System and method for producing collagen fibers

Abstract

A method and system for producing biopolymer collagen fibers comprises an acidified collagen solution that can be piped into a vertical forming buffer tank. The collagen solution can be extruded as a stream of fibrous lines (filaments) after passing through multiple holes formed in a disk that can be placed at the lower end of the vertical forming buffer tank. Each filament can be immersed in the surrounding buffer tank, polymerized, and form collagen subfilaments. The resulting subfilaments are extracted from the top of the vertical buffer tank, gathered together and bundled to produce collagen fibers.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 494,908, filed Apr. 7, 2023, the benefit of whose priority is claimed herein and which is hereby incorporated by reference in its entirety.

[0002] (Statement Regarding Government Support) The data presented in this application was supported, at least in part, by DARPA SBIR 140D0420C0005. The United States Government has certain rights in this invention.

Background Art

[0003] (Field of Disclosure) This disclosure relates to methods for manufacturing collagen fibers, as well as scaffolds prepared using collagen fibers and the incorporation of collagen fibers into implantable biocompatible devices. In particular, this disclosure relates to an extrusion method for collagen fibers having excellent mechanical strength, biocompatibility, and immunological properties.

[0004] (Description of Related Art) Collagen is a fibrous insoluble protein composed of bundles of small reticular fibrils. Collagen fibrils combine to form white, shiny, inelastic fibers that are a major component of connective tissues including skin, bone, ligaments, and cartilage.

[0005] Much effort has been made to manufacture tissue-like collagen-containing scaffolds for use in the body, particularly to replace damaged collagen body parts, including ligaments and tendons. Such implantable devices can directly replace damaged parts or facilitate the repair of damaged soft tissue, ultimately functioning to provide scaffolds for replacing damaged soft tissue. Such products must function in various challenging biomechanical environments, where multiple functional parameters must be addressed. These parameters include, for example, affinity with body tissues and fluids, strength, flexibility, durability, and biodegradability.

[0006] In this field, there is a need for systems and methods to address the aforementioned shortcomings. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In one embodiment, the present disclosure relates to a method for producing collagen biopolymer fibers. The method includes a first step of dissolving solid collagen in an acidic solution to form a collagen solution, and a second step of extruding the collagen solution through a plurality of holes in a spinneret located at the bottom of a vertical forming buffer tank to form a plurality of subfibers. The method also includes a third step of bundling at least two of the plurality of subfibers together with a collagen fiber as the at least two subfibers rise up the vertical forming buffer tank. Furthermore, the plurality of subfibers and the resulting collagen fiber have buoyancy such that they float above the bottom of the vertical forming buffer tank when extruded to the top of the vertical forming buffer tank. [Means for solving the problem]

[0008] In another embodiment, the present disclosure relates to a method for producing collagen biopolymer fibers, comprising: a first step of connecting a first container of collagen solution to be injected into a spindle via one or more tubes; a second step of inserting the spindle into the upper opening of a vertical forming buffer tank; a third step of releasing the spindle into the vertical forming buffer tank; a fourth step of pushing the collagen solution through a plurality of holes in the spindle as the spindle descends from the upper opening to the bottom of the vertical forming buffer tank; and a fifth step of forming a plurality of subfibers.

[0009] In another embodiment, the present disclosure relates to an apparatus for producing collagen biopolymer fibers. The apparatus may include a vertical forming buffer tank extending from the bottom to the top opening, a spinneret positioned along the bottom of the vertical forming buffer tank, a container for an acidified collagen solution, and a tubing system connecting the container for the collagen solution to the spinneret.

[0010] Other systems, methods, features, and advantages of the embodiments will be apparent to those skilled in the art upon consideration of the following drawings and detailed description. All such additional systems, methods, features, and advantages are contained within this specification and this summary, are within the scope of the embodiments, and are intended to be protected by the following claims. [Brief explanation of the drawing]

[0011] The embodiments can be better understood by referring to the following drawings and description. The components in the drawings are not necessarily to scale, and the emphasis is on illustrating the principle of the embodiments. Furthermore, with respect to the drawings, the same reference numerals indicate corresponding parts across different drawings.

[0012] [Figure 1] Figure 1 is a schematic flow diagram of an embodiment for producing biopolymer collagen fibers. [Figure 2]Figure 2 is a schematic diagram of an apparatus for producing biopolymer collagen fibers according to one embodiment. [Figure 3] Figure 3 is a schematic diagram of an embodiment of the fiber formation system. [Figure 4] Figure 4 is a schematic side view of one embodiment of the fiber formation system. [Figure 5] Figure 5 is a schematic perspective view of a vertical formation buffer tank for forming collagen fibers according to one embodiment. [Figure 6] Figure 6 is a schematic perspective view of a vertical formation buffer tank for forming collagen fibers according to one embodiment. [Figure 7] Figure 7 is a schematic diagram of a vertical forming buffer tank and a portion of the associated spinneret according to one embodiment. [Figure 8] Figure 8 is a cross-sectional view showing the internal structure of the spinneret shown in Figure 7 according to one embodiment. [Figure 9A] Figure 9A shows a perspective plan view of collagen fibers collected from a vertical forming buffer tank when they are pulled into a horizontal forming buffer tank according to one embodiment. [Figure 9B] Figure 9B shows a perspective plan view of collagen fibers collected from a vertical forming buffer tank when they are pulled into a horizontal forming buffer tank according to one embodiment. [Figure 10] Figure 10 is a flowchart showing a process for producing biopolymer collagen fibers according to one embodiment. [Modes for carrying out the invention]

[0013] Embodiments provide systems and methods for producing biopolymer fibers. Biopolymer fibers are typically formed from collagen. In particular, atelocollagen or telocollagen is typically obtained from any source (human, bovine, recombinant, jellyfish, etc.). Biocompatible polymers, such as silk fibroin; other types of collagen, such as type II collagen; fibrin / fibrinogen; basement membrane proteins; hyaluronic acid, polyethylene oxide, polyethylene glycol, polycaprolactone, polyethylene, polyhydroxybutyrate, PDLA; PDLLA and high molecular weight PDLLA; PLGA; and mixtures thereof can be mixed with collagen to form biopolymer fibers.

[0014] As described herein, collagen can be dissolved in an acidic solution to form a collagen solution. In one embodiment, the prepared collagen solution is then passed through or injected at a first rate through one or more openings formed in a spinneret having a first diameter. The spinneret is configured to allow the collagen solution to exit the slit as a plurality of elongated filaments. The spinneret itself is located in a filament formation buffer tank, such as a tank containing the formation buffer. For the purposes of this disclosure, the term “filament” (or fibrous line) refers to an acidified collagen solution that has been extruded but has not yet had sufficient exposure to the formation buffer to accumulate an outer sheath and become collagen fibrous (or sub-fiber).

[0015] The formation buffer in the disclosed embodiment can be configured as an elongated vertical reservoir, and the emergence of solution filaments from the opening can be positioned to occur near or from the bottom of the vertical reservoir. Thus, once the filaments emerge, they are immersed in the reaction zone for a sufficient time and rate to form sheath-like collagen subfibers (also referred to herein more simply as “subfibers”). The emerging filaments (which immediately transform into collagen subfibers) naturally float towards the top of the vertical reservoir due to their greater buoyancy compared to the surrounding formation buffer. These resulting subfibers can then be collected at the top of the vertical reservoir and drawn out. The subfibers may be collectively bonded to form a single collagen fiber, which may be crosslinked and dried. In one example, they are drawn onto a spool at a rate of about 2 to 10 times the injection rate to increase molecular alignment and reduce fiber diameter.

[0016] In various embodiments of this disclosure, biopolymer fibers or collagen fibers are produced from collagen or collagen with other suitable biopolymers. For ease of understanding, the features of this disclosure will be described in terms of collagen. However, collagen may be mixed or combined with suitable biopolymers in various combinations and proportions to obtain the types of fibers disclosed herein. In addition, throughout this specification, typical manufacturing processes, such as steps that are typically performed together between washing and drying or immersion and drying, may be performed appropriately or repeated to achieve the desired results. For example, in one embodiment, the composition may be washed and dried before proceeding to the next step. In some embodiments, the material may pass again through a vertical bath of forming buffer before proceeding to the next processing step. In other embodiments, the initial washing or drying step may be optional. Thus, a material that is normally washed and then dried can proceed directly to the drying step and then to the next processing step. An experienced practitioner can recognize situations in which a step may be repeated or eliminated.

[0017] In different embodiments, constructs such as scaffolds made from fibers allow for internal growth of cells, i.e., various types of cells from the animal tissue into which the fibers (and devices made from the fibers) are implanted grow within the pores of the scaffold and preferably proliferate in alignment with the fibers within the scaffold. The constructs and scaffolds can include single - layer and multi - layer articles that can be used as alternatives to known repair features, such as sutures used to re - attach opposing ends of a ruptured Achilles tendon, for example, to a body part. In addition to providing a support structure for use in repairing a ruptured or damaged tendon, embodiments of the present disclosure are also suitable for ligament repair. Thus, examples of other ligaments for which a scaffold or other exemplary support provided by the invention can be used include the ACL, MCL, PCL, UCL, as well as other human and animal ligaments. Other surgeries for which the products of the present disclosure are useful include superior capsular reconstruction as a treatment option for superior tendon avulsion, particularly for partial or complete avulsion that is otherwise impossible or difficult to repair by other methods. Similarly, the repair portion can be strengthened by overlapping the repair portion using a multi - layer sheet.

[0018] In particular, embodiments of the present disclosure can be suitable for the repair of ligaments, tendons, and other soft tissues of all types of animals. The collagen fibers of the present disclosure can be used, for example, to re - join ruptured ligaments and tendons, even in the case of partial ruptures. Multiple fibers can also be twisted, bundled, braided, woven together, or otherwise arranged to improve the shape factor, which can be more easily manipulated than a single fiber during, for example, surgery. Improving the shape factor can make it easier to accurately position the fiber or platform. Other shape factors can be constructed to function as reinforcement or internal braces for ruptured natural body parts. The brace connects from one bone to another to support a joint. Typically, the brace forms an isometric joint having restored biomechanics and the original joint isometry.

[0019] Figure 1 shows an embodiment of a system and method for manufacturing collagen fibers. The system and method can be described as comprising four sections or manufacturing areas. In the first section, a collagen solution is prepared, and in the second section, collagen fibers can be formed. Next, the collagen fibers are collected in the third section, and in the fourth section, they may be post-treated, or at the end of the process, post-treated to obtain wet or dry collagen fibers. The steps in the system and method shown in Figure 1 can be grouped into four categories as follows.

[0020]

Table 1

[0021] As seen in step 105 of Figure 1, the collagen is mixed with an acidic solution and can be thoroughly stirred in step 110. In some embodiments, the acid is acetic acid from about 0.01M to about 0.50M. In other embodiments, the acid is hydrochloric acid from about 0.01M to about 0.50M. In step 115, the solution can be degassed. In some optional embodiments, the solution can also be centrifuged, for example, to help remove residual air bubbles.

[0022] Next, in step 120, the obtained collagen solution can be injected into a forming solution tank to form multiple subfibers. The resulting formed subfibers can then incorporate coaxial sheaths (indicated by a cross-section that surrounds or encloses the extruded solution filaments) in step 130. The resulting product is the formed collagen subfibers, which can be bonded together to form collagen fibers. In a different embodiment, the fibers are then sent to a collection system, where they are separated from the forming buffer solution in step 135, pass through an ethanol tank, and are dehydrated in step 140. The ethanol tank increases the strength of the fibers. The collagen fibers are collected in step 145, collected on a spool, and air-dried in step 150. Post-processing may be performed thereafter. Some examples of these technologies are described in more detail in U.S. Patent No. 11,020,509, entitled "Microfluidic Extrusion," issued on June 1, 2021, by Francis et al. (hereinafter referred to as the "Francis Application"), the disclosures of which are incorporated herein by reference in their entirety.

[0023] Figure 1 is intended to provide a generalized diagram of a system and method for carrying out embodiments of the present disclosure. Further details and disclosures are included in the specific aspects and embodiments described below.

[0024] Figure 2 introduces an embodiment of the collagen fiber manufacturing apparatus 200 (hereinafter referred to as "apparatus 200"). In different embodiments, it may be understood that apparatus 200 includes a plurality of interconnected systems, including a fiber forming system 210, a fiber pulley system 220, an alcohol immersion tank system 216, a fiber drying system 230, and a fiber collection system 240. In one example, the systems are stabilized and held together by a framework 250. The appropriate configuration and operation of the fiber pulley system 220 and the alcohol immersion tank system 216 are described in (172-MBDY-038), the entire disclosure of which is incorporated herein by reference. Furthermore, a suitable forced air drying box section is described in (172-MBDY-039), the entire disclosure of which is incorporated herein by reference. The following description will mainly discuss embodiments and features relating to the fiber forming system 210.

[0025] For clarity, in the context of the larger apparatus 200, the distal and proximal directions (or portions) are referred to herein. As used herein, the distal direction is the direction away from the fiber forming system 210 toward the fiber collection system 240, and the proximal direction is the direction toward the fiber forming system 210 toward the fiber collection system 240. The proximal and distal directions can also be understood to refer to directions opposite to the longitudinal axis 262 shown in Figure 2. Thus, as used throughout this detailed description and claims, the term “longitudinal direction” refers to the direction extending between the proximal side 292 and the distal side 294 of the apparatus 200. For example, the first horizontal liquid tank 342 has a length that coincides with the longitudinal axis 262 extending proximal from the direction of the anchor portion.

[0026] Furthermore, the term “lateral” as used throughout this detailed description and claims refers to a direction extending along the width of the component / system. In other words, the lateral direction can extend between the inside 272 and outside 274 of the device 200, characterized by the lateral axis 264 in Figure 2. Moreover, the term “vertical” as used throughout this detailed description and claims refers to a direction generally perpendicular to the lateral and longitudinal directions. This is characterized by the vertical axis 266 in Figure 2, which extends in the direction between the top side 292 and bottom side 294 of the device 200. For example, if a component has an end closer to the ground surface, the vertical direction may extend upward from the ground surface along the length of each vertical tank. Thus, each of the three axes may be understood to be orthogonal to the other two axes. Furthermore, the term “inside” refers to a portion of a component that is positioned or enclosed by an outer surface, such as the inner chamber of a vertical tank holding a buffer. Similarly, the term “outside” refers to a portion of a component that is positioned further away from the inside.

[0027] For clarity, Figure 3 shows an isometric view of an embodiment of the fiber forming system 210. In this example, the fiber forming system 210 includes a set of components including a plurality of vertical liquid tanks 310, a plurality of horizontal liquid tanks 340, a plurality of containers 330 capable of holding collagen solution, a plurality of optional anchor parts 320, a plurality of spinnerets 350, a plurality of piping elements 360, a plurality of flow meters (shown in Figure 4), a computing device (shown in Figure 4), and a pressure controller device (shown in Figure 4). The device 200 can be observed to include a repeating arrangement of the components. In other words, the fiber forming system 210 can also be understood as comprising a plurality of substantially identical manufacturing assemblies, in which case each manufacturing assembly includes one vertical liquid tank, one horizontal liquid tank, one container, one optional anchor part, one spinneret, one flow meter, and one set of piping elements, these elements capable of communicating with the pressure controller and the computing device. The apparatus 200 enables mass production of collagen fibers and maintains continuity of production in the event of an operational error or malfunction of one of the assemblies by incorporating a larger number of assemblies.

[0028] For brevity, this description will focus on a single manufacturing assembly of the fiber forming system 210, while understanding that there are multiple such assemblies operating in cooperation or in parallel within the apparatus 200, as shown in Figure 2. In Figure 3, it can be understood that the first assembly includes a first vertical liquid tank 312, also referred to herein as a vertical forming buffer tank, extending from the uppermost first end 316 to the lowermost second end 314. In some embodiments, the first vertical liquid tank 312 may be mounted or fixed along a backbone or framework (e.g., a first anchor portion 322) that helps to stabilize the tank. The first assembly of the fiber forming system 210 further includes a first spinneret 352 located within the first vertical liquid tank 312, as shown in Figure 3. The terms “filament extrusion accelerator” or simply “extruder” may also be used instead of the term “spinneret.” In one embodiment, the first spinneret 352 may be positioned directly above or on the base 318. In one embodiment, the base 318 comprises a substantially continuous (single-piece) component that extends beneath and supports a plurality of tanks. The base 318 may be in contact with the lowest second end 314.

[0029] In different embodiments, the first assembly also includes a first container 332, such as a beaker, flask, or other container configured to hold a liquid, in which a reservoir of collagen solution can be stored and fixed. The fiber forming system 210 also includes a first piping subsystem 362, which includes one or more elongated tubes connecting the contents of the first container 332 to the interior of the first vertical reservoir 312 via a first spinneret 352. An optional first horizontal reservoir 342 may extend from or be directly adjacent to the first anchor portion 322, where the uppermost first end 316 of the first vertical reservoir 312 has an opening that allows the contents of the first vertical reservoir 312 to be in fluid communication with the contents of the first horizontal reservoir 342, providing an inverted L-shaped fluid storage arrangement.

[0030] For clarity to the reader, embodiments can be characterized by various directional adjectives and reference parts. These directional and reference parts can facilitate the description of parts of the system, its components, and / or the entire apparatus. Furthermore, these directional and reference parts may also be used when describing each assembly of the apparatus (e.g., the apparatus, mechanical components, and other structural features). Therefore, for consistency and convenience, directional adjectives are used throughout this detailed description corresponding to the illustrated embodiments.

[0031] Moving to Figure 4, a closer view of the components of the first assembly of the apparatus 200 is given. In different embodiments, the aspects and operation of the fiber formation process can be managed and / or monitored via a computing device 410. The computing device 410 may include equipment for communicating with each of the components of the apparatus 200, as well as controllers and other devices, and for processing information from them. The computing device 410 may include one or more processors and memory. The memory may include non-temporary computer-readable media. Instructions stored in memory may be executed by one or more processors. In addition, the computing device 410 may include a communication system, such as a radio or other equipment for communication using one or more communication methods. In particular, the communication system includes equipment for communicating with other nearby devices and / or platform 250 via network 202. For example, each communication system may include a Wi-Fi radio, a Bluetooth® radio, and / or a cellular network radio.

[0032] The processes and methods of the embodiments described in this detailed description and shown in the figures may be implemented using any type of computing system having one or more central processing units (CPUs) and / or graphics processing units (GPUs). The processes and methods of the embodiments may also be implemented using special-purpose circuits, such as application-specific integrated circuits (ASICs). The processes and methods of these embodiments may also be implemented on a computing system including read-only memory (ROM) and / or random-access memory (RAM), which may be connected to one or more processing units. Examples of computing systems and devices include, but are not limited to, servers, mobile phones, smartphones, tablet computers, notebook computers, e-book readers, laptop computers or desktop computers, all-in-one computers, and various types of digital media players.

[0033] The processes and methods of the embodiments may be stored as instructions and / or data on a non-temporary computer-readable medium. The non-temporary computer-readable medium may include any suitable computer-readable medium, such as RAM, ROM, flash memory, or any other type of memory known in the art. In some embodiments, the non-temporary computer-readable medium may include, for example, electronic storage devices, magnetic storage devices, optical storage devices, electromagnetic storage devices, semiconductor storage devices, or any suitable combination of such devices. More specific examples of non-temporary computer-readable media may include portable computer diskettes, floppy disks, hard disks, magnetic disks or tapes, read-only storage devices (ROM), random access storage devices (RAM), static random access storage devices (SRAM), portable compact disk read-only storage devices (CD-ROM), erasable storage devices (EPROM or flash memory), electrically erasable storage devices (EEPROM), digital general-purpose disks (DVDs and DVD-ROMs), memory sticks, other types of solid-state drives, and any suitable combination of these exemplary media. Non-transient computer-readable media as used herein should not be construed as transient signals such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through waveguides or other transmission media (e.g., optical pulses passing through optical fiber cables), or electrical signals transmitted through wires.

[0034] Instructions stored on a non-temporary computer-readable medium for performing the operation of the present invention may be instruction set architecture (ISA) instructions, assembler instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, configuration data for integrated circuits, state setting data, or source code or object code written in one or more programming languages, including object-oriented programming languages ​​such as Smalltalk, C++, or a suitable language, and procedural programming languages ​​such as the C programming language or a similar programming language.

[0035] As described above, in some embodiments, the collagen solution 430 can be stored or otherwise held in the first container 332. In different embodiments, the first assembly includes equipment for transporting or moving the fluid in the first container 332 to the first vertical tank 312. An example of this configuration includes, for reference, elements of a first piping subsystem 362 which may include a first tubing section 466, a second tubing section 464, and a third tubing section 462. A tubing section may represent the same tube or multiple tubing sections. The first tubing section 466 has an open end that can be immersed in the collagen solution 430 in the first container 332. The first tubing section 466 extends upward toward the first container 332 and exits the first container 332 through an optional cap section 432. The first piping subsystem 362 then continues toward the flow meter device 450 via the second tubing section 464. In some embodiments, the first pipe section 466 and the second pipe section 464 are segments of the same continuous pipe, while in other embodiments, the two sections are separate but connected to each other via connector elements.

[0036] The second tubular section 464 can be mated to a connector tab of a flow meter device 450 that adjusts the flow rate in conjunction with a pressure control device ("pressure controller") 420. It should be understood that the pressure controller 420 may include closed-loop feedback control. In some embodiments, the pressure controller 420 may include a syringe or syringe pump and / or a programmable pump, a pressure-based mass flow controller, a microfluidic flow control, and other available or standard pressure control devices.

[0037] The pressure controller 420 may include a pressure connector tube 422 that can be connected to the first vessel 332 and control the pressure within the first vessel 332. In a different embodiment, the pressure controller 420 provides positive pressure within the first vessel 332, allowing the collagen solution to be drawn through the piping subsystem. This configuration allows the collagen solution 430 to be drawn up at a measured, steady, and / or constant rate through the first tube section 466, through the second tube section 464, through the proximal side of the flow meter device 450, and from the distal side of the flow meter device into the third tube section 462.

[0038] Referring here to Figure 5, in some embodiments, the distal end / outlet of a third pipe section 462, which represents the distal end of the first piping subsystem 362, can be connected to a first spinneret 352, as will be described in more detail below. The first spinneret 352 can be located outside and above the first end 316 of the first vertical reservoir 312, so that the piping may first be connected to the first spinneret 352 before and during the initial loading stage. This is better seen in Figure 5, which shows a schematic diagram of the first vertical reservoir 312 and the first spinneret 352 in the initial loading configuration. In some embodiments, the vertical tank includes a fitting panel 510 which can be used to securely fasten or join to a corresponding opening in the first horizontal tank 342 (see, for example, Figures 9A and 9B), forming a seal for the liquid (i.e., buffer 512) held in the compartments of both the first horizontal tank 342 and the first vertical tank 312, thereby providing fluid communication between the two components.

[0039] Therefore, in some embodiments, during the loading stage, the first spinneret 352 may be positioned directly above both the opening 516 in the first vertical reservoir 312 and the opening in the first horizontal reservoir 342, and they may be stacked vertically together or sealed. The upper surface 552 of the first spinneret 352 faces directly upward, and the lower surface 554 opposite the first spinneret 352 faces directly downward toward the base 318 located below the first vertical reservoir 312. The end of the third tube section 462 can be fixed to a port provided along the lower surface 554 of the first spinneret 352 (see, for example, Figure 8). Since the third tube section 462 is connected below the first spinneret 352, the first spinneret is then directed to extend and then move away from the tube upward and toward the first container. In this initial loading configuration, the first spinneret 352 is located outside the first vertical reservoir 312 and is at a first height H1 on the top of the base 318, directly above the opening 516 at the first end 316, which provides access to the internal volume contained by the vertically aligned outer housing or surface vertical reservoir 312. In different embodiments, the opening 516 is substantially round, and the vertical reservoir 312 has a substantially circular cross-sectional shape along the horizontal plane and a substantially cylindrical three-dimensional shape. In some embodiments, the shape of the vertical reservoir 312 can be selected to match or align with the shape of the first spinneret 352 (in this case, a substantially cylindrical and squat shape, similar to a pack or disc). Thus, in other embodiments, the shapes of the spinneret and the vertical reservoir may differ, but alignment or matching can be maintained.

[0040] Once the first spinneret 352 is securely connected to or fitted to the open end of the third tubular section 462, fluid can flow from the opposite end of the first piping subsystem 362 (e.g., the collagen solution in the first container) into the first spinneret 352, and the loading stage is completed. Next, a deployment stage can be made in which the collagen dispersion assembly, containing the first spinneret 352, the first piping subsystem 362, and the collagen solution flowing through the first piping subsystem 362, can be released. In one example, the first height H1 is about 0.5 to 1.5 inches above the accompanying opening in the horizontal liquid tank before being dropped, but in other embodiments, the first height H1 may be closer to the surface of the buffer fluid and the passage leading to the interior of the vertical liquid tank. The collagen dispersion assembly drops or falls through the opening 516 into the internal chamber 520 of the first vertical liquid tank 312. The first spinneret 352 has a density that allows it to be easily submerged along the length of the first vertical liquid tank 312.

[0041] In other embodiments, the spinneret can be gently guided to the bottom and then released using an optional loading device (also referred to herein as a “guide device”) that grips or detachably attaches the first spinneret. For example, the spinneret may be positioned on or resting on a fixture that can be connected to the guide device, such as a plate or other support. The fixture may include a mating pin or other fastening element that, when fixed to the spinneret, helps prevent the spinneret from shifting position throughout the extrusion process. In some embodiments, the guide device can be used to gently move the spinneret down the length of the vertical tank at a set speed that may be the same as or approximately equal to a specified fiber collection speed. In one example, the guide device may be removed from or pulled back from the vertical tank at the end of an extrusion session. In some embodiments, the guide device remains in place once the extrusion process begins to function in maintaining the fixed fiber stretching start position.

[0042] In some embodiments, the outermost circumference of the first spinneret 352 can be slightly smaller than the outermost circumference of the opening 516, allowing the first spinneret 352 to pass through when placed in the vertical liquid tank 312 (see Figure 6). The guide device and its associated fixtures allow the spinneret to move through the tube while preventing the first spinneret 352 from rotating (i.e., thereby maintaining the orientation of the upper surface 552 and lower surface 554 relative to the vertical axis 226).

[0043] Next, referring to Figure 6, once the collagen dispersion assembly has submerged a first distance D1 from a first height H1 to a second height H2, the collagen solution can flow or be extruded through a number of openings formed in the central core of the first spinneret 352 (see, for example, Figure 8). In other words, since the collagen solution is supplied to the first spinneret 352 from the first container via the first piping subsystem, it can exit through small through-holes formed in the spinneret. The unfolding stage can be completed when a portion of the lower surface 554, along with the bent or curved portion of the third tubular section 462 attached to the first spinneret 352, contacts and rests firmly on the lowest second end 314 directly above the base 318.

[0044] In some embodiments, during the descent or fall of the first spinneret 352 into the tube, a substantially steady flow of viscous collagen solution 602 can be released or extruded from the first spinneret 352 in a microfluidic state (as filaments) having a fibrous tendon-like or thread-like structure at a substantially steady or constant rate, signaling the start of the collagen formation phase. Generally, in different embodiments, the first distance D1 can be selected to maximize the immersion time and the flow of the solution over the vertical immersion tank, with the understanding that experience with taller (longer) vertical immersion tanks and buffer immersion will correspondingly increase the strength of the subfibers. However, the first distance D1 should not exceed a threshold at which the weight of each sheathed subfiber, which increases as the fiber floats upward due to a sheath that grows continuously around the core (e.g., extruded solution filament) to prevent the subfiber from sinking before reaching the top of the vertical immersion tank, neutralizes or overcomes the natural buoyancy of the collagen solution. In other words, collagen fibers enter the tank when they are buoyant and have a lower density than the forming buffer, but as the fibers float upward, cross-linking reactions can remove water from the fibers, increasing the density of the collagen fibers. Ultimately, if the vertical buffer tank is too high, the density of the collagen fibers will become greater than that of the forming buffer fluid, and the collagen fibers will begin to sink slowly. Therefore, the maximum preferred height of the vertical buffer tank should be selected to be below this distance. If the vertical buffer tank exceeds this height, the fibers will begin to sink and will not clump together easily. Thus, in different embodiments, the height of the vertical buffer tank may be limited to ensure that as the tank is moved upward over a first distance D1, the density of the collagen fibers does not become greater than that of the forming buffer fluid.

[0045] In different embodiments, the initial release of the collagen solution strands or fiber lines can be configured to occur during deployment, for example, while the collagen dispersion assembly is falling into a vertical liquid tank. For example, as shown in Figure 6, the collagen solution 602 may be extruded through channels within the spinneret as the spinneret moves downward. In some embodiments, the immersion rate of the assembly is substantially constant. In one example, the immersion rate can be made to roughly match the pumping rate of the collagen solution from the top of the spinneret, enabling a "cast-in-place" type process of the filaments as the spinneret falls. As mentioned above, each extruded filament is buoyant relative to the surrounding buffer. Therefore, as the spinneret falls, the filaments (fiber lines) exiting the spinneret float upward and transform into sub-fibers whose strength increases along their upward movement. As the fibrous lines of acidified collagen emerge from the upper ends of each opening of the first spinneret 352 (see Figure 8), they flow into the reaction zone containing the fibril-forming buffer tank, or forming buffer solution, which causes the formation of a sheath around each collagen subfiber, and they begin to form as solid subfibers. These subfibers continue to rise upward toward the top of the vertical liquid tank.

[0046] In different embodiments, it may be understood that the extrusion process should be initiated by dropping the collagen dispersion assembly from top to bottom to overcome hydrostatic pressure that could prevent or hinder the initial extrusion and upward drift of individual subfibers. In other words, if extrusion is delayed until the spinneret reaches the bottom of the vertical reservoir, the buffer may "backflow" into the tube, and undesirable formation / coating may occur prematurely or accidentally upstream of the tube itself, rather than in the vertical reservoir. In one example, the buffer may clog the opening from which the filaments are extruded. Therefore, the initial droplet development and simultaneous casting / extrusion as the spinneret drops downward may be a critical and necessary aspect of the formation process.

[0047] It should be understood that the vertical extrusion described herein can be configured to help maintain uniform tension in each individual fiber until the strand is formed at the top. In addition, both the filament contact area and the filament contact time with the surrounding forming buffer can be greater compared to similar immersion in a horizontal tank rather than a vertical bath. This increase in filament contact area and filament contact time can increase fiber strength (e.g., breaking load), which facilitates the feasibility of subsequent assembly processing. In addition, vertical extrusion (compared to horizontal extrusion) promotes the circularity of the fiber rather than the production of fibers with a flat / ribbon-shaped profile.

[0048] In one example, a forming buffer can be used to neutralize the collagen solution and aid in fiber formation. In a different embodiment, a coaxially flowing collagen fiber line (filament) passes through a reaction zone containing a fibril-forming buffer tank at a time and volume flow rate sufficient to form sheath-like fibers having the strength described herein. In some embodiments, the forming buffer solution provided in a vertical tank may be any solution that aids in collagen fiber formation. The forming buffer solution may typically be a solution containing various salts and buffers. In some embodiments of this disclosure, the forming buffer solution may be a WSB containing 6.85 g / L of TES, 4.14 g / L of sodium monohydrogen phosphate dihydrate, 12.1 g / L of sodium dihydrogen phosphate, 7.89 g / L of NaCl, and 10 percent (w / v) of PEG (polyethylene glycol), with a pH of 8 or higher. Similar solutions may also be preferred.

[0049] In different embodiments, the flow rate of the collagen solution relative to the surrounding forming buffer solution as the collagen solution passes upward as subfibers along a vertical vat is adjusted to induce elongation in the collagen fibers and improve fiber quality. In fact, in this way, the collagen is encouraged to form relatively linear and continuous fibers without twisting and other physical morphological abnormalities. In some embodiments, the fibers may be substantially circular, oval, square, rectangular, ribbon-like, triangular, or irregular in shape. In some embodiments, the relative velocity as the collagen fibers float upward and the tension of the collection spool (see, for example, Figure 9) can be used to pull or stretch the collagen flow, creating an elongation technique that helps align the collagen monomers in a process called flow-induced crystallization. This alignment assists in the polymerization of collagen and increases the strength of the resulting product.

[0050] As described above, during the collagen formation stage, the filament is extruded at a substantially steady rate and then immersed in a buffer solution provided in a vertical reservoir. To clarify the reader's understanding, Figures 7 and 8 provide additional details regarding the spinneret and the extrusion process. Figure 7 illustrates the lower region of the first vertical reservoir 312 located above the base 318. The first vertical reservoir 312 has a continuous outer housing 712 extending from the top end to the bottom end, which in this case encloses a watertight volume (chamber) holding the formation buffer solution. In this example, the outer housing 712 is transparent (e.g., plexiglass) to better reveal the internal activity for the reader. However, in other embodiments, the outer housing 712 may be translucent or opaque. Figure 7 shows the first spinneret 352, which is placed on or positioned on the base 318, touching or abutting the second end 314 at the very bottom inside the first vertical reservoir 312. The third tubular section 462 can be seen emerging from below the lower surface 554 of the first spinneret 352 and is routed upward along the internal chamber of the first vertical reservoir 312.

[0051] In different embodiments, the first spinneret 352 may include a recessed region 730 in the central region of its upper surface 552. The center of the recessed region 730 (the bottom of the recess) is referred to as the extrusion zone 770. The extrusion zone 770 includes a substantially solid or continuous surface but has a plurality of through-hole openings formed on the surface (see, for example, Figure 8) (also referred to herein as “multiple holes”). From these openings, a plurality of flows of extruded solution-extruded collagen fiber lines ("filaments") 710, including the first filaments 720, are extruded and immersed in a buffer-forming buffer tank. As they are extruded, the filaments 710 have a natural buoyancy that causes them to float upward. By being exposed to the surrounding buffer-forming buffer tank for a certain period of time during their upward movement, each filament is gradually “covered with a sheath,” thereby being converted into a collagen subfiber. The further the subfibers travel through the buffer-forming buffer tank, the greater their exposure to the buffer, and the stronger the resulting subfibers become. In some embodiments, the first spinneret 352 may also include mechanical features such as a connector mechanism 740 for securing the lid portion 780 to the body portion 790. A recessed area 730 may be provided in the lid portion 780 and includes an outer wall (see extrusion perimeter wall 890 in Figure 8) that surrounds or forms the perimeter of the extrusion zone 770, helping to guide the extruded fibrous line upward, while the main extruded component remains within the body portion 790. Thus, before the collagen leaves the spinneret, it is in solution form, and once it leaves the spinneret, it becomes an extruded form (filament or fibrous line) that is wrapped to form collagen subfibers.

[0052] Further details regarding the structure of the spinneret are taken along line 8-8 in Figure 7 and shown in a cross-sectional view of the first spinneret 352 in Figure 8, which extends across the width of the vat. In Figure 8, it can be seen more clearly that the third tubular section 462 extends downward along the proximal side 854 of the first spinneret 352, curves inward, and terminates at the spinneret inlet port 862. The outlet 822 of the third tubular section 462 can be connected to or fitted into the inlet port 862 to form an airtight seal. Once the collagen solution 892 is fed through the tube, it can pass through the inlet port 862 and move upward through the receiving conduit 870, through which the collagen solution 892 is pushed into a wider dispersion chamber 880, where it diffuses upward until it reaches the extrusion plate 802. The extrusion plate 802 can be located directly below and adjacent to the extrusion zone 770 and can be understood to include the opposite side of the extrusion zone 770. Multiple through-holes ("openings") 860 are formed inside the extrusion plate 802 and extend across its entire thickness, forming a set of vertical channels including a first channel 810, a second channel 820, a third channel 830, a fourth channel 840, and a fifth channel 850. Each channel has an inlet or first opening at its lower end, which is in fluid communication with the dispersion chamber 880, and an outlet or second opening at its upper end, which is in fluid communication with the contents of the vertical liquid tank. Each channel can be sized and dimensional to allow the collagen solution to be extruded upward into the microfluidic filament. As the filament exits the opening 860, it passes through the space within the lid portion 780 (see Figure 7), which is enclosed by the extrusion perimeter wall 890 and the wider, inclined outer wall 892, together surrounding the extrusion zone 770, guiding the filament upward and away from the spinneret.

[0053] Generally, the internal chamber of the base's first spinneret 352 can be configured such that substantially equal amounts of fibers are extruded through the channels. In different embodiments, the number of openings (channels) provided can be understood to be approximately equal to the number of fiber lines extruded and coated simultaneously. In this example, 26 openings corresponding to exits for 26 through-hole channels allow for the simultaneous production of 26 collagen fibers. In some other embodiments, the spinneret may have more or fewer channels formed within its body. In one non-limiting example, a collagen solution can be passed through a tube with a diameter of approximately 3.175 mm or 1 / 8 inch to an inlet port formed in the spinneret housing. The cavity of the inlet port then expands to a larger size within the inlet conduit, for example, to a diameter of approximately 15 mm. In some embodiments, the inlet conduit may have a vertical length of approximately 7 mm. After passing through the inlet conduit, the collagen solution comes into contact with the extrusion plate, moves through the channels, and exits into a forming buffer in a vertical reservoir where subfibers can be formed.

[0054] The cross-sectional view in Figure 8 also shows the offset arrangement of the first spinneret 352 at the bottom of the vertical reservoir. In other words, it can be seen that one side of the first spinneret 352 (e.g., the distal side 858) is either closer to or not further from the outer housing 712 (represented here as the second distance D2) than the opposite side (e.g., the proximal side 854), which is represented as the third distance D3. This is due to the presence of a third tubular portion 462, which in this case is pressed between the proximal side 854 of the spinneret and the outer housing 712, thereby pushing the spinneret toward the distal side of the vertical reservoir. The internal size or diameter of the vat is selected based in part on the desired size or diameter of both the spinneret and the attached tube, and the assembly fits snugly and securely for stability, while maintaining its horizontal orientation (upward extrusion zone) while allowing free vertical movement, after which the spinneret can be easily retrieved or pulled up and removed from the vertical vat.

[0055] As described herein, as multiple subfibers float upward along the height of the vertical tank, the subfibers become stronger and more elastic. Next, referring to Figures 9A and 9B, isometric plan views of the interior 920 of the first horizontal tank 342 are shown. In the enlarged view of Figure 9B, it can be seen that a passage can be formed by stacking a panel opening 918 in the upper fitting panel 510 of the opening 516 of the first end 316 at the top of the first vertical tank 312, which can be continued by stacking tank openings 916 formed on the lower surface of the first horizontal tank 342. Thus, a single outlet 930 may exist from the vertical tank into the horizontal tank. In some embodiments, the forming buffer 512 can be held or stored in a compartment of the first horizontal tank 342 and can be continuous with the forming buffer 512 in the first vertical tank 312.

[0056] In Figure 9B, the obtained subfibers 710 reach the first end 316 of the first vertical liquid tank 312 and are further collected together along the guide rod 940. In one example, the collected subfibers 710 are gathered as a single bundle at point 950, pass along the grooved region 960, and then supplied to the horizontal forming buffer tank. In some embodiments, the collagen fibers may be wet or damp when collected. In such cases, the subfibers tend to stick together, especially when in contact during collection. Thus, when the subfibers are gathered into a bundle and wound together, the subfibers naturally adhere to each other to form a single collagen fiber 910. Any number of subfibers may be joined together, whether twisted or not, to form a bundle, and the bundles may be assembled into larger bundles consisting of multiple fibers. For example, a bundle may include one between two subfibers and about 10,000 fibers, or between about four subfibers and about 6,000 fibers, typically between about eight subfibers and about 4,000 fibers, or more typically between about twelve subfibers and about 2,000 fibers. The bundles may then be combined by twisting or other means to form a larger bundle. The bundles being combined do not need to have an equal number of fibers. Bundles may also be described by the number of fibers they contain. For example, a bundle of five fibers may be called a penta-fiber, and a bundle of eight fibers may be called an octa-fiber, and so on. In some embodiments, such bundles can be produced using systems and apparatus having a different number of nozzles or extruders.

[0057] In some embodiments, the bundled collagen fibers 910 may be held under tension by a tensioner as the fibers are dehydrated and / or until they are wound onto a collector. Typically, a grooved cylinder or spool can be a suitable collector, especially for wet fibers. For example, the spool at the end of the system can be rotated at a speed that yields a stretching speed of about 2 to 4 times the fiber formation speed, typically about 2.5 to 3.5 times the fiber formation speed, and more typically about 2.75 to 3.25 times the fiber formation speed. The translational speed may be adjusted to control the separation of fibers on the spool. In some embodiments, at the end of the polymerization period, the collagen fibers can be produced and separated from the formation buffer.

[0058] In embodiments of this disclosure, the bundled fibers may be biopolymer fibers containing collagen. Once dried, these biopolymer fibers have one or more properties: (a) an ultimate tensile strength of at least 170 MPa (about 3 N) to 340 MPa (about 6 N) or more; (b) an elastic modulus of about 1.4 GPa to about 8.5 GPa; (c) a breaking strain for elongation of about 4 percent to about 20 percent; (d) an average fiber diameter of about 110 μm (for a bundle of 16 fibers) to about 70 μm; and (e) maintaining a strength higher than that reported in the literature after immersion in biological fluid for 30 minutes or more. The fibers exhibit an orderly longitudinally oriented structure, and the fibers allow for adhesion and infiltration of cell proliferation. The manufactured biopolymer collagen fibers can be used to develop implantable biopolymer scaffolds for assisting in the repair of soft tissue damage or for repairing or replacing parts of the human body, wherein the scaffold comprises at least one biopolymer sheet containing biopolymer fibers. The sheet may contain fibers arranged in a typical manner for ease of handling during use. For example, a single fiber is very difficult to use due to its small diameter. Therefore, it may be necessary or appropriate to form a scaffold, or a structure larger than a single fiber, in order to provide a fiber-containing product suitable for repairing or replacing body parts. For example, it is possible to knit several fibers together to form a strand containing collagen fibers. Such a strand may be useful, for example, to cover a ruptured ligament or tendon.

[0059] In embodiments of this disclosure, atelocollagen and telocollagen are used to form microfluidic extruded collagen microfibers, which can then be crosslinked with biological and benign crosslinking agents such as glyoxal or DL-glyceraldehyde (DLG). These crosslinked fibers have a hydrate ultimate tensile strength of approximately 300 MPa and an elastic modulus exceeding 3 GPa, which is significantly stronger than 50 other crosslinking strategies tested, exceeding the strength of natural human Achilles tendon and anterior cruciate ligament. Glyoxal crosslinked fibers maintained 50% of their initial load-bearing capacity throughout 3 to 6 months in culture. Collagen fibers implanted in rats showed biocompatibility, promoting the production of novel host-generated aligned collagen growing along the fibers, and in the case of glyoxal crosslinking, promoting an enhanced pro-regenerative M2 macrophage response. Embodiments of this disclosure demonstrate a significant improvement in healing compared to other crosslinked fibers, making embodiments of this disclosure superior fibers for use as devices for generating strong collagen sutures or for repairing ligaments, tendons, or other soft tissues.

[0060] Figure 10 is a flowchart showing an embodiment of method 1000 for producing collagen biopolymer fibers. Method 1000 includes a first step 1010 of dissolving collagen (usually solid) in an acidic solution to form a collagen solution, and a second step 1020 of extruding the collagen solution through a plurality of holes in a spinneret located at the bottom of a vertical forming buffer tank to form a plurality of subfibers. Method 1000 also includes a third step 1030 of bundling at least two of the plurality of subfibers together (e.g., through a winding process) into a collagen fiber as at least two subfibers rise up the vertical forming buffer tank. Furthermore, the plurality of subfibers and the resulting collagen fiber have buoyancy such that they float above the bottom of the vertical forming buffer tank when extruded to the top of the vertical forming buffer tank.

[0061] In different embodiments, the method may include additional steps or aspects. For example, in some embodiments, method 1000 includes passing a collagen solution through a flow meter device communicating with a pressure controller, thereby maintaining a substantially constant flow rate. In another example, method 1000 includes connecting a first end of a tube from a container in which the collagen solution is placed, and connecting a second end of the tube to a spinneret, thereby providing fluid communication between the collagen solution and the spinneret. In some embodiments, method 1000 includes connecting the second end of the tube to an inlet port on the spinneret, the inlet port providing access to a first hole of a plurality of holes, and as a result, the collagen solution passes upward through a channel from the second end of the tube into a first opening of the first hole and is extruded from a second opening of the first hole as a first filament. In some embodiments, the second opening is directly above the first opening with respect to the vertical axis. In another example, Method 1000 includes forming a sheath around the first filament as the first filament is extruded, thereby forming a first subfiber that floats upward from the bottom to the top of the vertical forming buffer tank. In one embodiment, Method 1000 further includes extruding one filament through each of a plurality of holes in a spinneret. In another example, each of the plurality of holes corresponds to a substantially vertical channel extending between a first opening formed along the bottom and a second opening formed along the top, the bottom of which is housed within the spinneret and the top of which is positioned on the outer surface of the spinneret.

[0062] Other methods may be contemplated within the technical scope of this disclosure. For example, in some embodiments, a method for producing collagen biopolymer fibers includes a first step of connecting a first container of collagen solution to a spinneret via one or more tubes; a second step of inserting the spinneret into the upper opening of a vertical forming buffer tank; a third step of releasing the spinneret into the vertical forming buffer tank; a fourth step of pushing the collagen solution through a plurality of holes in the spinneret as the spinneret descends from the upper opening to the bottom of the vertical forming buffer tank; and a fifth step of forming a plurality of subfibers.

[0063] In such embodiments, the method may include additional steps or aspects. In some embodiments, the method includes the step of dissolving collagen in an acidic solution to form a collagen solution. In another embodiment, the method includes bundling or gathering at least two of a plurality of subfibers together into a collagen fiber. In some embodiments, the plurality of subfibers have buoyancy (relative to the surrounding forming buffer solution) so that they float from the bottom of the vertical forming buffer tank toward the upper opening after extrusion from the spinneret. In another embodiment, the method includes passing the collagen solution through a flow meter device in communication with a pressure controller to maintain a substantially constant flow rate of the collagen solution to the spinneret. In one embodiment, the method further includes drawing the collagen fiber out of the vertical forming buffer tank through the upper opening and passing the collagen fiber through a horizontal forming buffer tank. In some embodiments, the collagen fibers include a first subfiber and a second subfiber, and the method further includes determining that the first subfiber and the second subfiber have separated while being drawn out of the vertical forming buffer tank, and rejoining them as the first subfiber and the second subfiber pass through the horizontal forming buffer tank.

[0064] As described herein, some of the proposed embodiments may be understood to include an apparatus for producing collagen biopolymer fibers. The apparatus may include a vertical forming buffer tank (tank) extending from a lower end to an upper opening, a spinneret positioned along the lower end of the vertical forming buffer tank, a container for an acidified collagen solution, and a piping system connecting the container for the collagen solution to the spinneret. In some embodiments, the spinneret includes a plurality of holes, each corresponding to a substantially vertical channel extending between a first opening formed in the body portion of the spinneret and a second opening formed along the outer surface of the spinneret. In another example, the apparatus also includes a flow meter and a pressure controller. In one embodiment, the apparatus also includes a horizontal forming buffer tank that is in fluid communication with the vertical forming buffer tank and positioned perpendicular to the vertical forming buffer tank. In some embodiments, the spinneret is sized and dimensioned to fit snugly into the upper opening of the vertical forming buffer tank and descend to the bottom of the vertical forming buffer tank.

[0065] While various embodiments are described, the description is intended to be illustrative rather than restrictive, and it will be apparent to those skilled in the art that many more embodiments and implementations are possible within the technical scope of the disclosed embodiments. Many possible combinations of features are shown in the accompanying drawings and discussed in this detailed description, but many other combinations of the disclosed features are possible. Any feature or element of any embodiment may be used in combination with or in place of any other feature or element of any other embodiment, unless otherwise specified. Furthermore, unless otherwise specified, any step in the method or function of the system may be performed in any relative order in relation to any other step described herein.

Claims

1. A method for producing collagen biopolymer fibers, Dissolving collagen in an acidic solution to form a collagen solution, The collagen solution is extruded through multiple holes inside the spinneret located at the bottom of the vertical forming buffer tank to form multiple subfibers, To bundle at least two of the multiple subfibers together with the collagen fibers when at least two of the subfibers float in the vertical formation buffer tank, Includes, The multiple subfibers and collagen fibers have buoyancy such that they float up from the bottom of the vertical forming buffer tank when they are pushed to the top of the vertical forming buffer tank. A method for producing collagen biopolymer fibers.

2. The method according to claim 1, further comprising passing the collagen solution through a flow meter device in communication with a pressure controller, thereby maintaining a substantially constant flow rate.

3. The first end of the tube is connected to the container in which the collagen solution is placed, The second end of the tube is connected to the spinneret, thereby providing a path for the collagen solution to flow from the container to the spinneret. The method according to claim 1, further comprising:

4. The method according to claim 3, further comprising connecting the second end of the tube to an inlet port on the spinneret, wherein the inlet port provides access to the first of a plurality of holes, so that the collagen solution passes upward through a channel from the second end of the tube into the first opening of the first hole and is extruded from the second opening of the first hole as a first filament.

5. The method according to claim 4, wherein the second opening is directly above the first opening with respect to the vertical axis.

6. The method according to claim 4, further comprising forming a sheath around the first filament when the first filament is extruded, thereby forming a first subfiber that floats upward from the bottom of the vertical forming buffer tank to the top of the vertical forming buffer tank.

7. The method according to claim 1, further comprising extruding one filament through each of the multiple holes in the spinneret.

8. The method according to claim 1, wherein each of the plurality of holes corresponds to a substantially vertical channel extending between a first opening formed along the lower part and a second opening formed along the upper part, the lower part being housed inside the spinneret and the upper part being positioned on the outer surface of the spinneret.

9. A method for producing collagen biopolymer fibers, Connecting the first container of collagen solution to the spinneret via one or more tubes, Insert the spinneret into the upper opening of the vertical forming buffer tank, Discharging the spinneret into the vertical forming buffer tank, As the spinneret descends from the upper opening to the bottom of the vertical forming buffer tank, the collagen solution is pushed out through the multiple holes of the spinneret. Forming multiple subfibers, A method for producing collagen biopolymer fibers, including [the specified element].

10. The method according to claim 9, further comprising dissolving collagen in an acidic solution to form the collagen solution.

11. The method according to claim 9, further comprising bundling together at least two of the multiple subfibers to form a collagen fiber.

12. The method according to claim 9, wherein each of the subfibers has buoyancy such that it floats and rises from the bottom of the vertical forming buffer tank toward the upper opening after being extruded from the spinneret.

13. The method according to claim 9, further comprising passing the collagen solution through a flow meter device in communication with a pressure controller, thereby maintaining a substantially constant flow rate of the collagen solution to the spinneret.

14. The collagen fibers are drawn out of the vertical forming buffer tank through the upper opening, The collagen fibers are passed through a horizontal forming buffer tank. The method according to claim 11, further comprising:

15. The collagen fiber comprises a first subfiber and a second subfiber. moreover, Determining that the first subfiber and the second subfiber are separated while being withdrawn from the vertical forming buffer tank, As the first subfiber and the second subfiber pass through the vertical forming buffer bath, the first subfiber and the second subfiber are rejoined. The method according to claim 14, including the method described in claim 14.

16. Apparatus for manufacturing collagen biopolymer fibers, A vertical forming buffer tank extending from the lower end to the upper opening, A spinneret positioned along the lower end of the vertical forming buffer tank, A container for collagen solution, A tube system for connecting the container of the collagen solution to the spinneret, A device that includes this.

17. The apparatus according to claim 16, wherein the spinneret includes a plurality of holes, and each of the plurality of holes corresponds to a substantially vertical channel extending between a first opening formed on the inside of the body portion of the spinneret and a second opening formed along the outer surface of the spinneret.

18. moreover, Flow meter and, Pressure controller and The apparatus according to claim 16, including the apparatus described in claim 16.

19. The apparatus according to claim 16, further comprising a horizontal forming buffer tank that is in fluid communication with the vertical forming buffer tank and is positioned perpendicular to the vertical forming buffer tank.

20. The apparatus according to claim 16, wherein the spinneret is sized and sized so that it fits snugly into the upper opening of the vertical forming buffer tank and descends to the lower end of the vertical forming buffer tank.

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