Tangential current cassette HF emulation

Abstract

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

Description

Technical Field

[0001] Tangential flow filtration is widely used in bioprocess technology to remove liquid from a mixture of particles and liquid. For example, it can be used to concentrate cells or to remove liquid from a mixture of liquid and cells, cell debris, or other particulate matter. Tangential flow devices are complex three-dimensional devices that are fundamentally different compared to normal flow (dead ended) devices. Hollow fiber devices and most tangential flow devices have very small pores that are prone to clogging. Dead ended devices with very small pores will become clogged almost instantaneously by many large solids that are larger than the pores. Tangential flow devices recirculate the "Feed" within the loop. The "Permeate" typically has a fairly low flow rate, and thus larger suspensions will continue to stay in the direction of the "Retentate". As shown in Figure 1A, when the Retentate is recycled to the feed tank, the process is a batch process, and when the Retentate is collected and not recycled, the process is a single-pass tangential flow process.

Background Art

[0002] One type of tangential flow filtration device is called a hollow fiber membrane device and is shown in Figures 1B and 1C. The hollow fibers are packed ( "potted") inside the tube, so the feed is pumped through the hollow fibers and the permeate is collected outside the fibers within the tube. Figure 1B shows the exposed ends of the fibers as seen at the end of the tube. Figure 1C shows several tubes that house the hollow fiber membranes. The hollow fiber device has several drawbacks. The pore size of the membrane itself is a function of the extrusion process and the material properties of the fiber itself, and thus can only be controlled by producing various pore sizes. In addition, variation in the somewhat manual process of embedding the hollow fibers into the tubes results in variation in the effectiveness of each device, which can make the process design more difficult.

[0003] As shown in Figures 1D and 1E, other types of tangential flow apparatuses are stacked plate apparatuses that use flat membranes stacked between plates. The porosity of flat plate apparatuses, similar to hollow fiber apparatuses, is typically determined by the membrane fabrication process, and consequently, variations in the pore-forming process often result in a range of pore sizes. Furthermore, the process of fabricating the flat membrane may limit the size of the available pores.

[0004] U.S. Patent No. 5,651,900, titled "Microfabricated Particle Filter," describes a microfabricated particulate filter. The process disclosed in the '900 patent allows for the creation of pore sizes determined by the thickness of the deposited material layer. However, these devices utilize standard microprocessor technology to produce particulate filters made from semiconductor materials such as silicon and silicon dioxide. The '900 patent discloses one embodiment in which a polyimide matrix is ​​used to hold "islands" containing pores produced using conventional semiconductor construction methods using silicon and silicon dioxide. These filters have not been adopted by the bioprocess industry because they involve 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 contain horizontal passages that can deform when pressure is applied to the film.

[0005] The inventors of this invention have found a need for a biocompatible particulate filter having a uniform pore size distribution, which is particularly desirable for tangential flow filtration applications. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 5,651,900 [Overview of the Initiative] [Means for solving the problem]

[0007] In one embodiment, the present invention includes a biocompatible polymer filtration 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 and including a plurality of windows that expose each of the first membrane material strips, wherein each window comprises pores defined by uniform passages defined by the first membrane material layer strips and the second membrane material layer. The first and second membrane materials may include polyimide. The pores may have a thickness of 20 to 1000 nm, and the membrane may have a thickness in the range of 2 to 10 microns. In one embodiment, the membrane may have a thickness in the range of 2 to 10 microns, the first membrane may have a thickness in the range of 1 to 5 microns, and the second membrane layer may have a thickness in the range of 2.5 to 20 microns.

[0008] In other embodiments, the present invention includes a method for producing a biocompatible polymer filtration membrane, comprising: (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 pore delimiting sacrificial layer on the first membrane material strips; (d) patterning the pore delimiting sacrificial layer into strips perpendicular 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 pore delimiting sacrificial layer; and (g) selectively etching the pore delimiting sacrificial layer in each window to create pores defined by uniform passages defined by the first membrane material layer strips and the second membrane material layer.

[0009] In one embodiment, step (b) patterning a first film material layer includes a step of depositing a hard mask layer on the first film material layer. Step (f) etching a window in the second film material layer to expose a pore delimiting sacrificial layer includes a step of depositing a hard mask layer on the second film material layer. In one embodiment, the first film material and the second film material comprise polyimide. In one embodiment, the pores have a thickness of 20 to 1000 nm, and the film has a thickness in the range of 2 to 10 microns. In another embodiment, the film has a thickness of 2 to 10 microns, the first film has a thickness in the range of 1 to 5 microns, and the second film layer has a thickness in the range of 2.5 to 20 microns. [Brief explanation of the drawing]

[0010] [Figure 1A] This is a diagram of conventional tangential flow single-pass and batch filtration processes. [Figure 1B] This is a photograph of the end of a hollow fiber membrane tangential flow device. [Figure 1C] This is a cross-sectional view of a tube and hollow fiber used in a hollow fiber membrane tangential flow apparatus. [Figure 1D] This is a schematic diagram of a stacked plate tangential flow device. [Figure 1E] This is a detailed diagram of a conventional stacked plate tangential flow device. [Figure 2A] This is a diagram of the first film material layer deposited on a substrate during the process of fabricating a slotted biocompatible film. [Figure 2B] This diagram shows the patterning of the first film material layer deposited on a substrate during the process of fabricating a slotted biocompatible film. [Figure 2C] This is a diagram of the first film material layer patterned into a strip on a substrate during the process of fabricating a slotted biocompatible film. [Figure 2D]Another diagram of the first film material layer patterned into a strip on a substrate during the process of fabricating a slotted biocompatible film. [Figure 3A] This is a diagram of a pore-defining hard mask deposited on a first membrane material layer during the process of fabricating a slotted biocompatible membrane. [Figure 3B] Another figure of a pore-defining hard mask deposited on a first membrane material layer in the process of fabricating a slotted biocompatible membrane. [Figure 4A] This is a diagram of a second membrane material layer deposited on top of a first membrane material layer in the process of fabricating a slotted biocompatible membrane. [Figure 4B] Another diagram showing a second membrane material layer deposited on top of a first membrane material layer in the process of fabricating a slotted biocompatible membrane. [Figure 5A] This is one of the top perspective views after etching a window into the second membrane material layer to expose a portion of the hard mask layer during the process of fabricating a slotted biocompatible membrane. [Figure 5B] This is another top perspective view of the process for fabricating a slotted biocompatible membrane, after etching a window into the second membrane material layer to expose a portion of the hard mask layer. [Figure 5C] Figures 5A and 5B are bottom perspective views. [Figure 5D] This is another top perspective view of the process for fabricating a slotted biocompatible membrane, after etching a window into the second membrane material layer to expose a portion of the hard mask layer. [Figure 6A] This is a top perspective view after etching the hard mask material to create slits within the first and second membrane materials in the process of fabricating a slotted biocompatible membrane. [Figure 6B] Figure 6A is a bottom perspective view. [Figure 6C] This is a top-down view showing the slits within the membrane. [Modes for carrying out the invention]

[0011] Various embodiments and details are described herein with reference to the membranes disclosed herein and methods of making and using these membranes. The membranes are made using a combination of photolithography and masking techniques, particularly adapted to biocompatible materials. Such membranes can, for example, be composed of a flexible (non-brittle) biocompatible material and include vertically aligned pores having a minimum pore size that is tightly controlled and uniform throughout the membrane.

[0012] The biocompatible membranes herein include pores defined within the membrane material using a sacrificial layer, where the thickness of the sacrificial layer defines the minimum pore size for the membrane. Since the thickness of the sacrificial layer can be tightly controlled across the entire surface of the membrane, the pore diameter can be tightly controlled across the membrane surface. The width of the sacrificial layer strip defines the length of the slot-shaped pores formed in the membrane when the sacrificial layer is removed. The smaller the width of the sacrificial layer strip, the closer the pore shape will be to a square-shaped pore. When the width of the sacrificial layer strip is equal to its height, square-shaped pores are created within the membrane.

[0013] The pores formed within the membrane are preferably aligned within the material perpendicular to a line of sight extending completely through the membrane. Since filtration involves a differential pressure across the membrane, it is important that there are no pores that are deformed to a closed position by the pressure exerted in a direction perpendicular to the membrane surface. Further, vertically oriented pores tend to be less prone to clogging during use under tangential flow conditions. This provides an advantage for tangential flow applications, but the membrane filters described herein may be used in applications of tangential flow filtration as well as dead-end filtration.

[0014] In one aspect, the invention comprises a porous membrane for filtering a liquid, the porous membrane comprising a polymeric membrane layer having a surface area of 300,000 mm 2 or greater. The size of the membrane is limited only by the size of the equipment used in manufacturing the membrane. The membrane is 300,000 mm 2The films are formed on larger substrates and can be patterned into several smaller films using the lithography techniques described herein. The films have thicknesses ranging from 2 to 50 microns, preferably 5 to 25 microns, and more preferably 5 to 15 microns. The films contain pores, which are defined by the thickness of a sacrificial layer, here having defined minimum pore dimensions ranging from 10 to 1000 nm, preferably 20 to 500 nm, and more preferably 30 to 130 nm. Since the minimum pore dimensions are controlled by the thickness of the sacrificial layer, which can be controlled within + / - 10 nm across the entire workpiece surface, the minimum pore dimensions of the films have a standard deviation of less than 50 nm, preferably 20 nm or less, more preferably 10 nm or less, and most preferably 5 nm or less.

[0015] In one example, the process of fabricating the film begins with forming a strip of the first film material 101, as shown in Figure 2A. Although not shown in Figure 2A, the first film material is supplied onto a substrate 100, but it should be understood that the substrate is not shown in Figure 2A. The strip may be a biocompatible material and must have a coefficient of thermal expansion (CTE) that matches the substrate, coated onto a support substrate of controlled thickness. One suitable material is polyimide (PI), which can be spin-coated onto the support substrate. PI is available in several grades with varying CTEs, many of which differ from those of glass. In the case of a glass support substrate, the PI may be selected to have a CTE similar to that of glass. In addition, PI has the ability to withstand processing temperatures up to 400°C, which may be necessary to fabricate these components, and is well above the temperatures commonly encountered in filtration applications in bioprocesses. The first film material may be supplied onto a glass substrate, or it may be deposited onto a glass substrate using a coating process 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 film material.

[0016] After coating the substrate 100 with the first film material, the material can be cured at least partially. In one embodiment, the first film material is completely cured at this stage. However, partial curing at this step may be desirable to allow the second film material to be cured and the final curing to be completed at the same time. The bonding between the first and second film materials can be improved by allowing some additional curing of the first film material during the final curing step.

[0017] The strip formation process generally includes a patterning / etching / exfoliation sequence. The patterning / etching / exfoliation sequence begins with the deposition of a photoresist 102 on a first film material. The photoresist material is then patterned into a strip using photolithography, after which the photoresist is developed. In the case of positive-type photoresists, light from the photolithograph selectively exposes the portion of the photoresist that is intended to be removed. This is done because light makes the positive-type photoresist more soluble in the developer. Alternatively, exposure causes polymerization of the negative-type photoresist, thereby reducing its solubility in the developer. Figure 2B shows the patterned photoresist layer 102 on the first film material layer 101.

[0018] Next, the photoresist 102 and the underlying first film material 101 exposed through the photoresist 102 are etched until the portion of the first film material exposed through the photoresist is completely removed. Figures 2C and 2D show the resulting first material layer strip 101. Since PI is a polymer similar to photoresist, both materials tend to etch at roughly the same rate. If the film material is thicker than the photoresist, etching may remove all of the photoresist in the exposed portion before reaching the glass substrate. This case often occurs when the thickness of the first film material exceeds, for example, 2 microns.

[0019] For thicker first film material layers, it may be necessary to use a pattern hard mask (not shown) of the same pattern on top of the first film material layer, intended to protect the first film layer strip 101 from the etching process. The pattern hard mask material may be amorphous silicon nitride, typically deposited by chemical vapor deposition from silane (SiH4) and ammonia (NH3). It is desirable that the hard mask material is free of metals that could contaminate the film material. This may be important for films used in bioprocesses where metal contamination could interfere with use.

[0020] The process of patterning a first film material onto a strip using a pattern hard mask includes depositing a pattern hard mask on a layer of the first film material. A photoresist is then patterned onto the pattern hard mask layer using photolithography and development. Exposed portions of the pattern hard mask are etched away using selective wet etching. The first film material exposed through the pattern hard mask / photoresist layer is then etched. In this case, the pattern hard mask layer on the first film material, which is intended to remain as a strip, protects it, while the remaining exposed portions are etched down to the substrate. The pattern 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 buffer HF etching solution at approximately room temperature.

[0021] Next, as shown in Figures 3A and 3B, strips of pore-defining hard mask material 103 are formed on the first film material strip 101. The coating of the pore-defining hard mask 103 is "conformal" in this step, because it coats the sidewalls and top surface of the workpiece surface, including the sidewalls and top surface of the first film material strip 101. In the case of silicon nitride, the pore-defining hard mask layer can be deposited by chemical vapor deposition as described above. Naturally, conformal coatings may be deposited thicker on horizontal surfaces than on vertical surfaces, and it should be understood that the ratio of this to the film pore design must be taken into consideration, as this is the thickness of the pore-defining hard mask covering the vertical surface that defines the minimum pore size in the film described herein.

[0022] The pore-defining sacrificial spacer material 103 can be any material that can be deposited on the first film material 101, patterned, and selectively etched. 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 can result in a uniform minimum pore size definition across a large biocompatible film surface that is far better than previously possible. This step involves depositing the hard mask material on the substrate 100 and the first film strip 101. The same patterning / etching / exfoliation sequence is then used to pattern the hard mask layer. A 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 reveal the first film material strip 101 and the substrate 100. Next, the photoresist is peeled off, exposing the hard mask strip 103.

[0023] As shown in Figures 4A and 4B, a second film material 104 is deposited on the surface of the workpiece. This deposition is a "planarizing" deposition because it produces a flat topology on the upper surface despite the topology of the underlying workpiece surface. The second film material is preferably the same material as the first film material, for example, polyimide. The deposition of the second film material may involve the same coating and curing process used for the deposition of the first film material. As described above, the second curing process may involve further curing the partially cured first film material. Simultaneous or partial curing of both the first and second film materials at this stage can facilitate the formation of a stronger bond between the two materials. In some cases, it may be desirable to perform this curing step to result in the 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.

[0024] As shown in Figures 5A to 5D, the window 105 is then patterned within the second film material 104, as shown in Figure 5A. The patterning is performed in the same manner as the patterning of the first film material to the strip, using photolithography, photoresist development, etching, and then photoresist exfoliation. The window 105 is positioned within the second film material 104 so as to expose portions of the hard mask layers 103b and 103c covering the first film layer strip 101. Specifically, the vertical portion of the hard mask layer 103b coating the sidewalls of the first film layer strip 101 must be exposed through the window, as shown in Figure 5C. The portion of the hard mask 103a adjacent to the substrate 100 is not exposed as it is covered by the thicker portion of the second film material 104. The patterning of the window uses the same patterning / etching / exfoliation sequence described above.

[0025] If the thickness of the second film material exceeds 2 microns, a hard mask must be used to etch the window. The hard mask is deposited on top of the second film material layer. Then, a photoresist is deposited, exposed by photolithography, developed to expose the window and reveal 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 within the second film material layer toward the pore delimiting sacrificial spacer layer 103. The hard mask material deposited on top of the second film material layer prevents etching of the second film material layer outside the window.

[0026] Next, the pore delimiting sacrificial spacer material 103 is selectively etched against the first film material strip 101 and the second film material layer 104 to expose vertically oriented slot-shaped pores within the film, as shown in Figures 6A to 6C. If a hard mask is used over the second film material layer, it may be removed simultaneously with the removal of the pore delimiting sacrificial material 103 by wet etching. The slots 106 are formed from the removal of the vertical portion of the pore delimiting sacrificial layer 103b, which forms the pores in the film material. The top view in Figure 6C shows the slot-shaped pores 106 formed within the film, including the first film material layer strip 101 and the second film material layer 104.

[0027] The process may be concluded with a final curing step in which the first and second film materials are completely cured. The film can then be removed from the substrate. If a release material is provided between the substrate and the film material, the release layer may be dissolved or melted, resulting in the film peeling off from the supporting substrate.

[0028] From the examination and practice of the specification of the present invention disclosed herein, other embodiments and uses of the present invention will also be apparent to those skilled in the art. All references cited herein, including all U.S. and foreign patents and patent applications, are incorporated herein by reference in their entirety. The specification and examples are for illustrative purposes only, and the true scope and spirit of the present invention are set forth by the claims below. [Explanation of Symbols]

[0029] 100 circuit boards 101 First film material layer 102 Photoresist 103 Hard mask, pore-defining sacrificial spacer material 103a Hard Mask 103b Hard mask layer, pore-defining sacrificial layer 103c hard mask layer 104 Second film material layer 105 windows 106 slots, pores, and passages

Claims

1. A method for producing polymer filtration membranes, (a) A step of depositing a first film material layer (101) on a substrate (100), (b) The step of patterning the first film material layer (101) into a plurality of strips, (c) A step of depositing a pore-defining sacrificial layer (103) on a strip (101) of the first film material layer, (d) The step of patterning the pore-defining sacrificial layer (103) into strips perpendicular to the strips (101) of the first film material layer, (e) The step of depositing a second film material layer (104) on the substrate (100), (f) Etching a plurality of windows (105) within the second film material layer (104) in order to expose the pore-defining sacrificial layer (103), (g) A step of selectively etching the pore-defining sacrificial layer (103) to create pores (106) that are exposed within each window (105) of the second film material layer (104), wherein the pores (106) are positioned between a plurality of strips (101) of the first film material layer and the second film material layer (104), Methods that include...

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

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

4. The method according to any one of claims 1 to 3, wherein the strip (101) of the first film material layer and the second film material layer (104) contain polyimide.

5. The method according to any one of claims 1 to 4, wherein the pore (106) has a thickness of 20 to 1000 nm.

6. The method according to any one of claims 1 to 5, wherein the polymer filtration membrane has a thickness in the range of 2 to 10 microns.

7. The method according to any one of claims 1 to 6, wherein the strip (101) of the first film material layer has a thickness in the range of 1 to 5 microns.

8. The method according to any one of claims 1 to 7, wherein the second film material layer (104) has a thickness in the range of 2.5 to 20 microns.

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