Improved filtration membrane and method for fabricating and using the same

Abstract

This invention provides an improved filtration membrane suitable for in vivo blood filtration. [Solution] The improved filtration membrane exhibits resistance to damage with minimal area penalty due to the presence of a support system on the back of the membrane. This minimal area penalty is achieved by using a support that provides a hierarchical scaffold including ribs of two different heights.

Description

[Technical Field]

[0001] cross reference This application is U.S. Provisional Patent Application No. 63 / 063,038, filed on August 7, 2020. , and the benefits of U.S. Provisional Patent Application No. 63 / 070,999 filed on August 27, 2020 Claiming to be of interest, these applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Chronic renal failure affects more than 2 million people worldwide.[1] Current treatment options include The options are dialysis and organ transplantation. Kidney transplantation offers the best clinical outcome, but the donor organ is deep Due to the critical shortage, kidney patients are often forced to undergo dialysis for extended periods (several years). This is leading to a decline in quality of life and an increase in mortality rates. In addition, dialysis centers... Regular transfers to and from the dialysis system, and the undesirable accumulation of urea and other toxins in the bloodstream between dialysis sessions. The accumulation tends to have a negative impact on the patient's overall health [2-4]. Most important kidney function It can perform its function, is compact, portable, mass-producible, and ultimately embeddable. Obtaining a capable "bio-artificial kidney" would be extremely beneficial.

[0003] Due to the main limitations of dialysis treatment and the limited availability of organs for kidney transplantation, alternative kidney Interest in replacement therapy is growing. Approaches currently under development include fully functional replacement organs. Cell-based strategies aimed at creating vessels [5-6], patients outside of the clinical setting for extended periods A wearable artificial kidney device based on dialysis technology that enables frequent treatment. S[7~8], and biohybrids that attempt to mimic the main functions of native nephrons This includes the do-device [9~10].

[0004] To achieve such alternative kidney replacement therapy, sufficient filtration that demonstrates resistance to damage is necessary. The development of submicron-thickness filtration membranes that provide a surface is essential. This disclosure relates to these and others Address the need for this. [Overview of the project]

[0005] This disclosure provides an improved filtration membrane suitable for in vivo blood filtration. Filtration membranes have a minimal area penalty due to the presence of a support system on the back of the membrane. The tee exhibits resistance to damage. This minimal area penalty is described in detail herein. A support structure that provides a hierarchical scaffold including ribs of at least two different heights. This is achieved by using the filtration membrane. Methods for fabricating and using the filtration membrane are also provided. [Brief explanation of the drawing]

[0006] [Figure 1] The concept of an implantable bio-artificial kidney. The hemofilter removes toxins from the blood, and the bioreactor encapsulates kidney cells to provide metabolic function. Silicon nanoporous membranes provide the basic enabling technology for both the hemofilter and the bioreactor. [Figure 2] To reinforce the nanoporous membrane, integrated ribs are added only to the reverse side, without obstructing blood flow. [Figure 3] Comparison of Gen1 and Gen2 ribbed films. In Gen2, much of the wafer frame is replaced by longer, shorter "mega-ribs" beneath the polysilicon film, thus freeing up more filter area. [Figure 4]Computational fluid dynamics (CFD) simulation of fluid flow (from left to right) passing through an array of closely spaced 400 μm-height wafer-thickness supports (Gen1, left) and shorter (h=40 μm) megaribs (Gen2, right). In the case of Gen2, the liquid flow enters the etching cavities, thereby promoting toxin removal. The illustrated cavity is 1 mm in length (L) × 400 μm in depth (d). Simulation results show that the mass transport coefficient can be nearly four times higher. [Figure 5] Finite element analysis (FEA) results showing the maximum deflection ("m.d.") for Gen2 megarib membranes of various sizes (0.6×4 mm, 0.8×4 mm, and 1.0×4 mm). To speed up the simulation, a quarter membrane model was used to take advantage of design symmetry. The small unit cell at the bottom right represents the old Gen1 (rib-free) design. [Figure 6] Flow chart of the megarib membrane manufacturing process. Compared with previous work

[21] , (a) to (d) represent newly added steps that enable the formation of double-depth trenches, and thus allow ribs of different heights. In particular, step (b) essentially forms the megarib mold, and step (d) forms the minirib mold. In addition, the dry oxidation in step (h) forms a thin oxide that determines the accurate width of the nanopores, and thus the main filtration characteristics of the membrane. [Figure 7] Scanning electron microscope (SEM) images of a megarib membrane: (a) top view, (b) cross-sectional view showing miniribs and megaribs, (c) close-up top view of nanopores, (d) backside image of the megarib membrane showing a silicon wafer "frame" and megaribs, (e) further close-up showing megaribs and miniribs, (f) further close-up showing miniribs and nanopores. [Figure 8] (a) Backlit optical image of a fully released 100 mm-diameter nanoporous membrane wafer with megaribs, showing an almost perfect device yield; (b to c) backlit optical microscopy images of actual individual nanoporous membranes, showing the increase in available membrane area from Gen1 (b) to Gen2 (c). [Figure 9]Porosity (top) and burst pressure (bottom) measured for Gen1 membranes and Gen2 membranes. For each data point, at least seven devices were measured. It can be seen from the data that Gen2 devices (i.e., megalib membranes) exhibit significantly higher porosity at the cost of lower (but still acceptable) burst pressure. Labels "A", "B", and "C" indicate membrane types (sizes) of 0.6×4 mm, 0.8×4 mm, and 1.0×4 mm, respectively.

[0007] Definitions All publications, patents, and patent applications cited herein, whether mentioned above or below , are incorporated herein by reference in their entireties.

[0008] In describing the present invention, the following terms are used and are defined as set forth below as intended.

[0009] As used in this specification and the appended claims, the singular forms "a", "an ", and "the" include plural references unless the content clearly dictates otherwise . It should be noted that, for example, reference to "a membrane" includes a plurality of two or more or more such membranes. It is further noted that the claims may be drafted to exclude any optional element . Accordingly, this statement is intended to serve as antecedent basis for use of exclusive terminology such as "solely", "only" or use of negative limitations in connection with the recitation of claim elements. .

[0010] "Subject" or "individual" means humans and other primates, including non-human primates such as chimpanzees, other apes, and monkey species, farm animals such as cattle, sheep, pigs, goats, and horses ​Animals, domesticated mammals such as dogs and cats, birds, and mice, rats and guinea pigs, etc. Any member of the subphylum Chordata, including but not limited to experimental animals such as rodents. It means "bar". This term does not indicate a specific age. Thus, it refers to adults and newborns. Both living individuals are intended to be the target. Individuals are patients who require hemodialysis, for example. , impaired kidney function and / or requiring dialysis, impaired cardiac function and / or This could be a patient with impaired liver function.

[0011] When referring to measurable values ​​such as physical quantities or temporal periods, the term "approximately" as used herein is used. The term "[...] is typical of measurements that characterize the disclosed device." Or, to be appropriate for carrying out the disclosed method, ±20% from the specified value. This means including variables such as ±10%, ±5%, ±1%, and ±0.1%. .

[0012] As used herein, “substantially” means bringing about a change in the underlying functionality. It can be applied to correct quantitative expressions that may fluctuate within an acceptable range. For example, In fact, substantially parallel structures can encompass structures that are slightly disparallel to each other.

[0013] "Multiple" includes at least two members. In certain cases, plural means: At least 10, at least 20, at least 30, at least 40, at least 50, At least 70, at least 90, at least 100, at least 1000, at least 10,000, at least 100,000, at least 10 6 , at least 10 7 , few Kutomo 10 8, or at least 10 9 It may have, or more than, members.

[0014] As used herein, "biocompatibility" means that the biocompatibility of Without, and without causing significant damage or deterioration of the material at the subject, This refers to the properties of materials that enable long-term contact with tissue.

[0015] As used herein, the term "plane" may be applied to describe the three-dimensional shape of any object. Here, the length scales of two dimensions that are substantially perpendicular to each other (e.g., length and width) are , the length scale of a third dimension (e.g., thickness) that is substantially perpendicular to both of the other two dimensions It is longer than the length of one of the two longer dimensions. The dimensions may be the same as or different from those of the plane. When a plane is used in the context of a surface... This refers to a substantially flat surface, as opposed to a surface containing protrusions. The film layers provided herein are It is substantially flat, that is, its length and width are smooth as they do not contain any significant protrusions or indentations. A first surface defining a smooth planar surface, and a surface having, for example, protrusions or ribs that are substantially smooth. A non-planar third having projections or ribs extending from a second surface separated by It may include a second surface opposite to the first surface. The first surface of the film formed from the film layer is a protruding surface. Extending from the region where the origin exists, between the first and second surfaces where nanopores do not exist. It has multiple nanopores.

[0016] As used herein, "nanopore" refers to a pore that penetrates a membrane from one end to the other, and the pore is, At least one in the nanometer range, for example, in the range of 1.0 nm to 1,000 nm The lateral dimensions (e.g., width and / or length, but not including the height / thickness of holes crossing the substrate) (It is not.)

[0017] As used herein, the term "polysilicon" refers to a material deposited as a thin film. It refers to the polycrystalline form of silicon. It is used for micro-electronics in transistors and wiring. Used in electronics. In MEMS, polysilicon is typically used for devices. It is used as a structural material.

[0018] In the context of blood circuits, "pumpless" refers to a system that drives blood flow through the individual's circulatory system. This means that there are no pumping mechanisms other than the heart.

[0019] As used herein, the term "filtration" means passing particulate matter to a significant degree. By passing through a fluid carrier via a culture medium, the fluid changes from liquid to particulate. This refers to the process of separating a substance from a fluid.

[0020] As used herein, the term "dialysis" refers to a form of filtration or selective filtration through a membrane. This refers to the diffusion process, where low molecular weight solutes typically diffuse through a membrane, while colloids do not. And from high molecular weight solutes (such as albumin and immunoglobulins) and suspended substances (such as cells) It is used for separation. In some embodiments, the fluid supply passes through a semipermeable membrane. The dialysis fluid supply passes through to the other side of the membrane, and the membrane becomes wet with one or both of the fluids. There is diffusion transport of solutes between fluids. Using the composition of one fluid, the dialysate, the other fluid This can deplete the composition of the supply fluid by several or more molecules.

[0021] As used herein, the term "ultrafiltration" means filtering a fluid under pressure. This refers to a process where the filtered material is very small and typically contains colloidal, dissolved particles in the fluid. Containing a solute or a very fine solid material, the filter is microporous, nanoporous, or It is a semipermeable medium. A typical medium is a membrane. The fluid being filtered is called the "supply fluid." During ultrafiltration, the supply fluid is filtered through the filter into a "permeate" or "filtrate". " or "ultrafiltrate" and a portion of the supply fluid that was not filtered through the medium, or retained within the membrane It is separated into the "retained substance". In ultrafiltration, the dialysate is passed to the other side of the membrane. It's not necessary.

[0022] As used herein, the term “dialysis fluid” means that low molecular weight solutes first render these solutes It is used to refer to a fluid that diffuses through a membrane from another fluid (typically a supply fluid). ru. [Modes for carrying out the invention]

[0023] This disclosure provides an improved filtration membrane suitable for in vivo blood filtration. Filtration membranes have a minimal area penalty due to the presence of a support system on the back of the membrane. The tee exhibits resistance to damage. This minimal area penalty is described in detail herein. A support structure that provides a hierarchical scaffold including ribs of at least two different heights. This is achieved by using the filtration membrane. Methods for fabricating and using the filtration membrane are also provided.

[0024] Before describing the present invention in detail, it should be noted that the present invention is not limited to specific materials or process parameters. It should be understood that this is not fixed and, naturally, can be changed. The terms used in this specification are defined in this document. This is merely for the purpose of describing specific embodiments of the invention, and is not intended to be limiting It should also be understood that.

[0025] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.

[0026] Filtration membrane Disclosed is a filtration membrane suitable for filtering blood in vivo. The filtration membrane comprises a membrane portion and a support portion. The membrane portion comprises a planar first surface, a second surface opposite the first surface, and a plurality of nanopores, and the second surface comprises a ribbed surface. The ribbed second surface includes first height ribs and second height ribs that are higher than the first height ribs. The first height ribs define a plurality of first windows arranged in a grid pattern, and the first windows have the plurality of nanopores disposed therein. The second height ribs define a plurality of second windows arranged in a grid pattern, and each of the plurality of second windows comprises a plurality of said first windows. The support portion forms a third window including the plurality of second windows, the support portion is attached to the second surface of the membrane portion around the periphery of the membrane portion, and has a third height that is higher than the second height of the ribs. The surface area of the second surface of the membrane exposed by the third window is 0.1 mm 2 to 10 mm 2 , for example 0.5 mm 2 to 10 mm 2 , 1 mm 2 to 10 mm 2 , or 1 mm 2 to 5 mm 2 .

[0027] The ribbed second surface comprises ribs separated by planar regions provided with nanopores. The Ribs of height 1 and height 2 are described, but the second surface has ribs of height 3. It is understood that this may further include one or more of the fourth height ribs, for example, ribs The second surface includes a rib of first height, a rib of second height, and a rib of third height. See, the third height is higher than the second height, and the second height is higher than the first height. A rib of height 1 defines multiple first windows arranged in a grid pattern, and the first windows are multiple It contains a number of nanopores. The second height ribs have multiple second windows arranged in a grid pattern. Defined, each of the multiple second windows includes multiple first windows. The third height rib is a lattice Define multiple third windows arranged in a turn, and each of the multiple third windows is a multiple second window The support portion forms a fourth window which includes a plurality of third windows, and the support portion is the circumference of the membrane portion. In the enclosure, a fourth is attached to the second surface of the membrane portion and is higher than the third height rib It has height. Including additional ribs in which the height of the ribs increases in a hierarchical manner, it is supported by the support portion. The surface area of ​​the membrane that does not need to be held increases further, and the surface area of ​​the membrane that can be used for filtration increases further. There is a possibility that this will happen.

[0028] The film portion can be deposited or grown on a micro or nanoscale, any preferred method. It can be formed from suitable materials. For example, the film can be made from silicon, polysilicon, or silicon carbide. Ultra-nanocrystalline diamond, diamond-like carbon, silicon dioxide, SU-8, Tungsten, silicon nitride, polytetrafluoroethylene, polymethyl methacrylate, poly It can be made from film materials such as ethylene, silicon, or various other materials. The film material is low pressure It can be deposited by any suitable means such as chemical vapor deposition (LPCVD). The thickness of the film layer is Less than 5 μm, for example, 5 μm to 0.5 μm, 4 μm to 0.5 μm, 3 μm to 0.5 μm, 2μm~0.5μm, 1μm~0.5μm, 0.8μm~0.4μm, 0.4μm~0. The thickness may be 1 μm, 0.1 μm to 0.01 μm, or 0.05 μm to 0.01 μm. (Membrane material) Examples of material selection include polysilicon, silicon, silicon nitride, silicon carbide, graphite Examples include corn, diamonds, and combinations thereof.

[0029] The support portion is designed to prevent clogging when exposed to aqueous fluids, such as when filtering ultrafiltrate across the membrane. It can be formed from any inert material. In some cases, semiconductor materials such as silicon wafers may be used. The support portion can also be formed using materials. As enumerated by Miller indices,

[0100] A silicon wafer that may have various crystal orientations, including planar orientation. The support portion contains germanium, Group IV elements of the periodic table, and gallium arsenide (Group III-V). Formed from composites, II-IV compounds containing zinc tellurium, p and n doped compounds, etc. It can be formed from a substrate. The substrate may be substantially planar and may have circular or straight edges. The substrate can be cut into rectangular or circular pieces after or before the formation of the filtration film. The thickness of the substrate is Approximately less than 400 μm, approximately 500 μm, approximately 600 μm, approximately 700 μm, approximately 900 μm, etc. It can be more than that. In some cases, the support portion is formed using a silicon wafer. It will be done.

[0030] Nanopores can have a depth of approximately 1 μm or less. For example, nanopores can have a depth of approximately 0.9 μm to 1 μm. It may have a depth of 0 nm, 0.8 μm to 100 nm, or 0.8 μm to 500 nm. In this embodiment, the multiple nanopores are 1 nm to 500 nm, for example, 1 nm to 90 nm. 2nm~50nm, 3nm~40nm, 4nm~50nm, 4nm~40nm, 5nm~ 50nm, 5nm~20nm, 4nm~20nm, 7nm~100nm, 12nm~20 A circular or slit-shaped opening having a diameter or width of nm, or 5 nm to 10 nm, respectively. It has a portion. In certain embodiments, the multiple holes are slit-shaped and are arranged in this specification. The ranges listed are 1 μm to 10 μm, for example, 2 μm to 3 μm, 3 μm to 4 μm, 4 μm m~5μm, 5μm~6μm, 6μm~7μm, 7μm~8μm, 8μm~9μm, or It has a length in the range of 9 μm to 10 μm. In certain cases, the slit shape is, that is, The rectangular holes have a depth of 100-900 nm, a width of 3 nm-50 nm, and a diameter of 1 micron-5 Length in microns, for example, 5nm~50nm × 1 micron~2 microns × 200nm~5 It has a width × length × depth of 00 nm. The pore depth ranges from 0.01 microns to 100 microns. It can be a range and can be defined by the thickness of the film. In certain embodiments, nanopores are It is not present in the region of the film portion that extends to form the pore. In other words, nanopores are, The second surface is non-planar and does not exist in the region of the film that extends to form ribs. In a certain embodiment, nanopores are not present in the region of the film covered by the support portion.

[0031] The first height ribs extend from the second surface of the membrane and are arranged in a grid pattern, with multiple [number] Define a window 1. Multiple nanopores exist within each of the first windows. For example, in Figure 7 Please refer to panel (f). This shows a rib of the first height and a na supported by the rib. This shows the region of the membrane containing nopores. These ribs can also be seen in panel (e) of Figure 7. However, nanopores are not visible at this magnification. These ribs are also called miniribs. These ribs, each 1 in height, are arranged so that the first windows are aligned in a two-dimensional configuration with adjacent orientations. They can be arranged in a grid pattern. The first window can be rectangular, for example, a square. The thickness of the first height rib on the second surface of the film is 0.5 μm to 5 μm, for example, 1 μm. It can be m~2.5μm. The height of the first height rib is 2μm~10μm, 3μm~8 The size may be μm, or 3μm to 6μm. The size of each of the first windows is 200 to 5000μm. m 2 For example, 300-5000 μm 2 , 500~5000μm 2 , 800~5000μ m 2 , 200~1000μm 2 , 300~1000μm 2 , 500~1000μm 2 ,also is 100-5000 μm 2 This may be the case. In a particular embodiment, the first window is rectangular in shape. It may be present. The length of the first window may be 20 to 100 μm. The width of the first window is 10 It can be up to 50 μm.

[0032] The second height ribs extend from the second surface of the membrane and consist of multiple ribs arranged in a grid pattern. Define two windows, where multiple first windows exist within each of the second windows. For example See panels (d) and (e) in Figure 7. These are the grid pattern of the first window. This shows the second height rib present around the ridge (see panel (e). Figure 7) In panel (d), the individual first windows are not visible, but the grid pattern of the second window is visible. See also panel(a) in Figure 7. The second window is rectangular in shape, for example, a square. It is also acceptable. The number of first windows within each second window is approximately 10 to 100, and approximately 10 to 5. The first window may be 0, approximately 10-40, approximately 10-30, or approximately 10-20. Second height These ribs are also called mega ribs. The height difference between the first height rib and the second height rib. This is shown in panel (b) of Figure 7. In a particular embodiment, the second height rib is the first Approximately 5 to 50 times the height of the rib, for example, 5 to 40 times, 5 to 30 times, 5 to the height of the first rib. 20 times, or 5 to 10 times, for example, up to 6, 7, 8, or 10 times the height of the first rib. It may be 15 times, 25 times, or 35 times. In certain embodiments, the second height rib is approximately 20-250 μm, for example, 20-200 μm, 20-100 μm, 20-80 μm, 2 It can have a height of 0-50 μm or 30-50 μm. On the second surface of the film The thickness of the second height rib is 1 μm to 20 μm, for example, 1 μm to 15 μm, 5 μm to It can be 20 μm, or 5 μm to 15 μm.

[0033] The ribs may be tapered in a shape where the width of the rib decreases as it extends from the membrane. In the construction form, the ribs may have a uniform thickness. The ribs may be a single wall structure. Alternatively, it may be a double wall. A double-walled rib requires less membrane material, and therefore, the membrane material It can be used to reduce costs related to the volume of material. Example of a rib with a double-wall structure. This refers to panel (f) of Figure 7 showing double-walled mini-ribs and panel (f) of Figure 7 showing double-walled mega-ribs. This is shown in a), (b), and (e).

[0034] The support portion forms a third window and runs along the periphery of the membrane. This third window allows the fluid to be filtered. It provides access to nanopores for flow to the back of the membrane. The third window allows for the fabrication of the filtration membrane. As described in the section on the method, the plane used to form the support portion It is formed by creating a cavity in the substrate. Therefore, this third window is also a cavity. The walls of the cavity, which may be called, are formed by the supporting parts. Multiple second windows are, for example, shown in Figure 7. As can be seen in panel (d), it is located within the third window.

[0035] As discussed in the Examples section, the main feature of the disclosed filtration membrane is the second of the membrane The increased availability of membranes for filtration is due to the hierarchical support structure present on the surface. The surface and support portion is longer than the second height rib and longer than the first height rib. It has a first height rib that is flat on the first and second surfaces and contains nanopores. These ribs support the membrane portion. These ribs are also referred to as miniribs in this specification. B defines multiple first windows. These multiple first windows are arranged in order to the first height It is structurally supported by a second, even higher rib. These ribs are as follows: Also called megaribs. These megaribs are membranes that do not need to be supported by supporting structures. This allows for an increase in area. In other words, including megaribs means that the support portion is shaped The position of the support portion such that the resulting third window occupies the minimum surface area of ​​the membrane per square meter of the membrane. Allows for installation. The area of ​​the membrane supported by the support part is available for filtration. Therefore, increasing the surface area of ​​the membrane that does not need to be supported by the support structure will result in filtration. The area of ​​the film containing the resulting nanopores increases. The ribs of the second height come into contact with the second surface of the film. It is substantially thinner than the support portion, and therefore is blocked when the support portion is present. It does not block as much of the film surface as wax. See Figures 7 and 8. In addition, megaribs This is substantially lower in height compared to the height of the support portion, which in the case of a membrane, allows for fluid to flow on the back side. This makes it possible to improve the flow. See Figure 4. First height and second height The presence of the ribs is exposed within the cavity, as described in WO2019 / 222661. Compared to the area of ​​the membrane, the area enclosed by the third window is therefore available for filtration. This makes it possible to substantially increase the surface area of ​​the membrane. For example, the area exposed by the cavity The surface area on the back side of the film is 10,000 to 50,000 μm in WO2019 / 222661. m 2 This is the range. In contrast, it is exposed within the cavity, that is, enclosed by the third window. The area on the back of the membrane is 1 mm². 2 ~10mm 2 , 2mm 2 ~8mm 2 , or 3mm 2 ~ 6mm 2 This is within the range of cavities within the membrane disclosed in WO2019 / 222661. A comparison of the back side of the exposed film with the film of this disclosure is provided in panels (b) and (c) of Figure 8. In certain embodiments, the third window is substantially rectangular in shape (e.g., square). It may also be the case that the third window is about 1 cm long and about 1 cm wide. It has. In certain embodiments, the third window has a length of about 2000 μm to 5000 μm and 5 It has a width of 00 μm to 1000 μm. In a particular embodiment, the third window is approximately 4000 μm. It has a length of m to 5000 μm and a width of approximately 1000 μm. In a particular embodiment, the third The height of the window substantially corresponds to the thickness of the substrate used to form the support portion. The height may be 500 μm to 200 μm or 500 μm to 300 μm. The width of the contact support portion may have a thickness of approximately 20 μm to 50 μm or 30 μm to 50 μm. The multiple second windows within the third window may include 50 to 100 second windows. Membrane portion and support The components may be directly connected, or more typically, connected via an intermediate layer.

[0036] The first window, the second window, and / or the third window, and / or any window present on the back of the film The additional windows can have any shape, such as rectangles, hexagons, trapezoids, or circles. For example, for ribs. The molds are rectangular, hexagonal, trapezoidal, circular, or other shapes, or combinations of such shapes. They may be combined. In addition, the first window may be of a single shape, and the second window may be The third window may have a different shape, and may have the same or different shape as the first or second window. You may have it.

[0037] The filtration membranes described herein are multiple such filtration membranes arranged in an adjacent configuration. It can be used to fabricate filtration devices that include membranes. For example, a filtration device may have multiple membranes. Includes multiple filtration membranes formed using a single substrate on which membrane portions and support portions are formed. It is visible.

[0038] Method for preparing a filtration membrane A method for producing a membrane for in vivo filtration of blood is disclosed. The method involves a support substrate This may include depositing a first mask in a first pattern on a first surface of the first The turn covers and protects a specific area of ​​the first surface, while leaving an area on the first surface exposed. Obtained. This area is obtained from multiple first rectangles arranged in a grid pattern and arranged in a grid pattern. Defines the outlines of multiple second rectangles. Once formed, each of the multiple second rectangles This includes a plurality of first rectangles. The method involves placing a second mask on the first mask, and the second mask The screen covers the exposed area on the first surface that defines the contour of the first rectangular window, so as not to cover the exposed area on the first surface that defines the outline of the second rectangular window. This may further include deposition, thereby enabling etching of the first surface. A groove corresponding to the contour of the second rectangular window is created in the support substrate. For example, panel (a) in Figure 6. Please refer to this. This is a substrate (bulk silicon "bulk Si"), first mask ("acid The first surface is shown as a chromium, and the second mask ("photoresist"). Etching to create grooves, the grooves having depth and thickness. This may further include removing a second mask, and removing a second mask is multiple The method is to expose the area on the first surface that defines the outline of the first rectangle of the number. The surface is etched to increase the depth of multiple second rectangular grooves, and the depth of the second rectangular grooves Grooves are made in the support substrate corresponding to the contours of multiple first rectangles, such that the depth is greater than the depth of the first rectangle. This may further include creating these grooves as a base for creating a filled mold. It can also be called a trench created in a board. For example, the board in Figure 6 showing the mold for the megarib. Refer to panels (b) and (c) of Figure 6, as well as panels (d) to (e) showing the mold for the minirib. I want to be illuminated.

[0039] The method involves removing the first mask and depositing an intermediate layer on the support substrate. Furthermore, it includes: an intermediate layer is a thin layer deposited such that the thickness of the layer is substantially uniform, for example. For example, see panel (e) of Figure 6. In certain cases, the intermediate layer is acid on the substrate. It can be deposited by creating a phosphate layer, thereby creating a thin film on the surface of the substrate. It forms the intermediate layer, which can be a protective layer such as a dielectric layer. In some cases, the intermediate layer is It can be formed by depositing an oxide or nitride layer on a substrate, or formed on a substrate It can be extended. The intermediate layer is used for low-pressure CVD (LPCVD) and plasma-enhanced CVD (PECVD). It can be deposited by chemical vapor deposition (CVD), or by several other deposition methods. In some cases, the intermediate layer can be grown through thermal processes such as thermal oxidation. Silicon oxide, silicon oxynitride, silicon carbide, or other dielectric materials and combinations It may include several other material layers, including a double layer. The thickness of the intermediate layer is approximately 2 μm or less, for example, 2μm~0.1μm, 1μm~0.2μm, 1μm~0.5μm, or 0.8μm~0. It could be 5 μm.

[0040] The method involves depositing a film material to fill the first and second rectangular grooves created in the support substrate. This creates a film that includes a first planar surface and a second non-planar surface opposite the first surface. This may further include the following: the non-planar second surface corresponds to the depth of the first rectangular groove. Multiple ribs having a height of and multiple ribs having a second height corresponding to the depth of the second rectangular groove Including the ribs, the second height is higher than the first height. For example, panel (f) in Figure 6. Please refer to "poly1").

[0041] The method involves creating a pattern of fine grooves within the membrane region (see panel (g) in Figure 6). ) and further comprising depositing a sacrificial layer ("thin oxide") on the film. The sacrificial layer is It can be formed by oxidizing the film material, thereby on the exposed region of the film. A thin layer of oxide is formed. In some cases, the pore structure is later removed and the film layer is opened. Pores can be formed, and can be formed with sacrificial material. Nanopore structures can be formed by etching processes, or The film layer can be formed by other lithography processes. The film layer can be formed by electron beam, deep ultraviolet lithography. i, or another pattern that can form a pattern for creating the structure described herein. The resist can be patterned, which can be done via patterning techniques. The pattern is created on the film layer via reactive ion etching or a wet etching process. It can be transferred. Following patterning, the sacrificial layer of the material is on or inside the patterned film layer. It can be formed. The sacrificial layer may be less than 20 nm thick, grown via thermal oxidation. It could be a material. Alternatively, the layers could be approximately 15nm, 10nm, 7nm, 5nm, 3nm, 1nm. It can have thicknesses of m, 5 angstroms, or less. The layers of material may be conformal during growth. Thus, the film is produced by high-density plasma CVD (HDPCVD), or several other processes. The layer can be formed through more conformal processes, including conformal deposition processes. Cone, or any film that can be subsequently removed from the film layer to create a film having nanopores, It could be made of other materials.

[0042] The method may further include filling the fine grooves with an additional film material. The additional film material is the The initial deposited material may be the same or different material. Panel (i) in Figure 6 ("poly2 See ''. Next, the method removes any excess additional film material that has not been deposited in the fine grooves. The process involves removing the sacrificial layer (Figure 6, Paine; (j)), removing the sacrificial layer from the membrane, and removing the intermediate layer. This may include, and forming a cavity on the second surface of the support structure, the second surface being Multiple nanopores within the membrane, multiple first ribs having a first height To provide a window, a plurality of second windows defined by a plurality of ribs having a second height. The opposite side of the first surface, each of the multiple second windows includes the multiple first windows, and the third window It has a third height defined by the support structure, and is formed by the walls of the cavity, the third The height is greater than the second height, and the third window includes multiple second windows. For example, in Figure 6 See Nell(k). In this embodiment, two are used to form a film having nanopores. The use of the film material is described, but in other embodiments, the nanopore is made from a single film material. It may be formed within the film that is formed. For example, the film layer may be made of a film material and a pattern directly within the film layer. Nanopores formed within the film material by chemical treatment and etching can be formed from these nanopores. ru.

[0043] The various steps of the method can be carried out by any preferred means. Generally, the third window All steps leading up to its creation are carried out on the front side of the circuit board.

[0044] In certain embodiments, etching is performed using potassium hydroxide, tetramethylammonium, and slow This may involve wet etching using wet etching agents such as hydrofluoric acid or EDP. The decision of when to stop the etching process is made based on the desired depth of the groove. Yes, it is possible. Wet etching can be isotropic or orientation-selective, i.e., anisotropic. The ching can create grooves on straight or inclined sides. In other embodiments, The etching agent is more anisotropic, and little to no slope is generated on the groove wall. It can be used. Alternatively, reactive ion etching, such as the Bosch process, can be used. For example, deep reactive ion etching (DRIE) may be performed.

[0045] The substrate can function as a support for the film. For example, the second surface of the film is on the substrate. The remaining substrate that defines the boundary of the cavity may be exposed in the cavity, i.e. The third window provides mechanical support to the membrane.

[0046] The sacrificial material layer is then subjected to subsequent photoresist patterning and etching, covering a specific area. This allows for selective removal. This fixes the second film layer to the first film layer during subsequent deposition. It can provide an area for this. After removing the photoresist, the second film material provides an anchor cavity. , as well as the surface around the sacrificial layer in and around the trench formed in the first film material It can be deposited by filling a mass. This material is the same or a different film material as described above. It is possible. For example, the second film material could also be polysilicon. The second film material layer is sacrificed. The material is planarized to a level where it is at least exposed, thereby forming a porous structure. Planarization can occur with any polishing or etching technique, for example, by reactive ion etching. Ching may be included. In yet another example, the anchor deposits a second membrane material. It can be formed and filled after planarization is performed. Alternatively, the process may involve additional lithography. Raffistep, followed by direct etching, for example, reactive ion etching, followed by anchoring This can be done by performing a specific deposition of the material.

[0047] Nanopores can also be made denser by performing a series of patterning and deposition processes. A high degree of patterning can be achieved. For example, following the initial deposition of the film material, similar to the above. A secondary patterning step may be performed. Once the secondary patterning is performed, additional storage The protective layer can be deposited in the manner described above. Following the formation of the additional protective layer, the subsequent film material layer is: It can be formed to provide the required pore space. The iterative process creates two line and spatial patterns. It can be reduced by more than 0%. Alternatively, the iterative process reduces the linear and spatial patterns by more than 30%, approximately 40%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately It can be reduced by 85%, approximately 90%, or more. Protective material inside the hole during manufacturing. By maintaining this, the integrity of the pore can be preserved until the final release occurs.

[0048] A second protective layer may be applied on top of the film material before etching the back side of the substrate, forming a cavity. , exposing the film. The second protective layer is then acid-treated depending on the etching technique performed. It may contain nitrides, nitrides, or other compounds. For example, the nitride layer may be potassium hydroxide etched. If etching is performed, the deposited oxide layer may be tetramethyl hydroxide. If the material contains nitrogen-selective chemicals such as ammonium, it may be deposited.

[0049] How to use a filtration membrane The filtration membrane works in conjunction with the filtration membrane to form a channel for the blood that flows through the filtration device. The filtration membrane can be integrated into a housing that includes a modular partial channel. It can be inserted into a housing that has separate partial channels. Alternatively, a spaced method The filter membrane cassette formed by joining filter membranes in this manner has openings for partial channels. It can be attached to the opening and inserted into the housing and cassette.

[0050] The filtration device is used to filter the blood of patients who require blood filtration, in vivo or It can be used with ExVivo.

[0051] experiment The following are examples of specific embodiments for carrying out the present invention. These examples are illustrative. Provided solely for the purposes of this invention, and not intended to limit the scope of this invention in any way. do not have.

[0052] Efforts were made to ensure accuracy for the numbers used (e.g., quantity, temperature, etc.), A certain degree of experimental error and deviation should be acceptable.

[0053] Example 1 - Larger area, higher porosity nano for implantable bio-artificial kidneys Scalable hierarchical rib design for porous membranes Silicon nanoporous membranes are a fundamental basis for the development of implantable bioartificial kidneys. We provide the technology. These films are made from microfabricated slit holes that are nominally 10 nm wide. This apparatus is designed to enable highly efficient hemofiltration and immunoprotection for encapsulated cells. The company utilizes established semiconductor manufacturing technology to precisely control the dimensional dimensions of the pore width, thereby This enables highly selective filtration and a clear path to further miniaturization. This research is about membrane To further enhance this, by adding a significantly higher second level of "Mega Rib" tiers... This is based on previous results regarding "ribbed nanoporous membranes." A two-step deep digging reaction. Depending on the ion etching (DRIE) process, depths of 4 μm and 40 μm are available. Trenches are etched into the silicon substrate, a thermal oxide liner is grown, and polysilicon Layers are deposited within this "mold" to form a film. The film is then etched on the back side using DRIE etching. When released afterwards, it features a network of reinforcing ribs on the underside. Permeability per unit area By approximately doubling the transient, we manufactured and tested self-supporting membrane spans with a width up to 14 times wider than before. This new architecture improves the mass transfer speed between films and reduces chip manufacturing costs. It can also be done this way.

[0054] Using a biohybrid approach, we perform the most important renal functions and enable patients to undergo dialysis. We are developing an implantable bio-artificial kidney that can reduce the burden on the user. This device is a waste product. A biocompatible blood filter that selectively separates salt and water and works together to reabsorb them. As a fundamental technology for constructing renal tubular cell bioreactors, silicon nano Porous membranes are used [11-12] (Figure 1).

[0055] For many years, many companies have been developing silicon-based micro-electromechanical systems (MEMS) technology. We have been using this to develop porous membranes for biological and therapeutic applications [13-16] For the current project, a bio-artificial kidney, submicron-thick polysilicon To create precisely controlled nanopores (on the order of 10 nm) in films, thin oxidation is relied upon. We developed a highly reliable "silicon nanoporous film" process [17-18]. However, However, as this study progresses to more advanced stages of preclinical trials, the film device will not be absolutely robust. It is necessary to imprison them and ensure that their susceptibility to in vivo damage is negligible. ru.

[0056] Membrane-based devices typically fail at their weakest point (the membrane itself), so reinforcing that point is necessary. The most important thing is to do this. Obviously, the simplest solution is to thicken the entire membrane, but This prevents the goal of having a thin film to reduce fluid resistance through the pores from being achieved. Therefore, it is necessary to find a way to strengthen the structure without excessively adding thickness or mass. There is a need. Based on well-known mechanical principles, a film is made using a "rib" or beam. Take a route to reinforce

[19] and at the same time minimize the area penalty incurred. I did.

[0057] This study assumes that the rib or beam is located on the back side of the membrane (i.e., the filtrate side, not the blood side). This is complicated by the fact that it must be (Figure 2). Therefore, the film is formed. It is not possible to simply add extra features to the upper side of the wafer after it has been processed. In other words, what Even so, in this case, it must be done before the deposition of polysilicon. In a sense, This is the challenge faced by optical mirrors, which must keep the front of the device smooth. Different [19-20].

[0058] Previous studies on membranes with "miniribs"

[21] have shown that manufacturing satisfies such constraints. A path was provided. The wafer surface was pre-embossed (i.e., with a width of 1 μm and a depth of 4 μm). A network of trenches is etched onto the starting silicon substrate, followed by a thermal oxide liner. By adding polysilicon and then depositing it to form a membrane, a bio-artificial kidney can be created. The main reinforcement is the ability to manufacture a film with reinforced ribs on the back. However, there is still room for improvement in basic chip-level filtration efficiency. The development of bio-artificial kidneys that can be made more profitable from the order of magnitude increase in the mass transfer coefficient of the membrane. I am confident that it is possible.

[0059] At the membrane design level, one obvious factor that directly affects mass transfer efficiency is the active membrane area. This is the ratio of the chip area to the total chip area. In current "Gen1" devices, approximately 40% of the frames are deep reactive ion etching (DRIE) with a frame thickness equal to the total thickness of the starting substrate. Note that this is dead space occupied by the bulk Si "frame" (Figure 3 left). Therefore, a thinner and lighter scaffolding (Figure) is desired to leave more space for the active filter. We propose a "Gen2" design that has (3) right. However, (i) DRIE aspect (ii) Ratio limitations, and (ii) undercutting of the support frame during wet etching of the film. For various reasons, simply reducing the frame line width in the mask design is insufficient. When the lateral etching fronts of the embedded oxide layer meet from both sides of the "wall", The membrane loses its physical anchor and separates from the frame.

[0060] Innovation and Design In this study, we defined the majority of the DRIE-defined "wall" with a width of 40 μm and a height of 400 μm. By replacing it with polysilicon "mega ribs" (Figure 2, right) that are twice as narrow and 10 times shallower, the porous regions are filled. The goal is to increase the filling rate from 63% to 88% (i.e., an increase of 40%). Hit the dot. The height of the megarib (40 μm) is the same as the height of the original minirib (4 μm) of the wafer. Because it is designed to be the geometric mean of the total thickness (400 μm), the design is "hierarchical" It becomes quality.

[0061] Fluid-related considerations The adoption of these shallow megaribs is also partly determined by fluid dynamics. In artificial kidney design, blood flows parallel to the upper (flat) membrane surface, and the filtrate flows to the bottom (ribbed) (i) It flows in opposite parallel directions along the surface. However, due to the thickness of the wafer frame, Most of the flow of the filtrate actually occurs at a considerable distance (hundreds of micrometers) from the plane of the membrane. It is present, slowing down toxin removal and thus hindering intermembrane diffusion. Therefore, calculation Perform fluid dynamics (CFD) modeling to shorten or sparse the rear support structure. We investigated whether it was worth doing.

[0062] For the purpose of this simulation, ANSYS Fluent 19.2 software (Figure 4) was used. The geometric shape was set as 2D, and the material used was liquid water. The model was based on a steady state with a velocity inlet boundary condition of 0.02381 m / s and a static pressure outlet. Yes, it did. It widened the inlet area to allow for fully developed flow, while on the other hand, the membrane surface urea on the blood side The concentration was kept constant. Model performance was evaluated based on the water outlet concentration (urea removal).

[0063] In this analysis, by significantly reducing the height of the 400□m "obstacle" on the filtrate side, the membrane It was shown that the mass transport of molecules passing through it increased by almost four times. In other words, supporting the megarib Incorporating it into the structure will definitely help improve filtration efficiency.

[0064] Mechanical considerations In addition to microfluidic performance, the mechanical properties of the megarib membrane design are also important. In previous research... The standard membrane "window" was 100 × 400 μm, but this time, using megaribs, it was 10 They are trying to expand it to 00 × 4000 μm (that is, the area is 100 times larger). Therefore, the fact that such a large self-supporting span remains mechanically sound, that is, the membrane We must ensure that the rigidity is not excessively compromised by reducing the size of the support. stomach.

[0065] Therefore, in order to compare the old design with the new design, we relied on finite element analysis (FEA). In this study, ANSYS Mechanical 19.2 software was used for all machines. Used for mechanical modeling. A double plane of symmetry was used in all models to represent the device's geometry. This allowed only one-quarter of it to be modeled. A hexahedral mesh element was used. A constant support was applied to the boundary, and a pressure of 300 mmHg was applied to the blood-contact surface of the membrane. Figure 5 shows: Simple (non-ribbed) 100×400μm film vs. 1000×4000μm film under constant distributed load The FEA results for the Galib film are shown. The results show that the stiffness of the megarib film is up to 5 times lower, but still... This indicates that it is acceptable.

[0066] manufacturing Based on previous minirib membrane processes [17, 20], the megarib trench was initially 36 An additional step was added: an initial hidden oxide mask etched below a μm (Figure 6a-b). The photoresist mask above was removed with oxygen plasma and piranha, and then Megali Both the rib and the minirib are further etched down by 4 μm (Figures 6c-d). This process... The result is a network of double-depth trenches, thus forming two different rib heights. This makes it possible.

[0067] After this step, the process returns to the existing flow and conforms to the thermal oxide liner. The "embedded oxide" is grown (Figure 6e), and the first polysilicon layer ("Poly 1) is deposited to fill the trench and form a film layer (Figure 6f), and high-resolution lithography is performed. The Graphitech prints a high-density line-space array onto polysilicon. Next, the pattern Poly1 is anisotropically etched down to the embedded oxide, and the cross-section is mostly square. It forms a series of ridges and grooves (Figure 6g).

[0068] The timed drying oxidation step involves oxidizing 10 nm of material on the Poly1 surface, including the vertical sidewalls of the ridge. Thin oxide ("th") of the orderer (adjusted to correspond to the desired width of the final nanopore) Forms "inOx" (Figure 6h). A second polysilicon layer ("Poly2") is deposited. Next, fill the grooves of Poly1 (Figure 6i). (Periodic annealing is not shown here) Except for the Kerr region, Poly1 and Poly2 are separated by a thinOx layer. Please note: The plasma planarization step is Poly1-thinOx-Poly2 The tack is etched beyond the original Poly1 surface and is vertically oriented to eventually become a nanopore. Reveals the embedded thinOx "wall" (Figure 6j).

[0069] Finally, after the low-temperature oxide (LTO) passivation layer is deposited, the back side DRIE and Then, hydrofluoric acid (HF) wet etching is performed to remove the embedded oxides, and nano The contents of the pore are emptied (Figure 6k). This completes the entire manufacturing process and produces nanoporous material. The film is released. Figure 7 shows scanning electron microscope (SEM) images of several completed devices. ) indicates.

[0070] Each mega rib is actually designed to facilitate polysilicon filling without using excessive material. Note that it consists of a pair of narrow parallel trenches (Figure 7b). The amount of Poly1 required to obtain the same beam rigidity is reduced, thereby reducing the film resistance. It reduces force, wafer curvature, and load on subsequent etching steps. Also, from above Then, the film has a nanoscale slit pore in between, with Poly1 elements and Poly2 elements. Note that it is effectively constructed with an alternating array of elements (Figure 7c). On the other hand, The structural layers on the back side (wafer frame → megarib → minirib → nanopore) are shown in enlarged view in Figures 7d-f. It can be seen in the sequence.

[0071] Figure 8 shows a backlit optical image of a 100 mm diameter wafer with a 0.8 μm thick self-supporting film. As shown in a, the wafer shows almost perfect yield. On the other hand, the activation from Gen1 to Gen2 A significant increase in the filter region was observed in the morphology of a larger (light-transmitting) film region under optical microscopy (Figure 8b). ~c) You can see it below.

[0072] Measurement value The measured values ​​for hydraulic porosity and burst strength (see Table 1 and Figure 9) show that the megarib membrane is superior to the old design. It was shown to be at least three times more porous (more efficient) while having a five times lower burst pressure. This is consistent with the FEA results. The burst pressure remains within the acceptable safety threshold (5 psi). It is currently superior, but future development efforts will be made without sacrificing active filter area. To further enhance the mechanical robustness of the membrane, the mega-rib design should be improved (for example, the rib height should be increased). The focus will be on optimizing and eliminating sharp angles and other stress concentration areas. Ro. [Table 1]

[0073] conclusion Extending the proven rib-based design, it boasts significantly higher porosity and a high transport coefficient. Scalable and hierarchical rib architecture enables large-span, high-filling density nanoporous films. A new MEMS manufacturing approach has been developed.

[0074] From a manufacturing perspective, this approach reduces manufacturing costs while maintaining manufacturing yield. We promise to do so. From a design perspective, to optimize the balance between porosity and robustness By providing multiple design parameters that can be adjusted independently, flexibility is enhanced. Add.

[0075] Therefore, the above explanation merely illustrates the principles of this disclosure. Those skilled in the art will understand, Although not explicitly described or illustrated in this specification, the principles of the present invention are embodied, and the gist and essence of the invention are also described. It will be understood that various configurations can be devised within the range. Furthermore, the following are listed in this specification. All examples and conditional statements provided are primarily intended to illustrate the principles of the present invention and to promote the technology as demonstrated by the inventors. This is intended to help readers understand the concepts that have been contributed to the advancement of this idea. It should be interpreted that this invention is not limited to the examples and conditions specifically listed. All of the principles, aspects, and embodiments of the herein, as well as specific examples thereof, are listed herein. The description is intended to encompass both its structural and functional equivalents. Additionally, Such equivalents include both currently known equivalents and equivalents to be developed in the future, that is, It is intended to include any development elements that perform the same function regardless of their structure. Therefore, the scope of the present invention is limited to the exemplary embodiments illustrated and described herein. That was not the intention. References: [1] United States Renal Data System RDS), annual data report 2018. [2] DJ de Jager, JJ, Carrero, M. Verduij n,P.Ravani,J.de Meester,JGHeaf,P.Finne ,A.J.Hoitsma,J.Pascual,F.Jarraya,AVRei saeter,F. Collart,FWDekker,KJJager,“ Cardiovascular and noncardiovascular mor tality among patients starting dialysis, "JAMA 302, 1782-9 (2009)." [3] E. O'Lone, M. Connors, P Masson, S. Wu, P. J. Kelly, D. Gillespie, D. Parker, W. Whiteley, GFStrippoli, SCPalmer, JCCraig, ACW ebster,“Cognition in People With End-Sta ge Kidney Disease Treated With Hemodialy sis: A Systematic Review and Meta-analyses is,”Am.J.Kidney Dis.Off.J.Natl.Kidney Fo und.67,925-935 (2016). [4] J.D.Kopple,“Physical performance an d all-cause mortality in CKD,”J.Am.Soc.N ephrol.JASN 24,689-690(2013). [5] M.Takasato,P.X.Er,H.S.Chiu,B.Maier, G.J.Baillie,C.Ferguson,R.G.Parton,E.J.Wo lvetang,M.S.Roost,S.M.Chuva de Sousa Lop es,M.H.Little,“Kidney organoids from hum an iPS cells contain multiple lineages a nd model human nephrogenesis,”Nature 536 ,238(2016). [6] E.A.Ross,M.J.Williams,T.Hamazaki,N. Terada,W.L.Clapp,C.Adin,G.W.Ellison,M.Jo rgensen,C.D.Batich,“Embryonic stem cells proliferate and differentiate when seed ed into kidney scaffolds,”J.Am.Soc.Nephr ol.JASN 20,2338-2347(2009). [7] D.B.N.Lee and M.Roberts,“A peritone al-based automated wearable artificial k idney,”Clin.Exp.Nephrol.12,171-180(2008) . [8] V.Gura,A.S.Macy,M.Beizai,C.Ezon,T.A .Golper,“Technical breakthroughs in the wearable artificial kidney (WAK),”Clin.J .Am.Soc.Nephrol.CJASN 4,1441-1448(2009). [9] H.D.Humes,D.A.Buffington,L.Lou,S.Ab rishami,M.Wang,J.Xia,W.H.Fissell,“Cell t herapy with a tissue-engineered kidney r educes the multiple-organ consequences o f septic shock,”Crit.Care Med.31,2421-24 28(2003).

[10] H.D.Humes,D.A.Buffington,S.M.MacKa y,A.J.Funke,and W.F.Weitzel,“Replacement of renal function in uremic animals wit h a tissue-engineered kidney,”Nat.Biotec hnol.17,451-455(1999).

[11] W.H.Fissell,and S.Roy,“The implant able artificial kidney,”Semin.Dial.22,66 5-670(2009).

[12] M. Salani,S.Roy,W.H.Fissell,“Innov ations in Wearable and Implantable Artif icial Kidneys,”Am.J.Kidney Dis.Off.J.Nat l.Kidney Found.72,745-751(2018).

[13] T.A.Desai,D.J.Hansford,L.Leoni,M.E ssenpreis,M.Ferrari,“Nanoporous anti-fou ling silicon membranes for bio-sensor ap plications,”Biosensors and Bioelectronic s 15,453-462(2000).

[14] A.C.Hoogerwerf,C.Hinderling,S.Kris hnamoorthy,C.Hibert,V.Spassov,T.Overstol z,“Fabrication of Reinforced Nanoporous Membranes,”Proc.Transducers 2007,Lyon,Fr ance.

[15] M.Hajj-Hassan,M.C.Cheung,V.P.Choda varapu,“Ultra-thin porous silicon membra nes fabricated using dry etching,”Micro & Nano Lett.6,226-228(2011).

[16] A.A.Hamzah,H.E.Zainal Abidin,B.Yeo p Majlis,M.Mohd Nor,A.Ismardi,G.Sugandi, T.Y.Tiong,C.F.Dee and J.Yunas,“Electroch emically deposited and etched membranes with precisely sized micropores for biol ogical fluids microfiltration,”J.Microme ch Microeng.23,074007(2013).

[17] S.Roy,A.Dubnisheva,A.Eldridge,A.J. Fleischman,K.G.Goldman,H.D.Humes,A.L.Zyd ney,W.H.Fissell,“Silicon Nanopore Membra ne Technology for an Implantable Artific ial Kidney,”Proc.Transducers 2009,Denver ,CO,USA,2009.

[18] S.Kim,B.Feinberg,R.Kant,B.W.Chui,K .Goldman,J.Park,W.Moses,C.Blaha,Z.Iqbal, C.Chow,N.Wright,W.H.Fissell,A.Zydney,S.R oy,“Diffusive Silicon Nanopore Membranes for Hemodialysis Applications,”PLoS 201 6.

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Claims

1. A filtration membrane suitable for filtering blood in vivo, The membrane portion, A first surface containing multiple nanopores and having a planar surface, The first surface includes a ribbed second surface, the first surface being opposite to the second surface. 、 The ribbed surface comprises a rib of a first height and a rib of a second height that is higher than the first height. Ribs, and The first height rib defines a plurality of first windows arranged in a grid pattern, The first window includes the plurality of nanopores, The ribs of the second height define a plurality of second windows arranged in a grid pattern, Each of the plurality of second windows includes a membrane portion which includes the plurality of first windows, A support portion forming a third window including the plurality of second windows, wherein the support portion is Attached to the second surface of the film portion around the film portion, and the second high It comprises a support portion having a third height that is higher than the aforementioned rib, The surface area of ​​the second surface of the film exposed by the third window is 0.1 mm². ２ ~10mm ２ A filtration membrane, which is within the range of a filtration membrane.

2. The aforementioned film portion is made of polysilicon, silicon, silicon nitride, silicon carbide, graphene, Alternatively, the filter according to claim 1, formed from diamond, or a combination thereof. device.

3. The filtration device according to claim 1 or 2, wherein the support portion includes a silicon wafer.

4. The plurality of nanopores have a depth of about 1 μm or less, according to any one of claims 1 to 3. The filtration device described.

5. The plurality of nanopores have a depth of approximately 0.8 μm to 10 nm, according to any of claims 1 to 3. A filtration device as described in item one.

6. The aforementioned nanopores have a depth of approximately 0.8 μm to 100 nm or 0.8 μm to 500 nm. A filtration device according to any one of claims 1 to 3, comprising:

7. The surface area of ​​the second surface of the film surrounded by the third window is 1 mm² ２ ~1 0 mm ２ , 2mm ２ ~8mm ２ , or 3 mm ２ ~6mm ２ The range of claims 1 to 6 A filtration device as described in any one of the items.

8. The filtration device according to claim 1, wherein the third window is substantially rectangular in shape.

9. The third window has a length of approximately 2000 μm to 5000 μm and a width of 500 μm to 1000 μm. The filtration device according to claim 8, having a width.

10. The third window has a length of approximately 4000 μm to 5000 μm and a width of approximately 1000 μm. The filtration device according to claim 8.

11. The third height is in the range of 500 μm to 200 μm or 500 μm to 300 μm. , the filtration device according to any one of claims 1 to 10.

12. The support portion has a thickness of approximately 20 μm to 50 μm or 30 μm to 50 μm, claim A filtration device as described in any one of items 1 to 10.

13. The ribs of the second height are in the range of heights of 20 μm to 50 μm or 30 μm to 50 μm. A filtration device according to any one of claims 1 to 12, wherein the enclosure is as described above.

14. The rib of the second height has a thickness in the range of 20 μm to 5 μm or 15 μm to 5 μm. A filtration device according to any one of claims 1 to 13.

15. The rib of the first height is 2 μm to 10 μm, 3 μm to 8 μm, or 3 μm to 6 μm A filtration device according to any one of claims 1 to 13, wherein the height is in the range of m.

16. The first height rib is in the range of thickness of 0.5 μm to 5 μm or 1 μm to 2.5 μm. A filtration device according to any one of claims 1 to 15, wherein the enclosure is as described above.

17. The plurality of second windows includes 50 to 100 second windows, any one of claims 1 to 16. The filtration device described in item 1.

18. The plurality of first windows include 50 to 20 first windows, any one of claims 1 to 17 The filtration device described in the section.

19. The plurality of nanopores are slit-shaped nanopores, any one of claims 1 to 18 The filtration device described in the section.

20. The slit-shaped holes have a maximum length of 3 μm and a maximum width of 0.1 μm, or a maximum width of 2 μm. Length and width up to 50 nm, or length of 1 μm to 3 μm and width of 10 nm to 100 nm The filtration device according to claim 19, wherein the device has the features described in claim 19.

21. The nanopores are not located within the region of the film portion that extends to form the ribs, and / or covered by the support portion, the filtration according to any one of claims 1 to 20. device.

22. The aforementioned membrane portion and support portion are connected via an intermediate layer, as in any of claims 1 to 21. A filtration device as described in item 1.

23. Any of claims 1 to 22, including a plurality of filtration units arranged in an adjacent configuration. The filtration device described in item 1.

24. A method for producing a biocompatible filtration membrane suitable for filtering blood in vivo, 、 The method involves depositing a first mask in a first pattern on the first surface of a support substrate, The first pattern exposes an area on the first surface, and the area is a grid. Multiple first rectangles arranged in a pattern and multiple second rectangles arranged in a grid pattern The contour is defined, and each of the plurality of second rectangles includes the plurality of first rectangles, To make, A second mask is placed on the first mask, and the second mask outlines the contour of the first rectangular window. The exposed area on the first surface is defined and the outline of the second rectangular window is defined Demarcated by depositing the material so as not to cover the exposed area on the first surface. This enables etching of the first surface and the second rectangular window. Grooves corresponding to the aforementioned contour are created in the support substrate and deposited, The process involves etching the first surface to create the groove, wherein the groove has a depth and Having thickness, etching, Removing the second mask, which means removing the second mask To expose or remove an area on the first surface that defines the contours of multiple first rectangles. That thing, The first surface is etched to increase the depth of the plurality of second rectangular grooves. The depth of the groove in the second rectangle is greater than the depth of the first rectangle. Creating the groove corresponding to the first rectangular contour in the support substrate, Removing the first mask, Depositing an intermediate layer on the aforementioned support substrate, A film material is used to fill the first and second rectangular grooves created in the support substrate. By depositing, a planar first surface and a non-planar second surface opposite the first surface are formed. Including the creation of a film, wherein the non-planar second surface is the first rectangular groove A plurality of ribs having a first height corresponding to the depth of the second rectangular groove It includes a plurality of ribs having a second height corresponding to the depth, wherein the second height is the first To create something that is taller than the height, Creating a pattern of fine grooves in the region of the aforementioned film, Depositing a sacrificial layer on the aforementioned film, Filling the aforementioned fine grooves with additional film material, To remove any excess additional film material that has not accumulated in the aforementioned fine grooves, Removing the sacrificial layer from the aforementioned film, The intermediate layer is removed and a cavity is formed on the second surface of the support structure, The second surface is on the opposite side of the first surface, Multiple nanopores within the aforementioned film, A plurality of first windows defined by the plurality of ribs having the first height, A plurality of second windows defined by the plurality of ribs having the second height, Each of the plurality of second windows includes the plurality of first windows, A third height defined by the support structure and formed by the wall of the cavity A third window, wherein the height of the third window is greater than the height of the second window, and the third window is a composite A method comprising forming a third window, which includes a second window of numbers.

25. The plurality of nanopores are not located within the region of the film including the ribs, as per claim 24. Law.

26. Claim 2: The plurality of nanopores are not located within the region of the film that is in contact with the support structure. The method described in 4 or 25.

27. Depositing the first mask and / or the second mask is performed by chemical vapor deposition (CVD). The method according to any one of claims 24 to 26, including )

28. Depositing the first mask and / or the second mask is done by thermal oxidation. The method according to any one of claims 24 to 26, comprising growing a squirrel.

29. The aforementioned film is made of polysilicon, silicon, silicon nitride, silicon carbide, graphene, or or is formed from diamond, or a combination thereof, any one of claims 24 to 28 The method described in item 1.

30. The support substrate includes a silicon wafer, as described in any one of claims 24 to 29. Law.

31. The plurality of nanopores have a depth of about 1 μm or less, as per any one of claims 24 to 30. The method described in section [section number].

32. The plurality of nanopores have a depth of approximately 0.8 μm to 10 μm, according to claims 24 to 30. The method described in any one of the items.

33. The aforementioned nanopores have a depth of approximately 0.8 μm to 100 nm or 0.8 μm to 500 nm. The method according to any one of claims 24 to 30, comprising:

34. The surface area of the back side of the membrane surrounded by the third window is 1 mm ２ to 10 mm ２ , 2 m I understand ２ ~8mm ２ , or 3 mm ２ ~6mm ２ Any one of claims 24 to 33 is within the range of The method described in section [section number].

35. The third window is substantially rectangular in shape, as described in any one of claims 24 to 34. The method.

36. The third window has a length of approximately 2000 μm to 5000 μm and a width of 500 μm to 1000 μm. The method according to any one of claims 24 to 35, having a width.

37. The third window has a length of approximately 4000 μm to 5000 μm and a width of approximately 1000 μm. The method according to any one of claims 24 to 35.

38. The third height is in the range of 500 μm to 200 μm or 500 μm to 300 μm. or the method according to any one of claims 24 to 37.

39. The support substrate has a thickness of approximately 20 μm to 50 μm or 30 μm to 50 μm, claim The method described in any one of paragraphs 24 to 38.

40. The ribs of the second height are in the range of heights of 20 μm to 50 μm or 30 μm to 50 μm. The method according to any one of claims 24 to 39, wherein the method is enclosed.

41. The rib of the second height has a thickness in the range of 20 μm to 5 μm or 15 μm to 5 μm. A method according to any one of claims 24 to 40.

42. The rib of the first height is 2 μm to 10 μm, 3 μm to 8 μm, or 3 μm to 6 μm The method according to any one of claims 24 to 41, wherein the height is in the range of m.

43. The first height rib is in the range of thickness of 0.5 μm to 5 μm or 1 μm to 2.5 μm. The method according to any one of claims 24 to 41, wherein the method is enclosed.

44. The plurality of second windows includes 50 to 100 second windows, as in any of claims 24 to 43. The method described in item 1.

45. The plurality of first windows includes 50 to 20 first windows, as per any of claims 24 to 44. The method described in item 1.

46. The plurality of nanopores are slit-shaped nanopores, as per any of claims 24 to 45. The method described in item 1.

47. The slit-shaped holes have a maximum length of 3 μm and a maximum width of 0.1 μm, or a maximum width of 2 μm. Length and width up to 50 nm, or length of 1 μm to 3 μm and width of 10 nm to 100 nm The method according to claim 46.

48. The film and the support substrate are connected via the intermediate layer, according to any of claims 24 to 47. The method described in any one of the items.

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