, UBA2, UBA3, UBA5, UBA6, UBA7, ATG7, NAE1, SAE1; an E2 ubiquitin conjugating enzyme, e.g., UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2D4, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2 N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1(CDC34), UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, UFC1, and E3 ubiquitin ligases such as AFF4, AMFR, ANAPC11, ANKIB1, AREL1, ARIH1, ARIH2, BARD1, BFAR, BIRC2, BIRC3, BIRC7, BIRC8, BMI1, BRAP, BRCA1, CBL, CBLB, CBLC, CBLL1, CCDC36, CCNB1IP, CCNB2, CCNB3, CCNB4, CCNB5, CCNB6, CCNB7, CCNB8, CCNB9, CCNB10, CCNB11, CCNB12, CCNB13, CCNB14, CCNB15, CCNB16, CCNB17, CCNB18, CCNB19, CCNB20, CCNB21, CCNB22, CCNB23, CCNB24, CCNB25, CCNB26, CCNB27, CCNB28, CCNB29, CCNB30, CCNB31, CCNB32, CCNB33, CCNB34, CCNB35, CCNB36, CCNB36, CCNB37, CCNB38, CCNB39, CCNB40, CCNB41, CCNB42, CCNB43, CCNB44, CCNB45, CCNB46, CCNB47, CCNB48, CCNB49, CCNB50, CCNB51, CCNB52, CCNB53, CCNB54, CCNB55, CCNB56, CCNB57, CCNB58, CCNB61, CCNB62, CCNB63, CCNB64, CCNB65, CCNB66, CC 1, CGRRF1, CHFR, CNOT4, CUL9, CYHR1, DCST1, DTX1, DTX2, DTX3, DTX3L, DTX4, DZIP3, E4F1, FANCL, G2E3, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1 , HECW2, HERC1, HERC2, HERC3, HERC4, HERC5, HERC6, HLTF, HUWE1, IRF2BP1, IRF2BP2, IRF2BPL, ITCH, KCMF1, KMT2C, KMT2D, LNX1, LNX2, LONRF1, LONRF2, LONRF3, LRSAM1, LTN1, MAEA, MAP3K1, MARCH1, MARCH10, MARCH11, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6, MARCH7, MARCH8, MARCH9, MDM2, MDM4, MECOM , MEX3A, MEX3B, MEX3C, MEX3D, MGRN1, MIB1, MIB2, MIDI, MID2, MKRN1, MKRN2, MKRN3, MKRN4P, MNAT1, MSL2, MUL1, MYCBP2, MYLIP, NEDD4, NEDD4L, NEURL1,NEURL1B、NEURL3、NFX1、NFXL1、NHLRC1、NOSIP、NSMCE1、PARK2、PCGF1、PCGF2、PCGF3、PCGF5、PCGF6、PDZRN3、PDZRN4、PELI1、PELI2、PELI3、PEX10、PEX12 、PEX2、PHF7、PHRF1、PJA1、PJA2、PLAG1、PLAGL1、PML、PPIL2、PRPF19、RAD18、RAG1、RAPSN、RBBP6、RBCK1、RBX1、RC3H1、RC3H2、RCHY1、RFFL、RFPL1、RFPL2 、RFPL3、RFPL4A、RFPL4AL1、RFPL4B、RFWD2、RFWD3、RING1、RLF、RLIM、RMND5A、RMND5B、RNF10、RNF103、RNF11、RNF111、RNF112、RNF113A、RNF113B、RNF11 4、RNF115、RNF121、RNF122、NF123、RNF125、RNF126、RNF128、RNF13、RNF130、RNF133、RNF135、RNF138、RNF139、RNF14、RNF141、RNF144A、RNF144B、RNF14 5、RNF146、RNF148、RNF149、RNF150、RNF151、RNF152、RNF157、RNF165、RNF166、RNF167、RNF168、RNF169、RNF17、RNF170、RNF175、RNF180、RNF181、RNF18 2、RNF183、RNF185、RNF186、RNF187、RNF19A、RNF19B、RNF2、RNF20、RNF207、RNF208、RNF212、RNF212B、RNF213、RNF214、RNF215、RNF216、RNF217、RNF219 、RNF220、RNF222、RNF223、RNF224、RNF225、RNF24、RNF25、RNF26、RNF31、RNF32、RNF34、RNF38、RNF39、RNF4、RNF40、RNF41、RNF43、RNF44、RNF5、RNF6、RNF6 F7、RNF8、RNFT1、RNFT2、RSPRY1、SCAF11、SH3RF1、SH3RF2、SH3RF3、SHPRH、SIAH1、SIAH2、SIAH3、SMURF1、SMURF2、STUB1、SYVN1、TMEM129、TOPORS、TRAF2、TRAF3, TRAF4, TRAF5, TRAF6, TRAF7, TRAIP, TRIM10, TRIM11, TRIM13, TRIM15, TRIM17, TRIM2, TRIM21, TRIM22, TRIM23, TR IM24, TRIM25, TRIM26, TRIM27, TRIM28, TRIM3, TRIM31, TRIM32, TRIM33, TRIM34, TRIM35, TRIM36, TRIM37, TRIM38, TRIM39 , TRIM4, TRIM40, TRIM41, TRIM42, TRIM43, TRIM43B, TRIM45, TRIM46, TRIM47, TRIM48, TRIM49, TRIM49B, TRIM49C, TRIM49 D1, TRIM5, TRIM50, TRIM51, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58, TRIM59, TRIM6, TRIM60, TRIM61, TRIM62, TRIM63, TR IM64, TRIM64B, TRIM64C, TRIM65, TRIM67, TRIM68, TRIM69, TRIM7, TRIM71, TRIM72, TRIM73, TRIM74, TRIM75P, TRIM77, TR IM8, TRIM9, TRIML1, TRIML2, TRIP12, TTC3, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR1, UBR2, UBR3, UBR4, UBR 5, UBR7, UHRF1, UHRF2, UNK, UNKL, VPS11, VPS18, VPS41, VPS8, WDR59, WDSUB1, WWP1, WWP2, CIAR, ZBTB12, ZFP91, ZFPL1, ZNF280A, ZNF341, ZNF511, ZNF521, ZNF598, ZNF645, ZNRF1, ZNRF2, ZNRF3, ZNRF4, ZSWIM2, ZXDC.

[0062] Improvement agents introduced without drug circulation CSF can be treated in several ways (e.g., chronically, intermittently, or similarly) according to various embodiments of the systems and methods of the present invention. For example, CSF can be presented at a high flow rate through a stationary or substantially stationary ameliorant that is entirely embedded within a mammalian subject but outside the SAS. For example, untreated CSF can leave the SAS, be ameliorated by an agent outside the SAS, and then returned to the SAS. Typically, such an approach may require the use of multiple catheters (and multiple insertion sites) and / or the use of a multi-lumen catheter (and optionally only a single insertion site) to transport CSF back to the SAS and / or outside the body. CSF flow can occur naturally by active or passive pumping. Advantages of such an approach include less invasiveness to the SAS, easier access to structures associated with the stationary ameliorant, and more space provided for the stationary ameliorant and any pump elements. This approach involves active circulation of CSF and CSF fluid flow, which requires careful control.

[0063] In another approach, the ameliorator may be located in the SAS on a structure (e.g., a substrate such as a solid substrate that is locally immobilized), which may be disintegrable or flexible, and untreated CSF may be circulated through the ameliorator. In some applications, it may be desirable for the ameliorator to remain stationary or substantially stationary. In other applications, the ameliorator may be purposely actuated. The term substantially stationary means that the ameliorator does not actively move, but the movement of the structure or the fluctuation of the movement within the structure may be caused by physiological CSF movement.

[0064] Typically, the flow of CSF may occur naturally, but in some applications, it may be desirable to actively or passively pump the CSF to improve activity and efficiency. Depending on the circulation method implemented and / or the system or device used, the flow of CSF may remain entirely within the SAS. However, in some embodiments, the CSF may be transported from one portion of the SAS, outside the SAS, and back to another portion of the SAS, which may require one or more catheter insertion sites.

[0065] In various embodiments, to reduce the possibility of infection, structures and / or system components associated with the ameliorative agent (e.g., subcutaneous ports and reservoirs, active or passive pumps, etc.) may be implanted beneath the epidermis, within the SAS or outside the SAS. Subcutaneous ports and reservoirs may be provided in the system to facilitate the introduction or removal of (e.g., solid) substrates, the introduction, removal, or replenishment / renewal of ameliorative agents, and / or the administration (e.g., introduction and chronic maintenance) of drugs to the CSF (e.g., by bolus administration or continuously).

[0066] In the absence of active circulation of the drug, the in situ improvement element may also reduce the target biomolecule (e.g., DPR) concentration in the CSF space. Assuming that the bulk flow is slow (e.g., about 0.5 mL / min), the improvement effect is dominated by the pulsatile flow, which may be due to the respiratory or cardiac cycle. Assuming that the enzyme device has an effective cross-section in the pre- and post-flow (i.e., pulsatile) flow that is 10% of the cross-sectional area of ​​the flow, and assuming that one collision or interaction between the biomolecule and the enzyme device improves the biomolecule, the probability that the molecule will be improved (i.e., converted) in n passes is:

[0067] P(n)=1-(1-0.1) n .

[0068] Therefore, if P(n)>95%, then n>ln(0.05) / ln(0.9)=28, or exposure time (t)>n×3 sec=85 sec.

[0069] Methods of localized fluid flow across an element (e.g., cilia) to which an improvement agent is applied are shown diagrammatically in FIGS. 1A-1C. In some embodiments, an improvement agent-applied (e.g., flexible or foldable, solid) structure or substrate 100 may be introduced into the SAS without the need to circulate the improvement agent. In some applications, the structure or substrate 100 may be implanted into the SAS via a catheter. CSF may be selectively circulated (e.g., naturally, by actively pumping the CSF, and / or by passively pumping the CSF) through a stationary or substantially stationary improvement agent. Thus, the flow of CSF may be equal to or greater than the natural CSF flow rate. Active and passive pumping, as well as natural circulation, may be performed entirely within the SAS, or CSF may be routed in and out of the SAS. Sources and power sources for hydraulic or pneumatic actuation may be located outside the SAS. The surfaces and structures may be made of any suitable compliant, resilient, biocompatible material, including polymers, elastomers, thermoplastic elastomers (TPEs), etc. Although various embodiments are described in connection with hydraulically or pneumatically actuated surfaces, the structures may alternatively or additionally include shape memory surfaces.

[0070] In some embodiments, the structure or substrate 100 may include an inner core 10a (FIGS. 1A and 1C), 10b (FIG. 1B) and an outer shell 20a (FIG. 1C), 20b (FIGS. 1A and 1B), each of which has a collapsed or contracted state (a) and an expanded or expanded state (b). A plurality of (e.g., hair-like or filamentous) cilia 25 may be integral with or fixedly attached to the outer shell 20a, 20b, or the outer shell 20a, 20b (e.g., its outer peripheral surface). Advantageously, during operation, various amounts of the improving agent 30 may be applied or attached to each of the cilia 25 and / or the core and shell. The outer shell 20a, 20b may also include an inlet / outlet port 35, as well as a plurality of openings 40. The inlet / outlet ports 35 are in fluid communication with a source (e.g., hydraulic, pneumatic, etc.) capable of selectively inflating and deflating the shells 20a, 20b by introducing fluid to the inside of the shells 20a, 20b and removing fluid from the inside of the shells 20a, 20b, respectively. The plurality of openings 40 are structured and arranged to provide fluid communication between the inner and outer circumferential surfaces of the shells 20a, 20b.

[0071] The inner cores 10a, 10b may also include inlet / outlet ports 45 that are also in fluid communication with a source (e.g., hydraulic, pneumatic, etc.) that can selectively expand and contract the inner cores 10a, 10b by introducing fluid to the inside of the inner cores 10a, 10b and removing fluid from the inside of the inner cores 10a, 10b, respectively.

[0072] In a first step of operation, from a resting state in which both the inner core 10a and the outer shell 20a are deflated or contracted (FIG. 1C), an expanding fluid can be introduced (e.g., via the inlet / outlet port 35) into the deflated or contracted outer shell 20a, causing it to expand or dilate, creating a void 15 between the deflated or contracted inner core 10a and the expanded outer shell 20b (FIG. 1A). The void 15 contains the initially or partially processed CSF. More specifically, as the deflated or contracted outer shell 20a expands or expands, the CSF flows through the openings 40 of the expanding outer shell 20b, across the cilia 25 to which the improving agent 30 has been applied, and into the void 15, enhancing the possibility that the improving agent 30 will enzymatically digest biomolecules in the CSF.

[0073] In a next step (FIG. 1B), an expanding fluid can be introduced (e.g., via inlet / outlet port 45) into the deflated or contracted inner core 10a, causing it to expand or expand. Advantageously, as the deflated or contracted inner core 10a expands, the initially or partially processed CSF in the void 15 is forced through the opening 40 of the expanded outer shell 20b. As the CSF exits the opening 40, the unprocessed CSF flows across the cilia 25 that have been treated with the improvement agent 30, enhancing the possibility that the improvement agent 30 will enzymatically digest biomolecules in the CSF.

[0074] In the next step (FIG. 1C), the expanding fluid previously introduced into the expanded inner core 10b and into the expanded outer shell 20b may be expelled from the expanded inner core 10b and the expanded outer shell 20b, causing each to collapse or contract to a resting state exemplified by the collapsed or contracted inner core 10a and the collapsed or contracted outer shell 20a. Advantageously, as the expanded outer shell 20b collapses or contracts, the CSF flows across the cilia 25 to which the ameliorative agent 30 has been applied, enhancing the possibility that the ameliorative agent 30 will enzymatically digest biomolecules within the CSF.

[0075] Another embodiment of a method and system for localized fluid flow across an element (e.g., cilia) to which an improvement agent is applied is shown in Figures 2A-2C. In some embodiments, a (e.g., flexible or foldable, solid) structure or substrate 200 may be introduced into the SAS without the need to circulate the improvement agent. In some applications, the structure or substrate 200 may be implanted into the SAS via a catheter. The CSF may be selectively circulated (e.g., naturally, by actively pumping the CSF, and / or by passively pumping the CSF) through a stationary or substantially stationary improvement agent. The active and passive pumping, as well as the natural circulation, may be performed entirely within the SAS, or the CSF may be routed in and out of the SAS. The source and power source for hydraulic or pneumatic actuation may be located outside the SAS. Although various embodiments of the present invention are described in connection with hydraulically or pneumatically actuated surfaces, the structure may alternatively or additionally include a shape memory surface. Passive pumping may include peristaltic or other forward displacement pumps, or may use pressure changes within the body to power the circulation of CSF in the embodied system. In some embodiments, the structure or substrate 200 may include a monolithic bistable substrate 205a, 205b having a plurality of appendages 210 forming a plurality of invagination 210a and eversion 210b structures between the structural body 215. As shown in FIG. 2B, a plurality of cilia 220 may be integral with or fixedly attached to the outer circumferential surface of the appendages 210 so as to protrude from the outer circumferential surface of the everted appendages 210b, as well as integral with or fixedly attached to the surface of each invagination appendage 210a and the structural body 215, thus covering the pocket formed thereby. Advantageously, during operation, various amounts of an improving agent may be applied to or attached to each of the appendages 210, including the cilia 220, and the body 215.

[0076] The structure or substrate 200 may also include inlet / outlet ports 225 for providing fluid communication between the bistable substrates 205a, 205b and a source (e.g., hydraulic, pneumatic, etc.) that can selectively expand and contract the bistable substrates 205a, 205b by introducing fluid into and removing fluid from the interior of the substrates 205a, 205b, respectively.

[0077] From a resting state (FIG. 2A) in which the bistable substrate 205a is collapsed or substantially collapsed, in a first step (FIG. 2C), an expanding fluid can be introduced (e.g., via inlet / outlet port 225) into the bistable substrate 205a, causing it to expand or expand 230. Advantageously, as the bistable substrate 205b and appendages 210b expand 230, the expanding substrate 205b and expanding appendages 210b mix the CSF and expose a greater amount of CSF to the agent-treated cilia 220 (FIG. 2B), enhancing the likelihood that the agent will enzymatically digest biomolecules within the CSF.

[0078] In the next step, the fluid previously introduced to expand the substrate 205b and appendages 210b can be expelled, causing the substrate 205b to collapse or contract 235 (FIG. 2A) to a quiescent state. Again, as the bistable substrate 205a and appendages 210a contract 235, the contracting substrate 205a and the contracting appendages 210a mix the CSF and expose a large amount of CSF to the cilia 220 coated with the ameliorative agent, increasing the possibility that the ameliorative agent will enzymatically digest biomolecules in the CSF. Thus, multiple expansion and contraction cycles of the structure or substrate 200 generate a mixing motion of the CSF, further increasing the interaction between the CSF and the ameliorative agent-coated cilia 220, and the possibility that the ameliorative agent will enzymatically digest biomolecules in the CSF.

[0079] Further embodiments of methods for localized fluid flow across an element (e.g., a fenestration) to which an improvement agent is applied are shown in FIG. 3. In some embodiments, a (e.g., flexible or foldable, solid) structure or substrate 300 may be introduced into the SAS without the need for circulation of the improvement agent. In some applications, the structure 300 may be implanted into the SAS via a catheter. CSF may be selectively circulated (e.g., naturally, by actively pumping the CSF, and / or by passively pumping the CSF) through the stationary or substantially stationary improvement agent. Thus, the flow of CSF may be equal to or greater than the natural CSF flow rate. The active and passive pumping, as well as the natural circulation, may be performed entirely within the SAS, or the CSF may be routed in and out of the SAS. The sources and power sources for hydraulic or pneumatic actuation may be located outside the SAS. The surfaces and structures may be made of any suitable compliant, resilient, biocompatible material, including polymers, elastomers, thermoplastic elastomers (TPEs), and the like. Although various embodiments and implementations of the present invention have been described in relation to hydraulically or pneumatically actuated surfaces, the structures may alternatively or additionally include shape memory surfaces.

[0080] In some embodiments, the structure of the substrate 300 may include a substrate 305 having multiple appendages (i.e., fenestrations 310) and gaps 315. Advantageously, different amounts of the improvement agent 350 may be applied to or attached to each of the fenestrations 310.

[0081] In operation, after the substrate 305 is introduced into the SAS, the substrate 305 may alternately expand and contract as described above. Multiple expansion and contraction cycles of the structure 300 generate a mixing motion of the CSF, further increasing the interaction between the CSF and the improvement agent 350 applied to the fenestrations 310, as well as the possibility that the improvement agent will enzymatically digest biomolecules within the CSF. Alternatively, or in addition, the substrate 305 may be oscillated back and forth or slowly rotated / twisted to generate a micromotion. The back and forth rotation or oscillating micromotion may also increase the interaction between the CSF and the improvement agent 350 applied to the fenestrations 310, as well as the possibility that the improvement agent will enzymatically digest biomolecules within the CSF. Advantageously, the structure 300 may be manufactured from a single material and / or a single piece of material, reducing the risk of mechanical failure.

[0082] Yet another system or device and method for localized fluid flow across an element (e.g., an extensible fiber) on which an improvement agent is applied is shown in Figures 4A and 4B. In some applications, the structure or substrate 400 may be implanted in the SAS via a catheter. The CSF may be selectively circulated (e.g., naturally, by actively pumping the CSF, and / or by passively pumping the CSF) through the stationary or substantially stationary improvement agent. Thus, the CSF flow may be at or above the level (e.g., flow rate) of natural CSF flow. The active and passive pumping, as well as the natural circulation, may be performed entirely within the SAS, or the CSF may be routed in and out of the SAS. The sources and power sources for hydraulic or pneumatic actuation may be located outside the SAS. The surfaces and structures may be made of any suitable compliant, resilient, biocompatible material, including polymers, elastomers, thermoplastic elastomers (TPEs), and the like. Although some embodiments and applications of the present invention are described in relation to hydraulically or pneumatically actuated surfaces, the structures may alternatively or additionally include shape memory surfaces.

[0083] In some embodiments, the structure 400 may include a (e.g., tubular) structure or casing (e.g., catheter 405) that includes a plurality of hair-like fibers 410a, 410b (e.g., brush fibers). Advantageously, the fibers 410a, 410b are retractable and extendable, such that when the catheter 405 is introduced or withdrawn from the SAS, the fibers 410a may remain in a retracted state (FIG. 4A), but upon exposure to CSF ​​flow (FIG. 4B), the retracted fibers 410a may deploy to extend from the catheter 405 into the SAS. Optionally or alternatively, the structure or casing 400 may be oscillated or rotated / twisted to create micro-motion to facilitate localized CSF movement across the extended fibers 410b.

[0084] Advantageously, different amounts of the improvement agent 415 can be applied or attached to each of the fibers 410a, 410b, so that when the fiber 410b is extended into the CSF space, the extended fiber 410b provides a large amount for interacting with the CSF, increasing the interaction between the CSF and the improvement agent 415, as well as the likelihood that the improvement agent 415 will enzymatically digest biological molecules within the CSF.

[0085] Although the above embodiments have been described with the corresponding structures fully embedded within the SAS, one skilled in the art can appreciate that some parts of the structures may be embedded within the SAS and other parts may be embedded within the mammalian subject's body but external to the SAS. In such an arrangement, the CSF must be circulated from the SAS, through the structures embedded external to the SAS, and then back to the SAS. The sources and power sources for hydraulic or pneumatic actuation may be located external to the SAS.

[0086] A further method of localized fluid flow using an improved agent-loaded structure is shown in FIG. 5. In some embodiments, the embodied structure 505 may be introduced (i.e., fully implanted) into the SAS (e.g., the cerebral aqueduct, near the fourth ventricle, etc.) without the need for circulating improved agents. Instead, CSF may be selectively circulated by actively pumping CSF and / or passively pumping CSF in the presence of improved agents. Active and passive pumping of CSF, as well as natural circulation of CSF, may occur entirely within the SAS, or CSF may be routed in and out of the SAS.

[0087] 5, in some embodiments, structure 500 may include a stent 505 having an inner circumferential surface to which an improvement agent may be coated, dispensed, or otherwise applied. Placing the stent 505 within the SAS in a location that experiences relatively high CSF flow (e.g., near the cerebral aqueduct, the fourth ventricle, etc.) increases the interaction between the CSF and the improvement agent, as well as the likelihood that the improvement agent will enzymatically digest biomolecules within the CSF.

[0088] In another embodiment, structure 500 may include a thin sheet (e.g., planar, contoured, spiral, etc.) onto which the ameliorative agent may be coated or otherwise applied. Placing the coated sheet within the SAS in a location experiencing relatively high CSF flow (e.g., over the motor cortex, within the SAS cistern, etc.) increases the interaction between the CSF and the ameliorative agent, as well as the likelihood that the ameliorative agent will enzymatically digest biomolecules within the CSF.

[0089] Enzymatic digestion and size filtration 6, an exemplary embodiment of a system 600 is shown that combines enzymatic digestion (i.e., using an enzymatic digester) with size filtration. In some applications, the system 600 may include multiple size-charge filters 605a, 605b in combination with a structure (e.g., an enzymatic digester) that includes an improving agent 610.

[0090] The loop-flow embodiment shown in Figure 6 utilizes countercurrent exchange. During operation, unprocessed CSF having the highest concentrations of small components 615, large non-toxic biomolecules 620, and large biomolecules 625a may enter the system 600 flowing in a first direction (e.g., to the right) away from the highest concentrations.

[0091] After the high concentration of untreated CSF enters the system 600, it encounters a first size-charge filter (e.g., a porous wall) 605a, which separates the high concentration of untreated CSF moving in a first direction from the low concentration of filtered and treated CSF moving in a second and opposite direction. The size of the openings in the first porous wall 605a can be selected to allow small components 615 to pass through the filter, which typically occurs when small components 615 flow from high to low concentrations. As the small components 615 filter across the first porous wall 605a, some of the smaller components 615 are separated (i.e., filtered away) from the large non-toxic biomolecules 620 and the large biomolecules 625a. The filtered small components 615 can flow out of the system 600 along with the treated CSF.

[0092] In a next step, the filtered CSF may encounter or come into contact with a ameliorative agent 610 (e.g., in an enzymatic digestion tank). The ameliorative agent 610 may be selected by design to have little or no effect on remaining small components 615 or large non-toxic biomolecules 620, while the agent 610 ameliorate (e.g., enzymatically digest) large toxic biomolecules 625a, causing a reduction in the size of these ameliorated biomolecules 625b.

[0093] As the treated CSF continues to flow right from the enzyme digestion tank and improver 610, it encounters a second size-charge filter (e.g., a porous wall) 605b to separate the improved biomolecules 625b from the larger non-toxic biomolecules 620 that are not affected by the enzyme digestion. The size of the openings in the second porous wall 605b can be selected to allow the improved biomolecules 625b to pass across the filter 605b, which occurs when the improved biomolecules 625b tend to flow from higher to lower concentrations. Some smaller components 615 can also filter across the second porous wall 605b. These smaller components 615 and improved biomolecules 625b filtered out by the second porous wall 605b can be discharged to a bladder or elsewhere (e.g., as waste). The processed CSF, including the small components 615 and some of the larger non-toxic biomolecules 620, can then exit the system 600 to the left (eg, in a countercurrent pattern).

[0094] Referring to another filtration system depicted in FIG. 17, a schematic diagram of an embodiment of a tangential flow filtration stage in combination with an enzyme cartridge 1707 is shown. The system 1700 shows a fluid (e.g., CSF) being drawn from a patient's subarachnoid space (SAS) by a catheter and circulated to a filtration subsystem 1700. The liquid at this point contains multiple potential components including cells, tissue fragments, immunoglobulins, target toxic proteins of interest (TDP-43, dipeptide repeat proteins (DRPs), phosphorylated tau, etc.), albumin, glucose, ions, and other species. The CSF enters the first stage of tangential flow filtration (TFF) 1701, where the CSF is separated into retentate 1702 and permeate 1703 streams by a membrane with a molecular weight cut-off (MWCO). For example, in the first stage, a MWCO of approximately 55 kDa allows cells and albumin to pass but filters out smaller proteins, glucose, and ions. The permeate 1703 may then be passed to a second stage TFF 1704 having a lower MWCO (e.g., about 3 kDa). The second stage 1704 filters smaller species such as ions and glucose as permeate 1705, while larger proteins are retained as retentate 1706. The retentate 1706 may then be passed to an enzyme cartridge 1707. In this cartridge 1707, an enzyme (e.g., trypsin) digests the target protein and passes the fragments in output 1708. Advantageously, to increase the residence time and thus expose the retentate 1706 to the enzyme (e.g., trypsin) disposed within and / or applied on the cartridge 1707, the CSF flow may follow a dual flow pattern through the cartridge 1707, i.e., the mobile phase may pass once or repeatedly in a bidirectional flow across the stationary phase. In this pattern, the CSF is aspirated and expelled for one or more cycles before being passed to the output. In this variation, the output port of the cartridge 1707 may be the same as the input port of the cartridge 1707.

[0095] The output 1708 of the enzyme cartridge 1707 may then be passed to a third TFF stage 1709 with a MWCO sufficient to separate the digested fragments from the whole protein.

[0096] The digested fragments, including potentially autolyzed trypsin, may then be passed to waste 1710. Retentate stream 1712 may contain undigested whole target protein and enzymes separated from the substrate in 1707. This stream may then be passed to a second cartridge 1711 containing a "getter", e.g., immobilized alpha-1 antitrypsin, which serves to capture any free-floating trypsin released from the first cartridge 1707. More specifically, to prevent or minimize loose enzymes previously disposed and / or applied to the first cartridge 1707 from reaching the SAS via the processed CSF, a getter may be located downstream of the first cartridge 1707, thus capturing or capturing loose or free enzymes contained in the output stream 1712. In some embodiments, when the enzyme is trypsin, the preferred getter material is alpha-1 antitrypsin AAT, while benzidiamide, benzamidine (e.g., Benzamidine Sepharose 4 Fast Flow (High Sub), GE Healthcare Lifescience, Cytiva), etc. may be more commonly used for proteases. In some variations, the getter material may be immobilized on a surface such as a lumen, bead, microlattice, cilia, fibrous structure, etc. Finally, output stream 1712 is combined with the other streams 1702 and 1705 into stream 1713, which is reintroduced into the patient and recycled. The MWCO stages may be adjusted to best suit the desired target species.

[0097] Advantageously, this filtration system is less susceptible to clogging by tissue and cell debris due to the nature of the tangential flow filtration step. Additionally, this configuration removes toxic protein digestion fragments from the enzyme cartridge 1707. Additionally, the second cartridge captures any enzymes that dissociate from the first cartridge. Finally, the cartridge has a cleaner feed stream due to the earlier TFF step.

[0098] Fluid flow and augmentation of fluid flow In some embodiments of the systems, methods, and devices described herein, the allowance of natural CSF flow is acceptable, while in other embodiments, the use of active and / or passive pumping techniques to control CSF flow may be desirable. Pumping techniques may include pumps, valves, actuators, and combinations thereof. For example, pumps may include peristaltic pumps, rotary vane pumps, archimedes screws, air bladders, pneumatic bladders, hydraulic bladders, displacement pumps, electric pumps, passive pumps, automated pumps, valveless pumps, bidirectional pumps, and combinations thereof. Valves may include one-way valves, bicuspid valves, tricuspid valves, ruby ​​valves, and combinations thereof.

[0099] Improvement techniques involving the use of improvement agents (as opposed to those using a processing system) may involve the active (or proactive) implementation of a flow from one location (e.g., within the SAS or from outside the SAS) to another location, either inside or outside the SAS. Indeed, the circulation of the CSF may present a high improvement agent, which may increase the interaction between the CSF and the improvement agent, thereby increasing the likelihood that the improvement agent will enzymatically digest biomolecules within the CSF. In implementing a fluid flow, the CSF may circulate through a stationary or substantially stationary structure that has been applied or coated with the improvement agent, the structure that has been applied or coated with the improvement agent may circulate through the CSF, or both the CSF and the structure that has been applied or coated with the improvement agent may circulate through each other.

[0100] In the case of CSF circulation, such movement may occur as part of the natural flow of fluid, or, alternatively, the natural flow may be actively or passively augmented. Such active or passive augmentation (i.e., pumping) may occur simultaneously, periodically, continuously, etc. Furthermore, as noted above, the CSF may be made to circulate entirely within the SAS, or, alternatively, after the CSF has circulated through the ameliorative agent, the CSF may be transported out of the SAS, but later reintroduced into the SAS.

[0101] As previously noted, pressure and / or volume changes associated with naturally flowing fluids and / or fluids whose flow is artificially enhanced within the SAS should be regulated to avoid or minimize effects that may result in spinal cord injury or even death to the subject. Thus, when fluid is removed from and / or reintroduced into the SAS, pressure transients may depend, at least in part, on the duty cycle and flow rate of the procedure involved.

[0102] In some applications, turbulent mixing of CSF may be desirable, but traditionally, high levels of fluid motion in the CSF space may also cause discomfort to the subject.Therefore, whether fluid flow is actively pumped in the SAS, passively pumped in the SAS, or pumped out of the SAS and reintroduced into the SAS, it should be controlled to avoid excessive or undesirable mixing of fluid.Indeed, while some mixing is desirable and beneficial, excessive or undesirable mixing is generally undesirable.

[0103] The supplies and power sources for the system components and associated operations may be located external to the SAS. The power required for the pump may be

[0104] P h(kW) =qρgz / (3.6×10 6 ),

[0105] During the ceremony,

[0106] Ph(kW) =Hydraulic power (kW),

[0107] q=Flow capacity (m 3 / hour),

[0108] ρ = density of fluid (kg / m 3 ),

[0109] g=gravity (9.81m / sec 2 ), and

[0110] z = differential head (m).

[0111] The required flow rate (q) is approximately 20 mL / h, or approximately 20 × 10 -6 m 3 / h. The density of CSF (ρ) is approximately 1.00059 × 10 3 kg / m 3 The average spine length (z) is about 0.5 m. With a pump efficiency of 0.6, this gives P = 27 μW.

[0112] A lithium thionyl chloride battery (e.g., an LTC-EP-200014 battery manufactured by Eagle Picher of St. Louis, MO) has a capacity of 8 Ah. Thus, in principle, this battery can be used for approximately 8 Ah / (30 μW / 3 V) = 8 × 10 5 System losses will reduce this time value, but the natural flow of CSF will reduce, if not completely relieve, the pumping requirements.

[0113] 7A and 7B, an exemplary monolithic and hydraulically actuated peristaltic pump 700 that can be implanted in the SAS or elsewhere in the subject's body is shown. In some embodiments, the pump 700 can include several chambers 705, 710 in which a pair of opposing selectively inflatable bladders 715a, 715b are located. The two-chamber pump 700 shown in FIG. 7A includes an ante-chamber 705 and a post-chamber 710, although more chambers are possible. Upstream and downstream of each chamber 705, 710 can be bicuspid valves 720a, 720b, 720c that can be structured and positioned in close proximity to the bladders 715a, 715b. Advantageously, the unidirectional nature of the bicuspid valves 720a, 720b, 720c prevents backflow back into the pump 700 or the previous chambers 705, 710.

[0114] For example, actuation of the bladders 715a, 715b by inflating and deflating them in alternating succession causes fluid (e.g., CSF or ISF) to enter the antichamber 705 through the first bicuspid valve 720a. For example, when the bladder 715a within the antichamber 705 deflates or contracts from a previously inflated or inflated state, the contraction of the bladder 715a causes a decrease in pressure within the antichamber 705, drawing fluid from outside the antichamber 705 into the antichamber 705 through the first bicuspid valve 720a. As the bladder 715b within the post chamber 710 simultaneously deflates or contracts from a previously inflated or inflated state, the contraction of the bladder 715b causes a decrease in pressure within the post chamber 710, drawing fluid from the antichamber 705 into the post chamber 710 through the second bicuspid valve 720b. On the next cycle, when the bladder 715b within the post chamber 710 expands from its previously collapsed or contracted state, the expansion of the bladder 715b forces fluid out of the post chamber 710 and out of the post chamber 710 through the third bicuspid valve 720c.

[0115] In some embodiments, a structure having a passive pump that can be fully implanted in the SAS (e.g., cranial or spinal) may be desirable. Referring to Figures 8A-8C, a structure 800 is shown having a passive pump 805 that uses the normal pressure fluctuations of the CSF itself to circulate fluid through the structure 800. In some variations, the structure 800 may also be connected to an implanted subcutaneous adapter, which facilitates introduction, maintenance, and removal of the structure 800.

[0116] In some applications, the structure 800 may include a cartridge 810 (e.g., a catheter body) having a first opening and a second opening in which a first one-way valve 815a and a second one-way valve 815b are operably disposed. Each of the openings and the one-way valves 815a, 815b are in fluid communication with the CSF space 820.

[0117] The cartridge 810 may be rigid or flexible. In some variations, the rigid cartridge 810 may include multiple metal spiral or helical structures that may be configured to support a radially patent lumen. While rigidity is desirable to facilitate fluid flow into the cartridge 810, the cartridge 810 must maintain sufficient flexibility to conform to anatomical contours within the SAS 820. In other variations, the cartridge may be flexible (e.g., elastic) such that as the (e.g., compressed) shape of the cartridge 810 resumes, the shape recovery may drive the inflow of fluid from the SAS into the cartridge 810.

[0118] In some embodiments, the passive pump 805 (e.g., an air bladder or an automatic bladder) may be located within the cartridge 810. The remedial agent 825 may be applied to an interior surface of the cartridge 810.

[0119] Although the structure 800 is described as being fully implanted in the spinal SAS, those skilled in the art can understand that it can also be implanted in the cranial SAS. For example, in one embodiment, the structure 800 is implanted in the spinal SAS and extends significantly in the rostral-caudal direction, so that CSF can circulate and improve between the brainstem and lumbar regions. Advantageously, such a location induces mixing of the brain's SAS fluid as well as the spinal SAS fluid. In another embodiment, the structure 800 can be implanted in the cranial SAS to operatively direct flow between locations therein (e.g., between the cisterna magna and the frontal lobe, between the two lateral hemispheres, etc.).

[0120] The operation of the passive pump 805 is described in several stages, but in reality the series of steps should be considered as a more continuous process. In a first stage (FIG. 8A), the passive pump 805 in the cartridge 810 may be in an expanded state, so that the pressure (P′) in the passive pump 805 830 is equal to the (e.g., relatively low) pressure (P) in the spinal space 820. As shown in FIG. 8B, as the pressure (P) in the spinal space increases, the increasing external pressure (P) compresses the passive pump 805, causing it to deflate. When the passive pump 805 contracts in the cartridge 810, the pressure (P′) in the cartridge decreases (i.e., is less than the external pressure (P)) and fluid flows into the cartridge 810 through the first one-way valve 815a. The second one-way valve 815b remains closed. Advantageously, when untreated CSF enters the cartridge 810 through the first one-way valve 815a, the untreated CSF can be exposed to a surface area to which the improving agent 825 is applied, increasing the likelihood that the improving agent 825 will enzymatically digest biological molecules within the CSF.

[0121] When the pressure (P) in the SAS drops again, the passive pump 805 expands again, forcing the processed CSF from within the cartridge 810 out through the second one-way valve 815b. As the expanding passive pump 805 creates an overpressure within the cartridge 810, the first one-way valve 815a remains closed.

[0122] In another embodiment, the pump 805 may be connected to an external pressure fluctuation source, either an active gas reservoir or pump, or another location in the anatomy where pressure periodically changes (e.g., the abdominal or pleural cavities), which then drives a balloon actuator within the pump.

[0123] In yet another embodiment depicted in Figure 8D, the device 800' includes a porous partition 850 that separates the ameliorative agent 825 from the CSF circulating through the device's lumen 830. Advantageously, this configuration presents a significantly larger surface area of ​​the ameliorative agent to the CSF than can be applied to the interior surface of the cartridge 810.

[0124] 8D, an embodiment includes a cartridge 810' that includes a porous wall (or partition) 850. The porous wall 850 separates the main lumen 830 from the separate lumen 835. In some variations, the porous wall 850 may be concentric and coaxial with the cartridge 810. However, in some applications, the porous wall 850 may be eccentric with respect to the cartridge 810.

[0125] In some embodiments, the ameliorative agent 825 is provided and confined in a separate lumen 835 while the CSF is circulated through the main lumen 830. As the CSF flows through the main lumen 830, the untreated or partially treated CSF has the opportunity to interact with the ameliorative agent 825, which may be applied, for example, on a plurality of beads. Advantageously, the size of the pores in the porous wall 850 is dimensioned to retain and confine the beads coated with the ameliorative agent 825 within the separate lumen 835 while allowing the biomolecules to pass through the porous partition 850. A pair of one-way valves 815a, 815b are formed at both ends of the cartridge 810 in fluid communication with the CSF space. A passive pump (e.g., an automatic pump) 805 may be located within the main lumen 830.

[0126] The operation of 800 ′ is similar to that of 800 , with the difference that the remedial agent 825 is sequestered behind a porous wall 850 .

[0127] Referring to FIG. 8E, a laboratory-scale embodiment of an open-ended balloon catheter automated pump 800'' for continuous extracorporeal use is shown to illustrate the principles of the automated pump 800''. In some embodiments, the automated pump 800'' includes an inflatable balloon 860 disposed within the lumen of a rigid or substantially rigid catheter 855. In some variations, a cartridge 865 may also be disposed within the lumen of the catheter 855. An improved agent may be disposed within the cartridge 865. Alternatively, the improved agent may be attached to the inner surface of the cartridge 865.

[0128] A first check valve 870a may be disposed upstream of the balloon catheter 855 and a second check valve 870b may be disposed downstream of the balloon catheter 855. A T-connection 875 may be disposed upstream of the balloon catheter 855 but downstream of the first check valve 870a. A conduit 880 providing fluid communication between a pressure source 885 and the balloon 860 is disposed within the T-connection 875. The pressure source 885 is an external source of pressure fluctuations, either an active gas reservoir or a pump, structured and arranged to selectively or cyclically inflate and deflate the balloon 860 to move the CSF through the automated pump 800''.

[0129] In operation, the upstream end 890a of the automated pump 800'' may be inserted into a first location of the mammalian subject to provide fluid communication with the CSF space, while the downstream end 890b of the automated pump 800'' may be inserted into a second location of the mammalian subject to provide fluid communication with the CSF space 820. In some applications, each inflation and deflation cycle of the balloon 860 draws in and expels a volume of CSF, which is then exposed to an ameliorative agent contained in or attached to a cartridge 865 disposed within or in fluid communication with the catheter 855. More specifically, when the balloon 860 is deflated (e.g., by a pressure source 885), a pressure differential is created between the lumen and the exterior of the catheter 855. This pressure difference causes the first (e.g., upstream) check valve 870a to open and the second (e.g., downstream) check valve 870b to remain closed, thus drawing fluid into the catheter 855 from the upstream end 890a. When the pressures are equalized, both check valves 890a, 890b close. Then, when the balloon 860 is inflated (e.g., by the pressure source 885), a pressure difference is created between the lumen and the outside of the catheter 855. This pressure difference causes the second (e.g., downstream) check valve 870b to open and the first (e.g., upstream) check valve 870a to remain closed, thus discharging fluid from and out of the catheter 855 and the cartridge 865 disposed within the catheter 855 toward the downstream end 890b.

[0130] Referring to FIG. 8F, a laboratory-scale embodiment of a closed-ended balloon catheter automated pump 800''' for batch extracorporeal use is illustrated to illustrate the principles of the automated pump 800''. In some implementations, the automated pump 800''' includes an inflatable balloon 860 disposed within the lumen of a rigid or substantially rigid catheter 855. In some variations, a cartridge 865 may also be disposed within the lumen of the catheter 855. An improved agent may be disposed within or in fluid communication with the cartridge 865. Alternatively, the improved agent may be attached to the inner surface of the cartridge 865. In operation, after a volume of fluid, i.e., a batch, is removed from a patient, that volume of fluid may be contained in a closed loop, and with dual flow capabilities, the removed volume of fluid may be repeatedly introduced and reintroduced back and forth or sequentially through the cartridge 865 to increase residence time and exposure of the removed fluid to the improved agent within the cartridge 865. The processed amount of fluid, or batch, can then be returned to the patient in a closed loop once processing of that batch is complete. Additional batches of fluid can then be removed from the patient and the batch processing process repeated.

[0131] More specifically, a first check valve 870a may be disposed upstream of the balloon catheter 855 and a second check valve 870b may be disposed downstream of the balloon catheter 855. A T-connection 875 may be disposed upstream of the balloon catheter 855 but downstream of the first check valve 870a. A conduit 880 providing fluid communication between a pressure source 885 and the balloon 860 is disposed within the T-connection 875. The pressure source 885 is an external source of pressure fluctuations, either an active gas reservoir or a pump, structured and arranged to selectively or cyclically inflate and deflate the balloon 860 to move the CSF through the automated pump 800''.

[0132] During operation, the upstream end 890a and the downstream end 890b of the automated pump 800'' are physically attached to the junction 890c. In some applications, each inflation and deflation cycle of the balloon 860 draws in and expels a volume of CSF, which is then exposed to an ameliorative agent contained in or attached to a cartridge 865 disposed within the lumen of the catheter 855. More specifically, when the balloon 860 is deflated (e.g., by a pressure source 885), a pressure differential is created between the lumen of the catheter 855 and the outside. This pressure differential causes the first (e.g., upstream) check valve 870a to open and the second (e.g., downstream) check valve 870b to remain closed, thus drawing fluid from the upstream end 890a into the lumen of the catheter 855. When the pressures are equalized, both check valves 870a, 870b close. Balloon 860 is then inflated (e.g., by pressure source 885), creating a pressure differential between the lumen and the outside of catheter 855. This pressure differential causes second (e.g., downstream) check valve 870b to open while first (e.g., upstream) check valve 870a remains closed, thus allowing fluid to exit and retract from the lumen of catheter 855 toward downstream end 890b.

[0133] The open-ended automated pump 800'' can be modified with suitable valving in a closed loop to the closed-ended automated pump 800''' to access batches of fluid from a patient, isolate the patient, treat the fluid, and then return the treated batches of fluid to the patient.

[0134] 13, a schematic diagram of a laboratory-scale embodiment of an automated pump 1300 within a pressurized chamber 1305 is shown. In some implementations, the CSF can be introduced into an arrangement including a cartridge 1310 (e.g., a flexible tube) containing an ameliorating agent. A first conduit 1315 provides fluid communication with a first end of the cartridge 1310 from a location outside the chamber 1305, and a second conduit provides fluid communication with a second end of the cartridge 1310 to a location outside the chamber 1305. A first check valve 1320a can be disposed upstream of the cartridge 1310 at the first end, and a second check valve 1320b can be disposed downstream of the cartridge 1310 at the second end. The cartridge 1310 can be immersed in the liquid contained within the pressurized chamber 1305.

[0135] A pressure generating source (e.g., an air compressor, a pressure differential device, etc.) 1325 capable of generating pressure fluctuations may be disposed in fluid communication with the interior plenum space of the pressurized chamber 1305. A relief valve 1330 for relieving pressure may also be disposed in fluid communication with the plenum space of the pressurized chamber 1305.

[0136] In operation, a quantity of CSF may be introduced into the cartridge 1310 via a first conduit 1315 via a suitable fluid connection. The pressure source 1325 increases the gas (e.g., air) pressure contained within the pressurized chamber 1305, and the relief valve 1330, when opened, decreases the gas pressure within the pressurized chamber 1305. The increase in gas pressure results in an increase in liquid (e.g., water) pressure, which causes the flexible cartridge 1310 to collapse. The collapsing cartridge 1310 expels a quantity of CSF from the cartridge 1310 via the second check valve 1320b and the second conduit. As it is expelled through the pressurized gas relief valve 1330, the liquid (e.g., water) pressure decreases, causing the flexible cartridge 1310 to expand. The expanding cartridge 1310 draws a new quantity of CSF into the cartridge 1310 via the first check valve 1320a and the first conduit 1315. The cycle can then be repeated.

[0137] 14A-14C, an embodiment of an automatic pump 1400 is shown with a balloon 1405 enclosed within a lumen of a cartridge body 1410. A first check valve 1420a may be disposed upstream of the cartridge body 1410 and the balloon 1405, and a second check valve 1420b may be disposed downstream of the cartridge body 1410 and the balloon 1405. A change in fluid pressure within the reservoir causes the balloon 1405 to expand and inflate 1405b (FIGS. 14A and 14C) or collapse or deflate 1405a (FIG. 14B). In clinical operation, either end of the automatic pump 1400 may be disposed in two different locations within the SAS.

[0138] In clinical operation, CSF fills the automated pump 1400 and also surrounds the device. At lower ambient CSF pressure, the balloon 1405b inflates or expands (FIG. 14C). At higher ambient CSF pressure, the balloon 1405a collapses or deflates (FIG. 14B). As the balloon inflates 1405b, the first check valve 1420a closes and the second check valve opens, allowing fluid to exit the cartridge body 1410. As the balloon deflates 1405a, the first check valve 1420a opens and the second check valve closes, allowing fluid to be drawn into the cartridge body 1410.

[0139] As a result, the balloon 1405 either inflates 1405b or deflates 1405a as the fluid pressure in the SAS space alternately increases and decreases. This repeated inflation and deflation of the balloon 1405 causes fluid flow unidirectionally through the check valves 1420a, 1420b, thereby implementing the CSF pump 1400 driven by internal pressure fluctuations. In some applications, the ameliorative agent may be disposed in the lumen of the cartridge body 1410. Alternatively, in other applications, the ameliorative agent may be disposed within or in fluidic series with the automated pump 1400.

[0140] 9A-9C, a fully implantable structure 900 for actively pumping (e.g., hydraulically, pneumatically, etc.) CSF is shown. Although the structure is described for use in combination with the previously described structures 100, 200, 300, 400, 500, 600, 700, 800, those skilled in the art will appreciate that the interior surface of the structure 900 may also be treated with an improvement agent, such that untreated or partially treated CSF may be actively pumped in one direction or another, and untreated or partially treated CSF may be exposed to the surface area that has the improvement agent applied, increasing the likelihood that the improvement agent will enzymatically digest biomolecules within the CSF.

[0141] The principle of operation of structure 900 uses pulsatile flow actuated hydraulically, pneumatically (e.g., using helium), etc. In some embodiments, structure 900 may include a cartridge 905 that includes a pair of bladders 910, 915 disposed at opposite ends of the cartridge 905. While this embodiment uses a cartridge 905, one skilled in the art can appreciate that a solid phase cartridge is not necessary and in some variations, the pair of bladders 910, 915 may instead be disposed in two locations along with the SAS itself.

[0142] From a neutral or resting state (FIG. 9B), one of the bladders may inflate and the other bladder may simultaneously deflate. To maintain no net volume change within the SAS, the inflated bladder may deflate and the deflated bladder may inflate. Preferably, the rate and extent of inflation / deflation should not result in pressure or volume changes that exceed or substantially exceed physiological variations or result in undesirable or excessive turbulence. As previously mentioned, in some cases, some degree of turbulence is desirable, for example, to mix treated CSF with untreated / partially treated CSF.

[0143] To create a pressure gradient from the neutral or intermediate state to the right (FIG. 9A), a first bladder 910b may be inflated 910a (e.g., hydraulically, pneumatically, etc.) and a second bladder 915b may be deflated 915a. This creates a pressure gradient from the inflated bladder 910a to the deflated bladder 915a, causing fluid flow from the inflated bladder 910a toward the deflated bladder 915a. Each of the inflated bladder 910a and the deflated bladder 915a may then be returned to a rest or intermediate state (FIG. 9B), requiring the inflated bladder 910a to be deflated 910b to the intermediate pressure and the deflated bladder 915a to be inflated 915b to the intermediate pressure.

[0144] To create a pressure gradient from the neutral or intermediate state to the left (FIG. 9C), the second bladder 915b may be inflated 915c (e.g., hydraulically, pneumatically, etc.) and the first bladder 910a may be deflated 910c. This creates a pressure gradient from the inflated bladder 915c to the deflated bladder 910c, causing fluid flow from the inflated bladder 915c toward the deflated bladder 910c. Each of the inflated bladder 915c and the deflated bladder 910c may then be returned to a rest or intermediate state (FIG. 9B), requiring the inflated bladder 915c to be deflated 915b to the intermediate pressure and the deflated bladder 910c to be inflated 910b to the intermediate pressure.

[0145] By circulating structure 900, CSF flow can be actuated and circulated within the SAS in a pulsatile manner without introducing or extracting fluid from the space. The phase and / or amplitude of the actuated CSF flow can, for example, augment or diminish the existing pulsatile flow of the subject's cardiac or respiratory cycle, or, alternatively, be independent of both.

[0146] In another embodiment, instead of movable valves, fixed structure valves such as those found in piezoelectric microfluidic pumps with nozzles can be used. The advantage of valveless pumps is that there are no separate moving parts to malfunction, as in the case of valved pumps. Furthermore, the nonlinear fluid behavior provides directionality to the flow.

[0147] Flow Control In some embodiments, the time-varying flow across the CSF space may be detected (e.g., by a sensor) and the flow may be adjusted to optimize the performance of the system. Exemplary common flow sensors may include hot wire, membrane, Karman vortex, Venturi tube, Pitot tube, Coriolis flowmeter, Doppler sensor, etc.

[0148] For example, the flow of what is circulating (whether CSF is circulating or a structure coated or provided with an improving agent is circulating) can be controlled to be, for example, pulse aware and / or breath aware. Control parameters can include, by way of illustration and not limitation, pH, temperature, pressure, local flow rate, mechanical stress, mechanical strain, electrical conductivity, and the like.

[0149] The control loops may include algorithms such as open loops, feedback loops, feedforward loops, etc. The feedback control may be bang-bang, PID, etc. Advantageously, the system may be analyzed at a system identification level so that kernels may be developed. Additionally, in some embodiments, perturbation actions (e.g., pseudo-random binary sequence pressure trains) may be applied to the system for greater control.

[0150] In some embodiments of the invention, alarm and safety rails may be established for parameter values. Exemplary alarm and safety rails may include pH (e.g., 7.1-7.7), pressure (e.g., intracranial pressure (ICP) of 5-15 mmHg), physiologically acceptable temperature ranges (e.g., 34-39 degrees Celsius), etc. In other embodiments, a safety bypass of flow may be incorporated into the design in the event of a clog or pump failure.

[0151] In some embodiments, diagnostic parameters may be collected in and by the system. For example, these parameters may include physical parameters (e.g., dynamic, kinetic, and chemical parameters), as well as parameters for the purposes of disease diagnosis or disease research (e.g., using artificial intelligence, big data analytics, etc.).

[0152] Improved system with bulk flow system 10A and 10B, an embodiment of a system 1000, 1000' for CSF improvement is shown, including a bulk flow system for actuating CSF flow. Actuating may include enhancing a naturally occurring flow of CSF. Augmenting may include enhancing the phase, direction, and / or amplitude of CSF flow. Advantageously, the bulk flow system may be implanted within the mammalian subject's body, within the SAS, or external to the SAS. Alternatively, substantially all or some portion of the bulk flow system may be implemented extracorporeally or external to the body.

[0153] The actuated (e.g., actively or passively pumped) flow may remain entirely within the SAS, may be transported from the SAS and reintroduced into the SAS, and / or may be transported outside the body and reintroduced into the SAS. In some embodiments, the structure 1005 associated with the ameliorative agent and having its own supporting catheter 1010 may be entirely implanted within the SAS. For purposes of illustration and not limitation, the structure 1005 and catheter 1010 are shown as being implanted within the brain SAS 1015 (e.g., a ventricular location) rather than the spinal SAS 1020 (e.g., a lumbar region location). Additionally, for purposes of illustration and not limitation, the output port 1025 is created in the brain SAS 1015 and the input port 1030 is created in the spinal SAS 1020. In other embodiments, the input port 1030 may be created in the brain SAS 1015 and the output port 1025 may be created in the spinal SAS 1020, or both the input port 1030 and the output port 1025 may be located in the brain SAS 1015 or alternatively the spinal SAS 1020. Each port 1025, 1030 may be implemented using a catheter. In some variations, a single port may be used that functions as both an output port and an input port (e.g., using a multi-lumen catheter).

[0154] The bulk flow system 1050 may provide fluid communication between the ports 1025, 1030. The bulk flow system 1050 may also be fully or partially implanted within the subject. In some applications, the bulk flow system 1050 may include a conduit 1035 through which the CSF flows. The CSF flow may remain in vivo or may be transported ex vivo, i.e., outside the body. One or more sensors 1040 may be provided in the conduit 1035, the bulk flow system 1050, as well as at separate locations within the SAS for providing data signals to the system controller 1045. Exemplary sensors 1040 may provide data signals for pH, temperature, pressure, flow rate, flow velocity, constituent concentration, UV radiation, IR radiation, turbulence, Raman scattering, dynamic light scattering, and the like.

[0155] CSF flow through the bulk flow system 1050 is allowed to occur at the natural flow rate of the CSF, but if active or passive pressure techniques are used, circulation of the CSF outside the SAS may be implemented or augmented using pumps 1055, actuators, valves, and combinations thereof. In some variations, the pumps 1055 may include peristaltic pumps, rotary vane pumps, archimedes screws, air bladders, pneumatic bladders, hydraulic bladders, displacement pumps, electric pumps, passive pumps, automated pumps, valveless pumps, bidirectional pumps, and combinations thereof. In other variations, the pumps 1055 may be similar in principle to valveless synthetic jet-based micropumps, bladder pumps, and the like. In some applications, algorithms, driver programs, and the like executed by the system controller 1045 may control the flow rate and flow rate of the CSF. The control algorithms may be open-loop, feed-forward, feedback, and the like. The system controller 1045 may include open-loop controllers, closed-loop controllers, PID controllers, PID threshold controllers, system identification algorithms, and the like.

[0156] Referring to FIG. 10B, a bulk flow system 1000' is shown that may be disposed substantially within the SAS 1015'. For purposes of illustration and not limitation, the ameliorative agent 1005' that may be disposed within a tube or cartridge 1060 is implanted entirely within the brain SAS 1015' (e.g., a location within the ventricle). One skilled in the art can appreciate that, alternatively, implantation may occur entirely within the spinal SAS (e.g., a location within the lumbar region). In some embodiments, flow actuators 1040a, 1040b may be disposed at either end of the cartridge 1060 for the purpose of forcing CSF flow through the cartridge 1060. Although two flow actuators 1040a, 1040b are shown, the flow actuators 1040a, 1040b may also be implemented singly.

[0157] A support catheter 1010' and a communication bus 1065 may also be provided. Although the support catheter 1010' and bus 1065 are shown to suggest that they are provided in separate locations, one skilled in the art will appreciate that a multi-lumen catheter may be used for both the support catheter 1010' and the communication bus 1065 such that both are confined to a single catheter location. In some variations, the communication bus 1065 may be configured to provide electrical and electronic communication between the remote system controller 1045' and the flow actuators 1040a, 1040b.

[0158] Improvement agents introduced with drug circulation In some applications, in addition to introducing the enzyme improving agent into the CSF (e.g., in the SAS), the improving agent can also circulate through the CSF, rather than remaining stationary or substantially stationary. In some embodiments, the improving agent can be, for example, implanted completely into the SAS (e.g., via a catheter) and circulated within the SAS, while in other embodiments, the improving agent can be implanted within the mammalian subject's body but outside the SAS, from which the improving agent can circulate in and out of the SAS. As mentioned above, when the improving agent is introduced without circulation, the CSF can leave the SAS, circulate through the improving agent, and return to the SAS.

[0159] 11, in some embodiments, the system or device may include a (e.g., multi-lumen) catheter 1105 that may be implanted under the epidermis 1160 and fully embedded within the SAS 1150, preferably at a location at or within the SAS 1150 to allow for circulation of a structure or support (e.g., a plurality of superparamagnetic beads) 1125 to which the ameliorative agent is applied. A supply reservoir 1130 may be located outside the SAS, and the beads 1125 may remain stationary or substantially stationary while the CSF may be circulated (e.g., naturally or using active or passive pumping techniques) through the supply reservoir 1130 to increase exposure and interaction between the CSF and the ameliorative agent-coated beads 1125, as well as the likelihood that the ameliorative agent will enzymatically digest biomolecules within the CSF.

[0160] In yet another embodiment, the improvement agent and the structure or support (e.g., beads) into which it is infused or applied can be introduced into or substantially within the SAS and circulated through the SAS, without the CSF being intentionally or artificially actuated (e.g., by active or passive pumping) to remove natural fluctuations and flow. Advantageously, in such an approach, the CSF can remain substantially entirely within the SAS during improvement, which is desirable.

[0161] Although the embodied structure 1100 is described for an embodiment that includes beads 1125 in a slurry and circulates the slurry through the multi-lumen catheter 1105 (e.g., mechanically, osmotically, by active or passive pumping, by gas-actuated bellows, etc.), one skilled in the art can appreciate that, for example, the magnetic properties of the superparamagnetic beads 1125 may help actuate the circulation of the beads 1125 in some applications. Indeed, by placing a magnetic field in the receiving reservoir, the superparamagnetic beads 1125 may be magnetically circulated through the SAS 1150, as the resulting magnetic force attracts the beads 1125. In some variations, the multi-lumen catheter 1105 may include an inner lumen 1110 structured and disposed within the outer lumen 1115. For example, a multi-lumen catheter 1105 with a closed tip (e.g., a spinal catheter or a dialysis membrane catheter) may be used. Advantageously, the multi-lumen catheter 1105 requires a single catheter insertion site.

[0162] Preferably, the outer lumen 1115 can be porous with pore sizes large enough to permit biomolecules in the CSF (e.g., diameters of about 10-100 nm) to pass through the porous membrane, but small enough to contain the beads 1125 (e.g., diameters greater than 1 μm). The diameter of some superparamagnetic beads can range from about 1-3 μm (e.g., LODESTAR beads manufactured by AGILENT® Technologies of Santa Clara, CA, are about 2.7 μm in diameter), while other beads can have much larger diameters (e.g., 45-165 μm for SEPHAROSE® 4B beads manufactured by SIGMA-ALDRICH® Corporation of St. Louis, MO).

[0163] In some embodiments, beads 1125 with an improving agent may be introduced (e.g., using a syringe and needle through an access port in the catheter) into a supply reservoir 1130, which may be fully implanted in the subject inside or preferably outside the SAS 1150. From the supply reservoir 1130, the beads 1125 may then be introduced (e.g., mechanically, osmotically, by magnetic attraction, by active or passive pumping, by gas-actuated bellows, etc.) into the inner lumen 1110. The beads 1125 circulate through the inner lumen 1110 down the length of the catheter 1105 and then enter the space 1120 between the inner lumen 1110 and the outer lumen 1115 before returning to the receiving reservoir 1135. While flowing through the space 1120 between the inner lumen 1110 and the outer lumen 1115, the circulating beads 1125 encounter untreated or partially treated CSF. Indeed, untreated or partially treated CSF containing biomolecules can freely pass through the porous outer lumen 1115 and into the space 1120 where it encounters the beads 1125, increasing the interaction between the CSF and the ameliorative agent-coated beads 1125, as well as the likelihood that the ameliorative agent will enzymatically digest the biomolecules within the CSF. Advantageously, the CSF can remain within the SAS 1150 while the beads 1125 circulate. The CSF can flow naturally in and out of the catheter 1105, or in some applications, the CSF can be actively or passively pumped while within the SAS 1150.

[0164] The beads 1125 can circulate side-by-side or coaxially, as in a continuous counter-flow tangential chromatography configuration. The beads 1125 that have passed through the catheter 1105 and are exposed to untreated or partially treated CSF can be removed from the receiving reservoir 1135 (e.g., via an exit port, using a syringe and needle). As previously described in connection with the supply reservoir 1130, the receiving reservoir 1135 can also be fully embedded in the subject, either inside or preferably outside the SAS 1150.

[0165] An upper limit for the required amount of agent-coated beads can be estimated by assuming that the DPR concentration is lower than that of the most common CSF neuroprotein (albumin), which has a concentration of approximately 69,000 g / mol, which is 4×10 -6 In mol / L, this corresponds to a concentration of approximately 300 mg / L. In contrast, the concentration of the least common CSF neuroprotein (protein 14-3-3) can be 8 to 10 orders of magnitude lower than that of albumin. The concentrations of all neuroproteins in CSF are >10 -12 ~10 -1 g / L range.

[0166] 100μm average bead diameter, 2×10 -7 Assuming a concentration of 1.5 × 10 mol / L (transferrin concentration), a CSF volume of 0.15 L, and a CSF production rate of 0.02 L / h, the amount of beads required is approximately 250 mL / week. Therefore, approximately 1.5 × 10 6 There can be beads / mL.

[0167] In an exemplary embodiment, there may be approximately one trillion functional reactive groups per bead, resulting in a capacity of approximately one billion affinity binding proteins per bead, thus approximately 2×10 per year for the envisioned concentrations, CSF volumes, and CSF production rates. 19 The number of molecules trapped is 2 × 10 at 250 mL / week (about 12 L / year). 10 Requires beads.

[0168] In contrast, superparamagnetic beads have an average bead diameter of about 1-3 μm, i.e., about two orders of magnitude smaller than the diameter used in the calculations above. If r corresponds to the radius of the bead, the ratio of surface area (A) to volume (V) is given by the equation,

[0169] A / V=4πr 2 / 4 / 3πr 3 =3 / r.

[0170] Thus, if the radius (r) of the beads is reduced by a factor of 100, the ratio increases by approximately 100. Thus, tens of mL of beads are needed per week to sweep even albumin-like concentrations of toxins. In contrast, if an enzyme is used instead of an antibody, much fewer beads are needed, since the enzyme remains active after interaction. Indeed, the amount of enzyme needed depends on the activity of the enzyme (e.g., k_m and k_cat), the flow rate, and the desired rate of CSF component conversion.

[0171] Instead of using and circulating beads through the raw CSF in the SAS, the thread-like structure with the improved agent can be introduced into the supply reservoir 1130 (e.g., on a spool-like structure), the inner lumen 1110 and the outer lumen 1115 can be threaded through the receiving reservoir 1135, the ends of the thread-like structure can be wound (e.g., on another spool-like structure), and the thread-like structure with the improved agent can be pulled through the raw CSF. Pulling the thread-like structure through the catheter 1105 increases the exposure and interaction between the CSF and the improved agent-coated thread-like structure, as well as the possibility that the improved agent will enzymatically digest biomolecules in the CSF. Multiple threads (e.g., thread structures) can be utilized, and the substrate or agent can be supported.

[0172] Focused flow of CSF without any improver In some embodiments, for example, focusing and increased flow from a first location of the SAS with a relatively low concentration of toxic biomolecules to a second location of the SAS with a relatively high concentration of toxic biomolecules may be desirable. Alternatively, transport from a first location with a high concentration of toxic biomolecules to a second location with a lower concentration of toxic biomolecules may be desirable. For example, focused CSF flow within the SAS, outside the SAS, across the central nervous system, and / or from motor neurons in the middle of the brain or the middle of the spinal cord may be desirable and effective. Preferably, the flow from the first location to the second location may be increased to provide effective treatment without the need for an improving agent. Instead, the flow itself may be adjusted to transport biomolecules from a stagnant location to another location where natural physiological degradation of biomolecules is occurring more effectively. Focused or increased flow to or from areas within the SAS with a higher density of improving agent and from or to areas within the SAS with a lower density of improving agent may also be desirable. An increase in natural CSF flow may be possible using an automatic bladder pump or the like. CSF flow is characterized by a large volume of circulation as well as by a strong pulsatile flow caused by cardiac and respiratory vibrations. The oscillatory movement of spinal CSF has a watershed at approximately the level of the heart. Since obstruction of the ventricular pathway leads to hydrocephalus, CSF must have a bulk flow. Caudal and cranial movements of CSF are observed, but the mechanism of this flow is controversial, although the bidirectional bulk movement of CSF in the spinal volume (approximately 1 cm / min) can be explained by the nonlinear cumulative effect of convective acceleration. CSF from the lumbar region proceeds to the cranial vault in approximately 15-20 min, and the time to renew the entire CSF volume in the spinal canal volume is several hours. Moreover, the movement of CSF within the cranial volume has different flow rates, ranging from 4 mm / s to 5 cm / s, across various parts of the brain SAS. Since CSF flow is a key component of the natural process of toxic biomolecular clearance in subjects, abnormalities in CSF flow may be a cause of neurodegenerative pathogenesis. In particular, alterations in flushing of specific regions of the SAS may decrease the clearance of toxic compounds and therefore may be implicated in the pathogenesis of many neurotoxic protein-mediated diseases.Thus, in some embodiments of the present invention, flow patterns are devised to advantageously address the uneven distribution of neurotoxic proteins. Furthermore, a coordinated flow system with spatial discrimination may be utilized to not only deliver drugs but also remove toxic components from the CSF.

[0173] The focused flow of CSF may be imparted by active and / or passive pumping mechanisms. If a particular flow pattern is desired to address a known disease situation and location, a system of catheters and pumps with varying flow rates may be implanted to achieve the desired focused flow pattern. For example, if in a pathological condition, CSF circulation in the frontal lobe is compromised, an active pump may increase flow to that area. This may be beneficial in itself, but may also be combined with ameliorative agents. The reason for a particular flow pattern to accommodate presumed sources and sinks of toxic proteins drives the design of the flow system. Three-dimensional flow fields may be calculated using methods of computational fluid dynamics. Examples of novel circulation pathways include reservoir to reservoir, ventricle to reservoir, and reservoir to lumbar. In addition, multiple simultaneous circulation paths may be implemented. The flow may be actuated by passive pumps, active pumps, or a combination thereof, as described elsewhere herein. An embodiment of the focused flow is shown in Figures 12A-12D.

[0174] For example, Figure 12A depicts a system that provides focused flow across the motor cortex. This system 1200 may include a first catheter 1205 implanted in the cisterna magna, a second catheter 1210 implanted in the cerebral SAS, such as above the motor cortex, and a passive (e.g., flow-through) pump 1215 that exposes the CSF that passes through or is transported through the pump 1215 to a ameliorative agent. In some embodiments, a ameliorative agent is not required. The pump 1215 may be implanted within the SAS or outside the SAS.

[0175] FIG. 12B depicts a system 1200' that provides focused flow to the spinal canal. The system may include a first catheter 1220a implanted in the lumbar to cervical region of the spine SAS in combination with an implanted (e.g., active or passive) pump 1225 that exposes the CSF transported through or passing through the pump 1225 to a ameliorative agent. Again, in some embodiments, a ameliorative agent is not required. The pump 1225 may be implanted outside the SAS and, in some variations, may include a subcutaneous access port. Advantageously, the flow may be rostral-caudal or vice versa. The contralateral catheter 1220b may continue the CSF flow circuit within the SAS.

[0176] FIG. 12C depicts a system 1200″ that provides focused flow from the ventricle to the lumbar sac. The system may include a first catheter (e.g., ventricular catheter) 1230, (e.g., subcutaneous) catheters 1235a and 1235b, and a third (e.g., lumbar / intraceutical) catheter 1245 in combination with an implanted (e.g., active or passive) pump 1240 that exposes the CSF to an ameliorative agent, i.e., passing through or being transported through the pump 1240, i.e., from the second catheter 1235a to the third catheter 1245 (or vice versa). The pump 1240 may be implanted outside the SAS and, in some variations, may include a subcutaneous access port. Advantageously, the flow may be rostral-caudal or vice versa.

[0177] FIG. 12D depicts a system 1200''' that may include a first catheter (e.g., ventricular drain) 1250, a lumbar puncture access (e.g., to the spinal volume) 1260, and a waste shunt 1270 (e.g., to the bladder) in combination with an implanted (e.g., active or passive) pump 1265 that exposes CSF to an ameliorative agent as it passes through or is transported from the first catheter 1250 to the lumbar puncture access 1260 (or vice versa). The pump 1265 may be implanted within the SAS. Advantageously, the flow may be rostral-caudal or vice versa. This system may be used in one embodiment with the filtration unit described in FIG. 6. These systems (FIG. 12) utilize the architecture of two common procedures: ventricular shunt to peritoneum for hydrocephalus and lumbar drug infusion spinal puncture.

[0178] Filtration method In some embodiments, improvements can be achieved by various filtration techniques or combinations thereof, including, but not limited to, dead-end (common syringe filters), depth filters, affinity filters, tangential flow filters, countercurrent cascade ultrafilters, and continuous countercurrent tangential chromatography.

[0179] In one aspect of the invention, the CSF is improved by a filter or cartridge containing a transforming agent. This treatment can be temporary or continuous. This promotes the movement of toxic proteins from the interstitial space to the blood volume and then to the CSF, or directly to the CSF in the perivascular space. Once the toxic proteins are in the CSF, the circulatory system will remove, degrade, or render the proteins non-toxic. The entire system thus has the effect of creating a high clearance rate of toxic proteins from the brain parenchyma. In another aspect of certain embodiments of the invention, the CSF is improved by a filter or cartridge containing a transforming agent, which promotes the movement of toxic proteins from the interstitial space directly to the CSF. Once the toxic proteins are in the CSF, the circulatory system will remove, degrade, or render these proteins non-toxic. The entire system thus has the effect of creating a high clearance rate of toxic proteins from the brain parenchyma. In one embodiment of the invention, the filters are of the following types: dead-end filters, tangential filters, cyclic countercurrent chromatography (PCC), multicolumn countercurrent solvent gradient purification (MCSGP), and continuous chromatographic processes such as continuous countercurrent tangential chromatography (CCTC), or single-pass tangential flow filtration (SPTFF), or combinations thereof.

[0180] In one embodiment of the present invention, the filtration method used by the filter is based on one or more of: (1) electromechanical methods, including but not limited to, radio frequency, electromagnetic, ultrasonic radiation, sonic, piezoelectric, electrostatic, nano-, molecular / biological forces, nuclear, and ultrasonic filtration and ultrafiltration based methods; (2) biochemical / physicochemical property and / or temperature methods, including but not limited to, size exclusion, pore flow, solution diffusion, protein size or secondary, tertiary or quaternary structure, diffusion, hydrophobic / hydrophilic, anion / cation, high / low binding affinity, chelator, magnetic or nanoparticle based systems, and various neurochemical filtration systems; and (3) biospecific affinity methods, including but not limited to, specific antibodies, immunotherapy based, immunomodulatory, ex vivo immunotherapy using immobilized antibodies or antibody fragments, nucleic acids, receptors, antibacterial, antiviral, anti-DNA / RNA, proteins / amino acids, carbohydrates, enzymes, isomerases, compounds with high or low biospecific binding affinity based systems.

[0181] In some embodiments, filtration is based on enzymatic digestion through the use of one or more enzymes, which may include trypsin; elastase; clostripain; calpains, including calpain-2; caspases, including caspase-1, caspase-3, caspase-6, caspase-7, and caspase-8; M24 homolog; human airway trypsin-like peptidase; proteinase K; thermolysin; Asp-N endopeptidase; chymotrypsin; LysC; LysN; glutamyl endopeptidase; staphylococcal peptidase; arg-C proteinase; proline-endopeptidase; thrombin; cathepsins, including cathepsin E, S, B, K, or L1; tissue type A; heparinase; granzymes, including granzyme A; meprin alpha; pepsin; endothiapepsin; kallikrein-6; kallikrein-5, and combinations thereof. In another embodiment, the filtration is based on affinity methods that depend on cell surface markers of the following groups: EpCAM, Notch1, HER2+, EGFR, Heparanase, and Notch1.

[0182] Tangential Fluid Flow In some embodiments, species of interest, such as proteins or other biological moieties, are separated from a mixture containing them by subjecting the mixture to tangential flow filtration (TFF). In some embodiments, the filtration process is utilized to retain solutes having molecular weights of about 1 kDa to about 1000 kDa. As used herein, the term tangential flow filtration or TFF refers to a process in which a fluid mixture containing components to be separated by filtration is recirculated at high velocities in a direction tangential to the plane of a membrane to increase the mass transfer coefficient of back diffusion. In such filtration, a pressure differential is applied along the length of the membrane, causing the fluid and filterable solutes to flow through the filter. This filtration is suitably performed as a batch process and a continuous flow process. For example, a solution may be repeatedly passed through the membrane while that (e.g., CSF) fluid passing through the filter is continuously drawn off to another unit, or the solution may be passed through the membrane once and the (e.g., CSF) fluid passing through the filter is continuously processed downstream.

[0183] Advantageously, TFF can fractionate by particle size, thereby preventing or inhibiting the formation of filter cakes, thus permitting long operation times. Additionally, in some embodiments, alternating tangential flows can be used to remove blockages. Of particular advantage, TFF overcomes the polarized concentration effect found in conventional filtration, where a polarized layer of solutes acts as an additional filter in series with the original ultrafiltration device, providing greater resistance to solvent filtration. In TFF, the feed stream is recirculated at high velocities in a direction tangential to the plane of the membrane, increasing the mass transfer coefficient of back diffusion. This fluid flow pattern enhances the transport of retained solutes away from the membrane surface and back to the bulk of the feed. Fluid flowing in a direction parallel to the filter membrane continuously washes the filter surface and prevents clogging by unfilterable solutes. In another similar embodiment, in a rotary filtration device that includes an outer cylinder and an inner cylinder, the inner cylinder is rotated to generate vortices and obtain high velocities without pressure changes. In TFF, a pressure differential gradient, called transmembrane pressure (TMP), is applied along the length of the membrane, causing fluid and filterable solutes to flow through the filter.

[0184] In one embodiment, the high performance tangential flow process described herein involves passing a mixture of species to be separated through one or more filtration membranes in an apparatus or module designed for a type of tangential flow filtration under specific conditions of TMP and flux. In particular, the TMP is maintained within the pressure dependent region of the flux vs. TMP curve, i.e., below the TMP value at the transition point. Thus, the filtration is operated at a flux ranging from about 5% to about 100% of the transition point flux. Moreover, the filtration is carried out such that the TMP is approximately constant with time or decreases throughout the filtration.

[0185] Maintaining the TMP within this pressure-dependent region reduces the retention of molecules with molecular weights lower than the membrane rating and improves the overall selectivity of the system for the species requiring purification, thereby overcoming the barrier of the concentration polarization layer. As a result, the species of interest is selectively retained by the membrane as the retentate and smaller species pass through the membrane as the filtrate, or the species of interest passes through the membrane as the filtrate and contaminants in the mixture are retained by the membrane. Note that the TMP does not increase with filtration time and does not necessarily remain constant throughout the filtration. The TMP may remain approximately constant over time or may decrease as the filtration progresses. If the retained species is concentrated, it may be preferable to lower the TMP over the course of the concentration step.

[0186] A preferred embodiment herein is to utilize two or more membranes having the same pore size, arranged in layers parallel to one another, preferably one on top of the other. Preferably, the number of membranes for this purpose is two, although additional membranes can be added.

[0187] The TMP does not need to be maintained substantially constant along the membrane surface, but it may be preferable to maintain the TMP substantially constant. Such conditions are generally achieved by creating a pressure gradient on the filtrate side of the membrane. Thus, the filtrate recirculates through the filtrate compartment of the filtration device in the same direction and parallel to the flow of the mixture in the retentate compartment of the device. The pressures at the inlet and outlet of the recycled material are adjusted so that the pressure drop across the filtrate compartment is equal to the pressure drop across the retentate compartment.

[0188] Certain embodiments of the present invention also contemplate a multi-stage cascade process in which the filtrate from the above process is passed through a filtration membrane having a smaller pore size than the membrane of the first device in a second tangential flow filtration device. The filtrate from this second filtration can be recycled to the first device and the process can be repeated. In this cascade process, the second filtration is usually a conventional filtration, the flux is held at a level greater than about 100% of the transition point flux, and generally the TMP is not held substantially constant along the membrane.

[0189] In a more preferred embodiment of the cascade process, both stages include tangential flow ultrafiltration, and the pore size is 1-1000 kDa. In a three-stage cascade process, the filtrate from the second filtration passes through a filtration membrane with a pore size smaller than that of the second membrane in a third tangential flow filtration device, and the filtrate from this third filtration is recycled back to the first filtration device, and the process is repeated. If only two high-performance filtrations are required in the cascade process, the third stage can be conventional, i.e., the flux is maintained at a level greater than about 100% of the transition point flux in this third stage. In a more preferred embodiment of this three-stage cascade process, all three stages involve tangential flow ultrafiltration.

[0190] An exemplary method may be for filtering material from the CSF of a human or animal subject. An exemplary method may include withdrawing a volume of fluid containing CSF from a CSF-containing space of the subject using a filtration system. An exemplary method may include filtering the volume of fluid into a permeate and a retentate using a first filter of the filtration system, the first filter including a tangential flow filter. An exemplary method may include returning the permeate to the CSF-containing space of the subject. An exemplary method may include filtering the retentate using a second filter of the filtration system. An exemplary method may include returning the filtered retentate to the CSF-containing space of the subject.

[0191] In some embodiments, the second filter of the filtration system includes a dead-end filter or a depth filter. For example, the method may include filtering the retentate using multiple second filters of the filtration system operating in parallel. In some examples, the method further includes combining the permeate and the filtered retentate in a combiner before returning the permeate and before returning the filtered retentate, and returning the combined permeate and filtered retentate to the CSF-containing space of the subject, thereby returning the permeate and returning the filtered retentate. An exemplary system may include a combiner having an inlet coupled to a permeate outlet and an outlet of the second filter. The combiner may be configured to combine the fluid filtered by the second filter with the retentate, and the combiner has an outlet for returning the fluid to the CSF-containing space of the subject. In some variations, the system may further include a third filter having an inlet coupled to the second retentate outlet, and a combiner coupled to the permeate outlet, the second permeate outlet, and the outlet of the third filter and configured to combine the retentate, the second retentate of the second filter, and the fluid filtered by the third filter. In some examples, the second filter includes a plurality of dead-end or depth filters arranged in parallel. In some examples, the parallel multiple dead-end or depth filters are self-regulating, such that when one of the dead-end or depth filters becomes full or clogged, pressure increases and more waste liquid is directed to one or more of the other dead-end or depth filters.

[0192] In some applications, the coupler may include a check valve configured to resist backflow into the second filter. In some variations, the method may further include calculating a waste rate of the filtration system and modifying one or more parameters of the system to maintain the waste rate below a threshold value. In some examples, the threshold value is based on a predicted rate of natural CSF production in the subject. In some examples, the threshold value is 0.25 milliliters of CSF per minute. In some examples, the threshold value is 0.20 milliliters of CSF per minute. In some examples, the second filter of the filtration system includes a tangential flow filter configured to filter the retentate into a second permeate and a second retentate, and returning the filtered retentate to the CSF-containing space of the subject includes returning the second permeate to the CSF-containing space of the subject. In some examples, the method further includes filtering the second retentate using a third filter of the filtration system and returning the filtered second retentate to the CSF-containing space of the subject.

[0193] Substrate countercurrent cascade ultrafiltration Another embodiment of the invention is directed to a countercurrent cascade separation system. In some embodiments, the countercurrent cascade separation system may include a series of interconnected stages, each stage including a diafilter receiving a flow stream. The diafilter of each stage is preferentially permeable to the target solute, and the diafilter preferentially passes the solute to the permeate stream while preferentially retaining the remaining solute in the retentate stream. Each stage also includes an ultrafilter receiving a permeate stream from the diafilter, the ultrafilter being selectively permeable to the solvent but not to the remaining solutes contained in the permeate stream. The stages of the system are interconnected such that each stage beyond the first stage receives a mixed flow stream formed by combining the retentate stream and the permeate stream from a different stage. The target solute is separated by countercurrent cascading through the series of interconnected stages.

[0194] In some preferred embodiments, the system may include three interconnected stages. Various preferred systems recycle the solvent collected by the ultrafilter and return the solvent to the flow stream. In certain embodiments, these systems include at least one stage that further includes a macroporous membrane capable of uniformly distributing the solvent on the diafilter.

[0195] Continuous Countercurrent Tangential Chromatography (CCTC) Another embodiment of the invention is directed to a system for continuous single-pass countercurrent tangential chromatography having multiple single-pass modules. The single-pass combining step module is used to combine (e.g., permanently, semi-permanently, or temporarily) the product from the raw product solution with the resin slurry. The single-pass washing step module is used to wash impurities from the resin slurry. The single-pass elution step module for eluting the output of the washing step module is used as the purified product solution. The single-pass regeneration step module is used to regenerate the resin slurry. Preferably, the resin slurry flows in a successive single pass through each of the single-pass modules. One or more of the single-pass modules includes two or more stages with a permeate flow countercurrent to the flow of the resin slurry in the single-pass module.

[0196] In some applications, the system includes multiple single-pass modules with one or more stages, each stage including an interconnected tangential flow filter and a static mixer. In a preferred embodiment, the single-pass module includes at least two stages, each stage including an interconnected tangential flow filter and a static mixer. The chromatography resin flows in a single pass through each module, while operations similar to those in a normal chromatography process (binding, washing, elution, regeneration, equilibration, etc.) are performed on the resin. Buffers for these operations are pumped into the modules in a countercurrent direction to the resin flow, and the permeate solution from the later stages is recycled back to the previous stages. This creates a concentration gradient in the permeate solution of the tangential flow filter countercurrent to the resin flow.

[0197] In Vitro Systems and Methods for Improvement An extracorporeal system for the improvement of CSF removed from a mammalian subject is shown in Figures 15A-15C. More specifically, Figures 15A-15C show a partially implantable system 1500 including an extracorporeally disposed cartridge 1515 and a fluid communication system 1535 that can be used to remove substances such as (e.g., toxic) proteins, cells, etc. that are detrimental to and symptomatic of disease. Applications include, by way of illustration and not limitation, neurodegenerative diseases, stroke, and immune-mediated diseases such as lupus.

[0198] Referring to FIG. 16, in conjunction with FIGS. 15A-15C, a method for ameliorating symptoms of a disease (e.g., neurological or non-neurological) is shown. In a first step, a medical professional selects a patient for treatment who exhibits one or more symptoms of a particular disease (Step 1). By way of illustration and not by way of limitation, these diseases may include amyotrophic temporal sclerosis (ALS), frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Guillain-Barr syndrome (GBS), meningitis, cerebral vasospasm, drug overdose, and the like.

[0199] At a first location 1505 of the mammalian subject, an outlet port access needle (e.g., a lumbar catheter) may be introduced (e.g., via a lumbar access port) into the subject's SAS space (e.g., lumbar CSF space) from which a volume of CSF may be withdrawn (step 2). In some embodiments, the volume of CSF withdrawn may range from about 1 mL to about 200 mL, and the flow rate of withdrawal may range from about 0.1 mL / min to about 100 mL / min. The flow rate of withdrawal may be controlled by a pumping device 1525, such as any of the active or passive pumps described herein. The withdrawn volume of CSF may be transported, for example, via conduit 1510a, to and introduced into cartridge 1515 for processing in the presence of an improvement agent, technique, and / or process (step 3). In some variations, processing (step 5) may begin immediately, while in other variations, processing may begin after expiration of a predetermined period of time (step 4). The predetermined period or time, or first waiting period, can range from short (measured in milliseconds to minutes) to long (measured in hours or more) to accommodate pump recycle time, cartridge pressure rise, and / or physiological re-equilibration time. In some variations, the process can be continuous or substantially continuous.

[0200] Once the removed amount of CSF is introduced into the cartridge 1515, the removed amount of CSF may be treated (step 5) (e.g., removed, neutralized, digested, converted, sequestered, etc.) to ameliorate biomolecules or toxic proteins (e.g., tau, cis p tau amyloid beta, TDP-43, SOD1, DPR, neurofilaments, alpha synuclein, etc.) contained or believed to be contained in the removed amount of CSF. Preferably, the cartridge 1515 includes an ameliorator for treating the biomolecules or toxic proteins. The ameliorator may be applied, deposited, attached, adhered, etc. to an interior surface of the cartridge 1515, may be applied, deposited, attached, adhered, etc. to beads (e.g., porous, chromatographic resin beads, etc.) disposed within the cartridge 1515, etc. As mentioned above, in some applications, the ameliorator may be, for example, an enzyme (e.g., trypsin; elastase; cathepsin; clostripain; calpains, including calpain-2; caspases, including caspase-1, caspase-3, caspase-6, caspase-7, and caspase-8; M2) for treating (e.g., by enzymatic digestion) biomolecules or toxic proteins, such as tau, cis-p-tau amyloid beta, TDP-43, SOD1, DPR, neurofilaments, alpha-synuclein, pin1, live cells, exosomes, enzymes ... 4 homolog; human airway trypsin-like peptidase; proteinase K; thermolysin; Asp-N endopeptidase; chymotrypsin; LysC; LysN; glutamyl endopeptidase; staphylococcal peptidase; Arg-C proteinase; proline-endopeptidase; thrombin; caspase E, S, B, K, L1; tissue type A; heparinase; granzymes including granzyme A; meprin alpha; pepsin; endothiapepsin; kallikrein-6; kallikrein-5; and combinations thereof).

[0201] Once the removed amount of CSF is processed within the cartridge 1515 (step 5), the processed amount of CSF may be returned to the mammalian subject via the return conduit 1510b (step 8). More specifically, the processed amount of CSF may be returned to the mammalian subject at a second location 1530 (step 8) using, for example, an entry port access needle (e.g., a cervical catheter, a ventricular catheter, etc.) that introduces the processed amount of CSF (e.g., via a subcutaneous access port) into the subject's SAS space (e.g., a cervical CSF space, a ventricular CSF space of the subject, etc.). Preferably, the pumping device 1525 is further structured and arranged to return the processed amount of CSF to the mammalian subject at a flow rate that is the same or substantially the same as the flow rate of the removed amount of CSF (step 8). Processing the removed amount of CSF may include dual flow capabilities such that a volume of CSF may be introduced and reintroduced bidirectionally or repeatedly in succession into the cartridge 1515 after the volume of CSF is removed from the patient (step 2) and before the treated CSF is returned to the patient (step 8) to increase residence time and exposure of the removed CSF to the ameliorative agents within the cartridge 1515. Although various steps of the method are described sequentially, one skilled in the art will appreciate that these steps can and may occur simultaneously or partially simultaneously as various amounts of CSF pass through various stages of the embodied method as the method is performed.

[0202] The systems and methods described herein are optionally bidirectional, such that at a first location 1505, an exit port access needle (e.g., a jugular catheter, a ventricular catheter, etc.) may be introduced (e.g., via a subcutaneous access port) into the subject's SAS space (e.g., the jugular CSF space, the subject's ventricular CSF space, etc.) from which a volume of CSF may be removed (step 2). Once the removed volume of CSF is processed within the cartridge 1515 (step 5), the processed volume of CSF may be returned to the mammalian subject at a second location 1530, e.g., via a return conduit 1510b, using an entry port access needle (e.g., a lumbar catheter) that introduces the processed volume of CSF (e.g., via a subcutaneous access port) into the subject's SAS space (e.g., the lumbar CSF space) (step 8).

[0203] In some variations, at least one sensing device may be disposed in the return conduit 1510b after the cartridge 1515 to capture a measurable characteristic of the processed volume of CSF (step 6) as the processed volume of CSF is returned to the mammalian subject (step 8). Optionally, a sensing device may be disposed in the upstream conduit 1510a. Exemplary characteristics of the processed volume may be captured using a sensing device configured to measure one or more of volume, pressure, temperature, pH, flow rate, etc. Advantageously, data from the sensing device may be transmitted to a control system 1520 (e.g., a microprocessor) which, among other things, receives and processes the data and further compares the sensed data provided by the sensing device to a predetermined threshold value stored in a memory included in the control system 1520 (step 7). Because of concerns about the adverse effects of returning the processed volume of CSF to the SAS space, for example, at a physiologically unacceptable flow rate, pressure, temperature, volume, etc. (i.e., at a rate, pressure, temperature, volume, etc. that may cause harm or discomfort to the mammalian subject), comparisons of the existing state of the control system 1520 to predetermined thresholds may be used by the control system 1520, using the communications subsystem, to control the flow of the processed volume of CSF to ensure that the operating parameters of the returned CSF are physiologically acceptable. These comparisons and sensed data may be used to update the parameters of the set of operating parameters. For example, if a sensor detects an increase in pressure, the pump rate is decreased or possibly reversed.

[0204] Once the treated amount of CSF is returned to the mammalian subject's SAS space (step 8), the method may be repeated (step 10) until the improvement goal is achieved. In some embodiments, a second period of time must elapse (step 9) before the method is repeated (step 10). The second period, or second waiting period, may be short (measured in milliseconds to minutes), long (measured in an hour or more), or a combination of variable lengths. For example, a physician may require a treatment regimen that includes substantially continuous CSF filtration for 9 hours, repeating the treatment regimen once a day for 5 or more consecutive or spaced days, observing other clinical measurements of the disease, and treating for about 3 months, more or less, repeating the treatment once a day.

[0205] Optionally, in addition to the tubing for the conduit 1510a and the return conduit 1510b, the CSF direction or circulation system 1535 may include access ports for injecting drugs or introducing a bolus into the tubing and / or removing waste from the untreated or treated volume of CSF. The CSF direction or circulation system 1535 may also include one or more of T-valves, shutoff valves, anti-reflux valves, etc., for controlling the flow of CSF through the conduits. Various valves may be used, for example, to prevent or minimize unintended reverse fluid flow and to allow one or more of priming, flushing, venting, removing blockages, maintenance operations (e.g., component replacement), etc. The CSF direction or circulation system 1535 may also include one or more filtration systems positioned before or after the cartridge 1515 as a primary or additional processing method. Exemplary filtration systems may include, for purposes of illustration and not limitation, size filtration, ion filtration, tangential flow filtration, countercurrent tangential flow filtration, ultrafiltration, notch filtration, serial filtration, cascade filtration, and combinations thereof. As the unprocessed volume of removed CSF or the processed volume of CSF passes through the CSF direction or circulation system 1535, the flowing CSF may flow through locations where the CSF may be exposed to electromagnetic fields, ultraviolet (UV) radiation, heat, bioaffinity interactions (with or without antibodies), etc. Optionally, bioaffinity interactions may occur with or be used in combination with manipulating agents (e.g., beads, nanoparticles, optical tweezers, etc.).

[0206] cartridge 18, one embodiment of a cartridge 1800 for use in processing CSF removed from a mammalian subject is shown. In some embodiments, the cartridge 1800 can be a commercially available chromatography column 1805, such as OPUS® MiniChrom (11.3 mm×5 mL, REP-001) manufactured by Repligen Corporation of Waltham, Massachusetts. The cartridge 1800 can have a first end to which a first cap 1810 can be removably attached (e.g., by friction fit, threading, snap-on, etc.), and a second end to which a second cap 1815 can be removably attached (e.g., by friction fit, threading, snap-on, etc.). Each of the caps 1810, 1815 can include an opening through which a first (e.g., upstream) conduit 1820 or a second (e.g., downstream) conduit 1825 can provide fluid communication to and through the cartridge 1800. In some embodiments, the inner plenum space 1830 of the cartridge 1800 may be filled with a plurality of compressively packed (e.g., porous chromatography resin) beads 1835. To prevent components from entering or escaping the cartridge 1800, a first filter membrane 1838 may be disposed at a first end of the cartridge 1800 and a second filter membrane 1840 may be disposed at a second end of the cartridge 1800. In some applications, an improving agent is applied to the beads 1835.

[0207] In some applications, the cartridge 1800 may be compression packed with a chromatography resin (e.g., agarose, epoxy methacrylate, amino resin, etc.) that has the protease covalently bound (i.e., immobilized) to a three-dimensional resin matrix. The resin is a porous structure with particle sizes generally ranging from 75-300 micrometers, and pore sizes generally ranging from 300-1800 Å, depending on the particular grade.

[0208] Aspects of the cartridge manufacturing process must be carefully controlled to maintain proper function and sterility of the cartridge 1800. For example, the activity of the cartridge 1800, or the availability of active sites for proteases to digest target proteins, and the inhibition of microbial growth within the resin matrix are important. In some embodiments, the particle size can be about 1-50 micrometers and the pore size can be about 8-12 nanometers. In some applications, a narrow distribution of pore sizes may be desired, while in other applications, a wide distribution of pore sizes may be desired. In still other applications, a diverse distribution of pore sizes may be desired.

[0209] For cartridge activity, it is common to fill column 1805 with a buffer for storage. The buffer is intended to inhibit autocatalysis and prevent the reduction of active sites on the available surface area of ​​the resin matrix. One example of a buffer that has been successfully implemented is 10 mM HCl with 20 mM CaCl2 at pH 2 and stored at 4°C. In some variations, buffers include: PBS 1X may be used as an immobilization buffer, ethanolamine 1M, pH 7.5 may be used as a blocking buffer, PBS 1X / 0.05% ProClin 300 may be used as a storage buffer, and HBSS may be used as a digestion buffer.

[0210] If microbial growth is inhibited, it is common to assemble similar components in a clean (e.g., compliant with ISO 14644-1 cleanroom standards) or sterile environment to avoid the introduction of microorganisms, followed by sterilization using proven approaches such as gamma irradiation, x-ray, UV, electron beam, ethylene oxide, steam, or combinations thereof.

[0211] Another variable that can be controlled to inhibit microbial growth and / or to affect inhibition of enzymatic autolysis is the pH level of the solution. Solutions with a pH of 2 can be successfully implemented, but solutions with a pH ranging from about 3 to about 7.5 are possible.

[0212] Yet another variable that can be controlled to inhibit microbial growth is temperature. Chromatography columns are typically stored at temperatures ranging from 2-8°C, a range that has proven effective and widely accepted. Storage can be kept within this temperature range until the cartridge is ready to be used.

[0213] Manufacturing of the cartridge 1800 may occur in a clean room (e.g., ISO class 8) environment at near ambient temperature. The manufacturing process includes packing the resin (with immobilized enzyme) into a chromatography column 1805 and packaging in a bi-layer film polypropylene package. The packaged cartridge 1800 may then be prepared for a sterilization process, which may be gamma sterilization. Gamma sterilization has been identified as an exemplary sterilization technique that is driven primarily by the presence of a liquid buffer. Techniques such as ethylene oxide and steam may be less likely to adequately penetrate and permeate liquids to achieve the required level of sterility. Ideally, the cartridge 1800 should be refrigerated as soon as it is manufactured and kept refrigerated during transportation to and from sterilization. Once the cartridge has gone through the sterilization process, it can be shipped (e.g., after refrigeration) to a final destination, such as a contract manufacturer or inventory holding area, where it can be stored at 2-8°C.

[0214] During use, the cartridge 1800 may be removed from its temperature controlled environment and staged at the point of care (POC). At the POC, the cartridge 1800 may be removed from its sterile packaging and subjected to a flushing protocol to wash away buffer solutions, as well as potentially undesirable residual components such as unbound enzymes. The flushing or washing reduces the risk of residual / detached trypsin or other remedial agents entering the body when the processed CSF is returned to the subject.

[0215] The flushing protocol may require multiple flushing steps using various amounts of flushing solution. Advantageously, the flushing protocol may ensure that any potential residual ameliorants or enzymes (e.g., trypsin) that may be eluted from the cartridge 1800 are washed away. For example, in some embodiments, the cartridge 1800 may be flushed with about one column volume (i.e., 1.0 CV) of solution (e.g., phosphate buffered saline (PBS)). PBS has been shown to remove trace amounts of residual enzymes. For added assurance, larger volumes of solution may be used. For example, the cartridge 1800 may be flushed with 5-6 CVs (or 25-30 Ml) into a 5 mL column 1805. In some variations, the temperature of the cartridge 1800 may be raised above ambient temperature for more consistent flow through the porous chromatography resin. An exemplary flushing protocol may include a 6 CV (or 30 mL) flush with PBS, followed by a second flush of 6 CV or 30 mL of Hank's Balanced Salt Solution (HBSS).

[0216] In one embodiment, the system may be used to deliver substances by cells or exosomes deposited or applied within the cartridge 1515. The cells or biomolecules used for the improvement may be selected based on beneficial molecules (e.g., trophic factors, anti-inflammatory molecules, etc.) that are secreted or genetically engineered to produce and release beneficial biomolecules (e.g., with trophic factors, anti-inflammatory factors, etc.). Thus, therapeutic materials may be delivered (e.g., by circulating CSF) to a mammalian subject (e.g., brain, spinal cord, etc.) using these beneficial molecules. Inasmuch as there is a barrier against inflammatory mediators and immune system cells on the cartridge 1515, the ex vivo nature of the application cartridge 1515 may also prevent or hinder the subject's immune system from attacking the foreign cells if the cells were otherwise directly implanted into the body.

[0217] More specifically, the embodied system 1500 uses exosomes and / or live cells in improving CSF derived from a mammalian subject in some applications. Exosomes are vesicles that contain, for example, DNA, RNA, proteins, lipids, and miRNA. Exosomes are typically found in the extracellular space and have various functions in the body. For example, exosomes are known to travel between cells, providing a method of intercellular communication. Exosomes have also shown protective activity, believed to be via the release of proteins from exosomes that are neuroprotective. Exosomes isolated from relevant cells known to have protective properties are loaded into the cartridge 1515, and the secreted molecules circulate to the brain and spinal cord.

[0218] In some embodiments, exosomes or cells may be loaded into a cartridge 1515 within the system, such that when CSF is removed from a subject, the CSF circulates through the exosome- or cell-loaded cartridge 1515, and then when the processed CSF is returned to the mammalian subject, secreted factors released by the exosomes or cells loaded into the cartridge 1515 may be distributed into the CSF and circulated through the brain and spinal cord.

[0219] Exosomes may also, in certain cases, have a detrimental effect on disease conditions. For example, exosomes may facilitate the transfer of misfolded proteins. It is also known that exosomes can cross the blood-brain barrier. In such cases, these exosomes that cross the blood-brain barrier need to be removed or degraded from the CSF to reduce their impact on the disease process. Research has also found that the content of exosomes found in the CSF may change in the presence of disease. In some embodiments, the system 1500 may be used to remove undesirable exosomes or cells from the CSF.

[0220] kit In some implementations of the various system and device embodiments described above, packaged kits containing desired or required system components and subsystems are useful. Referring to FIG. 19, a block diagram of an exemplary kit 1900 is shown. In some implementations, the kit 1900 may include devices for a ventricular CSF line, a lumbar CSF line, a CSF circulation system or set 1925, monitoring hardware 1930, and a pumping device 1940. In some variations, the ventricular CSF line may include a peritoneal catheter 1905, a ventricular catheter 1910, one or more catheter adapters, a subcutaneous access port 1920, and a subcutaneous access needle 1935. In some variations, the lumbar CSF line may include a peritoneal catheter 1905, a lumbar catheter 1915, one or more catheter adapters, a subcutaneous access port 1920, and a subcutaneous access needle 1935. In some variations, the second peritoneal catheter 1905 and / or the peritoneal catheter 1905 are optional if the lumbar catheter 1915 can reach the subject's lower abdomen, allowing the lumbar catheter 1915 to be directly connected to the subcutaneous access port 1920.

[0221] In some embodiments, the CSF circulation set 1925 may include a cartridge 1800 (FIG. 18), one or more pressure sensors (and / or other sensors), one or more sample ports, and pump-specific tubing. Advantageously, the cartridge 1800 may be packaged and stored separately. If the kit 1900 is needed, the cartridge 1800 may be added at the POC. The pump-specific tubing in the CSF circulation set 1925 of the kit 1900 may be selected to be compatible with the pumping device (e.g., peristaltic pump) 1940. The monitoring hardware 1930 may include a programmable microprocessor having a touch screen graphical user interface, random access memory, read-only memory, and a processing unit. Optionally, the monitoring hardware 1930 may include a cradle that may be structured and arranged to releasably attach the pumping device 1940 to the monitoring hardware 1930 (as shown in FIG. 15B), and to releasably attach the monitoring hardware 1930 to a standard IV pole or similar fixture (as shown in FIG. 15A).

[0222] Various Advantages of Some Embodiments of the Invention An important advantage of the variations and embodiments of the present invention is the removal of toxic proteins from the CSF. Other advantages and benefits are numerous. For example, a fully implanted device does not require explicit regulation of pressure or temperature while the CSF remains in the body. Furthermore, precise flow control is not required since there are conditions in the body where there is essentially no net flow, and therefore no change in the CSF volume in the subject's body.

[0223] By completely embedding the structure, the structure is more sterile, better tolerated, more portable, and easier to maintain. With an embedded structure, there are no fluid dead spaces and no extensive tubing that can become clogged.

[0224] If a flexible structure is introduced into the SAS, its flexible nature may permit it to enter the body through a smaller diameter opening.

[0225] In the absence of active pumping, the system can be more robust and simpler in its construction. The use of a monolithic embedded pump can combine moving parts into one component, which is simpler and potentially more robust than an external pump system.

[0226] Alternatively, advantages of external systems include the ability to replace, repair, or adjust components quickly and without major disruption, the ability to utilize non-biocompatible materials such as certain battery sources, and the ability to be easily configured for greater capacity of filtration, flow or power for temperature or pressure control.

[0227] Because the course of treatment and processing can be extensive, for example, once low levels of DPR in the CSF are achieved, the present invention provides for chronic use that is favored by its minimally invasive, implantable, outpatient, low power, low maintenance, and unrestricted attributes.

[0228] Alternatively, once low levels of the target protein are achieved, the extracorporeal system may be removed to allow patient mobility and then reattached for additional treatment.

[0229] Embodiments of the present invention also allow for focused or targeted flow to specific areas requiring treatment or processing, for example, before the DPR can affect other locations in the subject's body. For example, if cytotoxicity is identified in the lumbar region, embodiments of the present invention may be locally implanted in the lumbar region upstream or adjacent to the source of the DPR to treat (i.e., focus) the affected area. Such selectivity in locating structures adjacent to specific areas provides focus to the area of ​​interest while simultaneously reducing the spread of toxin-induced damage through transport via the CSF.

[0230] Advantageously, once the structure is fully implanted, it can also be used to optionally or alternatively sample CSF on a pseudo-continuous or periodic basis. This feature facilitates chronic monitoring and treatment of the subject. Having the structure fully implanted in the subject can also constitute a stand-alone diagnostic tool.

[0231] Various combinations and permutations of the systems, subsystems, components, and associated processing methods are contemplated and considered within the scope of the present invention. For example, embodiments of the present invention may include extracorporeal methods of processing neurological and non-neurological conditions, neurological and non-neurological trauma, and / or neurological and non-neurological deficiencies. For example, in one embodiment, the present invention may be used to remove toxic DPRs or other biomolecules from CSF, for example, by enzymatic digestion, thereby improving neurological or non-neurological conditions, neurological or non-neurological trauma, and / or neurological or non-neurological deficiencies, such as, for illustrative purposes and not for limitation, amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Guillain-Barr syndrome (GBS), meningitis, cerebral vasospasm, drug overdose, etc.

[0232] In some embodiments, the method may include modifying one or more of the dynamic, kinetic, and / or spatial arrangement of the biochemical environment (e.g., fungi, spores, prions, peptides, bacteria, viruses, antigens, blood cells, toxic proteins, dissolved gases, inflammatory mediators, etc.) and / or one or more of the physical properties (e.g., pH, volume, salinity, pressure, concentration, temperature, oncotic pressure, total protein content, etc.) of the CSF of a mammalian subject (e.g., human). In some applications, the dynamic modification may include ameliorating (e.g., toxic) biomolecules in the CSF by one or more of removing the CSF via a shunt, reducing the concentration of (e.g., toxic) biomolecules in the CSF, redistributing (e.g., toxic) biomolecules in the CSF, and / or focusing flow patterns in the CSF. Some embodiments of the dynamic modification may include processing methods based on implementing physiological processes including one or more of filtration, charge separation, exposure to ultraviolet light, exposure to infrared light, exposure to nuclear radiation, Raman scattering, dynamic light scattering, and the like. Kinetic modification may include affecting one or more of flow rate, local flow velocity, potential energy, and / or photon or chemical excitation. Spatial modification may include processing biological, chemical, and / or molecular components. For example, such processing for spatial modification purposes may include separation, disintegration, sterilization, irradiation, fixation, sequestration, aseptic separation, chemical reaction, molecular reorganization, disaggregation, local modification, combination of entities, etc.

[0233] Dynamic modification may include processing methods based on implementing focused CSF flow. In some embodiments, focused flow may be implemented such that the flow may be operable to reduce the concentration of one or more target species (e.g., biomolecules) at a separate target location. In other embodiments, focused flow may be implemented such that the flow may be operable to increase the concentration of a target species at a processing location. In yet other embodiments, focused flow may be implemented such that the flow may be operable to increase the transport of a target species from one location to another.

[0234] In some embodiments involving focused flow, a conditioning cartridge or other structure containing an improvement agent may be placed external to the subarachnoid space (SAS) while CSF is actively pumped (e.g., via multiple catheters) into and through the external conditioning cartridge, thus presenting a high circulation of CSF to the motor neuron location.

[0235] The spatial modification (e.g., modification of chemical components) may include introducing an improvement agent (e.g., an enzyme) operable to enzymatically (e.g., proteolytically) digest biomolecules in the CSF. In some embodiments, the improvement agent may be introduced to the CSF biomolecules in or outside the SAS without circulation of the improvement agent. The CSF may be naturally selectively circulated around the stationary or substantially stationary improvement agent, actively circulated, or passively circulated. In examples where the improvement agent is substantially stationary, the improvement agent may be disposed, for example, on a (e.g., solid) substrate, such that the improvement agent is applied to the outer surface of a plurality of porous beads, a porous monolithic structure contained within the cartridge, and the like. The cartridge allows the inflow of endogenous CSF to contact the improvement agent before exiting the cartridge. In some variations, the spatial modification may include a combination of improvement processes and / or a combination of improvement agents. For example, if the improvement agent is bound to a substrate, the CSF may be filtered, exposed to the improvement agent, and then filtered again. In some applications, the spatial modification may include a combination of an improvement process and focused flow, and / or a combination of an improvement agent and focused flow.

[0236] Spatial modification (e.g., modification of chemical components) may include introducing and circulating an improvement agent operable to enzymatically (e.g., proteolytically) digest biomolecules in the CSF. In some embodiments, the improvement agent may be introduced and circulated entirely within the SAS, introduced and circulated inside and outside the SAS, or introduced and circulated entirely outside the SAS. For example, in some variations, the improvement agent may be formed or applied on the outer surface of a plurality of (e.g., superparamagnetic) beads that are disposed in vivo (e.g., in a lumbar sac) as a slurry within a porous bag, tubular device, and / or dialysis-like (e.g., dialysis membrane) catheter. The beads with the improvement agent applied may be circulated within the SAS (e.g., by using magnetic attraction, actively pumping, etc.). The CSF may naturally circulate around the circulating improvement agent, or may be circulated actively or passively.

[0237] Further embodiments may include in vivo treatment methods that include introducing or disposing the ameliorative agent into the SAS (e.g., on a solid, foldable or flexible substrate, or in a tubular structure, cartridge, or catheter) without circulating the ameliorative agent. In various applications, the CSF may circulate naturally (e.g., by passive circulation) in the presence of the ameliorative agent, so that the CSF remains entirely within the SAS; the CSF may circulate in the presence of the ameliorative agent by actively pumping the CSF entirely into the SAS; the CSF may circulate in the presence of the ameliorative agent by passively pumping the CSF entirely into the SAS; or the CSF may circulate in the presence of the ameliorative agent by actively or passively pumping the CSF, which may include pumping the CSF from and back to the SAS.

[0238] The CSF may circulate in the presence of a (e.g., hydraulically or pneumatically) expandable substrate having multiple cilia protruding from the substrate or from multiple appendages incorporated into the substrate. Each of the cilia may be dosed with an improving agent, so that as the substrate cyclically expands and contracts, the CSF may be mixed and any biomolecules within the CSF may interact with (e.g., be enzymatically digested by) the improving agent.

[0239] The CSF may be circulated in the presence of a (e.g., hydraulically or pneumatically) expandable matrix having multiple exposed appendages incorporated into the matrix. Each of the exposed appendages may be dosed with an ameliorative agent, so that as the matrix cyclically expands and contracts, the CSF may be mixed and any biomolecules within the CSF may interact with (e.g., be enzymatically digested by) the ameliorative agent on the exposed appendages.

[0240] The CSF can be circulated in the presence of a tube-shaped structure with multiple fibers attached to the inside of a substrate. Each of the fibers can be treated with an improving agent, and can extend from the inside of the structure and retract back into the structure. Biomolecules in the CSF can interact with the improving agent on the fiber in the extended state (e.g., be enzymatically digested by the improving agent).

[0241] In a variation, the ameliorative agent is applied to an exposed surface of a stent or plate located within the SAS and circulates the CSF through the stent or across the plate. In some variations, the CSF can circulate naturally (e.g., by passive circulation) through the stent or across the plate. In other variations, the CSF can be circulated outside the SAS and returned to the SAS before circulating through the stent or across the plate. Some embodiments of the present invention may include a processing method that includes a bulk flow system having multiple sensors and several pumps, valves, and / or actuators controllable by a system controller.

[0242] Other embodiments may include methods of treating a mammalian subject suffering from a neurological or non-neurological condition, neurological or non-neurological trauma, or neurological or non-neurological deficit. In some embodiments, the method includes circulating CSF in a focused flow in the subject. In some applications, amelioration of toxic biomolecules in the CSF using amelioration agents, amelioration techniques, or combinations thereof. In other embodiments, amelioration agents are not utilized. In some embodiments, circulating CSF in a focused flow includes circulating CSF at natural flow levels, allowing CSF flow outside the subarachnoid space, restricting CSF flow only within the subarachnoid space, and / or using a passive pump.

[0243] Although exemplary embodiments of the present invention have been described herein, those skilled in the art will appreciate various other features and advantages of the present invention apart from those specifically described above. It is therefore to be understood that the foregoing is merely illustrative of the principles of the present invention, and that various modifications and additions, including all combinations and permutations of structural elements and method steps, may be made by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims should therefore not be limited to the specific features shown and described, but should also be construed to cover modifications and equivalents thereof.

Claims

1. 1. A method for treating a mammalian subject suffering from at least one of a pathology, trauma, neurological disease, non-neurological disease, or deficiency characterized by the presence of a toxic biomolecule in cerebrospinal fluid (CSF) by amelioration of said toxic biomolecule in said CSF using an amelioration agent, amelioration technique, or a combination thereof, comprising: selecting a patient having at least one of a risk, diagnosis, prognosis, or at least one symptom of a condition selected from the group consisting of a pathology, trauma, a neurological disease, a non-neurological disease, or a deficiency; removing a volume of CSF from a first location in the patient; treating the removed amount of CSF with an enzymatic activity using a cartridge; and returning the amount of treated CSF to the patient at a second location.

2. measuring a characteristic of the processed amount of CSF using a sensor; the first location comprises a lumbar CSF space of the patient; the second location comprises at least one of a cervical CSF space or a ventricular CSF space of the patient; 10. The method of claim 1, wherein the volume of processed CSF is returned to the patient at substantially the same rate as the volume of CSF is removed.

3. The method of claim 2, further comprising flowing the CSF through the cartridge sequentially or reversibly.

4. The method of claim 2 , wherein the steps occur at least partially simultaneously.

5. The method of claim 1 , further comprising repeating the retrieving, processing, and returning steps until one or more criteria for ceasing processing are met.

6. 10. The method of claim 1, further comprising filtering the treated amount of CSF with a getter.

7. 10. The method of claim 1, further comprising updating at least one parameter of a set of process operational parameters based on the measured fluid properties meeting or exceeding a predetermined threshold, the operational parameters being set to maintain at least one of a particular pressure, a particular volume change, or a particular flow rate within the patient's CSF space.

8. 2. The method of claim 1, wherein the neurological disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), Huntington's disease (HD), Parkinson's disease (PD), cancer, intracranial metastatic disease (IMD), diabetes, type 3 diabetes, lupus, poisoning, trauma, chronic traumatic encephalopathy (CTE), bacterial meningitis, aneurysm, stroke, cerebral vasospasm, and traumatic brain injury.

9. 2. The method of claim 1, wherein treating the amount of CSF comprises at least one of removing, reducing, modifying, sequestering, digesting, neutralizing, or inactivating one or more substances selected from the group consisting of tau, cis-p-tau, abeta, TDP-43, SOD1, DPR, neurofilament, and alpha-synuclein.

10. 10. The method of claim 1, wherein treating the quantity of CSF comprises filtering the quantity of CSF using at least one of size filtration, ion filtration, tangential flow filtration, countercurrent tangential flow filtration, ultrafiltration, notch filtration, serial filtration, or cascade filtration.

11. 2. The method of claim 1, wherein treating the amount of CSF comprises at least one of removing waste products, exposing the amount of CSF to enzymatic digestion, exposing the amount of CSF to a bioaffinity interaction with or without the use of an antibody, exposing the amount of CSF to ultraviolet radiation, exposing the amount of CSF to heat or cold or a temperature change, introducing the amount of CSF to at least one electromagnetic field, exposing the amount of CSF to a pressure change, exposing the amount of CSF to a pH change, or exposing the amount of CSF to at least one manipulating agent, alone or in combination with at least one bioaffinity agent.

12. The method of claim 11 , wherein the manipulating agent is selected from the group consisting of magnetic beads, nanoparticles, and optical tweezers.

13. 10. The method of claim 1, wherein the amount of CSF removed is between about 1 mL and about 200 mL.

14. 10. The method of claim 1, wherein the amount of CSF removed is equal to or greater than the amount of processed CSF returned.

15. The method of claim 1 , wherein the removing step comprises a flow rate of about 0.1 mL / min to about 100 mL / min.

16. waiting a first amount of time after withdrawing the amount of CSF from the patient; 10. The method of claim 1, further comprising the step of waiting a second amount of time after returning the processed amount of CSF to the patient.

17. 1. A cerebrospinal fluid (CSF) improving system for use in fluid communication with a mammalian subject, comprising: A substrate; A CSF improving agent disposed at least one of on or within the substrate.

18. The system of claim 17 , wherein the substrate comprises a cartridge.

19. 20. The system of claim 18, wherein the improving agent comprises at least one of an enzyme disposed within the cartridge or an enzyme applied to an interior surface of the cartridge.

20. The system of claim 18, wherein the ameliorative agent comprises at least one of pin1, exosomes, or live cells disposed within the cartridge.

21. The system of claim 18 , wherein the cartridge comprises a porous wall.

22. The system of claim 21 , wherein the remedial agent is retained by the porous walls.

23. The system of claim 17, wherein the improving agent modifies or degrades biological molecules present in the CSF by enzymatic digestion.

24. 24. The system of claim 23, wherein the improving agent comprises an enzyme including a protease for enzymatic digestion of the biomolecule.

25. 25. The system of claim 24, wherein the protease is selected from the group consisting of trypsin; elastase; cathepsin; clostripain; calpain, including calpain-2; caspases, including caspase-1, caspase-3, caspase-6, caspase-7, and caspase-8; M24 homolog; human airway trypsin-like peptidase; proteinase K; thermolysin; Asp-N endopeptidase; chymotrypsin; LysC; LysN; glutamyl endopeptidase; staphylococcal peptidase; arg-C proteinase; proline-endopeptidase; thrombin; cathepsin E, S, B, K, L1; tissue type A; heparinase; granzymes, including granzyme A; meprin alpha; pepsin; endothiapepsin; kallikrein-6; kallikrein-5; and combinations thereof.

26. 20. The system of claim 17, wherein the system is fully or partially implantable in the mammalian subject.

27. 20. The system of claim 17, wherein the substrate is at least one of foldable or flexible to facilitate catheter-based implantation within the subject.

28. The system of claim 17 , wherein the substrate comprises a plurality of cilia.

29. 30. The system of claim 28, wherein the cilia protrude from an outer shell portion of the substrate.

30. 30. The system of claim 28, wherein the cilia include at least one of fibers or brush fibers that are at least one of retractable and extendable from the substrate.

31. The system of claim 17 , wherein a plurality of beads are disposed within or on the substrate or comprise the substrate.

32. 32. The system of claim 31 , wherein the beads comprise superparamagnetic beads.

33. The system of claim 17 , wherein the substrate comprises a dialysis membrane catheter or a porous bag.

34. The system of claim 17 , wherein the substrate comprises a tubular device containing the ameliorative agent.

35. The system of claim 17 , wherein the substrate comprises a plurality of appendages.

36. Sampling the CSF; introducing, removing, or replenishing said ameliorative agent; introducing or removing said substrate; Introducing drugs, or 20. The system of claim 17, further comprising at least one subcutaneous port for at least one of:

37. 20. The system of claim 17, further comprising at least one CSF fluid loop including at least one access port for enhancing flow of CSF fluid across the substrate.

38. 40. The system of claim 37, wherein the CSF fluid loop comprises a first access port and a second access port.

39. 40. The system of claim 37, further comprising at least one sensor located within the CSF fluid loop.

40. 40. The system of claim 39, wherein the sensor is selected from the group consisting of a temperature sensor, a pressure sensor, a pH sensor, a UV sensor, an IR sensor, a turbulence sensor, a Raman scattering sensor, a dynamic light scattering sensor, a constituent concentration sensor, a flow sensor, and combinations thereof.

41. The system of claim 17 , further comprising at least one of a pump, a valve, or an actuator located within the CSF fluid loop.

42. 42. The system of claim 41, wherein the pump is selected from the group consisting of a peristaltic pump, a rotary vane pump, an archimedes screw, an air bladder, a pneumatic bladder, a hydraulic bladder, a displacement pump, an electric pump, a passive pump, an automatic pump, a valveless pump, a bidirectional pump, and combinations thereof.

43. 42. The system of claim 41, wherein the valve is selected from the group consisting of a one-way valve, a bicuspid valve, a tricuspid valve, a ruby ​​valve, and combinations thereof.

44. 20. The system of claim 17, further comprising a system controller operably coupled to at least one of the sensor, the pump, or the actuator.

45. 45. The system of claim 44, wherein the system controller is selected from the group consisting of an open loop controller, a closed loop controller, a PID controller, a PID threshold controller, a system identification algorithm, and combinations thereof.

46. The system of claim 17 , wherein the substrate comprises a stent.

47. The system of claim 17 , further comprising at least one of a pump and an actuator.

48. and a control system for maintaining at least one of a pressure or flow of CSF within the mammalian subject, the control system comprising: A programmable memory; A data processing system; The system of claim 17 further comprising a communications subsystem.

49. The CSF circulation system further includes a CSF direction system comprising: A pump, Tubing and One or more of the following: T-valves, check valves, or shutoff valves and one or more of an access port or a subcutaneous access port.

50. 20. The system of claim 17, further comprising at least one of a jugular catheter, a timber catheter, or a ventricular catheter.

51. 1. A cerebrospinal fluid (CSF) improving system for use in fluid communication with a mammalian subject, the system being operable to provide a focused flow of the CSF, Flow Controller, catheter, Pump, or A system including at least one or more of the structures for modifying fluid flow.

52. 52. The system of claim 51, further comprising a plurality of catheters positioned at a plurality of separate fluid access points to the subarachnoid space.

53. 53. The system of claim 52, wherein the fluid access points are located in a lateral ventricle and a lumbar capsule of the subject.

54. 53. The system of claim 52, wherein the fluid access points are located in the cisterna magna and lumbar pouch of the subject.

55. 53. The system of claim 52, wherein the fluid access points are located in the cisterna magna and frontal lobe of the subject.

56. 53. The system of claim 52, wherein the fluid access point is located in the lateral temporal subarachnoid space of the subject.

57. 53. The system of claim 52, wherein the fluid access points are located in the cervical subarachnoid space and the lumbar pouch of the subject.

58. 53. The system of claim 52, wherein at least one or more of the passive pump, the internal active pump, or the passive flow regulator are implanted substantially within the subarachnoid space.

59. 1. A cerebrospinal fluid (CSF) improving system for use in fluid communication with a mammalian subject, said system for providing a focused flow of said CSF, A substrate; a CSF improving agent disposed at least one of on or within the substrate; Flow Controller, catheter, Pump, or and at least one or more of a structure for modifying fluid flow.

60. A method for treating a mammalian subject suffering from at least one of a pathology, trauma, neurological disease, non-neurological disease, or deficiency characterized by the presence of a toxic biological molecule in the cerebrospinal fluid (CSF), comprising amelioration of the toxic biological molecule in the CSF using an amelioration agent, amelioration technique, or combination thereof.

61. 61. The method of claim 60, further comprising maintaining a reduced toxic biomolecule content in the CSF after the initial toxic biomolecule content in the fluid has been reduced.

62. 61. The method of claim 60, wherein ameliorating the toxic biomolecule comprises enzymatically digesting the toxic biomolecule.

63. 63. The method of claim 62, wherein enzymatically digesting the toxic biomolecule comprises enzymatically digesting the toxic biomolecule using a protease.

64. The amelioration of the toxic biomolecule comprises: Discarding at least one of pin 1, exosomes, or live cells into a cartridge; circulating the toxic biomolecule in the CSF through the cartridge.

65. 61. The method of claim 60, further comprising charge or size filtering the CSF to filter out at least a portion of the toxic biomolecules.

66. 61. The method of claim 60, further comprising antibody or nanobody treatment of the CSF to filter out at least a portion of the toxic biomolecules.

67. 61. The method of claim 60, further comprising a combination of enzymatic and charge or size filtration methods to filter out at least a portion of the toxic biomolecules.

68. 61. The method of claim 60, wherein amelioration of the toxic biomolecule occurs at least in part in the subject's ventricles.

69. 61. The method of claim 60, wherein amelioration of the toxic biomolecule occurs at least in part in the brain subarachnoid space of the subject.

70. 61. The method of claim 60, wherein the amelioration of the toxic biomolecule occurs at least in part in the lumbar region of the subject.

71. 61. The method of claim 60, wherein the ameliorative agent is in fluid contact with the CSF in the subarachnoid space of a subject.

72. 61. The method of claim 60, further comprising augmenting the naturally occurring flow of CSF.

73. 61. The method of claim 60, wherein the improving agent is disposed on a solid structure, a foldable structure, or a flexible structure.

74. 74. The method of claim 73, wherein the structure comprises at least one of a substrate, cilia, cilia extending from a substrate, fibers, fibers extending from a substrate, appendages, appendages extending from a substrate, fenestrations, beads, bi-stable monolithic structures, exposed appendages, stents, catheters, cartridges, slurries, and combinations thereof.

75. 74. The method of claim 73, wherein the structure is implantable in the subject by catheter-based implantation.

76. 74. The method of claim 73, wherein the structure comprises cilia on a surface, the surface being selected from the group consisting of a hydraulically actuatable surface, a pneumatically actuatable surface, and a shape memory surface.

77. The surface includes an outer shell surrounding an inner core, and the method further comprises: Inflating the shell in which the cilia are located; expanding the inner core such that the CSF located between the inner core and the outer shell passes through the cilia; 77. The method of claim 76, further comprising: collapsing said inner core and said outer shell.

78. 74. The method of claim 73, wherein the structure comprises fibers, the method further comprising extending the fibers from within a delivery device into the CSF.

79. 80. The method of claim 78, further comprising storing the fibers within the delivery device.

80. 74. The method of claim 73, wherein the structure comprises a monolithic bistable structure with an appendage.

81. expanding the monolithic bistable structure to deploy the appendages into the fluid and expose them from the monolithic bistable structure; 81. The method of claim 80, further comprising: collapsing the monolithic bistable structure to retract the appendages and provide a mixing motion within the CSF.

82. The improvement technique is: introducing an ameliorative agent outside the subarachnoid space of the subject; and allowing or directing circulation of CSF through said ameliorating agent.

83. 83. The method of claim 82, wherein circulating the CSF comprises using an active or passive pump.

84. The circulation of CSF is Disposing the ameliorative agent into a catheter or cartridge; and flowing CSF through the catheter or cartridge.

85. 85. The method of claim 84, further comprising returning the treated CSF to the subarachnoid space.

86. 86. The method of claim 85, wherein circulating the CSF and returning treated CSF comprises transporting CSF by multiple catheters through multiple catheter insertion sites that access the subarachnoid space.

87. 86. The method of claim 85, wherein circulating the CSF and returning treated CSF comprises transporting the CSF via at least a single catheter insertion site that accesses the subarachnoid space by a multi-lumen catheter arrangement.

88. 86. The method of claim 85, wherein circulating the CSF and returning the treated CSF comprises active circulation by active or passive pumping to maintain a controlled fluid flow.

89. 61. The method of claim 60, further comprising augmenting the naturally occurring flow of CSF.

90. 90. The method of claim 89, wherein enhancing the naturally occurring flow of the CSF comprises enhancing at least one of a phase, a direction, or an amplitude of fluid flow.

91. 90. The method of claim 89, further comprising circulating an ameliorative agent through the CSF of the subject.

92. 90. The method of claim 89, wherein the enhanced flow comprises focused flow.

93. 61. The method of claim 60, wherein the improvement technique comprises circulating CSF in a flow from a first location in the subarachnoid space to a second location in the subarachnoid space.

94. 94. The method of claim 93, wherein the flow remains substantially within the subarachnoid space.

95. 94. The method of claim 93, wherein circulating CSF comprises actively transporting the CSF using an automated bladder pump.

96. 94. The method of claim 93, further comprising allowing CSF to circulate outside the subarachnoid space.

97. 94. The method of claim 93, wherein circulating the CSF in a flow comprises circulating the CSF at a natural flow rate.

98. 94. The method of claim 93, wherein the CSF circulates from a first location having a low concentration of a biomolecule to a location having a higher concentration of said biomolecule.

99. 94. The method of claim 93, wherein the CSF circulates from a first location having a high concentration of a biomolecule to a location having a lower concentration of said biomolecule.

100. 61. The method of claim 60, wherein the ameliorative agent is circulated through the CSF of the subject.

101. 101. The method of claim 100, wherein the improving agent is circulated through the CSF flowing at a natural flow level.

102. 101. The method of claim 100, wherein the ameliorative agent is circulated through the CSF outside the subarachnoid space of the subject.

103. 101. The method of claim 100, wherein the ameliorative agent is circulated through the CSF substantially within the subarachnoid space of the subject.

104. Circulating the ameliorating agent through the CSF in the subarachnoid space comprises providing a plurality of beads comprising the improving agent; introducing the beads into the CSF in the subarachnoid space; and imparting movement to the beads.

105. 105. The method of claim 104, wherein introducing the beads into the CSF comprises containing the beads within a dialysis membrane catheter or a porous bag.

106. 105. The method of claim 104, wherein introducing the beads into the CSF comprises introducing the beads into a slurry.

107. 105. The method of claim 104, wherein introducing the beads into the CSF comprises containing the beads within a tubular device.

108. 105. The method of claim 104, wherein introducing the beads into the CSF comprises containing the beads in a multi-lumen catheter.

109. introducing the beads from a supply reservoir into a first lumen of the multi-lumen catheter; circulating the beads through a first lumen and a second lumen of the multi-lumen catheter; 109. The method of claim 108, further comprising introducing the beads from the second lumen into a receiving reservoir.

110. 110. The method of claim 109, wherein the first and second lumens of the multi-lumen catheter comprise a plurality of pores sized to allow biomolecules to pass through the pores while preventing the beads from passing through the pores.

111. 109. The method of claim 108, wherein the multi-lumen catheter is operable to allow counterflow.

112. Circulating the ameliorating agent through the CSF outside the subarachnoid space may include providing a plurality of beads comprising the improving agent; introducing the beads into the CSF outside the subarachnoid space; and circulating the beads.

113. 113. The method of claim 112, further comprising at least one of adding beads or removing beads using a syringe.

114. 1. A method of treating a mammalian subject suffering from a neurological condition, trauma, or deficiency, comprising circulating cerebrospinal fluid (CSF) in a focused flow within the subject.

115. 115. The method of claim 114, further comprising ameliorating toxic biomolecules in the CSF using an amelioration agent, amelioration technique, or a combination thereof.

116. 115. The method of claim 114, wherein no ameliorative agent is utilized.

117. 115. The method of claim 114, wherein circulating the CSF in a focused flow comprises circulating the CSF at a natural flow level.

118. 115. The method of claim 114, wherein circulating CSF in a focused flow comprises allowing CSF flow outside the subarachnoid space.

119. 115. The method of claim 114, wherein circulating CSF in a focused flow comprises restricting CSF flow only within the subarachnoid space.

120. 115. The method of claim 114, wherein circulating the CSF in a focused flow comprises using a passive pump.

121. 1. A kit for use in improving cerebrospinal fluid (CSF) obtained from a mammalian subject, comprising: a ventricular line segment removably attachable to a first location of the subject; a waistline portion removably attachable to a second location on the object; and a circulatory system in fluid communication between the ventricular line portion and the lumbar line portion, the circulatory system optionally including a cartridge containing an improvement agent for improving the CSF.

122. The ventricular line segment A ventricular catheter; one or more catheter adapters removably attachable to the ventricular catheter; A subcutaneous access port; and a subcutaneous access needle.

123. 123. The kit of claim 122, further comprising a peritoneal catheter.

124. The waist line portion is A lumbar catheter; one or more catheter adapters removably attachable to the lumbar catheter; A subcutaneous access port; and a subcutaneous access needle.

125. 125. The kit of claim 124, further comprising a peritoneal catheter.

126. Monitoring hardware, or 122. The kit of claim 121, further comprising at least one of a pumping device for withdrawing the CSF, for circulating the CSF, and for returning the CSF to the subject.

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