CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119 of U.S. Provisional Application No. 63/407,309 filed September 16, 2022, the content of which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Aspects of the present disclosure generally relate to a substate. More specifically, aspects relate to a substate for use in a bioreactor to grow cells.

[0003] Bioreactors may use hollow-fiber filaments as substrates to grow cells. Nutrients flow through the fibers and cells grow on the fibers. The fibers may be compressed into a chamber of the bioreactor, but may be disordered within the chamber, some fibers overlapping others, some fibers compressing others, voids or dead spaces between fibers etc. As a result nutrients may flow through the fibers at different rates, resulting in erratic and uneven cell growth in such bioreactors.

[0004] A need exists for ways to improve efficiency of cell growth in bioreactors.

SUMMARY

[0005] Aspects of the present disclosure include a bioreactor with growth substrate having passages that are integrally connected with one another, aligned, support one another, and are compactly arranged. Nutrients may flow through the passages and cells may grow on walls thereof. Such a substrate may be produced by extrusion, and materials of the substrate may be polymer or co-extruded polymer, for example. Such a substate has a uniform and even distribution of passages, and may be free of dead space.

[0006] According to an aspect of the present disclosure a bioreactor includes a growth substrate comprising a first end, a second end, and walls defining passages within the growth substrate, where the passages are aligned with one another and open to the first and/or second ends. In operation, the bioreactor may further include fluid carrying nutrients for cell growth, where the fluid flows through the passages of the growth substrate. Further still, the bioreactor may include cells growing on the w alls of the growth substrate. [0007] Additional features and advantages are set forth in the detailed description that follows, and in part will be readily apparent to those skilled in the art from the description or recognized by practicing the technology as described in the written description and claims hereof, as well as the appended drawings. It is to be understood that both the foregoing general description and the following detailed description are merely exemplary and are intended to provide an overview or framework to understand the nature and character of the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0008] The accompanying figures are included to provide a further understanding and are incorporated in and constitute a part of this specification. The drawings of the figures illustrate one or more aspects of the present disclosure, and together with the detailed description explain principles and operations of the various aspects. As such, the disclosure will become more fully understood from the following detailed description, taken in conjunction with the accompanying figures, in which:

[0009] FIG. 1 is a digital image of a growth substrate for a bioreactor from a perspective view according to an aspect of the present disclosure.

[0010] FIG. 2 is a conceptual diagram in cross-section of a bioreactorfluid flowing through a growth substate, such as with the growth substrate of FIG. 1, with cells growing on walls thereof.

[0011] FIG. 3 is a conceptual diagram in cross-section of another bioreactor, fluid flowing through a growth substate with cells growing on walls thereof.

DETAILED DESCRIPTION

[0012] Before turning to the following detailed description and figures, which illustrate aspects of the present disclosure in detail, it should be understood that the present inventive technology is not limited to the details or methodology set forth in the detailed description or illustrated in the figures. For example, as will be understood by those of ordinary skill in the art, features and attributes associated with an aspect shown in one of the figures or described in the text relating to an aspect may be applied to another aspect shown in another of the figures or described elsewhere in the text. [0013] Referring to FIGS. 1-2, a bioreactor 210 includes a grow th substrate 110 comprising a first end 112, a second end 114, and walls 116 defining passages 118 within the grow th substrate 110, where the passages 118 are aligned with one another and open to the first and/or second ends 112, 114. In operation, the bioreactor 210 may further include fluid 212 carrying nutrients for cell growth, where the fluid 212 flows through the passages 118 of the growth substrate 110. Further still, the bioreactor 210 may include cells 214 growing on the walls 116 of the growth substrate 110.

[0014] According to an aspect, the first and second ends 112, 114 of the growth substrate 110 are on opposite sides of the growth substrate 110. More specifically, the first and second ends 112, 114 face away from one another and are on opposing ends of the growth substrate 110. Further the first and second ends 112, 114 may generally define surfaces that are orthogonal to a longitudinal axis or axial direction L of the growth substrate 110. Such an arrangement may be manufactured by extruding the growth substrate 110 and then singulating extruded structures to form the first and second ends 112, 114.

[0015] According to an aspect, the growth substrate 110 includes multiple passages 118 in the same integral structure (e.g., monolith). For example, the growth substrate 110 of FIG. 1, includes more than 10 passages 118, such as more than 20, more than 50, more than 100 passages, as shown for example. Use of multiple passages 118 allows the walls 116 of adjoining passages 118 to reinforce one another Further, narrower passages 118 may allow for more surface area per volume of the respective growth substrate 110, providing more opportunity for cell growth.

[0016] As shown in FIG. 1, some or most (or conceivably all) of the passages 118 may have a consistent cross-sectional geometry shared with one another and/or extending longitudinally along the growth substrate 110. Consistency in geometry of the passages 118 may allow for uniform flow rates and pressures of fluid.

[0017] According to an aspect, at least some of the passages 118 have consistent cross- sectional area with one another such that, for a given cross-section of the growth substrate 110 taken orthogonally to the length, at last 2, 3, 4, 5, and/or 10 passages 118 have crosssections with areas that are each within 20% of an average thereof, such as within 10%, such as within 5%. [0018] According to an aspect, at least some of the passages 118 have consistent cross- sectional area such that, when measured at 10 locations spaced apart from one another by about 1/10 of a length of the respective passage 118, areas of the cross-sections are each within 20% of an average thereof, such as within 10%, such as within 5%. .

[0019] According to an aspect, growth substrate 110 comprises more than one passage 118, such as at least 3, 4, 5, 10, 20, 50 passages. According to an aspect, the passages 118 extend in a longitudinal direction of the growth substrate 110 between the first and second ends 112, 114. For example, the passages 118 may extend in a straight line between the first to second ends 112, 114, or alternatively the passages 118 may wind around a geometric center of the growth substrate 110 extending through the growth substrate 110 in the length direction of the growth substrate 110.

[0020] According to an aspect, two of the passages 118 share a common wall 116 partitioning the two. Sharing walls 116 allows structures of the passages 118 to reinforce one another, increasing strength and rigidity of the overall growth substrate 110 so that the passages 118 retain their shape even if the growth substrate 110 is loaded in deployment or operation, thereby maintaining consistent flow rates, avoiding dead space, and efficiently using volume of the growth substrate 110 for growing cells. For example, when loaded axially, the growth substrate 1 10 supports at least 7 kPa without plastic deformation and/or fracture failure, such as at least 10 kPa, 30 kPa, 50 kPa, 100 kPa, 500 kPa. According to an aspect, two of the passages 118 extend side-by-side with one another from the first end 112 of the growth substrate 110 to the second end 114.

[0021] According to an aspect, the passages 118 are elongate, having a length at least twice, three-times, five-times, ten-times, one-hundred-times a respective largest cross-sectional dimension thereof orthogonal to the length, such as a width or diameter. Further, the walls 116 may be narrow (e.g., < 300 pm thick, such as < 200 pm, < 100 pm, < 70 pm) and at least semi-porous, having channels or pinholes extending therethrough, wide enough to allow exchange of gasses, nutrients, and biomolecules between passages 118 through the walls 116. According to an aspect, at least some of the walls 116 have a thickness of less than 1 mm, such as less than 500 pm, 300 pm, 200 pm, 150 pm, 100pm, and/or 50 pm. Further, the passages 116 may be most of the growth substrate 110, in terms of volume thereof. [0022] According to an aspect, material of a first wall of the walls 116 continuously extends into others of walls 116. The material may include a synthetic polymer having a melt flow index, as per ASTM D1238, within a range of 0.08 to 1.33. As such, the growth substrate 110 may be extruded (e.g., die-extruded) to form the presently disclosed structures. Such a growth substrate 110 may be dip coated or otherwise further processed beyond the extrusion.

[0023] According to an aspect, the material is a first material and the first wall further comprises a second material overlaying the first material. For example, the first material may include polypropylene and the second material may include polystyrene overlaying and coextruded with the polypropylene. It is further contemplated that the first and/or second material may include acrylonitrile-butadine-styrene, acrylic, ethylene-vinyl-acetate, polyvinyl chloride (PVC), high- or low-density polyethylene, polycarbonate, polyurethane, rigid PVC, thermoplastic elastomers, thermal plastic vulcanite, styrene, thermal plastic olefin. Or, the first and/or second material may include a glass or a ceramic. Alternatively, the walls 116 may only include the first or the second material.

[0024] Referring to FIG. 3, a bioreactor 310 includes a growth substrate 312 comprising a first end 314, a second end 316, and walls 318 defining passages 320 within the growth substrate 310, wherein the passages 320 are aligned with one another and open to the first and/or second ends 314, 316. In operation, the bioreactor 310 may further include fluid 322 carrying nutrients for cell growth, where the fluid 322 flows through the passages 320 of the growth substrate 312. Further still, the bioreactor 310 may include cells 324 growing on the walls 318 of the growth substrate 310. As shown in FIG. 3, some of the passages 320 may be plugged or routed into another of the passages 320 to form a tortuous flow path for the fluid. Fluid may flow in opposite directions in adjoining passages 320.

[0025] Construction and arrangements of the compositions, structures, assemblies, and structures, as shown in the various aspects, are illustrative only. Although only a few examples of the aspects have been described in detail in this disclosure, modifications are possible (e.g., variations in sizes, dimensions, structures, shapes, and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations) without materially departing from the novel teachings and advantages of the subject matter described herein. The order or sequence of any process, logical algorithm, or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various aspects without departing from the scope of the present inventive technology.