Tangential flow cassette - HF simulation

Abstract

A biocompatible polymeric membrane includes pores (106) defined between two layers of material, wherein a first layer of membrane material (101) includes strips, and a second layer of membrane material (104) is bonded to each of the plurality of first layer of membrane material strips (101), including a plurality of windows (105) that expose each first layer of membrane material strip (101). The biocompatible polymeric filtration membrane includes pores (106) defined by uniform channels within each window (105) defined by the first layer of membrane material strip (101) and the second layer of membrane material (104).

Description

[0001] background

[0002] Tangential flow filtration is widely used in bioprocess technologies to remove liquids from mixtures of particles and liquids, and can be used, for example, to concentrate cells or remove liquids from mixtures of liquids and cells, cell debris, or other particulate matter. Tangential flow devices are complex three-dimensional devices, fundamentally different from normal flow (dead-end) devices. Hollow fiber devices and most tangential flow devices have very small pores, which are prone to scaling. Dead-end devices with very small pores are scaled almost immediately by many large solids larger than the pores. Tangential flow devices recirculate the “feed” in the loop. The “permeate” typically has a much lower flow rate, so larger suspended solids continue to move in the direction of the “retentate.” If the retentate is recovered into the feed tank, the process is a batch process, and if the retentate is extracted and not recovered, it is a single-pass tangential flow process, as shown in Figure 1A.

[0003] One type of tangential flow filtration equipment is called a hollow fiber membrane equipment and is shown in Figures 1B-C. Hollow fibers are loaded into tubes (“cans”) so that feed is pumped through the hollow fibers and permeate is collected outside the fibers inside the tubes. Figure 1B shows the exposed ends of the fibers when they appear at the ends of the tubes. Figure 1C shows several tubes containing the hollow fiber membrane. Hollow fiber equipment has several disadvantages. The pore size of the membrane itself is a function of the extrusion process and the material properties of the fibers themselves, and can only be controlled to produce a certain range of pore sizes. Furthermore, the effectiveness of each device is variable due to the variability of the slightly manual process of embedding the hollow fibers into the tubes, which can make process design more difficult.

[0004] Another type of tangential flow equipment is the stacked plate equipment, which uses flat sheet membranes stacked between plates, as shown in Figures 1D-E. Similar to hollow fiber equipment, the porosity of flat sheet equipment typically depends on the membrane manufacturing process, and due to the variability of the pore-forming process, it usually results in a range of pore sizes. Furthermore, the process of manufacturing the flat sheet membrane may limit the size of the available pores.

[0005] Micromachining particle filters are described in the US publication titled "Micromachining Particle Filters".

[0006] As described in '900 Patent 5,651,900. The process disclosed in the '900 patent allows for the fabrication of pore sizes determined by the thickness of the deposited material layer. However, these devices utilize standard microprocessor technology to produce particulate filters made of semiconductor materials such as silicon and silica. The '900 patent discloses an embodiment using a polyimide matrix to maintain "islands" of pores, which are produced using conventional semiconductor fabrication methods utilizing silicon and silica. These filters have not yet been adopted in the bioprocessing industry because they comprise rigid components and rely on complex manufacturing processes. These components are brittle and cannot withstand the typical conditions required for membrane filters. Furthermore, the polyimide matrix is ​​used with pores that include horizontal channels, which can deform when pressure is applied to the membrane.

[0007] The inventors have recognized that the need for biocompatible particulate filters with uniform pore size distribution is particularly ideal for tangential flow filtration applications.

[0008] Overview

[0009] In one aspect, the present invention relates to a biocompatible polymer filter membrane comprising: a plurality of first membrane material layer strips; and a second membrane material bonded to each of the plurality of first membrane material layer strips, the second membrane material including a plurality of windows exposing each first membrane material strip, wherein the biocompatible polymer filter membrane includes a pore defined within each window by a uniform channel defined by the first membrane material layer strips and the second membrane material layer. The first and second membrane materials may comprise polyimide. The pores may have a thickness of 20-1000 nm, and the membrane may have a thickness in the range of 2-10 micrometers. In one aspect, the membrane may have a thickness of 2-10 micrometers, the first membrane has a thickness in the range of 1-5 micrometers, and the second membrane layer has a thickness in the range of 2.5-20 micrometers.

[0010] In another aspect, the present invention relates to a method for manufacturing a biocompatible polymer filter membrane, the method comprising the steps of: (a) depositing a first membrane material layer on a substrate; (b) patterning the first membrane material layer into a plurality of strips; (c) depositing a sacrificial layer defining pores on the first membrane material strips; (d) patterning the sacrificial layer defining pores into strips orthogonal to the first membrane material strips; (e) depositing a second membrane material layer on a substrate; (f) etching windows in the second membrane material layer to expose the sacrificial layer defining pores; and (g) selectively etching the sacrificial layer defining pores to produce pores defined by uniform channels defined by the first membrane material layer strips and the second membrane material layer within each window.

[0011] In one aspect, step (b) of patterning the first membrane material layer includes depositing a hard mask layer on the first membrane material layer. Step (f) of etching a window in the second membrane material layer to expose the sacrificial layer defining the aperture includes depositing a hard mask layer on the second membrane material layer. In one aspect, the first and second membrane materials comprise polyimide. In one aspect, the aperture has a thickness of 20-1000 nm, and the membrane has a thickness in the range of 2-10 μm. In another aspect, the membrane has a thickness of 2-10 μm, the first membrane has a thickness in the range of 1-5 μm, and the second membrane layer has a thickness in the range of 2.5-20 μm. Brief description of the attached diagram

[0013] Figure 1A shows the tangential flow single-pass and batch filtering processes of the prior art.

[0014] Figure 1B shows the end of the hollow fiber membrane tangential flow device.

[0015] Figure 1C shows the tube used in the hollow fiber membrane tangential flow device, and the cross-section of the hollow fiber.

[0016] Figure 1D shows a schematic diagram of a stacked plate tangential flow device.

[0017] Figure 1E shows details of a conventional stacked board tangential flow device.

[0018] Figure 2A The image shows the first layer of membrane material deposited on the substrate during the fabrication of a grooved biocompatible membrane.

[0019] Figure 2B The patterning of the first layer of membrane material deposited on the substrate during the fabrication of a grooved biocompatible membrane is shown.

[0020] Figure 2C The image shows the first layer of membrane material patterned into strips on a substrate during the fabrication of a slotted biocompatible membrane.

[0021] Figure 2D This shows another view of the first layer of membrane material patterned into strips on a substrate during the fabrication of a slotted biocompatible membrane.

[0022] Figure 3A This shows a view of a hard mask with defined pores deposited on the first layer of membrane material during the fabrication of a slotted biocompatible membrane.

[0023] Figure 3B This shows another view of a hard mask with defined pores deposited on the first layer of membrane material during the fabrication of a slotted biocompatible membrane.

[0024] Figure 4AThis shows a view of a second membrane material deposited on top of a first membrane material during the fabrication of a slotted biocompatible membrane.

[0025] Figure 4B This shows another view of the second membrane material deposited on top of the first membrane material during the fabrication of a grooved biocompatible membrane.

[0026] Figure 5A This is a top-down view showing a window etched in the second membrane material to expose a portion of the hard mask layer during the fabrication of a slotted biocompatible membrane.

[0027] Figure 5B Another view shows a top-down view of the process of etching windows in the second membrane material to expose a portion of the hard mask layer during the fabrication of a slotted biocompatible membrane.

[0028] Figure 5C Showing Figure 5A -B bottom view.

[0029] Figure 5D Another view shows a top-down view of the process of etching windows in the second membrane material to expose a portion of the hard mask layer during the fabrication of a slotted biocompatible membrane.

[0030] Figure 6A This shows a top-view view after a hard mask material is etched to create slits within the first and second membrane materials during the fabrication of a slotted biocompatible membrane.

[0031] Figure 6B Showing Figure 6A The bottom-view perspective.

[0032] Figure 6C The image shows a top-down view, revealing the slits in the membrane.

[0033] Detailed description

[0034] Various implementations and details are described with reference to the membranes disclosed herein and the methods for manufacturing and using these membranes. The membranes are fabricated using a combination of photolithography and masking techniques specifically suited for biocompatible materials. For example, such membranes can be made of flexible (non-brittle) biocompatible materials with vertically aligned pores, the minimum pore size of which is strictly controlled and uniform throughout the membrane.

[0035] The biocompatible membranes described in this paper include pores defined within the membrane material using a sacrificial layer, the thickness of which defines the minimum pore size of the membrane. Because the thickness of the sacrificial layer can be tightly controlled across the entire surface of the membrane, the pore size can be tightly controlled across the membrane surface. The width of the sacrificial layer strip defines the length of the groove-like pores formed in the membrane when the sacrificial layer is removed. As the width of the sacrificial layer strip decreases, the pore shape becomes closer to a square pore. When the width of the sacrificial layer strip equals its height, a square pore is created in the membrane.

[0036] The pores formed in the membrane are preferably aligned perpendicularly to a line of sight that extends fully through the membrane. Since filtration involves a pressure differential across the membrane, it is important that there are no pores that would deform into a closed position due to pressure applied in a direction orthogonal to the membrane surface. Furthermore, perpendicularly oriented pores are more likely to resist clogging when used under tangential flow conditions. While this provides an advantage for tangential flow applications, the membrane filter described herein can be used for both tangential flow filtration and dead-end filtration applications.

[0037] In one aspect, the present invention includes a liquid filtration porous membrane, the porous membrane comprising a porous structure having a diameter greater than 300,000 mm. 2 Polymer films with an area of ​​300,000 mm or larger. The size of the membrane is limited only by the size of the equipment used to manufacture it. 2 It is formed on a large substrate or larger and patterned into several smaller films using the photolithography technique described herein. The film thickness is 2-50 micrometers, preferably 5-25 micrometers, and more preferably 5-15 micrometers. The film includes pores having a defined minimum pore size determined by the thickness of the sacrificial layer, wherein the minimum pore size is 10-1000 nm, preferably 20-500 nm, and more preferably 30-130 nm. Since the minimum pore size is controlled by the thickness of the sacrificial layer, which can be controlled within + / -10 nm across the entire working surface, the standard deviation of the minimum pore size is less than 50 nm, preferably 20 nm or less, more preferably 10 nm or less, and most preferably 5 nm or less.

[0038] In one example, the membrane manufacturing process begins with forming strips of a first membrane material 101, such as... Figure 2A As shown. Although Figure 2A Although not shown, it should be understood that the first membrane material is provided on the substrate 100, although the substrate is not shown. Figure 2AAs shown in the diagram. The strip can be a biocompatible material, which can be coated onto the support substrate at a controlled thickness and should have a coefficient of thermal expansion (CTE) matching that of the underlying substrate. A suitable material is polyimide (PI). This material can be spun and coated onto the support substrate. PI is available in several grades with different CTEs, many of which differ from those of glass. In the case of a glass support substrate, PI can be selected to have a CTE similar to that of glass. Furthermore, PI has the ability to withstand processing temperatures up to 400°C, which may be necessary for manufacturing these components and is far higher than the temperatures typically encountered in bioprocess filtration applications. The first membrane material can be supplied on the glass substrate or deposited onto the glass substrate using coating processes such as spin coating and curing. In some cases, it may be desirable to provide a release layer (not shown) between the glass substrate and the first membrane material.

[0039] After the substrate 100 is coated with the first film material, the material can be at least partially cured. In one aspect, the first film material is fully cured at this stage. However, partial curing in this step may be necessary to allow final curing to occur simultaneously with the curing of the second film material. Allowing some additional curing of the first film material during the final curing step can improve the adhesion between the first and second film materials.

[0040] The process of forming stripes typically involves a patterning / etching / stripping sequence. The patterning / etching / stripping sequence begins with the deposition of photoresist 102 on a first film material. Then, photolithography is used, followed by development of the photoresist, to pattern the photoresist material into strips. In the case of positive photoresist, light from the photolithography process selectively exposes the photoresist portions intended to be removed. This occurs because light makes the positive photoresist more soluble in the developer solution. Alternatively, exposure to light causes the negative photoresist to polymerize, thereby reducing its solubility in the developer solution. Figure 2B A patterned photoresist layer 102 is shown on the first film material layer 101.

[0041] Next, the photoresist 102 and the underlying first film material 101 exposed through the photoresist 102 are etched until that portion of the first film material exposed through the photoresist is completely removed. The resulting first material layer strip 101 is as follows: Figure 2C-2D As shown. Since PI is a polymer similar to photoresist, the two materials tend to etch at roughly the same rate. If the film material is thicker than the photoresist, etching can remove all the photoresist before reaching the glass substrate in the exposed portion. This is generally more likely to occur when the thickness of the first film material exceeds, for example, 2 micrometers.

[0042] When the first membrane material layer is relatively thick, it may be necessary to employ a patterned hard mask (not shown) on the first membrane material layer with the same pattern intended for the first membrane layer strip 101 to protect the material from the etching process. The patterned hard mask material can be amorphous silicon nitride, which is typically deposited by chemical vapor deposition of silane (SiH4) and ammonia (NH3). It is desirable that the hard mask material lacks metals that could contaminate the membrane material. This may be important for membranes used in biological processes in which metal contamination could hinder their use.

[0043] The process of patterning a first film material into strips using a patterned hard mask involves depositing a patterned hard mask on a first film material layer. Photoresist is then patterned on the patterned hard mask layer using photolithography and development. Exposed portions of the patterned hard mask are etched away using selective wet etching. The first film material exposed through the patterned hard mask / photoresist layer is then etched away. In this case, the patterned hard mask layer on the first film material, intended to be retained as a strip, protects it, while the remaining exposed portions are etched down to the substrate. The patterned hard mask material on the first film layer strip 101 is then removed using selective wet etching. Selective wet etching of silicon nitride can be performed in a buffered HF etchant close to room temperature.

[0044] Next, as Figures 3A-3B As shown, a strip of hard mask material 103 defining an aperture is formed on a first membrane material strip 101. The coating of the hard mask 103 defining the aperture in this step is "conformal" because it coats the sidewalls and top surface of the working surface, including the sidewalls and top surface of the first membrane material strip 101. In the case of silicon nitride, the hard mask layer defining the aperture can be deposited by chemical vapor deposition as described above. It should be understood, of course, that the conformal coating may be thicker on a horizontal surface than on a vertical surface, and this ratio needs to be considered in the membrane aperture design because the thickness of the hard mask defining the aperture covering the vertical surface defines the minimum aperture in the membrane described herein.

[0045] The sacrificial spacer material 102 defining the apertures can be any material that can be deposited, patterned, and selectively etched relative to the first film material 101. In one example, the hard mask material is silicon nitride. As described above, amorphous silicon nitride can be deposited using plasma-enhanced chemical vapor deposition (PECVD). The thickness of the deposited SiN film can be controlled within + / - 10 nm. This makes it possible to define uniform minimum aperture sizes on large biocompatible film surfaces to a greater extent than previously possible. This step involves depositing a hard mask material on the substrate 100 and the first film strip 101. Next, the hard mask layer is patterned using the same patterning / etching / stripping sequence. Photoresist is deposited on the hard mask material, patterned using photolithography, and developed to expose the underlying hard mask material strip. The exposed hard mask material strip is etched away to expose portions of the first film material strip 101 and the substrate 100. The photoresist is then stripped away to expose the hard mask strip 102.

[0046] like Figure 4A As shown in Figure -B, a second film material 104 is deposited on the surface of the workpiece. This deposition is a "planarization" deposition because it produces a flat topology on the upper surface regardless of the topology of the underlying work surface. Ideally, the second film material is the same material as the first film material (e.g., polyimide). The deposition of the second film material may include the same coating and curing process used for depositing the first film material. As described above, the second curing process may include further curing of the partially cured first film material. At this stage, simultaneous or partial curing of both the first and second film materials may contribute to a stronger adhesion between the two materials. In some cases, this curing step may be necessary to result in complete curing of both the first and second film material layers. The second film material 104 covers the first film material strip 101 and the patterned hard mask strip 103.

[0047] like Figure 5A As shown in -D, window 105 is then patterned in the second film material 104, as follows: Figure 5A As shown. Patterning is performed in the same manner as patterning the first film material into strips using photolithography, developing the photoresist, etching, and then stripping the photoresist. Window 105 is positioned within the second film material 104 to expose portions of the hard mask layers 103b and 103c covering the first film strip 101. Specifically, the vertical portions of the hard mask layer 103b coating the sidewalls of the first film strip 101 should be exposed through the window, as shown. Figure 5C As shown. The portions of the hard mask 103a adjacent to the substrate 100 are not exposed because they are covered by the thicker portion of the second film material 104. The patterning of the windows uses the same patterning / etching / stripping sequence described above.

[0048] If the thickness of the second film material exceeds 2 micrometers, a hard mask is required to etch the window. The hard mask is deposited on the second film material layer. Photoresist is then deposited, exposed by photolithography, and developed to expose the window containing the hard mask material. The hard mask material is then selectively etched through the photoresist layer to expose the second film material layer. The window is then etched down into the second film material layer to the sacrificial spacer layer 103 defining the aperture. The hard mask material deposited on the second film material layer prevents etching of the second film material layer outside the window.

[0049] Next, the sacrificial spacer material 103 defining the holes is selectively etched relative to the first film material strip 101 and the second film material layer 103 to expose vertically oriented groove-shaped holes in the film, such as... Figures 6A-6C As shown. If a hard mask is used on the second membrane material layer, the sacrificial material 103 defining the aperture can be removed simultaneously by wet etching. The groove 106 is formed from the vertical portion of the sacrificial layer 103b from which the aperture is removed, forming an aperture in the membrane material. Figure 6C The top-down view shows the groove-shaped holes 106 formed in the membrane, which includes a first membrane material layer strip 101 and a second membrane material layer 104.

[0050] The process can be concluded with a final curing step to fully cure the first and second membrane materials. The membrane can then be removed from the substrate. If a release material is provided between the substrate and membrane materials, the release layer can be dissolved or melted, causing the membrane to release from the supporting substrate.

[0051] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and inventive practice disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are expressly and entirely incorporated herein by reference. The specification and embodiments are intended to be illustrative only, and the true scope and spirit of the invention are indicated by the appended claims.

Claims

1. A method for manufacturing a biocompatible polymer filter membrane, comprising the following steps: (a) Depositing a first film material layer (101) on a substrate (100); (b) Patterning the first membrane material layer (101) into multiple stripes; (c) Depositing a sacrificial layer (103) defining pores on a strip of first membrane material; (d) Pattern the sacrificial layer (103) that defines the aperture into strips orthogonal to the first membrane material strips; (e) Deposit a second film material layer (104) on the substrate (100); (f) Etching a window (105) in the second membrane material layer (104) to expose the sacrificial layer (103) defining the pore; and (g) Selectively etch the sacrificial layer (103) defining the aperture to produce an aperture (106) defined by a uniform channel defined by a first membrane material strip and a second membrane material layer (104) within each window (105).

2. The method according to claim 1, wherein step (b) of patterning the first membrane material layer (101) into a plurality of stripes includes depositing a hard mask layer on the first membrane material layer (101).

3. The method according to claim 1 or 2, wherein step (f) of etching a window (105) in the second membrane material layer (104) to expose the sacrificial layer (103) defining the aperture includes depositing a hard mask layer on the second membrane material layer (104).

4. The method according to claim 1 or 2, wherein the first membrane material and the second membrane material comprise polyimide.

5. The method according to claim 1 or 2, wherein the pore (106) has a thickness of 20-1000 nm.

6. The method according to claim 1 or 2, wherein the biocompatible polymer filter membrane has a thickness in the range of 2-10 micrometers.

7. The method according to claim 1 or 2, wherein the first membrane material layer (101) has a thickness in the range of 1-5 micrometers.

8. The method according to claim 1 or 2, wherein the second membrane material layer (104) has a thickness in the range of 2.5-20 micrometers.

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