Hemofiltration devices with flow diverters and recesses

Abstract

Traditional hemofiltration devices can include a linear blood channel, a linear dialysate channel, or both. Additionally, the blood channel or dialysate channel can be modified so that one region has a recess in a channel wall and a filtration membrane can be positioned along the edge of the recess. However, due to fluid dynamics, some blood or dialysate could linger within the recess by moving slowly. Therefore, other fractions of the blood or dialysate would simply bypass the recess and filtration membrane by flowing through the center of the channel. This flow pattern would reduce filtration efficiency since some blood or dialysate remains far from the filtration membrane. However, positioning a flow diverter adjacent to the recess could force most or all of the blood or dialysate into the recess, thereby increasing filtration efficiency. In other words, the flow diverter would modify the fluid dynamics in a manner that would reduce the dead space in the blood channel or dialysate channel and increase filtration efficiency.

Description

HEMOFILTRATION DEVICES WITH FLOW DIVERTERS AND RECESSESCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit under 35 U.S.C. § 119(e) of provisional application 63 / 712,826, filed October 28, 2024, which application is hereby incorporated by reference in its entirety.INTRODUCTION

[0002] End Stage Renal Disease (ESRD) remains a major public health problem in the United States, afflicting over 615,000 people with nearly 116,000 new patients initiating treatment each year. Due to the shortfall in organ availability, the majority of ESRD patients in the United States undergo in-center, 3-4 hour, thrice weekly dialysis, such as hemodialysis or peritoneal dialysis.

[0003] Hemodialysis involves passing a patient's blood against a synthetic or semisynthetic membrane and inducing diffusive transport of toxins from the blood into a bath of dialysate on the other side of the membrane. In peritoneal dialysis, the patient’s parietal peritoneal epithelium performs the function of the dialysis membrane.

[0004] However, the efficiency of hemodialysis can be limited by several different factors. For example, the efficiency can be limited by slow diffusion of blood compounds through the membrane and into the dialysate.SUMMARY

[0005] Traditional hemofiltration devices can include a linear blood channel, a linear dialysate channel, or both. Additionally, the blood channel or dialysate channel can be modified so that one region has a recess in a channel wall and a filtration membrane can be positioned along the edge of the recess. However, due to fluid dynamics, some blood or dialysate could linger within the recess by moving slowly. Therefore, other fractions of the blood or dialysate would simply bypass the recess and filtration membrane by flowing through the center of the channel. This flow partem would reduce filtration efficiency since some blood or dialysate remains far from the filtration membrane. However, positioning a flow diverter adjacent to the recess could force most or all of the blood or dialysate into the recess, thereby increasing filtration efficiency. In other words, the flow diverter would modify the fluid dynamics in a manner that would reduce the dead space in the blood channel or dialysate channel and increase filtration efficiency.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 A shows a channel segment of a blood conduit of a hemofiltration device with a single recess.

[0007] FIG. IB shows a second view of the FIG. 1 A embodiment that includes three directional axes.

[0008] FIG. 1C shows a third view of the FIG. 1A embodiment with a boundary between two different sections of lumen.

[0009] FIG. 2A shows a second embodiment of a channel segment that includes two different recesses.

[0010] FIG. 2B shows another view of the FIG. 2A embodiment that includes the boundaries between the different lumens.

[0011] FIG. 3A shows three panels that can be vertically compressed in order to form several individual channel segments.

[0012] FIG. 3B shows a cross-section of a single channel segment formed from the FIG. 3A panels.

[0013] FIG. 4 shows how fluid flow changes due to the presence of a recess in the channel segment.

[0014] FIG. 5 shows a hemofiltration device with multiple blood conduits.DETAILED DESCRIPTION

[0015] Traditional hemofiltration devices can include a linear blood channel, a linear dialysate channel, or both. Additionally, the blood channel or dialysate channel can be modified so that one region has a recess in a channel wall and a filtration membrane can be positioned along the edge of the recess. However, due to fluid dynamics, some blood or dialysate could linger within the recess by moving slowly. Therefore, other fractions of the blood or dialysate would simply bypass the recess and filtration membrane by flowing through the center of the channel. This flow pattern would reduce filtration efficiency since some blood or dialysate remains far from the filtration membrane. However, positioning a flow diverter adjacent to the recess could force most or all of the blood or dialysate into the recess, thereby increasing filtration efficiency. In other words, the flow diverter would modify the fluid dynamics in a manner that would reduce the dead space in the blood channel or dialysate channel and increase filtration efficiency. bloodbloodbloodbloodbloodbloodblood

[0016] Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0017] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and exemplary methods and materials may now be described. Any and all publications mentioned herein arc incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0019] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any element, e.g., any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.

[0020] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. To the extent the definition or usage of any term herein conflicts with a definition or usage of a term in an application or reference incorporated by reference herein, the instant application shall control.

[0021] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recitedmethod can be carried out in the order of events recited or in any other order which is logically possible.DEFINITIONS

[0022] The terms “subject” and “patient” are used interchangeably herein to refer to an individual animal, such as a mammal, such as a human. The individual may be a patient with a compromised kidney function and / or in need of dialysis, compromised heart function, and / or compromised liver function.

[0023] “Nanoporc” refers to a pore that penetrates a substrate from one side to another, where the pore has at least one lateral dimension (e.g., width and / or length, but not the height / thickness of the pore across the substrate) that is in the nanometer range, e.g., in the range of 1.0 nm to 1,000 nm.

[0024] “Pumpless” as used in reference to a device connected to a blood vessel or a blood circuit is meant to refer to the absence of a pump mechanism other than the heart that drives blood flow through the circulatory system of an individual.

[0025] “Filtration” refers to a process of separating smaller particulates and larger particulates present in a fluid, by passing the fluid through or over a filtering material that will not pass particulates having a size larger than pores in the filter. Filtration is also affected by flow rate of the fluid as well as concentration and pressure gradient across the filter. The filter may be a semipermeable membrane.

[0026] “Dialysis” refers to a form of filtration, or a process of selective diffusion through a membrane; it is typically used to separate low-molecular weight solutes that diffuse through the membrane from the colloidal and high-molecular weight solutes which do not. In some embodiments, a feed of fluid is passed over a semipermeable membrane, and a feed of dialysate is passed over the other side of that membrane; the membrane is wetted by one or both fluids, and then there is diffusive transport of solutes between the fluids. The composition of one fluid, the dialysate, may be used to deplete the composition of the other fluid, the feed fluid, of some molecule or molecules.

[0027] “Dialysate” refers to the fluid into which low-molecular weight solutes diffuse through a membrane from another fluid (typically, the feed fluid) initially containing these solutes.

[0028] “Ultrafiltration” refers to subjecting a fluid to filtration under pressure, where the filtered material is very small; typically, the fluid includes colloidal, dissolved solutes or very fine solid materials, and the filter is a microporous, nanoporous, or a semi-permeable medium. A typical medium is a membrane. The fluid to be filtered is referred to as the “feed fluid.” During ultrafiltration, the feed fluid is separated into a “permeate” or “filtrate” or “ultrafiltrate,” whichhas been filtered through the filter, and a “retentate,” which is that part of the feed fluid which did not get filtered through the medium, or which is retained within the membrane. Ultrafiltration does not require a dialysate be passed over the other side of the membrane.

[0029] “Polysilicon” refers to a polycrystallinc form of silicon that is deposited as a thin film. It is used in microelectronics for transistors and wiring. In MEMS, polysilicon is usually used as structural material for devices.DEVICESDevices with a recess and a solid flow diverter

[0030] Provided are hemofiltration devices, which are also referred to as hemofilter devices and hemofilters. In some embodiments, the hemofiltration devices can be implanted in the subject, and therefore they can be used to filter blood in vivo.

[0031] In some cases, each hemofiltration device comprises a housing and a first fluid conduit, wherein the conduit is dialysate or blood, wherein the conduit comprises one or more channel segments that each comprise: one or more walls: a top filtration membrane; a first opening; a second opening; an overall lumen comprising a central lumen and a top recess lumen; and a solid flow diverter positioned within the overall lumen, wherein the overall lumen is defined by the one or more walls, the first opening, the second opening, the top filtration membrane, and optionally one or more additional filtration membranes, wherein the top recess lumen is defined by the top filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, wherein a reference point is located: within the solid flow diverter, along a longitudinal axis that intersects the central lumen, the first opening, and the second opening, along a vertical axis that is perpendicular to the longitudinal axis and that intersects the top recess lumen, and along a z-axis that is perpendicular to the longitudinal axis and the vertical axis.

[0032] In some cases, first fluid is dialysate. Hence, the first fluid conduit is a dialysate conduit. As such, the second fluid will be blood.

[0033] In some cases, the first fluid is blood. Hence, the first fluid conduit is a blood conduit. As such, the second fluid will be dialysate.

[0034] As described herein, a first fluid can flow through the device while a second fluid flows along an external surface of the membranes, thereby causing filtration. For example, the first fluid can be dialysate and the second fluid can be blood. In other cases, the first fluid is blood and the second fluid is dialysate.

[0035] The housing is a structure that partially or completely encloses the first fluid conduit and other elements of the hemofiltration device. For example, the housing can be a three-dimensional rectangular box with six sides. The hemofiltration device can include an first fluid inlet and a, first fluid outlet that are each positioned at openings within the housing, e.g. a blood inlet and a blood outlet or a dialysate inlet and a dialysate outlet. Additionally, the first fluid conduit can connect the first fluid outlet to the first fluid inlet. For example, the first fluid inlet can be a short section of pipe or tubing that penetrates the housing, thereby allowing first fluid to flow through the first fluid inlet and into the first fluid conduit where it can filtered when it passes adjacent to the filtration membranes. The blood or dialysate can then exit the first fluid conduit and reach the first fluid outlet, which can be a short section of pipe or tubing that penetrates the housing. As such, the first fluid can then exit the housing by passing through the first fluid outlet.

[0036] Similarly, the hemofiltration device can include a second inlet and a second outlet, which can be positioned at openings in the housing. The second inlet and outlet are for a second fluid. If the original inlet and outlet are for dialysate then the second inlet and outlet are for blood, and vice versa. As such, the second fluid can flow into the inlet, past the filtration membranes, through the outlet, and out of the housing. In some cases, the second fluid can flow across the top filtration membrane in a direction that is substantially parallel to the z-axis. As used herein, “substantially parallel” means that the relative angle between two directions or between two planes is 15° or less, such as 10° or less, within 5° or less, or within 1° or less. As such, the substantially parallel flow is a flow that is within 15° or less of parallel with the z-axis, such as within 10° or less, or within 5° or less. In some cases, the device further includes one or more internal second fluid conduits that connect the second fluid inlet to a space adjacent to the filtration membrane, or that connect the space adjacent to the filtration membrane to the second fluid outlet.

[0037] As discussed above, the hemofiltration device includes a housing, a first fluid conduit, and optionally additional components. The first fluid conduit includes at least one channel segment. The term “channel segment” is used interchangeably herein with “first fluid channel segment”. Fach channel segment includes one or more walls, a top filtration membrane, a first opening, a second opening, an overall lumen, and a solid flow diverter. The solid flow diverter ispositioned within the overall lumen. The overall lumen includes a central lumen and a top recess lumen.

[0038] A first embodiment of the hemofiltration device is shown in FIGS. 1A-1C.

[0039] The hcmofiltcr device described herein comprises a housing and a first fluid conduit, wherein the first fluid conduit comprises one or more channel segments. FIG. 1A illustrates one embodiment of a channel segment. The channel segment has an overall lumen 106 with an outer surface that is geometrically defined by at least one wall 101, and a top filtration membrane 105b. The channel segment opens externally at both ends via a first opening 102 at one longitudinal end and a second opening 103 at another longitudinal end. In use, blood or dialysate may be directed to flow through the channel segment (i.e, through the overall lumen 106) by entering through the first opening 102 at one longitudinal end, flowing around solid flow diverter 104 and towards the second opening 103 at another longitudinal end of the channel segment and exit there through. When flowing around diverter 104 some of the blood of dialysate also flows along a bottom surface of the surface of the top filtration membrane 105b (and therefore along the surface of the silicon nanoporous membrane contained therein).

[0040] The length of the channel segment may be defined along a dimension defined by the general direction of flow of through the first fluid conduit. Thus, the length of the channel segment may be substantially the same as the length (i.e., longitudinal length) of the first fluid conduit. In other words, the channel segment and the first fluid conduit may be coextensive in length. In some cases, there are multiple channel segments in the first fluid conduit, and therefore the first fluid conduit is longer than any one channel segment. The first fluid conduit can also include tubing that does not have filtration membranes, i.e., to bring the blood or dialysate to another location.

[0041] The overall lumen 106 comprises a central lumen 106a and a top recess lumen 106b. In other words, the area of the overall lumen 106 is divided into a central lumen 106a area and a top recess lumen 106b area. The channel segment comprises a solid flow diverter 104 such that the said solid flow diverter 104 is placed inside the overall lumen 106. Particularly, the solid flow diverter 104 is positioned inside the central lumen 106a and below the top recess lumen 106b. In use, the solid flow diverter 104 diverts the some of the blood or dialysate into the top recess lumen 106b.

[0042] The central lumen 106a has an outer surface that is geometrically defined by one or more walls and the top recess lumen 106b. An inner surface of central lumen 106a is defined by the solid flow diverter 104, i.e. the central lumen 106a does not include diverter 104.

[0043] The top recess lumen 106b has an outer surface that is geometrically defined by one or more walls, the top filtration membrane 105b, and the central lumen 106a. In certain embodiments,the opposing face of the top filtration membrane 105b may be in a channel segment for a second fluid. Therefore, the first fluid can flow across a bottom surface of top filtration membrane 105b while the second fluid can flow across a top surface of top filtration membrane 105b. Therefore, if the first fluid is blood, then the blood can be filtered when some compounds pass through the membrane and into the dialysate.

[0044] FIG. IB illustrates another view of the channel segment of FIG. 1 A. There are three axes and a reference point 108a located at the intersection of the three axes. The reference point 108a is located within the solid flow diverter 104. The reference point 108a is located along a longitudinal axis 108b that intersects the central lumen 106a, the first opening 102, and the second opening 103. The reference point 108a is located along a vertical axis 108c that is perpendicular to the longitudinal axis 108b and that intersects the top recess lumen 106b. The reference point 108a is located along a z-axis 108d that is perpendicular to the longitudinal axis 108b and the vertical axis 108c.

[0045] FIG. 1C illustrates another view of the channel segment of FIGS. IB and 1C. The channel segment comprises a boundary 107b which is the intersection of central lumen 106a and top recess lumen 106b.

[0046] A second embodiment of the hemofiltration device is shown in FIGS. 2A-2B.

[0047] FIG. 2A illustrates one embodiment of the channel segment in the first fluid conduit of the hemofilter device. The channel segment has an overall lumen 206 having at least one wall 201, a top filtration membrane 205b, and a bottom filtration membrane 205c. The channel segment opens externally at both ends via a first opening 202 at one longitudinal end, and a second opening 203 at another longitudinal end. The top filtration membrane 205b and the bottom filtration membrane 205c are positioned in the channel segment such that the two membranes are oriented substantially parallel to each other in a spaced apart configuration.

[0048] In use, blood or dialysate may be directed to flow through the channel segment (i.e, through the overall lumen 206) by entering through the first opening 202 at one longitudinal end, flow along the surface of the top filtration membrane 205b and the bottom filtration membrane 205c (and therefore along the surface of the one or more silicon nanoporous membranes contained therein) towards the second opening 203 at another longitudinal end of the channel segment and exit there through.

[0049] The overall lumen 206 comprises a central lumen 206a, a top recess lumen 206b and a bottom recess lumen 206c. In other words, area of the overall lumen (206) is divided into a central lumen 206a area, a top recess lumen 206b area and a bottom recess lumen 206c area. The channel segment comprises a solid flow diverter 204 such that the said solid flow diverter 204 is placed within the overall lumen 206. Particularly, the solid flow diverter 204 is positioned in the centrallumen 206a, below the top recess lumen 206b and above the bottom recess lumen 206c. In use, the solid flow diverter 204 diverts the blood or dialysate into the top recess lumen 206b and the bottom recess lumen 206c.

[0050] The central lumen 206a has an outer surface that is geometrically defined by one or more walls, the top recess lumen 206b, and the bottom recess lumen 206c. Central lumen 206a has an inner surface that is defined by the solid flow diverter 204.

[0051] The top recess lumen 206b has an outer surface that is geometrically defined by one or more walls, the top filtration membrane 205b, and the central lumen 206a.

[0052] The bottom recess lumen 206c has an outer surface that is geometrically defined by one or more walls, the bottom filtration membrane 205c, and the central lumen 206a. In certain embodiments, the opposing face of the top filtration membrane 205b and the bottom filtration membrane 205c may be in a tubing for a dialysate.

[0053] FIG. 2B illustrates another view of the channel segment in the first fluid conduit of the hemofilter device. The channel segment comprises a boundary 207b that is the intersection of central lumen 206a and top recess lumen 206b. Boundary 207c is the intersection of central lumen 206a and bottom recess lumen 206c. The distance between boundary 207b and boundary 207c defines a height of the central lumen 206a.

[0054] A third embodiment of the hemofiltration device is shown in FIGS. 3A-3B.

[0055] FIG. 3B illustrates another embodiment of the channel segment in the first fluid conduit of the hemofilter device. The channel segment has an overall lumen 306 having a top filtration membrane 305b, and a bottom filtration membrane 305c. The channel segment opens externally at both ends via a first opening 302 at one longitudinal end, and a second opening 303 at another longitudinal end. The top filtration membrane 305b and the bottom filtration membrane 305c are positioned in the channel segment such that the two membranes are oriented substantially parallel to each other in a spaced apart configuration.

[0056] In use, blood or dialysate may be directed to flow through the channel segment (i.e, through the overall lumen 306) by entering through the first opening 302 at one longitudinal end, flow along the surface of the top filtration membrane 305b and the bottom filtration membrane 305c (and therefore along the surface of the one or more silicon nanoporous membranes contained therein) towards the second opening 303 at another longitudinal end of the channel segment and exit there through. In other words, the blood or dialysate flows around solid flow diverter 304.

[0057] The overall lumen 306 comprises a central lumen 306a, a top recess lumen 306b, a bottom recess lumen 306c and a rear lumen 306d. The channel segment comprises a solid flow diverter 304 such that the said solid flow diverter 304 is placed in the overall lumen 306. Particularly, the solid flow diverter 304 is positioned below the top recess lumen 306b and abovethe bottom recess lumen 306c. In use, the solid flow diverter 304 diverts the blood or dialysate into the top recess lumen 306b and the bottom recess lumen 306c.

[0058] The top recess lumen 306b has an outer surface that is geometrically defined by one or more walls, the top filtration membrane 305b, the central lumen 306a, the rear lumen 306d, and the solid flow diverter 304.

[0059] fhe bottom recess lumen 306c has an outer surface that is geometrically defined by one or more walls, the bottom filtration membrane 305c, the central lumen 306a, the rear lumen 306d and the solid flow diverter 304. In certain embodiments, the opposing face of the top filtration membrane 305b and the bottom filtration membrane 305c may be in a tubing for a second fluid. Stated in another manner, the first fluid can flow along the bottom surface of top filtration membrane 305b and the second fluid can flow along the top surface of top filtration membrane 305b. Therefore, hemofiltration can occur. A similar flow of blood and dialysate can occur at bottom filtration membrane 305c.

[0060] In some cases, the top recess lumen is not defined by the solid flow diverter. For example, in FIG. 1C the overall lumen 106 includes both central channel 106a and 106b, wherein boundary 107b separates lumen 106a and 106b. The solid flow diverter is relatively short in the vertical direction and docs not extend past boundary 107b.

[0061] In other cases, the top recess is partially defined by the solid flow diverter. For example, in FIG. 3B top recess 306b extends from top filtration membrane 305b to solid flow diverter 304. As shown in FIG. 3B, the top of diverter 304 has the same vertical coordinate as the bottom of recess 306b. Therefore, top recess 306b is partially defined by solid flow diverter 304.

[0062] In some cases, the “top-most” point on the solid flow diverter has the same vertical coordinate at the bottom-most point of the recess lumen. The term “top-most” means the point that has the highest vertical position. The term “bottom-most” means the point that has the lowest vertical position. FIG. 3B shows an embodiment that has this arrangement.

[0063] In some embodiments, the top-most point of the solid flow diverter has the same vertical coordinate as a horizontal section of a wall. For example, FIG. 3B shows that the top surface of diverter 305 is vertically aligned with the bottom of the upper wall near opening 302. The top surface of diverter 305 is also vertically aligned with the bottom of the upper wall near opening 303.

[0064] In some cases, a top surface of the solid flow diverter has the same vertical coordinate as an upper surface of a wall that partially defines the central lumen. FIG. 3B shows that diverter 304 has an upper surface with the same vertical coordinate as the wall adjacent to central lumen 306a.

[0065] As stated above, there is a reference point that is located at the intersection of the longitudinal axis, the vertical axis, and z-axis. For example, FIG. IB shows reference point 108a that is located at the intersection of the three axes. The longitudinal axis is also referred to herein as the “x-axis” and the vertical axis is also referred to as the “y-axis”. The reference point is not a physical object, but instead the reference point is simply a location in three-dimensional space. In some embodiments, the reference point is located at the centroid of the solid flow diverter, e.g. as shown in in FIG. IB. As used herein, the term “centroid” and “geometric mean” are used interchangeably to refer to the arithmetic mean position of all points on the outer surface of an object (e.g. the solid flow diverter).

[0066] It is understood that the hemofiltration device can be rotated in three-dimensional space. Therefore, the “vertical” axis might actually point in a horizontal direction if the device is implanted into a patient. The “vertical” axis might also point in a direction that is somewhat horizontal and somewhat vertical. The three-dimensional direction herein are merely given common names for clarity.

[0067] In some cases, the top recess lumen extends further in both longitudinal directions than the solid flow diverter. For example, FIGS. 1A-1C show an embodiment where recess lumen 106b extends further to the right than diverter 104. Additionally, recess lumen 106b also extends further to the left than diverter 104. In some embodiments, the longitudinal length of the solid flow diverter ranges from 30% to 95% of the longitudinal length of the top recess lumen. For example, in FIG. 3B the diverter is about 80% of the longitudinal length of the top recess lumen.

[0068] Further, in some cases: the overall lumen further comprises a bottom recess lumen that is defined by a bottom filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, and the vertical axis intersects the bottom recess lumen.

[0069] For example, FIGS. 1A-1C only include a top recess lumen. However, FIGS. 2A-2B include both top recess lumen 206b and bottom recess lumen 206c. The intersection of central lumen 206a and bottom recess lumen 206c is shown as boundary 207c. Boundary 207c is not a physical object, but instead boundary 207c is merely the location where element 206a meets element 206c. Therefore, bottom recess lumen 206c is defined by central lumen 206a, filtration membrane 205c, and adjacent walls. Also, there is a vertical axis that intersects bottom recess lumen 206c along with diverter 204 and top recess lumen 206b.

[0070] In some cases:the overall lumen further comprises a rear lumen with an outer surface that is geometrically defined by the top recess lumen, optionally the bottom recess lumen if present, one or more walls, the solid flow diverter, and the second opening, and the longitudinal axis intersects the rear lumen.

[0071] For example, FIG. 3B shows an embodiment with both top recess lumen 306b and bottom recess lumen 306c. FIG. 3B also includes both central lumen 306a and rear lumen 306d. Additionally, bottom recess lumen 306c contacts flow diverter 304 along with rear lumen 306d. Thus, bottom recess lumen 306c is defined by central lumen 306a, rear lumen 306d, filtration membrane 305c, diverter 304, and adjacent walls.

[0072] In some embodiments, such as FIGS. 1A and 2A, the central lumen extends from the first opening to the second opening. In other cases, such as FIG. 3B, a large solid flow diverter “splits” the central lumen into two pieces: the central lumen and the rear lumen. In such cases, the “central lumen” can also be referred to as the “front lumen”.

[0073] The top recess in the lumen can also be visualized in additional ways. For example, longitudinal axis 108b in FIG. IB extends horizontally across the picture. Axis 108b extends horizontally from first opening 102 to second opening 103. Similarly, there are line segments that arc parallel to the longitudinal axis and that extend from first opening 102 to second opening 103. The phrase “extend from first opening 102 to second opening 103” means that one endpoint of a line segment is at opening 102 and the second endpoint of the line segment is at opening 103. “Set A” is the combination of all line segments that fulfill this property.

[0074] In some cases, none of the lines in set A intersect any point within the top recess lumen. For example, as shown in FIG. 1C, no horizontal line extending from the left opening to the right opening would enter top recess 106b. Instead, all of the lines in set A would say within central lumen 106a. As such, the central lumen can also be described by set A. In some cases, the central lumen is defined by all points that: (i) are intersected by a line segment of set A, and (ii) are not located in the solid flow diverter.

[0075] In some embodiments, the channel segment also includes a bottom recess lumen. In such cases, none of the line segments in set A intersect any point within the bottom recess lumen. For instance, in FIG. 2B none of the line segments in set A intersect any point in bottom recess lumen 206c.

[0076] In some embodiments, none of the lines in set A intersect a wall of the channel segment.

[0077] The preceding description refers to a first fluid conduit that has a single channel segment. However, the first fluid conduit can also have 2 or more channel segments, such as 5 or more, 10 or more, 20 or more, or 100 or more.

[0078] In some cases, the first fluid conduit has both a first channel segment and a second channel segment. In such cases, the second opening of the first channel is in contact with the first opening of the second channel segment, and the one or more walls of the first channel segment arc in contact with the one or more walls of the second channel segment. As such, the blood or dialysate can flow from the first channel segment into the second channel segment. As such, the first fluid conduit can include numerous channel segments that are arranged “in series”. The first fluid conduit can also include channel segments that are arranged “in parallel”.

[0079] Additionally, the solid flow diverter can have various properties. The term “solid” indicates that the flow diverter is not a liquid, a gas, or another state of matter. For example, the solid flow diverter can include one or materials such as a metal, a ceramic, or a plastic. In some cases the solid flow diverter is composed of a single material, e.g. a metal. The solid flow diverter can be described by its Young’s modulus, which describes the stiffness of the material. In some embodiments, the Young’s modulus is 10 GPa or more at 20 °C, wherein metals such as aluminium and steel have values of around 50 to 200 GPa.

[0080] In some cases, a cross-section of the solid flow diverter in the vertical-z plane has a circular shape, a square shape, a rectangular shape, or an octagonal shape. In some embodiments, it has a rectangular shape.

[0081] In some cases, the solid flow diverter contacts a wall of the channel segment at a point along the positive z-axis. Stated in another manner, the solid flow diverter is held in position by being bonded to a wall of the channel segment. In some embodiments, the solid flow diverter also contacts a wall of the channel segment at a point along the negative z-axis.

[0082] In some embodiments, the solid flow diverter is part of the same material as a wall. In some cases, the walls that define the channel in the z-axis are part of the same object as the solid flow diverter. For example, FIG. 3A shows three panels that can be vertically compressed to create a hemofiltration device, wherein the middle panel is metal. FIG. 3B shows a side view of a single channel segment after the FIG. 3 A panels are compressed. In FIG. 3 A, there are numerous squares that are removed from the middle panel. As such, there are rectangular strips of metal that separate each pair of square holes. These rectangular strips of metal in FIG. 3A become the solid flow diverters 304 in FIG. 3B. Additionally, the top panel in FIG. 3A contains recesses and filtration membranes that become top recess 306b and top filtration membrane 305b in FIG. 3B. Similarly, the bottom panel in FIG. 3A contains recesses and filtration membranes that become the bottom objects in FIG. 3B.

[0083] In some cases, the hemofiltration device further comprises: a first fluid inlet and a first fluid outlet that are both positioned in openings in the housing and which are connected to each other by the first fluid conduit;a second fluid inlet and a second fluid outlet that are both positioned in openings in the housing.

[0084] In some cases, the filtration device further includes additional tubing between elements. Such tubing can be located inside the housing in some cases. As used herein, the terms “tube", “tubing”, “pipe”, and “line" are used interchangeably. The tubing can be plastic, metal, or any other suitable material. The tubing can be a rigid material, such as metal. The tubing can also be flexible, such as a plastic. The tubing can have a circular cross section, a square cross section, a rectangular cross section, or any other shape. In some cases, the device further comprises tubing that connects the first fluid inlet to the first fluid conduit. Additional tubing can connect the first fluid conduit to the first fluid outlet.

[0085] In cases where the first fluid is blood, the first inlet and outlet bloodallow the hemofiltration device to be connected to blood vessels of a patient in order to filter and then return their blood. The inlet and outlet for the second fluid allow the dialysate liquid to be brought into the device and then deposited in a receiving container. In some embodiments, the dialysate is taken from a reservoir of fresh dialysate and then deposited into a waste dialysate reservoir. In other cases, the dialysate is taken from a reservoir and then recirculated to the same reservoir.

[0086] In some cases, the opposite fluid flows arc used. Namely, the first fluid is dialysate and dialysate is taken from a reservoir of fresh dialysate and then deposited into a waste dialysate reservoir. Correspondingly, the second fluid is blood and the blood is flowed from a blood vessel of a patient and then returned to the patient.

[0087] When the first fluid flows across the underside of the top filtration membrane, the second fluid flows across the topside of the top filtration membrane. The second fluid can flow in any suitable direction. For example, the second fluid can flow parallel or antiparallel to the blood flow. The second fluid can also at 45° or 90° to the flow. In some cases, the second fluid inlet and second fluid outlet are positioned such that second fluid flows across the top filtration membrane in a direction that is substantially parallel to the z-axis. The hemofiltration device can also include second fluid tubing that moves the second fluid between different regions such as the inlet, the filtration membranes, and the outlet.

[0088] The presence of one or more recesses and a flow diverter provides for a technical advantage regarding filtration efficiency. A traditional hemofiltration devices can include a linear first fluid channel. Additionally, the first fluid channel could be modified so that one region has a recess in a channel wall and a filtration membrane can be positioned along the edge of the recess. However, due to fluid dynamics, some first fluid could move linger within the recess by moving slowly. Therefore, other fractions of the first fluid would simply bypass the recess and filtration membrane by flowing through the center of the channel.

[0089] As an analogy, large volumes of water flow down major rivers across the world. However, there are naturally formed recesses in the sides of these natural rivers, and water flows much slower in these recesses than in the center of the river. In fact, most river water simply flows down the center of the river and never enters the recesses. However, if a large boulder fell into the river adjacent to the recess, then more river water would be diverted into the recess.

[0090] This flow pattern within the first fluid channel would reduce filtration efficiency since some first fluid remains far from the filtration membrane. However, positioning a flow diverter adjacent to the recess could force most or all of the first fluid into the recess, thereby increasing filtration efficiency. In other words, the flow diverter would modify the fluid dynamics in a manner that would reduce the dead space in the channel and increase filtration efficiency.

[0091] This technical effect can be illustrated with FIG. 1 A and FIG. 4. FIG. 4 shows the flow of first fluid through a channel that includes a single recess but lacks a flow diverter. Notably, in FIG. 4 a large fraction of the first fluid simply bypasses the recess without entering it. In contrast, the FIG. 1A device includes flow diverter 104 that is positioned within central lumen 106a. When first fluid flows from opening 102 to opening 103, the first fluid is forced upwards or downwards by flow diverter 104. As such, more first fluid would flow into recess 106b, thereby increasing contact with filtration membrane 105b and increasing hemofiltration efficiency compared to the FIG. 4 device. Stated in another manner, adding flow diverter 104 reduces the dead space within the FIG. 1A device, thereby increasing hemofiltration efficiency.

[0092] In some cases, the filtration device is located inside a human body, such as through surgical implantation. As such, the device performs in vivo filtration. The device can also be located outside the patient and therefore perform ex vivo filtration.Devices with multiple blood conduits

[0093] In some cases, a hemofiltration devices includes channels that each comprise a plurality of first fluid conduits that are parallel to each other. For example, in some cases the hemofiltration device comprises: an inlet manifold; a plurality of filtration channels: and an outlet manifold, wherein the extended inlet manifold comprises: a first region comprising: a circular inlet configured for connection to a blood vessel of an individual; anda transition section in which lumen of the extended inlet manifold transitions from having a circular cross-section to having a rectangular crosssection; and a second region comprising a turn and followed by a linear section, wherein the linear section comprises a plurality of openings in fluid communication with the plurality of filtration channels, wherein the plurality of filtration channels are arranged in a spaced-apart stacked configuration and are in fluid communication with a plurality of openings in a first region of the outlet manifold, wherein each filtration channel comprises a plurality of first fluid conduits that are parallel to each other, and wherein each first fluid conduit is connected to one or two other first fluid conduits by a U-shaped section, wherein the first region of the outlet manifold is parallel to the linear section of the inlet manifold, wherein the outlet manifold further comprises a second region comprising: a transition section in which lumen of the outlet manifold transitions from having a rectangular cross-section to having a circular cross-section; and a circular outlet defined by the circular cross-section of the outlet manifold.

[0094] The “inlet manifold” can also be referred to as an “extended inlet manifold”. The “outlet manifold” can also be referred to as an “extended outlet manifold”.

[0095] For example, FIG. 5 shows a device within multiple first fluid conduits. The extended inlet manifold includes a first region including circular inlet 451 and transition section 452. If the first fluid is blood, then the circular inlet can connect to a blood vessel of an individual, e.g. with a vascular graft connector, and thus the blood enters the device at circular inlet 451. Next, the blood travels through transition section 452 wherein the lumen transitions from a circular to a rectangular cross-section. Afterwards, the blood moves into a second region of the inlet manifold that includes a turn followed by linear section 453. In some cases, the turn is a U-shaped turn. This “U-shaped turn” can also be referred to as a “U-shaped section”. In some cases, linear section 454 is tapered, i.e. its cross-section decreases while traveling through the linear section. In some cases the tapering is continuous, and in other cases the cross section increases at each junction. Additionally, linear section 454 includes a plurality of openings that are in fluid communication with filtration channels 454a, 454b, and 454c. Additionally the plurality of filtration channels are arranged in a spaced-apart and stacked configuration. In other cases, the first fluid is dialysate.

[0096] Furthermore, each of the filtration channels includes a plurality of first fluid conduits that are parallel to each other. For example, FIG. 5 shows that that filtration channel 454a hasfive parallel first fluid conduits that are parallel to each other. Additionally, each filtration channel is connected to one or two other first fluid conduits by a U-shaped section. For example, the top first fluid conduit in element 454a is connected one U-shaped section on the left and to an opening in linear section 453 on the right. The next first fluid conduit is connected to a U-shapcd section on the left and a U-shaped section on the right. The plurality of first fluid conduits can increase the efficiency of first fluid filtration by providing more surface area than a single first fluid conduit. Stated in another manner, the FIG. 5 device has three filtration channels arranged in parallel, wherein each filtration channel has five first fluid conduits arranged in series. Hence, there are a total of fifteen first fluid conduits in the FIG. 5 device.

[0097] Additionally, the bottom-left part of filtration channel 454a is connected to an opening in first region 455 in the outlet manifold. First region 455 of the outlet manifold is parallel to linear section 453 in the inlet manifold. In some cases, linear section 453 in the inlet manifold is tapered and first region 455 in the outlet manifold is reverse-tapered with reference to linear section 453.

[0098] The outlet manifold further includes a second region including transition section 456 and circular outlet 456. Transition section 456 has a lumen that transitions from rectangular cross section to circular cross section, and the circular outlet 456 has a circular cross section.

[0099] The hemofiltration device is configured for entry of first fluid through the inlet and for transporting the first fluid through the transition section of the extended inlet manifold to the tapered linear section, into the plurality of filtration channels to the first region of the outlet manifold, into the transition section of the outlet manifold, and exit via the circular outlet.

[0100] In some cases, the hemofiltration device is configured for entry of first fluid through the inlet and for transporting the first fluid through the transition section of the extended inlet manifold to the tapered linear section, into the plurality of filtration channels to the first region of the outlet manifold, into the transition section of the outlet manifold, and exit via the circular outlet.

[0101] In some embodiments, the “device with multiple first fluid conduits” includes the features of the “device with solid flow diverter”. Such a device would include an extended inlet manifold, a plurality of filtration channels, and an extended outlet manifold. Additionally, each filtration channel would include one or more channel segments with a solid flow diverter, as described previously.

[0102] As such, in some cases each first fluid conduit comprises one or more channel segments that each comprise: one or more walls; a top filtration membrane; a first opening;a second opening; an overall lumen comprising a central lumen and a top recess lumen; and a solid flow diverter positioned within the overall lumen, wherein the overall lumen is defined by the one or more walls, the first opening, the second opening, the top filtration membrane, and optionally one or more additional filtration membranes, wherein the top recess lumen is defined by the top filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, wherein a reference point is located: within the solid flow diverter, along a longitudinal axis that intersects the central lumen, the first opening, and the second opening, along a vertical axis that is perpendicular to the longitudinal axis and that intersects the top recess lumen, and along a z-axis that is perpendicular to the longitudinal axis and the vertical axis.

[0103] The channel segments can include any of the features previously discussed above.Additional Aspects

[0104] The devices may achieve a desirable rate of diffusive clearance of components in whole blood. In some cases, the device can achieve a diffusive clearance of about 25 ml / min / m2or more, e.g., about 50 ml / min / m2or more, about 75 ml / min / m2 or more, about 100 ml / min / m2or more, about 120 ml / min / m2or more, about 150 ml / min / m2or more, including about 200 ml / min / m2or more. In some embodiments, the device achieves a diffusive clearance of from about 25 ml / min / m2 to about 250 ml / min / m2, e.g., from about 50 ml / min / m2to about 200 ml / min / m2, from about 75 ml / min / m2to about 175 ml / min / m2, including from about 100 ml / min / m2to about 150 ml / min / m2. The diffusive clearance may be measured with respect to, e.g., creatinine, urea or phosphate (PO43-).

[0105] The device can be integrated into an artificial kidney to hemofilter blood in vivo.

[0106] The dimensions of the lumens of the channels or tubing may vary. In some cases, the lumen can have a dimension (e.g. a diameter, height, width, or depth) of 0.5 mm or more, such as 1.0 mm or more. The lengths of the channels and channel segments can vary, and for example can be 10 mm or more, such as 50 mm or more.

[0107] In some cases, the components are constructed from biocompatible materials, such as titanium, a titanium alloy, or a biocompatible plastic (e.g. polyether ether ketone (PEEK)).

[0108] In some cases, the filtration membranes are silicon nanoporous membranes. They can have any suitable properties, such as hydraulic permeability, sieving coefficient, and mechanicalintegrity. The silicon nanoporous membrane may generally include one or more effective membrane areas where filtration / dialysis can occur across the membrane (i.e., regions that contain the nanopores and allow substance exchange between fluid in the through channel (e.g., blood channel or dialysate channel) and fluid in the latently formed channel (e.g., filtratc / dialysatc channel or blood channel)). Suitable silicon nanoporous membranes and methods of making the same are described in, e.g., US20090131858, which is incorporated herein by reference.

[0109] In some cases, the silicon nanoporous membrane is a composite membrane of a nanoporous polysilicon layer deposited on a non-porous silicon substrate, where the effective membrane area maybe defined by windows created by selective removal of the silicon substrate. Thus, the thickness of the membrane may be thinner across the effective membrane area than it is across the other areas supported by the silicon substrate. In some embodiments, the thickness of the silicon nanoporous membrane (i.e., including the silicon substrate) is about 10 pm or more, e.g., about 20 pm or more, about 50 pm or more, about 100 pm or more, including about 200 pm or more, and in some embodiments, is about 1,000 pm or less, e.g., about 750 pm or less, about 500 pm or less, about 400 pm or less, including about 300 pm or less. In some cases, the thickness of the silicon nanoporous membrane is from about 10 pm to about 1,000 pm, e.g., from about 20 pm to about 750 pm, from about 50 pm to about 500 pm, including from about 100 pm to about 400 pm.

[0110] In some embodiments, the thickness of the silicon nanoporous membrane across the effective membrane area (i.e., the thickness of the polysilicon layer) is about 50 nm or more, e.g., about 100 nm or more, about 150 nm or more, about 200 nm or more, including about 250 nm or more, and in some embodiments, is about 1,000 nm or less, e.g., about 800 nm or less, about 600 nm or less, about 450 nm or less, including about 400 nm or less. In some cases, the thickness of the silicon nanoporous membrane across the effective membrane area is from about 50 nm to about 1,000 nm, e.g., from about 100 nm to about 800 nm, from about 150 nm to about 600 nm, including from about 200 nm to about 400 nm.

[0111] The nanopores may have any suitable dimensions to provide for desirable properties (e.g., hydraulic permeability, sieving coefficient) of the membrane. In some cases, the nanopores are slit-shaped, when viewed from above the plane of the membrane, the slit having a length (in the plane of the membrane) that is longer than a width. In some embodiments, the nanopores have a length of about 1.0 pm or more, e.g., about 2.0 pm or more, about 3.0 pm or more, about 4.0 pm or more, including about 5.0 pm or more, and in some cases, a length of about 50 pm or less, e.g., about 25 pm or less, about 20 pm or less, about 15 pm or less, about 10 pm or less, including about 5.0 pm or less. In some cases, the nanopores have a length of from about 1.0 pm to about 50 pm. e.g., from about 2.0 pm to about 25 pm, from about 3.0 pm to about 20 pm, from about3.0 (Jin to about 15 pm. from about 3.0 m to about 10 pm, including from about 4.0 pm to about 5.0 pm.

[0112] In some embodiments, the nanopores have a width of about 1.0 nm or more, e.g., about 2.0 nm or more, about 3.0 nm or more, about 5.0 nm or more, including about 7.5 nm or more, and in some cases, a width of about 100 nm or less, e.g., about 75 nm or less, about 50 nm or less, about 40 nm or less, about 30 nm or less, including about 20 nm or less. In some cases, the nanopores have a width of from about 1.0 nm to about 100 nm, e.g., from about 2.0 nm to about 75 nm, from about 3.0 nm to about 50 nm, from about 5.0 nm to about 40 nm, from about 5.0 nm to about 30 nm, including from about 7.5 nm to about 20 nm.

[0113] The nanopores may be arranged in any suitable manner, and in some cases, may be arranged in a regular pattern. In some cases, the nanopores are arranged in an array (e.g., of two or more rows and two or more columns of nanopores spaced regularly apart) (see, e.g., FIG. 3B). Adjacent nanopores (e.g., slit-shaped nanopores lying parallel next to each other) may be spaced apart by any suitable distance In some cases, adjacent nanopores may be spaced apart by about 1 .0 nm or more, e.g., about 3.0 nm or more, about 5.0 nm or more, about 7.5 nm or more, including about 10 nm or more, and in some cases may be spaced apart by about 1,000 nm or less, e.g., about 500 nm, about 200 nm or less, 100 nm or less, 50 nm or less, including 20 nm or less. In some cases, adjacent nanopores may be spaced apart by from about 1.0 nm to about 1,000 nm, e.g., from about 3.0 nm to about 500 nm, from about 5.0 nm to about 200 nm, from about 7.5 nm to about 100 nm, including from about 7.5 nm to about 20 nm.

[0114] The shape of an individual effective membrane area may vary, e.g., depending on the manner in which the silicon substrate is removed from a composite membrane and / or how the nanopores are fabricated on the polysilicon layer. Thus, in some cases, an area of a composite silicon nanoporous membrane from which a contiguous block of the silicon substrate is removed may define an individual effective membrane area. In some cases, the individual effective membrane area is substantially square, or substantially rectangular. In some cases, the nanopores are arranged to form concentric circles. Where the individual effective membrane area is substantially square or rectangular, the length or width of the area may be any suitable size. In some cases, the individual effective membrane area has a length and / or width of about 0.1 cm or more, e.g., about 0.2 cm or more, about 0.3 cm or more, about 0.5 cm or more, about 0.75 cm or more, including about 1.0 cm or more, and in some cases, a length and / or width of about 5.0 cm or less, e.g., about 4.0 cm or less, about 3.0 cm or less, about 2.5 cm or less, about 2.0 cm or less, including about 1 .5 cm or less. In some embodiments, the individual effective membrane area has a length and / or width of from about 0.1 cm to about 5.0 cm, e.g., from about 0.2 cm to about 4.0cm, from about 0.3 cm to about 3.0 cm, from about 0.5 cm to about 2.5 cm, including from about 0.75 cm to about 2.0 cm.

[0115] The silicon nanoporous membrane may have any suitable hydraulic permeability for use in the present devices. In some cases, the hydraulic permeability of the silicon nanoporous membrane is about 50 ml / h / mmHg / m2or greater, e.g, about 75 ml / h / mmHg / m2or greater, about 100 ml / h / mmHg / m2or greater, about 150 ml / h / mmHg / m2or greater, about 200 ml / h / mmHg / m2or greater, about 250 ml / h / mmHg / m2or greater, including about 300 ml / h / mmHg / m2or greater, and in some cases, is about 1,000 ml / h / mmHg / m2or less, e.g., about 900 ml / h / mmHg / m2or less, about 800 ml / h / mmHg / m2or less, about 700 ml / h / mmHg / m2or less, about 600 ml / h / mmHg / m2or less, including about 500 ml / h / mmHg / m2or less. In some embodiments, the hydraulic permeability of the silicon nanoporous membrane is from about 50 ml / h / mmHg / m2to about 1,000 ml / h / mmHg / m2, e.g., from about 100 ml / h / mmHg / m2to about 900 ml / h / mmHg / m2, from about 150 ml / h / mmHg / m2to about 800 ml / h / mmHg / m2, from about 200 ml / h / mmHg / m2to about 700 ml / h / mmHg / m2, including from about 200 ml / h / mmHg / m2to about 600 ml / h / mmHg / m2.

[0116] The silicon nanoporous membrane may be surface treated to provide desirable surface properties (e.g., antifouling, anticoagulant, protein and / or cell non-adhesive properties, etc.). In some embodiments, the surface treatment or modification promotes attachment of specific animal cells to the membrane, promotes attachment of desirable proteins, inhibits undesirable protein deposition on the membrane, or inhibits blood coagulation on or in the vicinity of the membrane. Such treatments or modifications may include but are not limited to patterned or unpatterned adsorption or covalent linkage to the membrane surface of RGD peptide moieties, integrins, fibronectin, laminin, collagens, oligosaccharides, or polyethylene glycol moieties. Particular cells or molecules attached to or located at the membrane surface and / or within the pores may be used to render the porous membrane more biocompatible, less thrombogenic, or may be used to alter the filtration characteristics of the pores. Furthermore, the cells may be used to process or modify the filtrate produced by the membrane. In some embodiments, modification of the pores includes but is not limited to covalent attachment of peptides or proteins, either alone or selected to promote attachment of cells such as endothelial or epithelial cells.

[0117] In some embodiments, the surface of the silicon nanoporous membranes of the present invention are modified with polyethylene glycol (PEG) or related compounds (e.g., oligosaccharide surfactant polymer monolayers). In some embodiments, the surface of the silicon nanoporous membranes of the present invention are modified with a zwitterionic polymer or copolymer, such as a polymer containing repeat units derived from sulfobetaine-containing and / or carboxybetaine-containing monomers. Suitable monomers include, without limitation, sulfobetaine methacrylate (SBMA), sulfobetaine acrylamide, sulfobetaine methacrylamide,carboxybetaine methacrylate (CBMA), carboxybetaine acrylamide and carboxybetaine methacrylamide. Examples of suitable zwitterionic polymers or copolymers include, without limitation, poly-sulfobetaine methacrylate (pSBMA), poly(carboxy betaine methacrylate) (polyCBMA), poly(carboxybctainc acrylamide), poly(carboxybctainc methacrylamide), poly (sulfobetaine acrylamide), and poly(sulfobetaine methacrylamide).

[0118] fhe vascular graft connectors may have a stiffness that provides flexibility for implanting at an implantation site, and to prevent excessive bending that may collapse the inner passageway (i.e., prevent kinking). In some embodiments, the stiffness of the connector is higher more proximal to the first fluid inlet or the first fluid outlet than the stiffness of the connector more distal to the first fluid inlet or the first fluid outlet of the hemofiltration device. The different stiffness may be provided using any suitable method. In some embodiments, the vascular graft connector is a composite connector, having a polymeric tubing that serves as the vascular graft, and a polymeric sleeve attached to the end of the tubing proximal the first fluid inlet or the first fluid outlet of the hemofiltration device, thereby providing structural reinforcement to the tubing. The polymeric sleeve may be made of any suitable biocompatible polymer, such as, but not limited to, silicone, polysiloxane, poliglecaprone, polydioxanone, polyglactin, caprolactone, polyorthocstcr, polyethylene glycol, poly terephthalate, tyrosine, poly(cstcr amide), polyisobutylene, poly(ethylene terephthalate), polytetrafluoroethylene, polyurethane, polystyrene, polyamide, polyimide, bisphenol-alpha-glycidyl methacrylate, triethyleneglycol dimethacrylate, hydroxyethyl methacrylate, poly-p-chloroxylylene, phenolic resins, and the like.

[0119] In some cases, the different stiffness along the vascular graft connectors may be provided by having a material forming the connector more proximal to the first fluid inlet or the first fluid outlet that is stiffer than the material forming the distal portions of the connector. In some cases, the vascular graft connectors may include ribbing to provide structural reinforcement, and the density of the ribbing may be higher more proximal to the first fluid inlet or the first fluid outlet than the density of the ribbing at more distal portions.

[0120] In some embodiments, the system further includes a bioreactor containing cells configured to receive retentate (i.e., blood that has been passed over a filter medium, such as a silicon nanopore membrane) and / or filtrate from the hemofiltration device, and to return components of the filtrate to the blood before the blood is returned to the individual’s circulation. The cells may express or provide one or more desired factors to a filtered blood that is to be returned to the individual. Suitable bioreactor systems are described in, e.g., US 20090131858, which is incorporated herein by reference. In some cases, a bioartificial kidney includes a device of the present disclosure functionally connected to a bioreactor.

[0121] A variety of cells may be used in the bioreactor. In some embodiments the cells of the bioreactor are liver, duodenal, intestinal, gastric, pancreatic, thyroid, parathyroid, adrenal, gonadal, pituitary, or hypothalamic cells. In some embodiments the cells of the bioreactor are bone marrow cells. In other embodiments the cells of the biorcactor arc stem cells, feeder cells, or other precursor cells. In still other embodiments, the cells of the bioreactor are derived from stem or precursor cells. In still other embodiments, the bioreactor comprises cells that induce the differentiation of nearby cells or attract nearby cells to the organ. In some embodiments, the cells comprise one or more transgenes (e.g., having inducible promoters).

[0122] In some embodiments, the cells of the bioreactor are from kidney or associated tissue, such as renal proximal tubule cells. These cells may replace the metabolic, endocrine, and immunologic functions of a damaged kidney. Renal proximal tubule cells may be grown on an appropriate surface in the bioreactor and then exposed to ultrafiltrate. The cell-exposed ultrafiltrate is then returned to the individual. The cell-exposed ultrafiltrate may contain serum and appropriate levels of desired biological components (e.g., 1,25 dihydroxy vitamin D3, sodium, glucose, etc.).SYSTEMS AND KITS

[0123] Hemofiltration systems as discussed herein include a hemofiltration device and one or more additional components. In some cases the system includes: a hemofiltration device according to any one of the previous claims; and one or more components selected from the group consisting of: a vascular graft connector for connecting the blood inlet to a blood vessel of a patient; a vascular graft connector for connecting the blood outlet to a blood vessel of the patient; a dialysate inlet line for connecting a dialysate reservoir to a dialysate inlet; a dialysate outlet line for connecting the dialysate outlet to a dialysate reservoir; and a dialysate reservoir.

[0124] For example, the systems can also include a vascular graft connector for connecting the blood inlet to a blood vessel of a patient. The system can also include a vascular graft connector for connecting the blood outlet to a blood vessel of the patient.

[0125] The system can also include a dialysate inlet line or a dialysate outlet line for connecting the dialysate inlet or outlet to a dialysate reservoir. In some cases, the inlet reservoir of fresh dialysate is different than the outlet reservoir of waste dialysate. In other cases, the inlet reservoirand the outlet reservoir are the same reservoir because the dialysate is continually recirculated. In some cases, the system further includes the one or two reservoirs.

[0126] Also provided are kits that include: hemofiltration device as described herein or a hemofiltration system as described herein; and packaging containing the hemofiltration device or hemofiltration system.

[0127] The present kit may include any other suitable components for performing hemofiltration and / or hemodialysis, as described herein. In some embodiments, the kit includes one or more vascular graft connectors with or without adaptors for connecting to the blood inlet or outlet of the device. In some embodiments, the kit includes one or more polymeric sleeves (e.g., silicone sleeves) for reinforcing the vascular graft connectors.

[0128] Components of a subject kit can be in separate containers; or can be combined in a single container. The kit may further include a suitable packaging for holding the device and one or more other components, as described above. Any one or more, or all components of the present kit may be substantially sterile.

[0129] In some cases, the present kit includes instructions for using the implantable, device. The instructions arc generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or subpackaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, digital versatile disc (DVD), flash drive, Blueray Disc™ etc. The instructions can include a quid-response code (QR code) printed on a material, such as paper. If the QR code contains the internet address of a website, then the QR code can direct a user to find additional information of the website. In yet other embodiments, the actual instructions are not present in the kit, but methods for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded. As with the instructions, the methods for obtaining the instructions are recorded on a suitable substrate.METHODS

[0130] Provided are methods of filtering blood of a patient. In some cases the method includes: flowing blood out of a blood vessel of the patient and through a hemofiltration device as described herein and then into a blood vessel of the patient; andflowing dialysate out of a source dialysate reservoir and through the hemofiltration device and then into a receiving dialysate reservoir, wherein the blood and dialysate simultaneously flow across opposite sides of a filtration membrane of the hemofiltration device.

[0131] The method includes both flowing blood and flowing dialysate. Additionally, as stated above, the blood and dialysate are simultaneously flowed across opposite sides of a filtration membrane. As such, the flowing of the blood and the flowing of the dialysate are performed simultaneously. In some cases, the flowing of blood and flowing of dialysate are begun at the time, ended at the same time, or both. In other cases the flowing of blood and flowing of dialysate begin at different times, end at different times, or both. This simultaneous flowing across opposite sides of the filtration membrane allows the hemofiltration to occur.

[0132] In some cases, the source dialysate reservoir and the receiving dialysate reservoir are different reservoirs. Therefore, the dialysate only travels through the hemofiltration device a single time. In other cases the dialysate is recirculated through the device multiple times and the source reservoir and the receiving reservoir are the same.

[0133] In some cases, the hemofiltration device is located inside a body cavity of the patient, c.g. after being surgically implanted. In some cases the blood being flowed docs not exit the body. Instead, the blood merely travels out of a first blood vessel, into the hemofiltration device, and back into a second blood vessel.Additional aspects

[0134] Devices of the present disclosure, and systems that includes the same, find use in performing hemodialysis and / or hemofiltration. In general terms, a method for hemodialysis may include connecting a blood inlet and a blood outlet of a device to an individual’ s circulatory system such that blood circulates from the circulatory system, through the device, and back into the circulatory system; and connecting the filtrate / dialysate inlet and outlet to a dialysate pump, such that dialysate circulates through the device. The connection may be made at a suitable point in the circulatory system, such as, without limitation, the renal artery and vein. Thus, in some embodiments, the blood inlet is connected to the renal artery, and the blood outlet is connected to the renal vein. A suitable vascular graft connector, as described above, may be used to connect the blood inlet and outlet to the circulatory system.

[0135] In some embodiments, the device connected to the circulatory system forms an extracorporeal blood circuit, where the device is outside the body of the individual. In some embodiments, the extracorporeal blood circuit does not include a pump for circulating blood from and to the body via the device.

[0136] In some cases, the present method includes implanting the device in the body of the individual. The device may be implanted using any suitable surgical means. In some cases, the device includes one or more (e.g., two or more, three or more, or four or more) suture tabs, and the device is positioned in an implantation site by suturing the device to a tissue wall of the implantation site via the suture tabs. In some embodiments, the device is enveloped in a biocompatible mesh (e.g., polymeric mesh, such as a polypropylene mesh), and the device is positioned in an implantation site by suturing the device to a tissue wall of the implantation site via the mesh.

[0137] Hemofiltration may be achieved using methods as described above, where the filtrate / dialysate inlet is blocked and the filtrate / dialysate outlet is connected to a waste reservoir (e.g., bladder or an extracorporeal waste receptacle).

[0138] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0139] Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.

[0140] The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. Tn the claims, 35 U.S.C. §1 12(f) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" orthe exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112(f) is not invoked.

Claims

CLAIMSWhat Is Claimed Is:

1. A hemofiltration device for filtering blood in vivo, the hemofilter comprising a housing and a first fluid conduit, wherein the first fluid is dialysate or blood, wherein the conduit comprises one or more channel segments that each comprising: one or more walls; a top filtration membrane; a first opening: a second opening; an overall lumen comprising a central lumen and a top recess lumen; and a solid flow diverter positioned within the overall lumen, wherein the overall lumen is defined by the one or more walls, the first opening, the second opening, the top filtration membrane, and optionally one or more additional filtration membranes, wherein the top recess lumen is defined by the top filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, wherein a reference point is located: within the solid flow diverter, along a longitudinal axis that intersects the central lumen, the first opening, and the second opening, along a vertical axis that is perpendicular to the longitudinal axis and that intersects the top recess lumen, and along a z-axis that is perpendicular to the longitudinal axis and the vertical axis.

2. The device of claim 1, wherein the top recess lumen is not defined by the solid flow diverter.

3. The device of claim 1, wherein the top recess lumen is partially defined by the solid flow diverter.

4. The device of any one of claims 1 -3, wherein a top-most point of the solid flow diverter has the same vertical coordinate as a bottom-most point of the top recess.

5. The device of any one of claims 1-4, wherein a top-most point of the solid flow diverter has the same vertical coordinate as a horizontal section of a wall.

6. The device of any one of claims 1-5, wherein a top surface of the solid flow diverter has the same vertical coordinate as an upper surface of a wall that partially defines the central lumen.

7. The device of any one of claims 1-6, wherein the reference point is located at the centroid of the solid flow diverter8. The device of any one of claims 1-7, wherein the top recess lumen extends further in both longitudinal directions than the solid flow diverter.

9. The device of claim 8, wherein the longitudinal length of the solid flow diverter ranges from 30% to 95% of the longitudinal length of the top recess lumen.

10. The device of any one of claims 1-9, wherein: the overall lumen further comprises a bottom recess lumen that is defined by a bottom filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, and the vertical axis intersects the bottom recess lumen.

11. The device of any one of claims 1-10, wherein: the overall lumen further comprises a rear lumen with an outer surface that is geometrically defined by the top recess lumen, optionally the bottom recess lumen if present, one or more walls, the solid flow diverter, and the second opening, and the longitudinal axis intersects the rear lumen.

12. The device of any one of claims 1-11, wherein: set A is a group including all line segments that are parallel to the longitudinal axis and which extend from the first opening to the second opening, and none of the line segments in set A intersect any point within the top recess lumen or the bottom recess lumen if present.

13. The device of claim 12, wherein none of the line segments in set A intersect a wall of the channel segment.

14. The device of any one of claims 1-13, wherein: the first fluid conduit comprises two or more channel segments, the second opening of the first channel is in contact with the first opening of the second channel segment, andthe one or more walls of the first channel segment are in contact with the one or more walls of the second channel segment.

15. The device of any one of claims 1-14, wherein a cross-section of the solid flow diverter in the vertical-z plane has a square shape, a rectangular shape, a circular shape, or an octagonal shape.

16. The device of any one of claims 1-15, wherein the solid flow diverter contacts a wall of the channel segment at a point along the positive z-axis.

17. The device of any one of claims 1-16, wherein the solid flow diverter comprises a metal material, a plastic material, or a ceramic material.

18. The device of any one of claims 1-17, wherein the hemofiltration device further comprises: a first fluid inlet and a first fluid outlet that are both positioned in openings in the housing and which arc connected to each other by the first fluid conduit; a second fluid inlet and a second fluid outlet that are both positioned in openings in the housing, wherein the second fluid is blood or dialysate, wherein the first fluid is different than the second fluid.

19. The device of claim 18, wherein the second fluid inlet and second fluid outlet are positioned such that second fluid flows across the top filtration membrane in a direction that is substantially parallel to the z-axis.

20. The device of any one of claims 1-19, wherein the hemofiltration device is located inside a human body.

21. A hemofiltration device for use in filtering in vivo, the hemofiltration device comprising: an inlet manifold; a plurality of filtration channels; and an outlet manifold, wherein the extended inlet manifold comprises: a first region comprising: a circular inlet configured for connection to a vessel of an individual; and a transition section in which lumen of the extended inlet manifold transitions from having a circular cross-section to having a rectangular crosssection; anda second region comprising a turn and followed by a linear section, wherein the linear section comprises a plurality of openings in fluid communication with the plurality of filtration channels, wherein the plurality of filtration channels arc arranged in a spaccd-apart stacked configuration and are in fluid communication with a plurality of openings in a first region of the outlet manifold, wherein each filtration channel comprises a plurality of second fluid conduits that are parallel to each other, and wherein each second fluid conduit is connected to one or two other second fluid conduits by a U-shaped section, wherein the first region of the outlet manifold is parallel to the linear section of the inlet manifold, wherein the outlet manifold further comprises a second region comprising: a transition section in which lumen of the outlet manifold transitions from having a rectangular cross-section to having a circular cross-section; and a circular outlet defined by the circular cross-section of the outlet manifold.

22. The device of claim 21, wherein second fluid conduit comprises one or more channel segments that each comprise: one or more walls; a top filtration membrane; a first opening; a second opening; an overall lumen comprising a central lumen and a top recess lumen; and a solid flow diverter positioned within the overall lumen, wherein the overall lumen is defined by the one or more walls, the first opening, the second opening, the top filtration membrane, and optionally one or more additional filtration membranes, wherein the top recess lumen is defined by the top filtration membrane, one or more walls, the central lumen, optionally the solid flow diverter, and optionally a rear lumen, wherein a reference point is located: within the solid flow diverter, along a longitudinal axis that intersects the central lumen, the first opening, and the second opening, along a vertical axis that is perpendicular to the longitudinal axis and that intersects the top recess lumen, andalong a z-axis that is perpendicular to the longitudinal axis and the vertical axis.

23. A hemofiltration system comprising: a hemofiltration device according to any one of the previous claims; and one or more components selected from the group consisting of: a vascular graft connector for connecting the blood inlet to a blood vessel of a patient; a vascular graft connector for connecting the blood outlet to a blood vessel of the patient; a dialysate inlet line for connecting a dialysate reservoir to a dialysate inlet; a dialysate outlet line for connecting the dialysate outlet to a dialysate reservoir; and a dialysate reservoir.

24. A kit comprising: hemofiltration device according to any one of the previous claims or a hemofiltration system according to any one of the previous claims; and packaging containing the hemofiltration device or hemofiltration system.

25. A method of filtering blood of a patient, the method comprising: flowing blood out of a blood vessel of the patient and through a hemofiltration device according to any one of the previous claims and then into a blood vessel of the patient; and flowing dialysate out of a source dialysate reservoir and through the hemofiltration device and then into a receiving dialysate reservoir, wherein the blood and dialysate simultaneously flow across opposite sides of a filtration membrane of the hemofiltration device.

26. The method of claim 25, wherein the source dialysate reservoir and the receiving dialysate reservoir arc different reservoirs.

27. The method of claim 25, wherein the source dialysate reservoir and the receiving dialysate reservoir are the same reservoir.

28. The method of any one of claims 25-27, wherein the hemofiltration device is located inside a body cavity of the patient, and wherein the blood does not exit the body.

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