Improved filtration membrane and method for fabricating and using the same

Abstract

The present disclosure provides an improved filtration membrane suitable for in vivo blood filtration. The improved filtration membrane exhibits resistance to breakage with minimal area penalty due to the presence of a support system behind the membrane. This minimal area penalty is achieved by using a support that provides a hierarchical scaffold containing ribs of two different heights, as disclosed herein.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 063,038, filed on 7 August 2020, and U.S. Provisional Patent Application No. 63 / 070,999, filed on 27 August 2020, which are incorporated herein by reference in their entirety. [Background technology]

[0002] Chronic renal failure affects more than two million people worldwide.[1] Current treatment options are dialysis and organ transplantation. While kidney transplantation offers the best clinical outcomes, a severe shortage of donor organs often forces kidney patients to undergo dialysis for extended periods (several years), contributing to a reduced quality of life and increased mortality. In addition, regular transfers to dialysis centers and the undesirable accumulation of urea and other toxins in the bloodstream between dialysis sessions tend to negatively impact the patient's overall health.[2–4] It would be highly beneficial to have a compact, portable, mass-producible, and ultimately implantable "biotoxin" capable of performing the most important kidney functions.

[0003] The main limitations of dialysis treatment and the limited availability of organs for kidney transplantation are driving interest in alternative kidney replacement therapies. Approaches currently under development include cell-based strategies aimed at creating fully functional replacement organs [5-6], wearable artificial kidney devices based on dialysis technology that would allow patients to receive long-term, frequent treatment outside of a clinical setting [7-8], and biohybrid devices that attempt to mimic the key functions of native nephrons [9-10].

[0004] To achieve such alternative kidney replacement therapy, the development of submicron-thick filtration membranes that provide a sufficiently filtration surface resistant to damage is essential. This disclosure addresses these and other needs. [Overview of the Initiative]

[0005] This disclosure provides an improved filtration membrane suitable for in vivo blood filtration. 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 at least two different heights of ribs, as described in detail herein. 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) simulations (from left to right) of fluid flow through a closely spaced array of wafers with a height of 400 μm (Gen1, left) and shorter (h=40 μm) megaribs (Gen2, right). In the case of Gen2, the liquid flow enters the etching cavity, thus facilitating toxin removal. The cavity shown has a length (L) of 1 mm and a depth (d) of 400 μm. The simulation results showed that the mass transport coefficient could be nearly four times higher. [Figure 5]Finite element analysis (FEA) results showing the maximum deflection ("md") for Gen2 megarib membranes of various sizes (0.6×4mm, 0.8×4mm, and 1.0×4mm). A quarter-membrane model was used to accelerate the simulation and utilize the design's symmetry. The small unit cell in the lower right represents the old Gen1 (ribless) design. [Figure 6] Flowchart of the megarib membrane fabrication process. Compared to previous studies

[21] , (a) to (d) represent newly added steps that enable the formation of double-depth trenches and thus ribs of different heights. In particular, step (b) essentially forms a megarib mold, and step (d) forms a minirib mold. Also, the dry oxidation in step (h) forms a thin oxide that determines the precise width of the nanopores and thus the main filtration properties of the membrane. [Figure 7] (a) Top view of the megarib film, (b) Cross-sectional view showing miniribs and megaribs, (c) Close-up top view of nanopores, (d) Back view image of the megarib film showing the silicon wafer "frame" and megaribs, (e) Further close-up showing megaribs and miniribs, (f) Scanning electron microscope (SEM) images of further close-up showing miniribs and nanopores. [Figure 8] Backlit optical image of a fully emitted 100 mm diameter megarib nanoporous film wafer showing near-perfect device yield (a), (b-c): Backlit optical microscope images of actual independent nanoporous films showing the increase in available film area from Gen1 (b) to Gen2 (c). [Figure 9] Porosity (top) and burst pressure (bottom) measured for Gen1 and Gen2 membranes. At least seven devices were measured for each data point. The data shows that Gen2 devices (i.e., megarib membranes) exhibit significantly higher porosity at the expense of lower (but still acceptable) burst pressures. 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] definition All publications, patents, and patent applications referenced herein, whether above or below, are incorporated herein by reference in their entirety.

[0008] In describing the present invention, the following terms are intended to be used and defined as follows:

[0009] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the content explicitly indicates otherwise. Thus, for example, a reference to “film” includes multiple such films, two or more. It should be further noted that claims can be drafted to exclude any arbitrary element. Therefore, this statement is intended to serve as a precedent for the use of exclusive terms such as “exclusively,” “only,” or “negative” restrictions in relation to the enumeration of elements of claims.

[0010] "Subject" or "individual" means any member of the subphylum Chordata, including but not limited to humans, other primates including chimpanzees and other apes and monkey species, farm animals such as cattle, sheep, pigs, goats and horses, domestic mammals such as dogs and cats, birds and laboratory animals such as mice, rats and guinea pigs. This term does not indicate a specific age. Thus, both adult and neonatal individuals are intended to be subjects. An individual may be a patient requiring hemodialysis, for example, a patient with impaired renal function and / or requiring dialysis, impaired cardiac function and / or impaired hepatic function.

[0011] When referring to measurable values such as physical quantities, temporal time periods, etc., the term "about" as used herein means to encompass variations including ±20%, ±10%, etc., ±5%, etc., ±1%, ±0.1% from the specified value, such that such variations are typical of the measurements characterizing the disclosed devices or are appropriate for performing the disclosed methods.

[0012] As used herein, "substantially" may be applied to modify a quantitative expression that may vary within an acceptable range without causing a change in the associated basic function. For example, substantially parallel may include structures that are slightly non-parallel to each other.

[0013] "Plurality" includes at least two members. In certain cases, the plurality may have 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 、at least 10 8 、or at least 10 9 、or more members.

[0014] "Biocompatibility" as used herein refers to the property of a material that enables long-term contact with tissues in a subject without causing significant toxicity or significant injury, and optionally without causing significant damage or degradation of the material.

[0015] As used herein, “plane” may be applied to describe the three-dimensional shape of any object, where the length scales of two dimensions substantially perpendicular to each other (e.g., length and width) are longer than the length scale of a third dimension (e.g., thickness) substantially perpendicular to both of the other two dimensions. The length scale of one of the two longer dimensions may be the same as or different from that of the other longer dimension. When used in the context of a surface, a plane refers to a substantially flat surface as opposed to a surface containing protrusions. A film layer provided herein may include a first surface that is substantially flat, i.e., a smooth planar surface whose length and width define a smooth planar surface that does not contain significant protrusions or indentations, and a second surface opposite the first surface that may be non-planar, having protrusions or ribs extending from a second surface from which the protrusions or ribs are separated by a substantially smooth surface. The first surface of a film formed from a film layer has a plurality of nanopores extending between the first surface and the second surface, where nanopores are absent from regions where protrusions are present.

[0016] As used herein, "nanopore" refers to a hole that penetrates a film from one end to the other, and the hole has at least one lateral dimension (e.g., width and / or length, but not including the height / thickness of the hole across the substrate) in the nanometer range, for example, in the range of 1.0 nm to 1,000 nm.

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

[0018] In the context of blood circuits, "pumpless" refers to the absence of any pumping mechanism other than the heart that drives blood flow through the body's circulatory system.

[0019] As used herein, the term "filtration" refers to the process of separating particulate matter from a fluid, such as a liquid, by passing it through a fluid carrier via a culture medium that does not allow particulate matter to pass through to a significant degree.

[0020] As used herein, the term “dialysis” refers to a form of filtration or process of selective diffusion through a membrane, typically used to separate low molecular weight solutes that diffuse through the membrane from non-diffusing colloids and high molecular weight solutes (such as albumin and immunoglobulins) and suspended substances (such as cells). In some embodiments, a fluid feed passes through a semipermeable membrane, and a dialysate feed passes through the other side of the membrane, with the membrane being moistened by one or both liquids, and there is diffusive transport of solutes between the fluids. The composition of the dialysate, one of the fluids, can be used to deplete the composition of the feed fluid, the other fluid, of several or more molecules.

[0021] As used herein, the term “ultrafiltration” refers to filtering a fluid under pressure, where the material being filtered is very small, typically the fluid contains colloidal, dissolved solutes, or very fine solid materials, and the filter is a microporous, nanoporous, or semipermeable medium. A typical medium is a membrane. The fluid being filtered is referred to as the “feed fluid.” During ultrafiltration, the feed fluid is separated into a “permeate,” “filtrate,” or “ultrafiltrate” filtered through the filter, and a portion of the feed fluid not filtered through the medium, or a “retainer” held within the membrane. Ultrafiltration does not require passing the dialysate to the other side of the membrane.

[0022] As used herein, the term “dialysis fluid” is used to refer to a fluid in which low molecular weight solutes initially diffuse through a membrane from another fluid containing these solutes (typically a feed fluid). [Modes for carrying out the invention]

[0023] This disclosure provides an improved filtration membrane suitable for in vivo blood filtration. 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 at least two different heights of ribs, as described in detail herein. Methods for fabricating and using the filtration membrane are also provided.

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

[0025] Several methods and materials similar to or equivalent to those described herein may be used in carrying out the present invention, but preferred materials and methods are described herein.

[0026] Filtration membrane A filtration membrane suitable for filtering blood in vivo is disclosed. The filtration membrane includes a membrane portion and a support portion. The membrane portion includes a planar first surface, a second surface opposite the first surface, and a plurality of nanopores, the second surface including a ribbed surface. The ribbed second surface includes ribs of a first height and ribs of a second height that are higher than the first height. The ribs of the first height define a plurality of first windows arranged in a grid pattern, the first windows including a 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 including a plurality of first windows. The support portion forms a third window including a 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 ribs. The surface area of ​​the second surface of the membrane exposed by the third window is 0.1 mm². 2 ~10mm 2 For example, 0.5mm 2 ~10mm 2 , 1mm2 ~10 mm 2 or 1 mm 2 ~5 mm 2 and is in the range of.

[0027] The second surface with ribs includes ribs separated by a flat portion with nanopores. Although ribs of a first height and a second height are described, it is understood that the second surface may further include one or more of ribs of a third height, ribs of a fourth height, etc. For example, the second surface with ribs may include ribs of a first height, ribs of a second height, and ribs of a third height, where the third height is higher than the second height and the second height is higher than the first height. The ribs of the first height define a plurality of first windows arranged in a grid pattern, and the first windows include a plurality of nanopores. The ribs of the second height define a plurality of second windows arranged in a grid pattern, and each of the plurality of second windows includes a plurality of first windows. The ribs of the third height define a plurality of third windows arranged in a grid pattern, and each of the plurality of third windows includes a plurality of second windows. The support portion forms a fourth window including the plurality of third windows, and the support portion is attached to the second surface of the membrane portion around the membrane portion and has a fourth height higher than the ribs of the third height. When additional ribs with hierarchically increasing rib heights are included, the surface area of the membrane that does not need to be supported by the support portion may further increase, and the surface area of the membrane available for filtration may further increase.

[0028] The film portion can be formed from any suitable material, which can be deposited or grown on a micro or nanoscale. For example, the film can be made from film materials such as silicon, polysilicon, silicon carbide, supernanocrystalline diamond, diamond-like carbon, silicon dioxide, SU-8, titanium, silicon nitride, polytetrafluoroethylene, polymethyl methacrylate, polystyrene, silicon, or various other materials. The film material can be deposited by any suitable means, such as low-pressure chemical vapor deposition (LPCVD). The thickness of the film layer can be less than 5 μm, for example, 5 μm to 0.5 μm, 4 μm to 0.5 μm, 3 μm to 0.5 μm, 2 μm to 0.5 μm, 1 μm to 0.5 μm, 0.8 μm to 0.4 μm, 0.4 μm to 0.1 μm, 0.1 μm to 0.01 μm, or 0.05 μm to 0.01 μm. Examples of film material selections include polysilicon, silicon, silicon nitride, silicon carbide, graphene, and diamond, as well as combinations thereof.

[0029] The support portion can be formed from any inert material that does not clog when exposed to aqueous fluids, such as when filtering an ultrafiltrate across the film. In some cases, semiconductor materials such as silicon wafers can also be used to form the support portion. Silicon wafers can have various crystal orientations, including planar orientation, as enumerated by Miller indices. In other cases, the support portion can be formed from a substrate formed from germanium, Group IV elements of the periodic table, III-V compounds including gallium arsenide, II-IV compounds including zinc tellurium, p and n doped compounds, etc. The substrate can 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 can be less than about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 900 μm, etc., or more. In some examples, the support portion is formed using a silicon wafer.

[0030] Nanopores may have a depth of approximately 1 μm or less. For example, nanopores may have a depth of approximately 0.9 μm to 10 nm, 0.8 μm to 100 nm, or 0.8 μm to 500 nm. In a particular embodiment, multiple nanopores have circular or slit-shaped openings with diameters or widths of 1 nm to 500 nm, for example, 1 nm to 90 nm, 2 nm to 50 nm, 3 nm to 40 nm, 4 nm to 50 nm, 4 nm to 40 nm, 5 nm to 50 nm, 5 nm to 20 nm, 4 nm to 20 nm, 7 nm to 100 nm, 12 nm to 20 nm, or 5 nm to 10 nm, respectively. In certain embodiments, the pores are slit-shaped and have widths listed herein, and lengths ranging from 1 μm to 10 μm, for example, 2 μm to 3 μm, 3 μm to 4 μm, 4 μm to 5 μm, 5 μm to 6 μm, 6 μm to 7 μm, 7 μm to 8 μm, 8 μm to 9 μm, or 9 μm to 10 μm. In certain cases, the slit shape, i.e., the rectangular pore, has a depth of 100 to 900 nm, a width of 3 nm to 50 nm, and a length of 1 to 5 microns, for example, 5 nm to 50 nm × 1 to 2 microns × 200 nm to 500 nm (width × length × depth). The pore depth can be defined by the film thickness, which may range from 0.01 microns to 100 microns. In certain embodiments, nanopores are not present in areas of film portions that extend to form ribs. In other words, nanopores are absent in regions of the film where the second surface is non-planar and extends to form ribs. In certain embodiments, nanopores are absent in regions of the film covered by supporting portions.

[0031] The first height ribs extend from the second surface of the film and define a plurality of first windows arranged in a grid pattern. Multiple nanopores are present within each of the first windows. See, for example, panel (f) of Figure 7, which shows the first height ribs and the region of the film containing the nanopores supported by the ribs. These ribs are also seen in panel (e) of Figure 7, but the nanopores are not visible at this magnification. These ribs are also called miniribs. These first height ribs may be arranged in a grid pattern such that the first windows are arranged in a two-dimensional configuration with adjacent orientations. The first windows may be rectangular, for example, square. The thickness of the first height ribs on the second surface of the film may be 0.5 μm to 5 μm, for example, 1 μm to 2.5 μm. The height of the first height ribs may be 2 μm to 10 μm, 3 μm to 8 μm, or 3 μm to 6 μm. The size of each of the first windows is 200-5000 μm. 2 For example, 300-5000 μm 2 , 500~5000μm 2 , 800~5000μm 2 , 200~1000μm 2 , 300~1000μm 2 , 500~1000μm 2 , or 100-5000 μm 2 This is possible. In certain embodiments, the first window may be rectangular in shape. The length of the first window may be 20 to 100 μm. The width of the first window may be 10 to 50 μm.

[0032] The second height ribs extend from the second surface of the membrane and define a plurality of second windows arranged in a grid pattern, where a plurality of first windows exist within each of the second windows. See, for example, panels (d) and (e) of Figure 7. These show the second height ribs that exist around the grid pattern of the first windows (see panel (e)). In panel (d) of Figure 7, the individual first windows are not visible, but the grid pattern of the second windows is. See also panel (a) of Figure 7. The shape of the second windows may be rectangular, for example, a quadrilateral. The number of first windows present within each of the second windows may be about 10 to 100, about 10 to 50, about 10 to 40, about 10 to 30, or about 10 to 20 first windows. The second height ribs are also called megaribs. The height difference between the first height ribs and the second height ribs is shown in panel (b) of Figure 7. A particular implementation In some embodiments, the height of the second height rib may be approximately 5 to 50 times the height of the first rib, for example, 5 to 40 times, 5 to 30 times, 5 to 20 times, or 5 to 10 times the height of the first rib, for example, up to 6, 7, 8, 10, 15, 25, or 35 times the height of the first rib. In certain embodiments, the height of the second height rib may be approximately 20 to 250 μm, for example, 20 to 200 μm, 20 to 100 μm, 20 to 80 μm, 20 to 50 μm, or 30 to 50 μm. The thickness of the second height rib on the second surface of the film may be 1 μm to 20 μm, for example, 1 μm to 15 μm, 5 μm to 20 μm, or 5 μm to 15 μm.

[0033] The ribs may be tapered in a shape in which the width of the rib decreases as it extends from the membrane. In other embodiments, the ribs may have a uniform thickness. The ribs may be a single-wall structure or a double-wall structure. Double-wall ribs require less membrane material and may therefore be used to reduce costs associated with the volume of membrane material. Examples of ribs with a double-wall structure are shown in panel (f) of Figure 7, which shows a double-wall mini-rib, and in panels (a), (b), and (e) of Figure 7, which show a double-wall mega-rib.

[0034] The support portion forms a third window, which runs along the periphery of the membrane. This third window provides access to nanopores for fluid to flow to the back of the filtration membrane. The third window is formed by creating a cavity in the planar substrate used to form the support portion, as described in the section on how to fabricate the filtration membrane. Thus, this third window may also be called a cavity, and the walls of the cavity are formed by the support portion. Multiple second windows are present within the third window, as can be seen, for example, in panel (d) of Figure 7.

[0035] As discussed in the Examples section, the main feature of the disclosed filtration membrane is the increased surface area of ​​the membrane available for filtration due to a hierarchical support structure present on the second surface of the membrane, the support portion having a height longer than the second height ribs and longer than the first height ribs. The first height ribs are flat on the first and second surfaces and support portions of the membrane containing nanopores. These ribs are also referred to herein as miniribs. These ribs define a plurality of first windows. A plurality of such first windows are, in turn, structurally supported by second height ribs that are higher than the first height. These ribs are also referred to herein as megaribs. These megaribs allow for an increase in the area of ​​the membrane that does not need to be supported by the support portion. In other words, the inclusion of megaribs allows for the positioning of the support portion such that the third windows formed by the support portion occupy the minimum surface area of ​​the membrane per square area of ​​the membrane. Since the area of ​​the membrane supported by the support portion is not available for filtration, increasing the area of ​​the membrane that does not need to be supported by the support portion increases the area of ​​the membrane containing nanopores where filtration can occur. The ribs of the second height are substantially thinner than the support portion that contacts the second surface of the membrane, and therefore do not obstruct as much of the membrane surface as would be obstructed if the support portion were present. See Figures 7 and 8. In addition, the megaribs are substantially lower in height compared to the height of the support portion, which, in the case of the membrane, allows for better fluid flow on the back side. See Figure 4. The presence of the ribs of the first and second heights allows for a substantially increased area of ​​the membrane enclosed by the third window and therefore available for filtration, compared to the area of ​​the membrane exposed in the cavity, as described in WO2019 / 222661. For example, the area of ​​the back side of the membrane exposed by the cavity is, in WO2019 / 222661, 10,000 to 50,000 μm². 2 This is the range. In contrast, the area of ​​the back side of the membrane that is exposed within the cavity, i.e., surrounded by the third window, is 1 mm². 2 ~10mm 2 , 2mm 2 ~8mm 2 , or 3mm 2 ~6mm2 This is within the range. A comparison of the back side of the film exposed by cavities within the film, as disclosed in WO2019 / 222661, with the film of this disclosure is provided in panels (b) and (c) of Figure 8. In certain embodiments, the third window may be substantially rectangular in shape (e.g., square). In certain embodiments, the third window has a length of about 1 cm and a width of about 1 cm. In certain embodiments, the third window has a length of about 2000 μm to 5000 μm and a width of 500 μm to 1000 μm. In certain embodiments, the third window has a length of about 4000 μm to 5000 μm and a width of about 1000 μm. In certain embodiments, the height of the third window substantially corresponds to the thickness of the substrate used to form the support portion. The third height may be 500 μm to 200 μm or 500 μm to 300 μm. The width of the support portion in contact with the membrane 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. The membrane portion and the support portion may be directly connected, or more commonly, connected via an intermediate layer.

[0036] The first window, the second window, and / or the third window, and / or any additional windows present on the back of the film, may have any shape, such as a rectangle, hexagon, trapezoid, or circle. For example, the mold for the rib may be rectangular, hexagonal, trapezoidal, circle, or another shape, or a combination of such shapes. In addition, the first window may have only one shape, the second window may have a different shape, and the third window may have the same shape as or a different shape from the first or second window.

[0037] The filtration membranes described herein may be used to fabricate a filtration device comprising multiple such filtration membranes arranged in an adjacent configuration. For example, the filtration device may include multiple filtration membranes formed using a single substrate on which multiple membrane portions and support portions are formed.

[0038] Method for preparing a filtration membrane A method for producing a membrane for in vivo filtration of blood is disclosed. The method may include depositing a first mask in a first pattern on a first surface of a support substrate. The first pattern may cover and protect a specific area of ​​the first surface, leaving an area on the first surface exposed. This area defines the contours of a plurality of first rectangles and a plurality of second rectangles arranged in a grid pattern. Once formed, each of the plurality of second rectangles contains a plurality of first rectangles. The method may further include depositing a second mask on the first mask such that the second mask covers the exposed area on the first surface defining the contours of the first rectangular windows, but does not cover the exposed area on the first surface defining the contours of the second rectangular windows. This allows etching of the first surface to create grooves in the support substrate corresponding to the contours of the second rectangular windows. See, for example, panel (a) of Figure 6. This shows a substrate (bulk silicon "bulk Si"), a first mask ("oxide"), and a second mask ("photoresist"). The method is to etch a first surface to create grooves, the grooves having depth and thickness, and further to remove a second mask, the removal of which exposes an area on the first surface defining a plurality of first rectangular contours. The method is to etch the first surface to increase the depth of a plurality of second rectangular grooves, creating grooves in a support substrate corresponding to a plurality of first rectangular contours such that the depth of the second rectangular grooves is greater than the depth of the first rectangles. These grooves may also be referred to as trenches created in the substrate to create a filled mold. See, for example, panels (b) and (c) of Figure 6 showing a megarib mold, and panels (d) to (e) of Figure 6 showing a minirib mold.

[0039] The method further includes removing a first mask and depositing an intermediate layer on a support substrate. The intermediate layer is a thin layer deposited such that the thickness of the layer is substantially uniform; see, for example, panel (e) of Figure 6. In certain cases, the intermediate layer may be deposited by creating an oxide layer on the substrate, thereby forming a thin film on the surface of the substrate. The intermediate layer may be a protective layer, such as a dielectric layer. In some cases, the intermediate layer may be formed by depositing an oxide or nitride layer on the substrate or by growing it on the substrate. The intermediate layer may be deposited by chemical vapor deposition (CVD), including low-pressure CVD (LPCVD) and plasma-enhanced CVD (PECVD), or by some other deposition means. In some cases, the intermediate layer may be grown by a thermal process, such as thermal oxidation. The intermediate layer may include some other material layers, including silicon nitride, silicon oxide, silicon oxynitride, silicon carbide, or other dielectric materials and combinations thereof. The thickness of the intermediate layer may be approximately 2 μm or less, for example, 2 μm to 0.1 μm, 1 μm to 0.2 μm, 1 μm to 0.5 μm, or 0.8 μm to 0.5 μm.

[0040] The method may further include depositing a film material to fill first and second rectangular grooves created in a support substrate to create a film having a planar first surface and a non-planar second surface opposite the first surface, the non-planar second surface having a plurality of ribs having a first height corresponding to the depth of the first rectangular groove and a plurality of ribs having a second height corresponding to the depth of the second rectangular groove, the second height being greater than the first height. See, for example, panel (f) ("poly1") of Figure 6.

[0041] The method may further include creating a pattern of fine grooves within a region of the film (see panel (g) in Figure 6) and depositing a sacrificial layer ("thin oxide") on the film. The sacrificial layer may be formed by oxidizing the film material, thereby forming a thin layer of oxide on the exposed region of the film. In some cases, pore structures may be formed with the sacrificial material, which can later be removed to form pores through the film layer. Nanopore structures may be formed by an etching process or other lithography process. The film layer may be patterned with a photoresist, which may be performed via an electron beam, deep ultraviolet lithography, or another patterning technique capable of forming patterns for fabricating the structures described herein. The resist pattern may be transferred onto the film layer via reactive ion etching or a wet etching process. Following patterning, a sacrificial layer of material may be formed on or within the patterned film layer. The sacrificial layer may be an oxide grown via thermal oxidation, with a thickness of less than 20 nm. Alternatively, the layers may have thicknesses of approximately 15 nm, 10 nm, 7 nm, 5 nm, 3 nm, 1 nm, 5 angstroms, etc. The material layer may be conformal during growth, and thus the film may be formed via a more conformal process, including high-density plasma CVD (HDPCVD) or several other conformal deposition processes. The layer may be silicon oxide, or any other material that can subsequently be removed from the film layer to create a film with nanopores.

[0042] The method may further include filling the fine grooves with additional film material. The additional film material may be the same material as initially deposited or a different material. See panel (i) ("poly2") of Figure 6. The method may then include removing any excess additional film material not deposited in the fine grooves (Figure 6, pane (j)), removing the sacrificial layer from the film, removing the intermediate layer, and forming a cavity on a second surface of the support structure, the second surface being opposite to the first surface so as to provide a plurality of nanopores in the film, a plurality of first windows defined by a plurality of ribs having a first height, a plurality of second windows defined by a plurality of ribs having a second height, each of the plurality of second windows containing a plurality of first windows, and a third window having a third height defined by the support structure and formed by the cavity wall, the third height being greater than the second height, and the third window containing a plurality of second windows. See panel (k) of Figure 6, for example. In this embodiment, the use of two film materials to form a film having nanopores is described, but in other embodiments, the nanopores may be formed within a film formed from a single film material. For example, a film layer may be formed from a film material and nanopores formed within the film material by directly patterning and etching within the film layer.

[0043] The various steps of the method can be carried out by any preferred means. In general, all steps up to the creation of the third window are carried out on the front side of the substrate.

[0044] In certain embodiments, etching may be wet etching using a wet etchant such as potassium hydroxide, tetramethylammonium, buffered hydrofluoric acid, or EDP. The decision of when to stop the etching process can be made based on the desired depth of the groove. Wet etching may be isotropic or orientation-selective, i.e., anisotropic. Etching may create grooves on straight or inclined sides. In other embodiments, the etchant may be more anisotropic and used in a way that creates little or no inclination of the groove walls. Alternatively, reactive ion etching, such as deep reactive ion etching (DRIE), which relies on the Bosch process, may be performed.

[0045] The substrate can function as a support for the film. For example, the second surface of the film may be exposed in a cavity in the substrate, and the remainder of the substrate defining the boundary of the cavity, i.e., a third window, provides mechanical support to the film.

[0046] The sacrificial material layer can be selectively removed in specific areas by subsequent photoresist patterning and etching. This may provide an area for fixing the second film layer to the first film layer during subsequent deposition. After the photoresist is removed, the second film material can be deposited by filling the anchor cavities and the area around the sacrificial layer in and around the trenches formed in the first film material. This material may be the same or a different film material as described above. For example, the second film material may also be polysilicon. The second film material layer is planarized to a level in which at least the sacrificial material is exposed, thereby forming a pore structure. Planarization can be achieved by any polishing or etching technique, and in one example may include reactive ion etching. In yet another example, anchors may be formed and filled after the second film material has been deposited and planarized. Alternatively, the process may be carried out by an additional lithography step, followed by direct etching, e.g., reactive ion etching, followed by the specific deposition of the anchor material.

[0047] Nanopores can also be patterned more densely by performing a series of patterning and deposition processes. For example, following the initial deposition of the film material, a secondary patterning step similar to that described above may be performed. Once the secondary patterning is performed, an additional protective layer may be deposited in the manner described above. Following the formation of the additional protective layer, subsequent film material layers may be formed to provide the required pore density. Iterations can reduce the linear and spatial patterns by 20% or more. Alternatively, iterations can reduce the linear and spatial patterns by approximately 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc., or more. By maintaining the protective material within the pores during manufacturing, the integrity of the pores can be maintained until the final release is performed.

[0048] A second protective layer may be applied on top of the film material before etching the back side of the substrate, creating a cavity and exposing the film. Depending on the etching technique subsequently performed, the second protective layer may contain an oxide, nitride, or another compound. For example, a nitride layer may be deposited if potassium hydroxide etching is performed, and an oxide layer may be deposited if the subsequent etching involves a nitrogen-selective chemical such as tetramethylammonium hydroxide.

[0049] How to use a filtration membrane The filtration membrane may be integrated into a housing containing assembled partial channels, which work in conjunction with the filtration membrane to form a flow path for blood flowing through the filtration device. The filtration membrane may be inserted into a housing that individually comprises assembled partial channels. Alternatively, a filtration membrane cassette, formed by joining filtration membranes in a spaced manner, may be inserted into a housing and cassette, which are attached to the openings of the partial channels.

[0050] The filtration device can be used in vivo or ex vivo to filter the blood of patients who require blood filtration.

[0051] experiment The following are examples of specific embodiments for carrying out the present invention. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0052] While efforts were made to ensure accuracy in the figures used (e.g., quantities, temperatures, etc.), a certain degree of experimental error and deviation should be acceptable.

[0053] Example 1 - Scalable hierarchical rib design for larger area, higher porosity nanoporous membranes for implantable bioartificial kidneys Silicon nanoporous membranes provide a fundamental technology for the development of implantable bioartificial kidneys. These membranes consist of finely machined slit pores nominally 10 nm wide, enabling highly efficient hemofiltration and immunoprotection for encapsulated cells. This approach utilizes established semiconductor manufacturing techniques to precisely control pore width, thereby enabling highly selective filtration capabilities and a clear path to further miniaturization. This study builds on previous results for “ribbed nanoporous membranes” by adding a second level of significantly higher “mega-ribs” to further enhance the membrane. Relying on a two-step deep reactive ion etching (DRIE) process, trenches 4 μm and 40 μm deep are etched into a silicon substrate, a thermal oxide liner is grown, and a layer of polysilicon is deposited within this “mold” to form the membrane. The membrane, upon release after DRIE etching on the back side, features a network of reinforcing ribs on the underside. Self-supporting membrane spans up to 14 times wider than before were fabricated and tested, with approximately double the transmittance per unit area. The new architecture can also improve the mass transfer speed between films and reduce chip manufacturing costs.

[0054] Using a biohybrid approach, we will develop an implantable bioartificial kidney that can perform the most critical renal functions and reduce the burden of dialysis for patients. This device utilizes silicon nanoporous membranes as a fundamental foundational technology to construct a biocompatible hemofilter and renal tubular cell bioreactor that work together to selectively separate waste and reabsorb salt and water [11-12] (Figure 1).

[0055] For many years, numerous companies have used silicon-based microelectromechanical systems (MEMS) technology to develop porous membranes for biological and therapeutic applications [13–16]. For the current project, a bioartificial kidney, a reliable “silicon nanoporous membrane” process [17–18] has been developed that relies on thin oxidation to produce precisely controlled nanopores (on the order of 10 nm) in submicron-thick polysilicon membranes. However, as this research progresses to more advanced stages of preclinical trials, it is necessary to make the membrane device absolutely robust and ensure that its susceptibility to in vivo failure is negligible.

[0056] Since membrane-based devices typically fail at their weakest point (the membrane itself), reinforcing that point is paramount. Obviously, the simplest solution is to thicken the entire membrane, but this defeats the purpose of having a thin membrane to reduce fluid resistance through the pores. Therefore, we need to find a way to strengthen the structure without adding excessive thickness or mass. Based on well-known mechanical principles, we decided to take the route of reinforcing the membrane using "ribs" or beams

[19] , while simultaneously minimizing the area penalty incurred.

[0057] This study is complicated by the fact that the ribs or beam must be located on the back side of the film (i.e., the filtrate side, not the blood side) (Figure 2). Therefore, it is not possible to simply add extra features to the top side of the wafer after the film has been formed. In other words, whatever is done in this case must be done before the polysilicon is deposited. In a sense, this is different from the challenges faced by optical mirrors, which must keep the front side of the device smooth [19-20].

[0058] Previous research on membranes with “mini-ribs”

[21] has provided a manufacturing route that satisfies such constraints. By pre-embossing the wafer surface (i.e., etching a network of trenches 1 μm wide and 4 μm deep into the starting silicon substrate), then adding a thermal oxide liner, and finally depositing polysilicon to form a membrane, it was possible to manufacture the commercially available membranes with reinforced ribs on the back, which are the main enhancement of bio-artificial kidneys. However, there is still room for improvement in filtration efficiency at the basic chip level. We believe that the development of implantable bio-artificial kidneys will greatly benefit from the orders of magnitude increase in the mass transfer coefficient of the membrane.

[0059] At the film design level, one obvious factor that directly affects mass transfer efficiency is the ratio of the active film area to the total chip area. Note that in current "Gen1" devices, approximately 40% of the chip area is dead space occupied by a deep reactive ion etching (DRIE) bulk Si "frame" (Figure 3 left), where the frame is the full thickness of the starting substrate. Therefore, we propose a "Gen2" design with a thinner and lighter scaffold (Figure 3 right) that leaves more room for the active filter. However, simply reducing the frame linewidth in the mask design is insufficient due to various reasons, including (i) limitations on the DRIE aspect ratio and (ii) undercutting of the support frame during film-extracting wet etching. When the lateral etching fronts of the embedded oxide layer meet from both sides of the "wall," the film loses its physical anchor and separates from the frame.

[0060] Innovation and Design This study focuses on replacing most of the DRIE-defined "walls," which are 40 μm wide and 400 μm high, with polysilicon "mega-ribs" (Figure 2, right) that are four times narrower and ten times shallower, aiming to increase the fill density of the porous region from 63% to 88% (i.e., a 40% increase). The height of the mega-ribs (40 μm) is designed to be the geometric mean of the height of the original mini-ribs (4 μm) and the total thickness of the wafer (400 μm), thus giving the design a "hierarchical" nature.

[0061] Fluid-related considerations The adoption of these shallow megaribs is also partly determined by fluid dynamics. In current bioartificial kidney designs, blood flows parallel to the upper (flat) membrane surface, and the filtrate flows inversely parallel along the bottom (ribbed) surface. However, due to the thickness of the wafer frame, the majority of the active filtrate flow actually occurs at a considerable distance (hundreds of micrometers) from the membrane plane, slowing toxin removal and thus hindering intermembrane diffusion. Therefore, we performed computational fluid dynamics (CFD) modeling to investigate whether it would be worthwhile to shorten or sparse the support structures on the back side.

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

[0063] This analysis showed that significantly reducing the height of the 400mm-high "obstacle" on the filtrate side increased the mass transport of molecules through the membrane by almost four times. In other words, incorporating megaribs into the support structure definitely helps to improve filtration efficiency.

[0064] Mechanical considerations In addition to microfluidic performance, the mechanical properties of the megarib membrane design are also important. Previous studies have shown that a standard membrane "window" is 100 × 400 μm, but now we are attempting to expand it to 1000 × 4000 μm (i.e., 100 times larger in area) using megaribs. In doing so, we must ensure that such a large self-supporting span remains mechanically sound; that is, that the membrane's rigidity is not excessively compromised by the reduction of the support structure.

[0065] Therefore, finite element analysis (FEA) was used to compare the old and new designs. In this study, ANSYS Mechanical 19.2 software was used for all mechanical modeling. Double symmetry planes were used in all models, allowing only a quarter of the device geometry to be modeled. Hexahedral mesh elements were used. A fixed 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 the FEA results for a simple (non-ribbed) 100 × 400 μm membrane versus a 1000 × 4000 μm (mega-ribbed) membrane under a constant distributed load. The results show that the stiffness of the mega-ribbed membrane is up to 5 times lower, but still acceptable.

[0066] manufacturing Building upon previous minirib film processes [17, 20], an initial hidden oxide mask step was added in which the megarib trenches are first etched down to 36 μm (Figure 6a-b). The photoresist mask above is removed with oxygen plasma and piranha, after which both the megaribs and miniribs are further etched down to 4 μm (Figure 6c-d). This process sequence allows for the formation of a dual-depth trench network, and thus two different rib heights.

[0067] Following this step, the process returns to the existing flow, a conformal thermal oxide liner ("filled oxide") is grown (Figure 6e), a first polysilicon layer ("Poly1") is deposited to fill the trenches and form a film layer (Figure 6f), and a high-resolution lithography step prints a high-density line spatial array onto the polysilicon. The pattern is then anisotropically etched to Poly1 down to the filled oxide, forming a series of ridges and grooves with mostly square cross-sections (Figure 6g).

[0068] The timed drying oxidation step forms a thin oxide ("thinOx") on the Poly1 surface, on the order of 10 nm (adjusted to correspond to the desired width of the final nanopore), including the vertical sidewalls of the ridges (Figure 6h). A second polysilicon layer ("Poly2") is deposited to fill the grooves in Poly1 (Figure 6i). (Note that Poly1 and Poly2 are separated by the thinOx layer, except for periodic anchor regions not shown here.) The plasma planarization step etches the Poly1-thinOx-Poly2 stack beyond the original Poly1 surface, revealing vertically oriented, embedded thinOx "walls" that will eventually become nanopores (Figure 6j).

[0069] Finally, after the deposition of a low-temperature oxide (LTO) passivation layer, backside DRIE and hydrofluoric acid (HF) wet etching are performed to remove the embedded oxide and empty the nanopore (Figure 6k). This completes the entire fabrication process and releases the nanoporous film. Figure 7 shows scanning electron microscope (SEM) images of several completed devices.

[0070] Note that each megarib is actually composed of a pair of narrow parallel trenches (Figure 7b) to facilitate polysilicon filling without using excess material. This reduces the amount of Poly1 required to obtain the same beam stiffness, thereby reducing film stress, wafer curvature, and the load on subsequent etching steps. Also note that, viewed from above, the film is effectively composed of an alternating array of Poly1 and Poly2 elements with nanoscale slit pores in between (Figure 7c). On the other hand, the back-side structural hierarchy (wafer frame → megarib → minirib → nanopore) can be seen in the enlarged sequence in Figures 7d-f.

[0071] Figure 8a shows a backlit optical image of a 100 mm diameter wafer with a 0.8 μm thick self-supporting film, demonstrating near-perfect yield. Meanwhile, a significant increase in the active filter region from Gen1 to Gen2 can be observed under an optical microscope (Figures 8b-c) in the form of a larger (light-transmitting) film region.

[0072] Measurement value Measurements of hydraulic porosity and burst strength (see Table 1 and Figure 9) show that the megarib membrane is at least three times more porous (efficient) than the previous design, while having a five times lower burst pressure, consistent with FEA results. Although the burst pressure is still acceptablely above the safety threshold (5 psi), future development efforts will focus on enhancing the megarib design (e.g., optimizing rib height and eliminating sharp corners and other stress concentration areas) to further increase the mechanical robustness of the membrane without sacrificing active filter area. [Table 1]

[0073] conclusion By extending proven rib-based designs, a scalable, hierarchical rib-based MEMS fabrication approach has been developed that enables large-span, high-filling nanoporous membranes with significantly higher porosity and high transport coefficients.

[0074] From a manufacturing perspective, this approach promises to reduce manufacturing costs while maintaining manufacturing yield. From a design perspective, it adds flexibility by providing multiple design parameters that can be independently adjusted to optimize the balance between porosity and robustness.

[0075] Therefore, the above description merely illustrates the principles of this disclosure. Those skilled in the art will understand that various configurations embodying the principles of the present invention and falling within its spirit and scope can be devised, although these are not expressly described or illustrated herein. Furthermore, all examples and conditional statements listed herein are intended primarily to assist the reader in understanding the principles of the present invention and the concepts to which the inventors have contributed to the advancement of the art, and should be interpreted not as limitations to such specifically listed examples and conditions. In addition, all descriptions herein listing the principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and future-developed equivalents, i.e., any development elements that perform the same function regardless of their structure. Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments illustrated and described herein. References: [1] United States Renal Data System (USRDS), annual data report 2018. [2] D.J.de Jager,J.J.,Carrero,M.Verduijn,P.Ravani,J.de Meester,J.G.Heaf,P.Finne,A.J.Hoitsma,J.Pascual,F.Jarraya,A.V.Reisaeter,F. Collart,F.W.Dekker,K.J.Jager,“Cardiovascular and noncardiovascular mortality 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,G.F.Strippoli,S.C.Palmer,J.C.Craig,A.C.Webster,“Cognition in People With End-Stage Kidney Disease Treated With Hemodialysis: A Systematic Review and Meta-analysis,”Am.J.Kidney Dis.Off.J.Natl.Kidney Found.67,925-935 (2016). [4] J.D.Kopple,“Physical performance and all-cause mortality in CKD,”J.Am.Soc.Nephrol.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.Wolvetang,M.S.Roost,S.M.Chuva de Sousa Lopes,M.H.Little,“Kidney organoids from human iPS cells contain multiple lineages and 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.Jorgensen,C.D.Batich,“Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds,”J.Am.Soc.Nephrol.JASN 20,2338-2347(2009). [7] D.B.N.Lee and M.Roberts,“A peritoneal-based automated wearable artificial kidney,”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.Abrishami,M.Wang,J.Xia,W.H.Fissell,“Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock,”Crit.Care Med.31,2421-2428(2003).

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

[11] W.H.Fissell,and S.Roy,“The implantable artificial kidney,”Semin.Dial.22,665-670(2009).

[12] M. Salani,S.Roy,W.H.Fissell,“Innovations in Wearable and Implantable Artificial Kidneys,”Am.J.Kidney Dis.Off.J.Natl.Kidney Found.72,745-751(2018).

[13] T.A.Desai,D.J.Hansford,L.Leoni,M.Essenpreis,M.Ferrari,“Nanoporous anti-fouling silicon membranes for bio-sensor applications,”Biosensors and Bioelectronics 15,453-462(2000).

[14] A.C.Hoogerwerf,C.Hinderling,S.Krishnamoorthy,C.Hibert,V.Spassov,T.Overstolz,“Fabrication of Reinforced Nanoporous Membranes,”Proc.Transducers 2007,Lyon,France.

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

[16] A.A.Hamzah,H.E.Zainal Abidin,B.Yeop Majlis,M.Mohd Nor,A.Ismardi,G.Sugandi,T.Y.Tiong,C.F.Dee and J.Yunas,“Electrochemically deposited and etched membranes with precisely sized micropores for biological fluids microfiltration,”J.Micromech Microeng.23,074007(2013).

[17] S.Roy,A.Dubnisheva,A.Eldridge,A.J.Fleischman,K.G.Goldman,H.D.Humes,A.L.Zydney,W.H.Fissell,“Silicon Nanopore Membrane Technology for an Implantable Artificial 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.Roy,“Diffusive Silicon Nanopore Membranes for Hemodialysis Applications,”PLoS 2016.

[19] B.J.Lutzenberger,D.Dickensheets,“Fabrication and modeling of rib-stiffened thin films,”J.Micromech.Microeng.,19(2009).

[20] J. Drake and H. Jerman, “A Micromachined Torsional Mirror for Track Following in Magneto-Optical Disk Drives”, Proc. Hilton Head Solid-state Sensors and Actuators Workshop, 2000, SC, USA.

[21] BWChui, P. Taheri-Tehrani, N. Wright, J. Ly, S. Roy, “Ribbed Nanoporous Membranes for the Implantable Bio-artificial Kidney,” Hilton Head Solid-state Sensor & Actuator Workshop, 2018, SC, USA. [Item 1] A filtration membrane suitable for filtering blood in vivo, The membrane portion, A first surface containing multiple nanopores and having a planar surface, A second surface with ribs, the first surface being opposite to the second surface, The ribbed surface includes a rib of a first height and a rib of a second height that is higher than the first height. The rib of the first height defines a plurality of first windows arranged in a grid pattern, and the first windows include the plurality of nanopores. The ribs of the second height define a plurality of second windows arranged in a grid pattern, and 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, the support portion comprising: a support portion attached to the second surface of the membrane portion around the membrane portion and having a third height higher than the rib of the second height; A filtration membrane in which the surface area of ​​the second surface of the membrane exposed by the third window is in the range of 0.1 mm² to 10 mm². [Item 2] The filtration device according to item 1, wherein the membrane portion is formed from polysilicon, silicon, silicon nitride, silicon carbide, graphene, or diamond, or a combination thereof. [Item 3] The support portion includes a silicon wafer, as described in item 1 or 2. [Item 4] The plurality of nanopores have a depth of approximately 1 μm or less, and the filtration device is as described in any one of items 1 to 3. [Item 5] The plurality of nanopores have a depth of approximately 0.8 μm to 10 nm, and the filtration device is as described in any one of items 1 to 3. [Item 6] The filtration device according to any one of items 1 to 3, wherein the plurality of nanopores have a depth of approximately 0.8 μm to 100 nm or 0.8 μm to 500 nm. [Item 7] The filtration device according to any one of items 1 to 6, wherein the surface area of ​​the second surface of the membrane surrounded by the third window is in the range of 1 mm² to 10 mm², 2 mm² to 8 mm², or 3 mm² to 6 mm². [Item 8] The third window is substantially rectangular in shape, as described in item 1 of the filtration device. [Item 9] The filtration device according to item 8, wherein the third window has a length of approximately 2000 μm to 5000 μm and a width of 500 μm to 1000 μm. [Item 10] The filtration device according to item 8, wherein the third window has a length of approximately 4000 μm to 5000 μm and a width of approximately 1000 μm. [Item 11] The filtration device according to any one of items 1 to 10, wherein the third height is in the range of 500 μm to 200 μm or 500 μm to 300 μm. [Item 12] The filtration device according to any one of items 1 to 10, wherein the support portion has a thickness of approximately 20 μm to 50 μm or 30 μm to 50 μm. [Item 13] The filtration device according to any one of items 1 to 12, wherein the ribs of the second height are in the range of 20 μm to 50 μm or 30 μm to 50 μm in height. [Item 14] The filtration device according to any one of items 1 to 13, wherein the rib of the second height is in the range of 20 μm to 5 μm or 15 μm to 5 μm in thickness. [Item 15] The filtration device according to any one of items 1 to 13, wherein the ribs of the first height are in the range of heights of 2 μm to 10 μm, 3 μm to 8 μm, or 3 μm to 6 μm. [Item 16] The filtration device according to any one of items 1 to 15, wherein the rib of the first height has a thickness in the range of 0.5 μm to 5 μm or 1 μm to 2.5 μm. [Item 17] The plurality of second windows comprises 50 to 100 second windows, as described in any one of items 1 to 16. [Item 18] The plurality of first windows comprises 50 to 20 first windows, as described in any one of items 1 to 17. [Item 19] The filtration device according to any one of items 1 to 18, wherein the plurality of nanopores are slit-shaped nanopores. [Item 20] The filtration device according to item 19, wherein the slit-shaped pores have a maximum length of 3 μm and a maximum width of 0.1 μm, or a maximum length of 2 μm and a maximum width of 50 nm, or a length of 1 μm to 3 μm and a width of 10 nm to 100 nm. [Item 21] The filtration device according to any one of items 1 to 20, wherein the nanopores are not located within the region of the membrane portion extending to form ribs and / or are covered by the support portion. [Item 22] The filtration device according to any one of items 1 to 21, wherein the membrane portion and the support portion are connected via an intermediate layer. [Item 23] A filtration device according to any one of items 1 to 22, comprising multiple filtration units arranged in an adjacent configuration. [Item 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 a first surface of a support substrate, The first pattern exposes an area on the first surface, the area defines the outlines of a plurality of first rectangles arranged in a grid pattern and a plurality of second rectangles arranged in a grid pattern, and each of the plurality of second rectangles includes the plurality of first rectangles, and is deposited. A second mask is deposited on the first mask such that the second mask covers the exposed area on the first surface defining the contour of the first rectangular window, but does not cover the exposed area on the first surface defining the contour of the second rectangular window, thereby enabling etching of the first surface and creating grooves in the support substrate corresponding to the contour of the second rectangular window. Etching the first surface to create the groove, wherein the groove has depth and thickness, Removing the second mask, which means removing the area on the first surface that defines the contours of the plurality of first rectangles, Etching the first surface increases the depth of the grooves of the plurality of second rectangles, and creating grooves in the support substrate corresponding to the contours of the plurality of first rectangles such that the depth of the grooves of the second rectangles is greater than the depth of the first rectangles, Removing the first mask, Depositing an intermediate layer on the aforementioned support substrate, A film is created by depositing a film material to fill the first and second rectangular grooves created in the support substrate, thereby creating a film comprising a planar first surface and a non-planar second surface opposite the first surface, wherein the non-planar second surface includes a plurality of ribs having a first height corresponding to the depth of the first rectangular groove and a plurality of ribs having a second height corresponding to the depth of the second rectangular groove, the second height being greater than the first 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, wherein 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 method for providing and forming a third window, comprising: a third window having a third height defined by the support structure and formed by the wall of the cavity, wherein the third height is greater than the second height, and the third window includes the plurality of second windows. [Item 25] The method according to item 24, wherein the plurality of nanopores are not located within the region of the film including the ribs. [Item 26] The method according to item 24 or 25, wherein the plurality of nanopores are not within the region of the film that is in contact with the support structure. [Item 27] Depositing the first mask and / or the second mask is done by the method of any one of items 24 to 26, including chemical vapor deposition (CVD). [Item 28] The method according to any one of items 24 to 26, wherein depositing the first mask and / or the second mask comprises growing the mask by thermal oxidation. [Item 29] The method according to any one of items 24 to 28, wherein the film is formed from polysilicon, silicon, silicon nitride, silicon carbide, graphene, or diamond, or a combination thereof. [Item 30] The support substrate is the method according to any one of items 24 to 29, wherein the support substrate includes a silicon wafer. [Item 31] The plurality of nanopores have a depth of approximately 1 μm or less, as described in any one of items 24 to 30. [Item 32] The plurality of nanopores having a depth of approximately 0.8 μm to 10 μm, according to the method described in any one of items 24 to 30. [Item 33] The plurality of nanopores having a depth of approximately 0.8 μm to 100 nm or 0.8 μm to 500 nm, according to any one of items 24 to 30. [Item 34] The method according to any one of items 24 to 33, wherein the surface area of ​​the back side of the film surrounded by the third window is in the range of 1 mm² to 10 mm², 2 mm² to 8 mm², or 3 mm² to 6 mm². [Item 35] The third window is substantially rectangular in shape, as described in any one of items 24 to 34. [Item 36] The third window, as described in any one of items 24 to 35, has a length of approximately 2000 μm to 5000 μm and a width of 500 μm to 1000 μm. [Item 37] The third window is the method according to any one of items 24 to 35, having a length of about 4000 μm to 5000 μm and a width of about 1000 μm. [Item 38] The method according to any one of items 24 to 37, wherein the third height is in the range of 500 μm to 200 μm or 500 μm to 300 μm. [Item 39] The support substrate is the method according to any one of items 24 to 38, having a thickness of approximately 20 μm to 50 μm or 30 μm to 50 μm. [Item 40] The method according to any one of items 24 to 39, wherein the rib of the second height is in the range of 20 μm to 50 μm or 30 μm to 50 μm in height. [Item 41] The method according to any one of items 24 to 40, wherein the rib of the second height is in the range of 20 μm to 5 μm or 15 μm to 5 μm in thickness. [Item 42] The method according to any one of items 24 to 41, wherein the rib of the first height is in the range of height 2 μm to 10 μm, 3 μm to 8 μm, or 3 μm to 6 μm. [Item 43] The method according to any one of items 24 to 41, wherein the rib of the first height has a thickness in the range of 0.5 μm to 5 μm or 1 μm to 2.5 μm. [Item 44] The plurality of second windows, comprising 50 to 100 second windows, as described in any one of items 24 to 43. [Item 45] The plurality of first windows, comprising 50 to 20 first windows, as described in any one of items 24 to 44. [Item 46] The method according to any one of items 24 to 45, wherein the plurality of nanopores are slit-shaped nanopores. [Item 47] The method according to item 46, wherein the slit-shaped holes have a maximum length of 3 μm and a maximum width of 0.1 μm, or a maximum length of 2 μm and a maximum width of 50 nm, or a length of 1 μm to 3 μm and a width of 10 nm to 100 nm. [Item 48] The method according to any one of items 24 to 47, wherein the film and the support substrate are connected via the intermediate layer.

Claims

1. A filtration membrane suitable for filtering blood in vivo, The membrane portion, A plurality of nanopores having a depth defined by the thickness of the film portion, and the surface of the film portion having at least one transverse dimension in the range of 1 nm to 1000 nm; The first surface of a plane and; A second surface with ribs, The first surface of the plane is on the opposite side of the second surface with ribs, The ribbed second surface includes a rib of a first height and a rib of a second height that is higher than the first height, wherein the rib of the second height has a height in the range of 20 μm to 100 μm and a thickness in the range of 1 μm to 20 μm. The rib of the first height defines a plurality of first windows arranged in a grid pattern, the first windows being rectangular in shape, and the first windows containing the plurality of nanopores. The rib of the second height defines a plurality of second windows arranged in a grid pattern, the second windows being rectangular in shape, and each of the plurality of second windows includes a membrane portion containing the plurality of first windows. A support portion forming a third window including a plurality of second windows, wherein the third window is rectangular in shape, and the support portion is attached to the ribbed second surface of the membrane portion around 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 film surrounded 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 filtration device according to claim 1, wherein the membrane portion is formed from polysilicon, silicon, silicon nitride, silicon carbide, graphene, or diamond, or a combination thereof.

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

4. The filtration device according to any one of claims 1 to 3, wherein the plurality of nanopores have a depth in the range of 10 nm to 1000 nm through the membrane portion.

5. The filtration device according to any one of claims 1 to 3, wherein the plurality of nanopores have a depth in the range of 10 nm to 800 nm through the membrane portion.

6. The filtration device according to any one of claims 1 to 3, wherein the plurality of nanopores have a depth in the range of 100 nm to 800 nm through the membrane portion.

7. The surface area of ​​the second surface of the film surrounded by the third window is 1 mm² ２ 10mm ２ A filtration device according to any one of claims 1 to 6, which is within the range of claims 1 to 6.

8. The filtration device according to claim 1, wherein the third window has a rectangular shape.

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

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

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

12. The filtration device according to any one of claims 1 to 10, wherein the support portion has a thickness of 20 μm to 50 μm.

13. The filtration device according to any one of claims 1 to 12, wherein the rib of the second height is in the range of 20 μm to 80 μm in height.

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

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

16. The filtration device according to any one of claims 1 to 15, wherein the first height rib has a thickness in the range of 0.5 μm to 5 μm.

17. The filtration device according to any one of claims 1 to 16, wherein the plurality of second windows in the third window include 50 to 100 second windows.

18. The filtration device according to any one of claims 1 to 17, wherein each of the plurality of first windows in the second window comprises 20 to 50 first windows.

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

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

21. The filtration device according to any one of claims 1 to 20, wherein the nanopores are not located within the region of the membrane portion that extends to form the ribs and the ribbed second surface is non-planar, and / or the nanopores are not located within the region of the membrane portion that is covered by the support portion.

22. The filtration device according to any one of claims 1 to 21, wherein the membrane portion and the support portion are connected via an intermediate layer.

23. A filtration device according to any one of claims 1 to 22, comprising a plurality of filtration units arranged in an adjacent configuration.

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