Drug delivery systems and methods of use thereof

Abstract

A method of making an implantable biomaterial film includes inputting a combination of a polymer and a nerve regenerant or an immunosuppressive agent into an extruder. The method includes melting the polymer within the extruder. The method further includes extruding a combined polymer and a nerve regenerant or immunosuppressive agent to form the implantable biomaterial film.

Description

[0001] Cross - reference to related applications

[0002] This patent application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 476,268, filed on December 20, 2022, U.S. Provisional Patent Application No. 63 / 505,119, filed on May 31, 2023, and U.S. Non - Provisional Patent Application No. 18 / 542,454, filed on December 15, 2023. The entire contents of each of the above - mentioned applications are incorporated herein by reference. Technical field

[0003] The present disclosure generally relates to the fields of tissue repair and medicine. More specifically, the present disclosure relates to biomaterials and drug delivery devices or platforms containing regenerative compounds, including neuroregenerative compounds, methods of manufacturing biomaterials and drug delivery devices, and methods of treating using these biomaterials and drug delivery devices. Background art

[0004] Nerve injuries, regardless of the cause, can lead to significant and in some cases severe disabilities and dysfunctions. Specifically, nerve injuries can result in chronic pain, loss of sensation, partial or complete loss of muscle control, or other adverse effects. Addressing the harmful effects of peripheral nerve injuries is a considerable challenge, especially when nerve repair is delayed or when axons need to cross large nerve defects or long distances to re - establish connections with surrounding targets. In such cases, regenerating axons typically do not have the chemical and physiological cues required to effectively regenerate their end - target organs and re - innervate their end - target organs. For example, relatively long nerve gaps may experience depletion of neurotrophic factors at the proximal nerve stump, and the concentration of neurotrophic factors in the distal nerve stump may decline in a growth - supportive environment.

[0005] Despite the progress made in surgical techniques in recent years, only a limited number of patients with peripheral nerve injuries are able to regain full function. Therefore, there is a desire to develop clinically applicable techniques for treating nerve injuries and restoring sensory and functional outcomes after nerve injuries. To promote effective recovery of function and sensation after nerve injury and repair, the intervention or treatment should support axon regeneration and / or increase the number of neurons of the regenerating axons. Summary of the invention

[0006] According to the present disclosure, the biomaterial can include a regenerating agent, such as a nerve regenerating agent or an immunosuppressant. The biomaterial can be used at the site of tissue injury and direct repair (e.g., direct nerve repair) or used in conjunction with an implant (e.g., a nerve graft), can be attached to the implant (e.g., fixed to the implant surface), or can be incorporated as part of the implant. Specifically, the biomaterial can include FK506 incorporated into a biomaterial in the form of a film or sheet, which is suitable for implantation at or near the damaged nerve. Alternatively, the biomaterial can include rapamycin incorporated into a biomaterial in the form of a film or sheet. In another alternative, the biomaterial can include nimodipine incorporated into a film or sheet-like biomaterial. Thus, the biomaterial can be used to form a local drug delivery system to promote the repair of damaged tissue (e.g., nerve tissue).

[0007] In one aspect, a method of preparing an implantable biomaterial film can include feeding a combination of a polymer and a nerve regenerating agent or an immunosuppressant into an extruder. The method can include melting the polymer within the extruder. The method can further include extruding the combined polymer and nerve regenerating agent or immunosuppressant to form an implantable biomaterial film.

[0008] In another aspect, a method of preparing an implantable biomaterial film can include feeding a combination of a polymer and FK506 into an extruder. The method can include melting the polymer. The method can include extruding the polymer and FK506 using a film die to form an implantable biomaterial film. The method can further include cooling the implantable biomaterial film and collecting the implantable biomaterial film comprising the combined polymer and FK506.

[0009] In yet another aspect, the implant can include an extruded film comprising poly(p-dioxanone) (alone or copolymerized with a second polymer) and FK506, rapamycin, or nimodipine.

[0010] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. However, it should be understood that while the detailed description and examples illustrate exemplary embodiments of the present disclosure, they are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that just because a particular compound is assigned to a general formula does not mean that it cannot also belong to another general formula.

[0011] Unless the context dictates otherwise, the singular forms "a", "an", and "the" include plural referents. The terms "about" and "approximately" refer to being almost the same as the number or value mentioned. As used herein, the terms "about" and "approximately" are generally to be understood to encompass ±10% of the specified quantity or value. Although this disclosure supports definitions that merely refer to alternatives and "and / or", the use of the term "or" in the claims and the specification is used to mean "and / or" unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive. As used herein, "another" can mean at least a second or more. As used herein, the terms "implantable", "implanted", and "implant" do not require placement within a subject such that the implant is beneath the skin or other tissue. Rather, the term "implant" also encompasses patches placed on the skin tissue, skin tissue wrappings, and devices placed on or near a mucous membrane or other tissue surface.

[0012] Embodiments of the present disclosure relate to the use of a neuroregenerative agent or an immunosuppressive agent. As used herein, the phrase "neuroregenerative agent or immunosuppressive agent" refers to: the presence of one or more neuroregenerative agents (e.g., nimodipine) and no immunosuppressive agent, the absence of one or more neuroregenerative agents but the presence of an immunosuppressive agent, a single neuroregenerative agent and a single immunosuppressive agent that are different from each other, the presence of a single agent that is both a neuroregenerative agent and an immunosuppressive agent (e.g., FK506 or rapamycin), multiple neuroregenerative agents and multiple immunosuppressive agents, a single neuroregenerative agent and multiple immunosuppressive agents, or multiple neuroregenerative agents and a single immunosuppressive agent, regardless of whether the phrase "neuroregenerative agent or immunosuppressive agent" appears in the singular or plural form or is abbreviated to the term "(s) agent" or "agent". Further, although neuroregenerative agents for nerve repair are described herein, it is contemplated that regenerative agents suitable for tissues other than nerves can be used.

[0013] The foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the claimed features. As used herein, the terms "comprises", "comprising", "including", "having" or other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a series of elements includes not only those elements but also other elements not expressly listed or inherent to such process, method, article, or apparatus. The terms "film" and "sheet" are considered interchangeable and refer to a thin sheet of material of any shape having a thickness less than its length and width (e.g., having a thickness less than 200 μm). Additionally, the term "exemplary" is used herein in the sense of "example" rather than "ideal". Additionally, the term "between" used to describe a range of values is intended to include the minimum and maximum values described herein.

[0014] The terms and expressions employed are used as descriptive terms and not of limitation, and such terms and expressions are used not to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The following drawings form a part of this specification and are included to further illustrate certain aspects of the present disclosure. The present disclosure may be better understood by referring to one or more of these drawings in conjunction with the detailed description of the exemplary embodiments presented herein.

[0016] Figure 1 A schematic diagram showing an exemplary process for incorporating one or more nerve regenerative agents or immunosuppressive agents into a polymer, according to aspects of the present disclosure.

[0017] Figure 2 A schematic diagram showing an exemplary process for producing a film containing one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0018] Figure 3 A flowchart showing an exemplary process for incorporating one or more nerve regenerative agents or immunosuppressive agents into a polymer, according to aspects of the present disclosure.

[0019] Figure 4 A flowchart showing an exemplary process for producing a film containing one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0020] Figure 5A An exemplary nerve wrap implant formed with a biomaterial film comprising one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0021] Figure 5B Shows an exemplary nerve connector implant for use with a thin film of a biomaterial comprising one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0022] Figure 5C Shows an exemplary rolled nerve wrap implant for use with a thin film of a biomaterial comprising one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0023] Figure 5D Shows a tissue-derived implant for use with a thin film of a biomaterial comprising one or more nerve regenerative agents or immunosuppressive agents, according to aspects of the present disclosure.

[0024] Figure 6 Is a graph depicting the release of an exemplary nerve regenerative agent or immunosuppressive agent from a thin film, according to aspects of the present disclosure.

[0025] Figure 7 Is a graph depicting neurite outgrowth in an exemplary in vitro use of a thin film incorporating one or more nerve regenerative agents or immunosuppressive agents, and an exemplary control example, according to aspects of the present disclosure.

[0026] Figures 8A to 8D Is a fluorescence microscopy image corresponding to an exemplary in vitro use of a thin film incorporating one or more nerve regenerative agents or immunosuppressive agents, and an exemplary control example, according to aspects of the present disclosure. Detailed Description

[0027] The biomaterials serving as the local drug delivery devices of the present disclosure can incorporate one or more nerve regeneration agents or immunosuppressive agents into the polymeric material. The biomaterials can be used in conjunction with nerve implants or serve as nerve implants (e.g., nerve wraps, nerve connectors, pre-rolled nerve wraps, etc.), or can be implanted separately (e.g., at or near the injury site or other locations where the nerve implant is located or will be implanted) to form local drug delivery devices. The biomaterials can have a suitable shape, such as a continuous sheet, a rolled sheet, a perforated sheet, or multiple individual (e.g., discrete) sheets. One or more regeneration agents (e.g., nerve regeneration agents) or immunosuppressive agents can be distributed throughout the biomaterial or implant. The biomaterials can be distributed throughout a tissue implant (such as a nerve implant), can be confined to one or more surfaces or regions of the tissue implant, or can form part or all of the structure of the tissue implant. The biomaterials of the present disclosure can promote tissue regeneration, such as nerve regeneration, which in some aspects can in turn improve nerve regeneration outcomes. Exemplary biomaterials, their related preparation methods, and related methods of treating using the biomaterials are described in detail below. Although the local drug delivery systems, biomaterials, implants, and methods herein are discussed with respect to use at nerve sites, the local drug delivery systems, biomaterials, implants, and methods can be applied to other types of tissues and other locations of a subject.

[0028] The biomaterials can include polymers suitable for use in combination with nerve implants. The polymers can be compatible with one or more nerve regeneration agents or immunosuppressive agents. The polymers can be biodegradable after implantation into a human or non-human animal. The polymers can include homopolymers, copolymers, and / or polymer blends containing one or more of the following monomers: glycolide, lactide (d,l-lactide or l-lactide), caprolactone, p-dioxanone, trimethylene carbonate, cellulose derivative monomers, and monomers that can polymerize to form polyesters. The polymers can include poly(p-dioxanone) (PDS), polycaprolactone (PCL), poly(trimethylene carbonate), poly(glycolide) (PGL), poly-3-hydroxybutyrate (PHB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(propylene carbonate) (PPC), poly(butylene succinate) (PBS), poly(propylene fumarate) (PPF). The polymers can be formulated from two or more of these monomers. The polymers can be copolymers including p-dioxanone copolymerized with trimethylene carbonate, L-lactide, or caprolactone.

[0029] The polymer can be copolymerized with lactide and / or glycolide. The polymer can be a copolymer comprising p-dioxanone copolymerized with lactide and / or glycolide such that the polymerized p-dioxanone comprises the majority of the polymer by weight. The polymer can comprise polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). However, in some aspects, the polymer may be free of one or both of PLA and PLGA. The polymer (e.g., PDS copolymerized with PLA and / or PLGA) can be surface treated. For example, the polymer can be surface treated with polyethylene glycol (PEG) (such as PEG 1000).

[0030] One or more neuroregenerative agents or immunosuppressive agents can comprise immunophilin ligands. One or more neuroregenerative agents or immunosuppressive agents can comprise FK506 (tacrolimus), rapamycin (Rapamune or sirolimus), cyclosporin A, or nimodipine. One or more neuroregenerative agents or immunosuppressive agents can be hydrophobic and have a melting point below about 200 degrees Celsius, below about 120 degrees Celsius, below about 130 degrees Celsius, or below about 110 degrees Celsius.

[0031] One or more neuroregenerative agents or immunosuppressive agents can be mixed with the polymer at any suitable concentration, as described below. Biomaterials can be manufactured by creating a so-called "masterbatch," also referred to herein as the "stock" batch of the biomaterial, which contains the polymer and one or more neuroregenerative agents or immunosuppressive agents at the desired concentration (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6% or more neuroregenerative agent or immunosuppressive agent by weight, such as FK506, rapamycin, or nimodipine). Alternatively, biomaterials can be manufactured by combining the polymer with the neuroregenerative agent or immunosuppressive agent without using a stock batch (e.g., biomaterials formed by combining one or more neuroregenerative agents or immunosuppressive agents with a polymer free of these agents and performing a single extrusion to form a sheet-shaped biomaterial). The stock batch can be used to customize for specific uses for local drug delivery such that the stock batch material can be used for subsequent processing to produce one or more biomaterials having one of a variety of possible final forms and having a suitable concentration of the agent, as described below. If desired, the different biomaterials created can be used as building blocks, as needed, to create different local drug delivery systems.

[0032] Biomaterials can be provided in a suitable form factor, whether the biomaterial is an intermediate product (e.g., when the biomaterial is part of a raw material batch) or in a final form (e.g., a product intended to be incorporated into or attached to an implant (e.g., a nerve implant) or used independently of a nerve implant). The biomaterial can be formed into one or more pellets (e.g., a raw material batch of the biomaterial) or one or more films or sheets (e.g., a biomaterial for implantation). The film or sheet can have different thicknesses, widths, and / or lengths, and the thickness, width, and / or length can be selected according to the intended use or desired properties (e.g., desired processing properties).

[0033] As discussed above, the biomaterial can be provided in the form of one or more sheets. The sheet can be a non-woven sheet. The biomaterial can be formed via extrusion of a polymer, and due to the shape of the die through which the biomaterial is extruded, the polymer is formed into one or more sheets. The biomaterial sheet can include a constant or relatively constant concentration of one or more nerve regeneration agents or immunosuppressive agents along its width or length.

[0034] In some aspects, a biomaterial can be integrated with a nerve implant (e.g., one or more portions of the implant can be formed of or incorporate the biomaterial), the biomaterial can be attached to the implant (e.g., the biomaterial can wrap around the implant or otherwise be connected to an internal or external portion of the implant), or the biomaterial can be implanted in the same region as the nerve implant. The biomaterial can have any suitable form factor, whether integrated with the implant, attached to the implant, or implanted in the same region as the implant. The nerve implant can be used for various purposes, including as a nerve connector, nerve wrap, nerve graft, nerve protector, etc. Specifically, the biomaterial can be provided as part of or used with an implant, such as those implants described in the following cases: U.S. Patent Application No. 15 / 344,908, filed on November 7, 2016, which is issued as U.S. Patent No. 10,835,253; U.S. Patent Application No. 15 / 252,917, filed on August 31, 2016, which is issued as U.S. Patent No. 10,945,737; U.S. Patent Application No. 15 / 900,971, filed on February 21, 2018, which is issued as U.S. Patent No. 10,813,643; U.S. 16 / 381,860, filed on April 11, 2019, which is issued as U.S. Patent No. 11,166,800; U.S. Patent Application No. 16 / 192,261, filed on November 15, 2018, which is issued as U.S. Patent No. 11,477,558; U.S. Patent Application No. 14 / 036,405, filed on September 25, 2013, which is issued as U.S. Patent No. 9,629,997; U.S. Application No. 16 / 898,224, filed on June 10, 2020; or U.S. Patent Application No. 17 / 451,489, filed on October 20, 2021.

[0035] Although the implant can be a nerve implant, the implant can also be an implant other than a nerve implant. Any biomaterial discussed herein can be used for implants other than nerve implants. In some aspects, the biomaterial and / or implant can be used for vascular implants, implanted into or placed on the skin surface (e.g., as a topical, transdermal patch, etc.), bone implants, spinal implants, urinary system implants, tendon implants, muscle implants, and / or others. When incorporated into an implant other than a nerve implant, one or more nerve regenerative agents or immunosuppressive agents can be immunosuppressive agents. These agents may have other properties beneficial to the implant location, and / or may contain additional compounds that provide beneficial properties. For example, an implant intended for vascular implantation can include an anti-proliferative agent that inhibits neointimal hyperplasia, such as paclitaxel, in addition to one or more immunosuppressive agents.

[0036] When the implant is a nerve implant, the nerve implant can be formed from tissue (e.g., nerve graft tissue) attached to a film-shaped biomaterial. For example, the nerve tissue can have one or more film-shaped biomaterials applied to the outside of the nerve tissue (e.g., as a wrap). Nerve graft tissue suitable for processing according to the methods herein can be natural or synthetic. For example, the tissue can be soft biological tissue obtained from an animal (such as a mammal, including a human or non-human mammal; or a non-mammal, including a fish, amphibian, or insect). For a subject into which the graft is implanted, the tissue can be allogeneic or xenogeneic. The tissue can be nerve tissue, including, for example, peripheral nerve tissue or central nervous system tissue. Other types of tissue suitable for the present disclosure include, but are not limited to, epithelial tissue, connective tissue, muscle tissue, capillary tissue, dermal tissue, bone tissue, smooth muscle tissue, heart tissue, and adipose tissue. As described above, the soft biological tissue can be mammalian tissue, including human tissue and tissue of other primates, rodent tissue, horse tissue, canine tissue, rabbit tissue, porcine tissue, or ovine tissue. Additionally, the tissue can be non-mammalian tissue, selected from fish, amphibian, or insect tissue. The tissue can be synthetic tissue, such as, but not limited to, laboratory-grown tissue or 3D-printed tissue. According to some examples, the tissue is nerve tissue obtained from an animal (such as a human or non-human mammal). The tissue can be obtained and / or processed as disclosed in U.S. Patent Application No. 17 / 411,718, entitled "Nerve Graft and Method of Making the Same," filed on August 25, 2021, the entire content of which is incorporated herein by reference. In at least some embodiments, the exemplary tissue can be a processed human nerve allograft, such as the nerve graft from Axogen, Inc. (Alachua, Florida, USA).

[0037] Although the embodiments of the present disclosure are described with respect to biomaterials useful for nerve injury and particularly with respect to film-shaped biomaterials for forming or used with nerve implants for treating peripheral nerve injury, it is contemplated that other types of tissue, including any of the materials described above, can also be used in the methods and film-shaped biomaterials described herein.

[0038] Figure 1 Shows a method for producing a biomaterial (such as biomaterial 138( Figure 1Figure of an exemplary process 100 for particles (such as spheres, pellets, etc.) shown in, the biomaterial may include a polymer and an immunosuppressant or a nerve regenerator. The biomaterial 138 may be suitable for processing and subsequent implantation into a human or non-human animal. For example, the biomaterial 138 may be suitable for further processing and subsequent use with and / or implantation into a nerve implant in a human or non-human animal. The biomaterial 138 can also be formed using the process 100. The biomaterial 138 can form a "raw material batch" of the biomaterial, as described in detail below.

[0039] Figure 3 Flowchart of an exemplary process 300 for producing a biomaterial comprising a polymer and one or more immunosuppressants or nerve regenerators (such as FK506, rapamycin or nimodipine). Although process 300 is described below in connection with process 100 and Figure 1 and Figure 2 it should be understood that, compared to process 100, process 300 may include fewer steps, additional steps and / or different steps. Additionally, compared to Figure 3 each box shown (e.g., steps 302, 304, 306 and 308), process 300 may include fewer steps, additional steps and / or different steps, or the specific order of steps may be different. In some aspects, one or more of steps 302, 304, 306 and 308 may be repeated one or more times.

[0040] In step 302 ( Figure 3 ), a polymer 110 ( Figure 1 ) can be obtained. The polymer 110 may include a polyester. The polymer 110 may include poly(p-dioxanone) (PDS), polycaprolactone (PCL), polyglycolide (PGL), poly-3-hydroxybutyrate (PHB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(propylene carbonate) (PPC), poly(butylene succinate) (PBS), and poly(propylene fumarate) (PPF). The polymer 110 may include poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA).

[0041] However, in at least some embodiments, the polymer 110 may not contain both PLA and PLGA. Forming the polymer 110 without both PLA and PLGA can allow the biomaterial 138 to avoid generating acid at the implantation site, which may occur when PLA or PLGA degrades after implantation.

[0042] In at least some examples, polymer 110 can include p-dioxanone copolymerized with, for example, trimethylene carbonate, l-lactide, d,l-lactide, glycolide, or caprolactone. Specifically, polymer 110 can include a PDS / poly(trimethylene carbonate) random copolymer, a PDS / poly(trimethylene carbonate) block copolymer, a PDS / poly(l-lactide) random copolymer, a PDS / poly(l-lactide) block copolymer, a PDS / poly(caprolactone) random copolymer, or a PDS / poly(caprolactone) block copolymer. In some examples, polymer 110 can include a PDS / poly(glycolide) / poly(l-lactide) random copolymer, a PDS / poly(glycolide) / poly(l-lactide) block copolymer, a PDS / poly(d,l-lactide) random copolymer, or a PDS / poly(d,l-lactide) block copolymer. Using one or more random copolymers can reduce the crystallinity of the PDS material, making the film material softer.

[0043] In some aspects, including a softer or more drapable material can prevent kinking during use. For example, if used to wrap a nerve, kinking can be prevented, which can prevent nerve compression. Softness can be controlled (e.g., increased) by surface treating the polymer. For example, polyethylene glycol (PEG) can be used to surface treat polymer 110, such as PDS / poly(glycolide) / poly(l-lactide) or PDS / poly(d,l-lactide). The molecular weight of the PEG can be from about 1,000 daltons to about 10,000 daltons.

[0044] Introducing one or more copolymers can allow the polymer film to degrade faster and release incorporated drugs faster during use. For example, introducing one or more copolymers can cause the polymer to degrade within about 30 days, such as about 5 days to about 45 days, about 10 days to about 35 days, about 20 days to about 30 days, or about 5 days to about 30 days. In one aspect, the degradation rate of a PDS / poly(glycolide) / poly(l-lactide) or PDS / poly(d,l-lactide) copolymer can be about 60 days or less, about 45 days or less, or about 30 days or less. This degradation rate (i.e., faster degradation) can be increased by adding PEG to increase the hydrophilicity of the copolymer, resulting in increased degradation via hydrolysis. The faster degradation rate can also affect the release profile of any drugs incorporated into the copolymer. The physical properties and hydrophilicity of the copolymer can be altered by adjusting the ratio of the components of polymer 110, the molecular weight of the components, and / or the use of surface treatment.

[0045] In some aspects, polymer 110 includes PDS and one of the above copolymers in the form of a random copolymer (e.g., poly(trimethylene carbonate), poly(l-lactide), or poly(caprolactone)), with a molecular weight ratio of about 50 / 50 (PDS:copolymer), about 60 / 40 (PDS:copolymer), about 70 / 30 (PDS:copolymer), about 80 / 20 (PDS:copolymer), or about 90 / 10 (PDS:copolymer). In some aspects, polymer 110 includes 0 to 50% by molecular weight of the random copolymer, or up to about 50% by molecular weight of the random copolymer. In some aspects, the amount of PDS in polymer 110 (polymer 110 including the randomly copolymerized copolymer) can be about 40% to about 90% PDS by molecular weight, or about 50% to about 80% PDS.

[0046] In other aspects, polymer 110 includes PDS and one of the above copolymers in the form of a block copolymer (e.g., poly(trimethylene carbonate), poly(l-lactide), or poly(caprolactone)), with a molecular weight ratio of about 50 / 50 (PDS:copolymer), about 60 / 40 (PDS:copolymer), about 70 / 30 (PDS:copolymer), about 80 / 20 (PDS:copolymer), or about 90 / 10 (PDS:copolymer). In some aspects, the amount of PDS in the block copolymer may be reduced relative to the amount of the copolymer compared to the amount of PDS relative to the amount of the random copolymer. Thus, in some embodiments, polymer 110 contains PDS and a block copolymer, such as poly(trimethylene carbonate), poly(l-lactide), or poly(caprolactone), with a molecular weight ratio of about 45 / 55 (PDS:copolymer), about 55 / 45 (PDS:copolymer), about 65 / 35 (PDS:copolymer), about 75 / 25 (PDS:copolymer), or about 85 / 15 (PDS:copolymer). In some aspects, polymer 110 includes 0 to 50% by molecular weight of the block copolymer, or up to about 50% by molecular weight of the block copolymer. In some aspects, the amount of PDS in polymer 110 (polymer 110 including the block copolymer) can be about 50% to about 80% PDS, about 45% to about 85% PDS, about 55% to about 75% PDS, or about 60% to about 70% PDS by molecular weight.

[0047] In other aspects, polymer 110 includes PDS, poly(glycolide), and poly(l-lactide) in the form of a block or random copolymer. Measured by molecular weight, the amount of PDS in PDS / poly(glycolide) / poly(l-lactide) can be from about 55% to about 90%. Measured by molecular weight, the amount of poly(glycolide) in PDS / poly(glycolide) / poly(l-lactide) can be from about 5% to about 20%. Measured by molecular weight, the amount of poly(l-lactide) in PDS / poly(glycolide) / poly(l-lactide) can be from about 2% to about 10%. In one example, polymer 110 includes about 85% PDS, about 10% poly(glycolide), and about 5% poly(l-lactide). In one example, polymer 110 can include about 85% PDS, about 10% poly(glycolide), and about 5% poly(l-lactide). Any of the above PDS / poly(glycolide) / poly(l-lactide) copolymers can be surface-treated with PEG having a molecular weight of 1,000 daltons to about 10,000 daltons.

[0048] In other aspects, polymer 110 includes PDS and poly(d,l-lactide) in the form of a block or random copolymer. Measured by molecular weight, the amount of PDS in PDS / poly(d,l-lactide) can be from about 60% to about 90%. Measured by molecular weight, the amount of poly(d,l-lactide) in PDS / poly(d,l-lactide) can be from about 10% to about 40%. In one example, polymer 110 can include about 80% PDS and about 20% poly(d,l-lactide). Any of the above PDS / poly(d,l-lactide) copolymers can be surface-treated with PEG having a molecular weight of 1,000 daltons to about 10,000 daltons.

[0049] If desired, the total mass of PDS / poly(glycolide) / poly(l-lactide) or PDS / poly(d,l-lactide) can be from about 8,000 daltons to about 240,000 daltons, or from about 10,000 daltons to about 100,000 daltons. The molecular weight can be modified by selecting from the above ratios or otherwise modifying the ratio of the copolymer.

[0050] When polymer 110 contains poly(lactide) or poly(glycolide), a coating can be employed. Specifically, the coating can be reduced to lower the acidity that occurs during polymer degradation after implantation. Exemplary coatings include magnesium carbonate, sodium carbonate, or other basic salts. The amount of the basic salt can be from about 0.5% to about 10% by molecular weight. Specifically, the amount of the basic salt can be about 1% by molecular weight.

[0051] The obtained polymer 110 can be in any suitable form, such as powder, sheet, filament, granule (sphere, pellet, etc.), and so on. In some aspects, the polymer 110 can be obtained in a form other than powder. When the polymer 110 is in a form other than powder, step 302 can include forming a powder by grinding the particles, filaments, pellets, or another structure of the polymer 110 to obtain a powder of the polymer 110 with microparticles and / or granules of suitable size for facilitating the homogeneous mixing of the polymer 110 and the immunosuppressant or nerve regenerator 116. A centrifugal mill 112 can be used, for example, to grind the polymer 110 into a powder form. The process of grinding the polymer 110 can include obtaining the powdered polymer using the centrifugal mill 112 and drying the powder using a polymer dryer. An exemplary polymer dryer is a nitrogen dryer. When drying is performed, the dryer can be used to dry the ground polymer 110 for an appropriate period of time, such as 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, or longer.

[0052] If needed, step 302 can include synthesizing the polymer 110. For example, when the polymer 110 is PDS, the synthesis of the polymer 110 can include ring-opening polymerization of p-dioxanone. The synthesis of the polymer 110 can include causing a copolymerization reaction of the polymer 110, including random copolymerization or block copolymerization. Whether obtained in powder form, ground into powder, and / or synthesized during step 302, the polymer 110 can be a substantially pure powder suitable for mixing with one or more immunosuppressants or nerve regenerators, which can also be in powder form.

[0053] In step 304( Figure 3 ), one or more immunosuppressants or nerve regenerators 116( Figure 1 ) and the polymer 110 can be mixed together. The mixing can include physically blending the agent 116 with the polymer 110. For example, the agent 116 and the polymer 110 (where one or both are in powder form) can be thoroughly mixed together using a mixer 114 to produce a uniform, homogeneous blend of pellets with the desired ratio of the agent 116 and the polymer 110. The mixing can be performed, for example, using a double asymmetric centrifugal mixer. The polymer 110 and the agent 116 can be weighed separately and provided to the mixer 114 to obtain a homogeneous blend powder containing the desired ratio of the polymer 110 and the agent 116.

[0054] Although agent 116 and polymer 110 can be mixed when both are in a solid state, one or both of agent 116 and polymer 110 can be in a liquid form during mixing. For example, agent 116 and polymer 110 can be heated, dissolved in a solvent, etc. to form a liquid form suitable for mixing with another liquid. In embodiments where agent 116 and polymer 110 are mixed while in a liquid form, melting agent 116 and polymer 110 in step 306 below can be omitted.

[0055] Agent 116 and polymer 110 can be provided to extruder 120 after being mixed using mixer 114. For example, extruder 120 can include a hopper or feeder 118 configured to receive the mixed agent and polymer 110.

[0056] In some embodiments, agent 116 and polymer 110 can be provided separately to a system configured to perform two operations: mixing agent 116 and polymer 110, and melting polymer 110 (as described below with respect to step 306 of method 300). For example, extruder 120 can include multiple feeding devices, such as multiple feeders 118, for separately receiving agent 116 and polymer 110 in a solid form (e.g., powder form). When there are multiple hoppers or other feeding devices 118, these devices can be configured to compensate for variations in agent 116 and polymer 110 supplied to extruder 120, such as a decrease in weight as the material is depleted in the example of a gravity-fed feeding device.

[0057] Extruder 120 can be configured to supply a metered amount of agent 116 and a metered amount of polymer 110 to mixing section 124, whether agent 116 and polymer 110 are mixed using mixer 114 or via multiple hoppers or feeders 118. Feeder 118 can be configured to feed agent 116 and polymer 110 in a controlled manner, where agent 116 and polymer 110 are drawn into the interior of extruder 120.

[0058] Whether the medicament 116 and the polymer 110 are mixed before being supplied to the extruder 120 or are mixed by the extruder 120 itself, the medicament 116 and the polymer 110 can be metered such that the ratio of the medicament 116 to the polymer 110 is precisely controlled. For example, the concentration of the medicament 116 can be in the range of about 0.5 wt% to about 30 wt% of the biomaterial, in the range of about 1 wt% to about 20 wt%, or in the range of about 2 wt% to about 10 wt%. Specifically, the concentration of the medicament 116 can be about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 10 wt%, or about 20 wt%. The concentration of the medicament 116 in the biomaterial 138 formed from the material output from the extruder 120 can be substantially the same as the concentration of the medicament 116 received by the extruder 120, or the same as the concentration of the medicament 116 at any point within the extruder 120. In any case, the concentration of the medicament 116 within the extruded product can be any of the above concentrations.

[0059] Step 306 of process 300 ( Figure 3 ) can include melting the polymer 110 received by the extruder 120 ( Figure 1 ). This can include supplying the medicament 116 and the polymer 110 to the hopper 118 or other input ends connected to the extruder 120. For example, the hopper 118 can be a vibratory feeder that receives the pre-mixed medicament 116 and polymer 110. In some aspects, the polymer 110 can be obtained in liquid form (e.g., a form of polymer 110 that cures in the presence of air and / or a catalyst or by heating the polymer 110 before introducing it into the extruder 120). Thus, step 306 can be optional, or this step can be performed to maintain the polymer 110 in a liquid state.

[0060] The extruder 120 can be a single-screw or twin-screw extruder including an extruder screw 122, the screw 122 having one or more of a conveying section 124, a kneading section 126, a conveying section 128, a shearing section 130, and a metering section 132. The extruder 120 can be a twin-screw extruder including a pair of co-rotating or counter-rotating screws 122. The screw 122 can be appropriately sized for producing the biomaterial 138 with or without additional processing. For example, the screw 122 can have an outer diameter in the range of about 9 mm to about 36 mm, which is the maximum diameter of the screw 122. Specifically, the screw 122 can have a maximum outer diameter of about 18 mm.

[0061] The conveying section 124 of the extruder screw 122 may include threads sized to receive the medicament 116 and the polymer 110 and convey the two materials downstream. Additionally, the conveying section 124 may include a region that includes threads with a reduced pitch (threads closely spaced together) to generate heat to begin softening the polymer 110. The kneading section 126 may receive the medicament 116 and the polymer 110. The threads of the kneading section 126 may have a geometry suitable for generating heat by friction to melt the polymer 110. The heat generated by the kneading section 126 during step 306 may be sufficient to soften and at least partially melt the polymer 110 without adversely affecting the effectiveness of the medicament 116 due to overheating. The temperature may be in the range of, for example, about 40 degrees Celsius to about 200 degrees Celsius, or about 80 degrees Celsius to about 150 degrees Celsius. The temperature generated by the extruder 120 may be selected based on the softening and / or melting temperatures of the medicament 116 and the polymer 110, or to avoid temperatures at which the medicament 116 may be damaged or inactivated (e.g., denatured).

[0062] The second conveying section 128 may receive the heated material from the kneading section 126 and supply the material to the shearing section 130, which includes shearing threads or kneading threads configured to further increase the temperature of the medicament 116 and the polymer 110. The temperature generated by the shearing section 130 may be the highest temperature generated by the extruder 120. This highest temperature within the extruder 120 may be higher than the melting temperature of the medicament 116 and higher than the melting temperature of the polymer 110. In an example where the medicament 116 is FK506 and the polymer 110 is PDS, the shearing section 130 may be configured to generate a temperature in the range of about 110 degrees Celsius to about 155 degrees Celsius. In an example where the medicament 116 includes FK506, the shearing section 130 may increase the temperature of the medicament 116 and the polymer 110 from a temperature of about 100 degrees Celsius to a temperature in the range of about 120 degrees Celsius to about 155 degrees Celsius. Specifically, the shearing section 130 may increase the temperature of the medicament 116 and the polymer 110 to about 135 degrees Celsius. This temperature may be sufficient to ensure that the polymer 110 is in a liquid state before the medicament 116 and the polymer 110 are received by the die at the downstream end of the extruder 120.

[0063] In an example where medicament 116 includes rapamycin and polymer 110 is PDS, shear section 130 can be configured to produce a temperature in the range of about 100 degrees Celsius to about 250 degrees Celsius. For example, shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature in the range of about 150 degrees Celsius to about 250 degrees Celsius. Specifically, shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature in the range of about 175 degrees Celsius to about 225 degrees Celsius. Shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature above about 185 degrees Celsius.

[0064] In an example where medicament 116 includes nimodipine and polymer 110 is PDS, shear section 130 can be configured to produce a temperature in the range of about 100 degrees Celsius to about 200 degrees Celsius. For example, shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature in the range of about 120 degrees Celsius to about 180 degrees Celsius. Specifically, shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature in the range of about 130 degrees Celsius to about 170 degrees Celsius. Shear section 130 can raise the temperature of medicament 116 and polymer 110 to a temperature above about 125 degrees Celsius.

[0065] Although the heat generated by extruder 120 can be entirely due to the friction caused by the rotation of extruder screw 122, one or more heaters can be fixed to extruder 120 to assist in generating the desired amount of heat and maintaining the desired temperature at one or more locations within extruder 120. These heaters can be placed at one or more locations along the barrel of extruder 120 and can partially or completely surround kneading section 126, shear section 130, and / or any other section of extruder screw 122. The temperature can be monitored at one or more locations along the length of extruder 120. For example, one or more temperature sensors can be placed to detect the temperature within extruder 120. A control system in communication with these temperature sensors can control the heaters on the barrel of extruder 120 to maintain the desired temperature. Sensors can be provided to monitor and control one or more other aspects of the extrusion process, such as the torque applied to screw 122, the pressure within extruder 120, etc.

[0066] Step 308( Figure 3 ) can include, for example, extruding medicament 116 using extruder 120( Figure 1) and polymer 110. The medicament 116 and polymer 110 that are melted and mixed can be conveyed and metered via a metering section 132 downstream of the shearing section 130. The metering section 132 can supply the homogeneous medicament 116 and polymer 110 to an extruder die having an opening with a diameter of about 0.5 mm to about 8 mm, or other diameters suitable for extruding a rod with a final diameter of about 50 μm to about 3 mm or larger (e.g., using a draw die to reduce the diameter of the rod). In other aspects, the extruder die can have an opening with a diameter of about 50 μm to about 200 μm to produce an extruded rod with a final diameter of about 50 μm to about 200 μm. Specifically, the extruder die can have an opening with a diameter of about 1 mm.

[0067] The conveyor 134 can receive the material in the form of a fiber or rod output from the die of the extruder 120. The conveyor 134 can allow the material output from the extruder 120 to cool. The cooling can be performed passively or actively (e.g., by supplying a coolant to reduce the temperature of the conveyor 134, or by directing cooling air towards the surface of the conveyor 134).

[0068] The extruded material (including the medicament 116 and polymer 110) can be received by a granulator or other shaping device 136 downstream of the conveyor 134. Although the metering section 132 can be formed by a downstream portion of the extruder screw 122, the metering section 132 can include a metering pump (e.g., a gear pump) configured to push a precisely metered amount of the combined medicament 116 and polymer 110 to the output end of the extruder 120.

[0069] The metering section 132 can supply the combined medicament 116 and polymer 110 to the shaping device 136 at a desired rate via the conveyor 134. The shaping device 136 can be any suitable device or devices configured to modify or otherwise control the shape of the product extruded by the extruder 120, thereby allowing the production of a biomaterial 138 having a desired morphology (e.g., in the form of a sheet or film, as described below with respect to methods 200 and 400). In at least some embodiments, the extruder 120 can be configured to directly extrude a material having a desired size (e.g., diameter), and the extruded material is shaped into pellets or other suitable shapes by a shaping device 136 integrated into (e.g., included in) the extruder 120, thereby eliminating the need for a separate shaping device 136.

[0070] When the shaping device 136 is a granulator (e.g., as Figure 1As shown, the forming device 136 can be configured to cut the extruded material into a plurality of pellets or rods or other shapes to form the biomaterial 138. The biomaterial 138 can include the medicament 116 and the polymer 110, which are homogeneously mixed and have solidified after being extruded through the extruder 120. The content of the medicament 116 in the biomaterial 138 can substantially correspond to the ratio of the medicament 116 to the polymer 110 introduced during step 304, and can be equal to any one of the above concentrations or concentration ranges. For example, the concentration of the medicament 116 can be in the range of about 0.5 wt% to about 30 wt%, in the range of about 1 wt% to about 20 wt%, or in the range of about 2 wt% to about 10 wt%. Specifically, the concentration of the medicament 116 can be about 2 wt%, about 3 wt%, about 4 wt% or about 20 wt%.

[0071] In at least some embodiments, the biomaterial 138 can be formed from the medicament 116 at the desired concentration, so an additional step of diluting the medicament 116 is unnecessary. In these embodiments, the biomaterial 138 can be formed from a certain concentration of the medicament 116 suitable for use with a local drug delivery device (such as an implant). For example, the concentration of the medicament 116 within the biomaterial 138 can be in the range of about 0.5 wt% to about 8 wt%, in the range of about 1 wt% to about 6 wt%, or in the range of about 2 wt% to about 4 wt%. Specifically, the concentration of the medicament 116 within the biomaterial 138 can be about 2 wt%, about 3 wt% or about 4 wt%.

[0072] In other embodiments, the biomaterial 138 can be formed from a relatively high concentration of the medicament 116, thereby forming a raw material batch of one or more immunosuppressive agents or nerve regeneration agents bound to the polymer 110. The concentration of the medicament 116 in the raw material batch of the biomaterial 138 can be in the range of about 5 wt% to about 30 wt%, or in the range of about 8 wt% to about 20 wt%. Specifically, the concentration of the medicament 116 in the raw material batch of the biomaterial 138 can be about 8 wt%, about 10 wt%, about 15 wt% or about 20 wt%.

[0073] In an example where the biomaterial 138 is intended to be implanted after further processing (during which the relatively high concentration of the medicament 116 is reduced to the desired level), the process 300 described above can be repeated, for example, by using the same or different extruders 120 or one or more other devices to process the biomaterial 138, during which an additional polymer (e.g., additional polymer 110) is added to the biomaterial 138. This further execution of method 300 can facilitate a controlled reduction in the concentration of the medicament 116 within the biomaterial 138. If desired, further execution of process 300 can facilitate incorporation of one or more second polymers different from the polymer 110 used to produce the biomaterial 138. Additionally or alternatively, the processes 200 and / or 400 described below can reduce the concentration of the medicament 116 by adding an additional polymer 110.

[0074] Figure 4 A flowchart of an exemplary process 400 for producing a biomaterial comprising a polymer and one or more immunosuppressive or nerve regenerating agents (such as FK506, rapamycin, or nimodipine, in film form) is shown. Although process 400 is described below in conjunction with process 200 and Figure 2 it should be understood that process 400 can include fewer steps, additional steps, and / or different steps compared to process 200. Additionally, compared to Figure 4 each of the boxes shown (e.g., steps 402, 404, and 406), process 400 can include fewer steps, additional steps, and / or different steps, or the specific order of the steps can be different. In some aspects, one or more steps can be repeated.

[0075] In step 402 ( Figure 4 ), a mixture of the polymer 110 and the medicament 116 can be input into an extruder. This mixture can be obtained prior to performing step 402 or as part of step 402. The "mixture" can be a homogeneous or heterogeneous mixture comprising, for example, the polymer 110 and the medicament 116 extruded in processes 100 and / or 300. Although processes 100 and / or 300 provide examples of mixtures of the polymer 110 and the medicament 116 that may be suitable for producing input materials or mixtures for processes 200 and 400, it should be understood that processes 100 and 300 are optional. The mixture of the polymer 110 and the reagent 116 used in processes 200 and 400 can be obtained by any suitable process, including processes that are partially or completely different from processes 100 and 300.

[0076] Polymer 110 and agent 116, whether produced in processes 100 and 300, prefabricated, or produced by another method, can have the desired concentration of agent 116 and can be suitable for use in an extrusion process to form a film suitable for implantation into a human or non-human patient. As described above, polymer 110 and agent 116 can be present in biomaterial 138 in particulate form (e.g., spheres, pellets, or other forms).

[0077] A mixture of polymer 110 and agent 116 can be introduced into extruder 212, which can be configured to generate heat to melt polymer 110 and agent 116 in step 404, as described below. Extruder 212 can include a feed device 214 to facilitate introduction of the mixture into extruder 212, as well as an extruder screw 216 and a film die 218.

[0078] In some aspects, step 402 can include adding only biomaterial 138 to feed device 214, which is desired when biomaterial 138 contains the desired concentration of agent 116 (e.g., 2%, 3%, or 4% of agent 116, such as FK506, rapamycin, or nimodipine). In configurations where biomaterial 138 is a raw material batch containing an increased amount of agent 116, step 402 can include adding additional polymer 110, which can be the same polymer (e.g., PDS) or one or more different polymers. As described above, the amount of additional polymer 110 can be precisely controlled by a device to ensure that the desired ratio of biomaterial 138 and additional polymer 110 is introduced into extruder 212.

[0079] Feed device 214 can be a hopper of extruder 212 or can be a different type of feed device, such as a vibratory feeder, similar to feeder 118 discussed above.

[0080] Step 404 can involve using extruder 212, which includes a single extruder screw 216 or multiple extruder screws 216 having characteristics suitable for film extrusion. Extruder screw 216 can have threads with a Figure 2 constant pitch, a continuously varying pitch, or a pitch forming multiple stages or zones (e.g., as described above for extruder 120).

[0081] Regarding the characteristics of the extruder screw 216, the screw 216 can have a diameter of, for example, about 0.25 inches, about 0.5 inches, about 0.75 inches, about 1.0 inches, about 1.25 inches, about 1.5 inches, about 1.75 inches, or about 2.0 inches. The extruder screw 216 can be configured to generate a torque of, for example, about 25 Nm, about 50 Nm, about 75 Nm, about 100 Nm, about 150 Nm, about 200 Nm, or about 250 Nm. The extruder screw 216 can be configured to operate (and generate) a pressure of about 5,000 pounds per square inch (PSI), about 7,500 PSI, about 10,000 PSI, or about 15,000 PSI. In one example, the extruder 212 can be a single-screw extruder having an extruder screw 216 with a diameter of 0.5 inches, configured to generate a torque of 50 Nm and a pressure of 10,000 PSI.

[0082] During step 404, the extruder 212 can raise the temperature of the polymer 110 and the medicament 116 (e.g., in some examples, in addition to the friction generated by the screw 216, by using a heater) to a desired temperature above or at the melting point of the polymer 110. The desired temperature can depend on one or both of the polymer 110 and the medicament 116. Exemplary temperatures were described above with respect to step 306 of process 300. The extruder screw 216 can direct the molten polymer 110 and medicament 116 to the distal end of the film die 218 that is fluidly connected to the extruder 212.

[0083] Step 406 can include forming a film containing the extruded polymer 110 and medicament 116. For example, this can be performed by the film die 218. The film die 218 can include a distal opening 220 sized to form a sheet having a desired width and thickness. In some aspects, the die 218 can be configured to adjust the thickness of the extruded film and can have a fixed width. The fixed width of the opening 220 can be, for example, about 1.0 inch (25.4 mm), about 2.0 inches (50.8 mm), about 4.0 inches (101.6 mm or about 100 mm), about 6.0 inches (152.4 mm), or about 8.0 inches (203.2 mm). In some aspects, the width of the opening 220 can be greater than about 2.0 inches or greater than about 4.0 inches.

[0084] If desired, die 218 can be equipped with an amplitude modulation bar to facilitate the production of films having consistent, smooth edges. The amplitude modulation bar of die 218 can adjust the rate of material extrusion. Thus, the amplitude modulation bar of die 218 can define the opposite side edges of the extruded film such that these edges are uniform and substantially free of tears or irregularities. In embodiments without an amplitude modulation bar, a cutting device (not shown) can be connected downstream of extruder 212 and configured to remove material from one or both side edges of the material extruded from die 218.

[0085] The thickness defined by opening 220 can be adjusted between about 1 mm and about 60 mm, or can be adjusted between about 2 mm and about 40 mm, and can be configured to set the preliminary (e.g., non-final) or final thickness of the extruded film. Alternatively, both the width and thickness defined by slot-shaped opening 220 can be fixed, both the width and thickness can be adjustable, or the width can be adjustable.

[0086] The thickness of the film extruded from opening 220 of die 218 can be greater than the desired thickness. The film can be provided to film take-up unit 222 or other devices for additional processing of the extruded film in a controlled manner. Take-up unit 222 can be configured to perform one or more of cooling (actively or passively), compressing, and collecting (e.g., via rolling) the film exiting die 218.

[0087] As Figure 2 shown, take-up unit 222 can include a roller 224 for pulling the film from die 218. Roller 224 can pull the extruded film from die 218 while also stretching the film. The stretching of the film can reduce the thickness of the film compared to the thickness of the film exiting opening 220 of extruder 212. In some aspects, roller 224 rotates at a speed such that the film immediately downstream of roller 224 has a controllable translational speed. Suitable speeds for the film immediately downstream of roller 224 include speeds of about 1 foot per minute (about 0.3 meters per minute) to about 20 feet per minute (about 6.1 meters per minute), about 5 feet per minute (about 1.5 meters per minute) to about 15 feet per minute (about 4.6 meters per minute), or about 7 feet per minute (about 2.1 meters per minute) to about 10 feet per minute (about 3.0 meters per minute). In some aspects, suitable speeds for the film immediately downstream of roller 224 can include speeds of about 3 feet per minute (about 0.9 meters per minute) to about 14 feet per minute (about 4.3 meters per minute), or about 5 feet per minute (about 1.5 meters per minute) to about 12 feet per minute (about 3.7 meters per minute).

[0088] Stretching can be achieved by rotating the roller 224 at a speed greater than the speed at which the material exits the extruder 212. For example, the film immediately downstream of the roller 224 corresponding to one or more of the speed ranges of the roller 224 described in the previous paragraphs, for example, can be translated at a speed of at least twice (2X) the speed of the film immediately downstream of the opening 220. As another example, the film immediately downstream of the roller 224 can be translated at a speed of at least three times (3X) the speed of the film immediately downstream of the opening 220. Specifically, the film immediately downstream of the roller 224 can be translated at a speed of at least four times (4X) the speed of the film immediately downstream of the opening 220. As another example, the film immediately downstream of the roller 224 can be translated at a speed of at least five times (5X) the speed of the film immediately downstream of the opening 220. In some aspects, the speed of the roller 224 can be about twice, about three times, about four times, or about five times the speed of the film when it exits the opening 220 of the extruder 212. In some aspects, the speed of the roller 224 can be from about twice to about five times the speed of the film when it exits the opening 220 of the extruder 212, can be from about three times to about five times the speed of the film when it exits the opening 220 of the extruder 212, can be from about three times to about four times the speed of the film when it exits the opening 220 of the extruder 212, or can be from about twice to about four times the speed of the film when it exits the opening 220 of the extruder 212. In some aspects, maintaining a relatively consistent speed of the roller 224 can promote the consistency of the film thickness.

[0089] In some embodiments, the take-up unit 222 includes a pair of pressure rollers. A space may be formed between the pressure rollers, and the space is smaller than the thickness of the film material immediately before it enters the space. The space or gap G between the rollers can be measured in a direction aligned with the radial direction of one or both of the rollers. Since the size of the gap G is smaller than the width of the material entering the gap G, the pressure rollers may compress or increase the consistency of the thickness of the material passing through the gap. In some embodiments, the gap G is about 5 μm to about 70 μm, about 10 μm to about 60 μm, about 20 μm to about 50 μm, or about 30 μm to about 40 μm. In Figure 2 the configuration shown, the rollers 224 form the pressure rollers. In an alternative configuration, the pressure rollers can be positioned downstream of the roller 224 as a second or subsequent pair of rollers.

[0090] In some aspects, the size of the gap between the rollers 224 can be substantially similar to the thickness of the film material immediately before it enters the gap G, such that the rollers 224 do not cause significant compression of the film material. In such embodiments, the rollers 224 can control the speed of the film, can increase the consistency of the thickness of the film material passing through the gap, can allow the film material to pass through the gap smoothly, or can perform one or more other functions or combinations of functions.

[0091] The take-out unit 222 may include a coolant circulation system for supplying coolant to the roller 224 to actively cool the roller 224. Suitable coolants include, for example, water, ethylene glycol, and other fluids. One or both of these actively cooled rollers 224 may be part of a coolant circuit 226, where the coolant is pumped to each roller (e.g., the central portion of each roller 224) to maintain the roller 224 and the material extruded from the extruder 212 at or within a target temperature (collectively referred to as the "target temperature" for ease of description). The temperature and flow rate of the coolant may be controlled via a compressor, heat exchanger, pump, or other known devices.

[0092] In some embodiments, the target temperature measured in terms of the coolant temperature is from about 0 degrees Celsius to about 25 degrees Celsius. Specifically, the target temperature of the coolant may be about 0 degrees Celsius, may be about 5 degrees Celsius, may be about 10 degrees Celsius, may be about 15 degrees Celsius, may be about 20 degrees Celsius, or may be about 25 degrees Celsius. In some embodiments, the target temperature may be measured at the roller or at the film itself, and may be about 0 degrees Celsius, may be about 5 degrees Celsius, may be about 10 degrees Celsius, may be about 15 degrees Celsius, may be about 20 degrees Celsius, or may be about 25 degrees Celsius.

[0093] In a passively cooled take-out unit, one or more fans, an air conditioning system, etc. may be used in place of the coolant circuit 226. In some aspects, both a passive coolant system and an active coolant system may be used. The coolant system may include one or more sensors to determine the temperature of the coolant in real time. In a passive system, the ambient temperature or the temperature of one or more rollers 224 may be measured. Based on the signals from these sensors, the coolant system may automatically monitor and control the target temperature and / or display the current temperature for convenient manual observation and control. Cooling the roller 224 can reduce the stickiness of the film, thereby preventing it from adhering to the machinery of the take-out unit 222.

[0094] If desired, an anti-stick liner 228 may be introduced downstream of the opening 220. For example, the anti-stick liner 228 may be introduced at the roller 224, and the anti-stick liner 228 sandwiches the film extruded from 218 and prevents the film from contacting the material (e.g., metal) of the roller 224. The anti-stick liner 228 may be introduced at substantially the same speed as the rotation of the roller 224. The anti-stick liner 228 may include silicone or other non-stick materials that are configured to contact the film for a relatively long period of time and then be removed without damaging the film.

[0095] The wound film 232 can be collected, for example, on the collection roller 230. The film 232 can have a desired thickness. In some aspects, the thickness of the film 232 can be controlled (e.g., by compression) at least in part by a pressure roller separate from the extraction unit 222 or a pressure roller integrated into the pulling roller 224 of the extraction unit 222, as Figure 2 shown and described above. In other aspects, the extraction unit 222 can include both a pressure roller and a roller 224. In other aspects, the roller may not significantly affect the thickness of the film 232.

[0096] The film 232 can have a thickness of about 10 μm to about 200 μm, 30 μm to about 120 μm, such as about 30 μm to about 60 μm, about 50 μm to about 110 μm (or about 60 μm to about 90 μm) or about 90 μm to about 120 μm. In some aspects, step 406 can include setting the desired thickness for a particular application via the unit 222 or another device. In some aspects, the properties of the film 232 can be advantageously controlled by selecting the desired thickness. These controllable properties can include handling, the initial release of the agent 116 (e.g., burst release), the duration of delivering a therapeutic dose of the agent 116, the total amount of the agent 116 delivered, and the average (e.g., daily) amount of the agent 116 delivered.

[0097] If desired, the width of the film 232 can also be adjusted via the unit 222 (e.g., by using a die formed with a wider lip, a narrower lip, or an adjustable lip) or another device (such as a separate cutter). This can allow the width of the film 232 to be controlled in addition to the thickness of the film 232, and if desired, reduce the width of the film 232. Taking the film 232 extruded through an opening 220 with a width of about 2.0 inches (50.8 mm) as an example, the extraction unit 222 can reduce the width of the film 232 to about 1.5 inches (38.1 mm), about 1.0 inches (25.4 mm), about 0.75 inches (19.1 mm), about 0.5 inches (12.7 mm), or about 0.25 inches (6.4 mm). In a specific example, the film 232 can have a width of about 0.67 inches (17 mm) after being processed by the unit 222. These widths can exist in each configuration of the film 232 described below.

[0098] In some aspects, the width of the film 232 can be achieved by compressing and / or stretching the film 232 using the take-up unit 222 or other means such that the film 224 collected on the take-up roller 230 has the final desired width. If desired, the width of the film 232 on the 230 can be greater than the desired width and can be cut when preparing for use, transportation, or storage. The length of the film 232 can also be modified by cutting the collected film 232 before use, before transportation, or before storage.

[0099] Once formed as described with respect to polymer 110 and agent 116 in step 406, the film 232 can be suitable for use and requires no additional processing other than cutting and shaping. Alternatively, the film 232 can be sterilized (e.g., via gamma ray irradiation) or otherwise processed before use. To facilitate use as an implant or in conjunction with an implant, the film 232 can be further processed to add one or more attachment points (e.g., suture holes and / or surrounding features to increase the visibility of the holes and / or strengthen the suture points). These attachment points can be formed in the manner described in U.S. Patent No. 11,166,800, filed April 11, 2019, and issued November 9, 2021, the entire content of which is incorporated herein by reference.

[0100] Figures 5A to 5D Illustrated are various outer dimensions that can be achieved by the film 224 alone or by combining the film 224 with an implant (e.g., a nerve implant) to form an implant assembly or a biomaterial assembly. In Figure 5A In the first example shown, the film 224 can be suitable for implantation. The film 224 can be positioned at the site of an injury or other surgical site and can be formed as a generally tubular wrap 510 that surrounds nerve tissue (not shown). The wrap 510 can be relatively easy to suture, can have a structure for securing sutures (e.g., pre-formed attachment points and / or attachment points formed during use), and can be transparent to facilitate visualization of the nerve tissue wrapped by the wrap 510, although it may not be transparent in other embodiments. The wrap 510 can be in the form of a sheet cut from a larger film 224. In embodiments where the film 224 is used as the wrap 510 with one or more additional implant structures, the wrap 510 can be secured to the other implant structures via friction (i.e., without using an adhesive), using one or more layers of adhesive, and / or by sutures or other mechanical fasteners suitable for use on a subject. In some aspects, a wrap formed of other materials can be laminated with the wrap 510, e.g., alternating layers of other materials and the wrap 510, the wrap 510 sandwiched between layers of other materials, or the wrap 510 as one or more outer layers of a multi-layer wrap that includes other materials.

[0101] Other materials that can be used in combination with the wrapper 510 include, for example, porcine small intestinal submucosa ("SIS"), amniotic basement tissue (e.g., amnion / chorion), or recombinant denatured collagen. If desired, the materials used with the wrapper 510 can include one or more synthetic materials to replace or supplement natural materials such as SIS. Suitable synthetic materials can include resorbable polymers formed as one or more layers in a non-woven or woven structure, including homopolymers, copolymers, and / or polymer blends of one or more of the following monomers: glycolide, lactide, caprolactone, p-dioxanone, trimethylene carbonate, cellulose derivative monomers, and monomers that can polymerize to form polyesters. Additional synthetic materials that can be suitable for use with the wrapper 510 to replace or supplement natural materials include silicone membranes, expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (Dacron), polyurethane aliphatic polyesters, poly(amino acids), poly(propylene fumarate), copoly(ether esters), polyalkylene oxalates, polyamides, tyrosine-derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamide esters, amine-containing polyoxaesters, poly(anhydrides), polyphosphazenes, and blends thereof. Natural polymers suitable for use with the wrapper 510 can include collagen, elastin, thrombin, fibronectin, starch, poly(amino acids), gelatin, alginate, pectin, fibrin, oxidized cellulose, chitin, chitosan, profilin, hyaluronic acid, fibrin-based materials, collagen-based materials, hyaluronic acid-based materials, glycoprotein-based materials, cellulose-based materials, silk, and combinations thereof.

[0102] The wrapper 510 can have suitable handling properties and can be configured to cover around a damaged nerve or other tissue and can resist kinking, tearing, or wrinkling. The thickness of the film 224 (measured in a direction perpendicular to the plane defined by the wrapper 510), the length (measured along the direction of extrusion of the wrapper 510), and / or the width (measured perpendicular to the thickness and length), and thus the size of the wrapper 510, can be set prior to use. Alternatively, as described above, the thickness and width of the film 224 can be set prior to implantation (e.g., the film 224 can be about 30 μm to 200 μm thick, about 30 μm to 120 μm thick, about 30 μm to 60 μm thick, about 50 μm to 110 μm thick, about 60 μm to 90 μm thick, or about 90 μm to 120 μm thick), and the length can be determined by trimming the film 224 before winding the film 224 to define the wrapper 510. In some procedures and / or embodiments, the length of the film 224 can also be trimmed prior to implantation. In some aspects, the wrapper 510 can be sold in different sizes to accommodate different use cases.

[0103] In some aspects, the wrapper 510 can be configured to be implanted at the site of a peripheral nerve injury on a subject. The wrapper 510 can be formed by rolling up a substantially rectangular sheet or film 224 (as Figure 5A shown), a circular film, or a film having other regular or irregular shapes. Although Figure 5A a single film 224 is shown, the wrapper 510 can include multiple layers of sheets or films stacked and secured together. In some aspects, the proximal and distal ends of the wrapper 510 can be adapted to be fixed (e.g., with sutures, adhesives, or other mechanisms) to soft tissue, thereby forming a barrier that protects the nerve tissue during healing.

[0104] Figure 5B The biomaterial film 224 of the wrapper 510 is shown as being used as a wrapper around the tubular nerve wrapper implant 522 (also referred to as a nerve connector implant), thereby forming the implant assembly 520. Although Figure 5B the wrapper 510 is depicted as being located on the outer surface of the implant 522, in some aspects, the wrapper 510 can be used to cover the inner surface of the implant 522, or both the inner and outer surfaces. Although Figure 5B and those described below Figure 5C and Figure 5D show multiple wrappers 510 stacked on a particular implant (e.g., the nerve wrapper implant 522), it should be understood that a single wrapper 510 can be present on or within the implant 522. Additionally, one or more wrappers 510 can overlap, gaps can be formed where no wrapper 510 is present, ends of the implant 522 can be formed where no wrapper 510 is present, and so on. As understood, similar modifications can also be made to the implant assemblies 530 and 540 below.

[0105] In some aspects, the implant assembly 520 can be rectangular (e.g., provided in the form of one sheet or multiple sheets, or otherwise unfolded), and its length measured from the proximal end 524 to the distal end 526 is longer than the width of the implant assembly 520 measured in a direction perpendicular to the length. Specifically, the length of the implant assembly 520 (measured from the proximal end 524 to the distal end 526) can be in the range of about 5 mm to about 60 mm, in the range of about 10 mm to about 50 mm, or in the range of about 20 mm to about 40 mm. Specifically, the cylindrical body formed when the implant assembly 520 is rolled up (or before rolling up) can have a length of about 20 mm or about 40 mm.

[0106] When the implant component 520 is in a cylindrical (e.g., rolled or coiled) form, the implant component can define a tubular body having a diameter in the range of about 0.5 mm to about 10 mm, about 1.0 mm to about 8 mm, or about 1.5 mm to about 7 mm. Specifically, the diameter of the body of component 520 can be equal to about 1.5 mm, about 2.0 mm, about 3.0 mm, about 4.0 mm, about 5.0 mm, about 6.0 mm, or about 7.0 mm. The length of the body of the implant component 520 can be in the range of about 5 mm to about 20 mm, or in the range of 10 mm to about 15 mm. Specifically, the length of the cylindrical body 424 can be equal to about 10 mm or equal to about 15 mm.

[0107] The membrane or wrapper 510 of the implant component 520 can be disposed at different locations throughout the implant 522. In some aspects, a higher concentration of the agent 116 can be provided by placing the wrapper 510 at a location of the implant 522 that is expected to be near the damaged nerve (such as a nerve ending). In such cases, a higher concentration of the agent 116, such as FK506, can be provided at the proximal end 524, the distal end 526, and / or the axial central portion including the midpoint between the ends 524 and 526. Alternatively, the wrapper 510 can be distributed substantially uniformly and regularly throughout the implant 522. Additionally, while the biomaterial wrapper 510 can include a nerve regeneration agent or an immunosuppressant, the wrapper 510 can include, for example, one or more growth inhibitors that can prevent or reduce the formation of neuromas.

[0108] Figure 5C An exemplary implant component 530 that can be suitable for implantation into a subject is shown. In some aspects, the implant component 530 can extend from a proximal end 534 to a distal end 536 to define a rod or cylinder (like the implant component 520) having a hollow interior, which can serve as a nerve protector. If desired, the implant component 530 can be a pre-rolled implant 532 for ease of use. The implant component 530 can be configured to be implanted at a peripheral nerve injury site in a subject. Specifically, the implant component 530 can be configured to attach at a peripheral nerve injury site to provide a structural barrier for protecting one or more peripheral nerves or nerve endings and a structural reinforcement for supporting peripheral nerve reconstruction and healing. The implant component 530 can include an implant 532 having a cylindrical body formed as a rod or tube, where one or more wrappers 510 are attached to the outer peripheral surface of the implant 532 (as Figure 5C shown) or attached to the inner surface of the implant 532.

[0109] In some aspects, the length of implant component 530 can be longer than the length of implant component 520. Specifically, the length of the cylindrical body of implant component 530 (measured from end 534 to end 536) can be in the range of about 5 mm to about 60 mm, in the range of about 10 mm to about 50 mm, or in the range of about 20 mm to about 40 mm. Specifically, implant component 530 can have a length of about 20 mm or about 40 mm. Implant component 530 can have a diameter in the range of about 1.0 mm to about 20 mm, about 1.5 mm to about 15 mm, or about 2 mm to about 10 mm. Specifically, the diameter of the cylindrical body of component 530 can be about 2 mm, about 3.5 mm, about 5 mm, about 7 mm, or about 10 mm.

[0110] The biomaterial wrap 510 can be disposed at different locations along the entire cylindrical body of implant 532 when attached to or otherwise associated with implant 532. In some aspects, a higher concentration of agent 116 can be provided at distal end 534 and proximal end 536 compared to the axial central portion of implant 532, and vice versa. Alternatively, wrap 510 can be placed on implant 532 such that agent 116 is distributed substantially uniformly and regularly throughout implant 532, including along its length.

[0111] Figure 5D An exemplary implant component 540 that can be suitable for implantation into a subject is shown. In some aspects, implant component 540 can include a nerve graft implant 542 formed from acellular material that can be implanted at a peripheral nerve injury site within a subject. While implant components 520 and 530 can each have a hollow interior, implant component 540 can have a partially or fully solid interior. For example, implant 542 of component 540 can include acellular epineurium, acellular perineurium, and / or acellular endoneurium within its interior. One or more biomaterial films 224 can be placed and attached to the outer circumference of implant 542 to form an outer surface that is at least partially formed by biomaterial wrap 510, as Figure 5D shown.

[0112] The biomaterial wrap 510 of implant component 540 can extend generally along the length of component 540, as Figure 5DAs shown. Similar to implant components 520 and 530, the biomaterial wrapper 510 can supply relatively high concentrations at one or more locations, such as the proximal and distal ends of implant 542. In some aspects, if desired, the proximal and / or distal ends of implant 542 can be exposed and thus substantially free of biomaterial wrapper 510 and agent 116 during assembly and / or during initial implantation. If desired, implant 522 and implant 532 can similarly have ends without wrapper 510.

[0113] Each of the above embodiments (including wrapper 510 and implant components 520, 530, and 540) can be configured to deliver agent 116 in a local, sustained, and controlled manner. For example, these biomaterial components and implants can enable the accurate loading of active ingredients, such as one or more neuroregenerative agents or immunosuppressive agents (e.g., FK506, rapamycin, or nimodipine), into the polymer matrix so that the agent can be released in a controlled manner when combined with other devices or implants.

[0114] Specifically, incorporating FK506 into a polymer delivery system formed from one or more of the above biomaterials can allow for the local release of FK506 while axons regenerate towards the target end tissue or organ. It may be desirable to locally deliver one or more neuroregenerative agents or immunosuppressive agents to increase the number of neurons capable of regenerating axons and to increase the rate of axon regeneration. The production of biomaterials containing FK506 can be used as a general or modular delivery system that enables the formation of bioactive release implants and devices of a variety of different form factors, e.g., implants and devices that release FK506, which can be used for different types of injuries, particularly different types of peripheral nerve injuries. The above biomaterials can also be used to incorporate active ingredients, such as one or more neuroregenerative agents or immunosuppressive agents, without adding these agents after the formation of the delivery device (e.g., implant). These biomaterials can be used with one or more neuroregenerative agents or immunosuppressive agents, such as FK506, that have a molecular weight of less than about 1,200 g / mol or less than about 1,000 g / mol. The above biomaterials can also be used with hydrophobic neuroregenerative agents or immunosuppressive agents, such as FK506.

[0115] By using rapamycin as agent 116, at least some of the above advantages associated with using FK506 as agent 116 can be achieved. For example, rapamycin can promote axon regeneration and provide a neuroprotective function.

[0116] In addition, by using nimodipine as agent 116, at least some of the above advantages associated with using FK506 as agent 116 can be achieved. For example, nimodipine can promote axonal regeneration and myelination.

[0117] Examples

[0118] The present disclosure can be further understood by the following non-limiting examples. These examples are intended to illustrate embodiments of the above disclosure and should not be construed as narrowing its scope. Although these examples relate to the use of FK506 and PDS, it should be understood that the disclosed embodiments are not limited to such specific agents and polymers. Those skilled in the art will readily recognize many other ways in which these examples present embodiments in which the present disclosure can be practiced. It should be understood that many changes and modifications can be made while still remaining within the scope of the present disclosure.

[0119] Example 1, Part A: Incorporation of FK506 into Poly(p-dioxanone) (PDS) Films of Different Thicknesses

[0120] Biomaterial films were prepared using a two-stage process, including first forming a first stage of PDS pellets containing 2% FK506, and then using the PDS pellets to prepare biomaterial films with a target thickness in the second stage. Biomaterial films with three different target thicknesses were produced, each having a 2 wt% concentration of FK506, including a first target thickness of 30 μm to 60 μm, a second target thickness of 50 μm to 110 μm, and a third target thickness of 90 μm to 120 μm.

[0121] To prepare the pellets of the raw material batch, PDS flakes were cooled using liquid nitrogen. The cooled PDS flakes were then ground using a centrifugal mill to form powdered PDS. Residual moisture in the powdered PDS was removed using a polymer dryer overnight.

[0122] Then FK506 was mixed with the dried PDS powder using a high-speed mixer. The FK506 and PDS mixture contained 2 wt% of FK506. The mixture was collected and introduced into the hopper of a twin-screw extruder through a vibratory feeder. The extruder included a pair of screws with a diameter of 18 mm, and each screw was formed with a metering section, a kneading section, and a shearing section. The rotation of the pair of screws in the extruder heated the FK506 and PDS mixture to a temperature reaching up to 135 degrees Celsius by generating a torque not exceeding 71 Nm.

[0123] The extruded FK506 and PDS were received by a pelletizer in the form of rods. The pelletizer used a rotating knife configured to a speed of up to 24 meters per minute to break the extruded rods into multiple pellets (i.e., shortened rods).

[0124] Then, a film was prepared using PDS pellets containing 2% FK506. The pellets were introduced into the hopper of a single-screw extruder with a diameter of 0.5 inches. The heat generated by the extruder melted the pellets, and then the extrudate was supplied to a 2-inch die with an adjustable lip, which formed the film. The film was collected by a film take-up unit that pulled the film onto a cooling roller and compressed the film to the target thickness.

[0125] Example 1, Part B: Analysis of FK506 Release from PDS Films

[0126] Biomaterial samples were prepared according to Part A of Example 1, including a first set of six film samples with a target thickness of 30 μm to 60 μm; a second set of six film samples with a target thickness of 50 μm to 110 μm; and a third set of six film samples with a target thickness of 90 μm to 120 μm. Each set contained 2 wt% of FK506. Each of the three sets of samples was evaluated to determine the kinetics of FK506 release from the biomaterial films.

[0127] To prepare the three sets of films, the individual films were separated from the roller and placed into vials containing saline buffer solution. Each vial containing the biomaterial was placed in a bath maintained at 37 degrees Celsius to simulate body temperature. While maintaining the temperature of each biomaterial at approximately 37 degrees Celsius, the saline buffer was removed from each vial at different time points and analyzed for FK506 content using liquid chromatography tandem mass spectrometry (LC-MS / MS). After collection at each time point, the saline buffer in each vial was replaced with fresh saline buffer.

[0128] The buffer solution samples collected from each vial were analyzed by LC-MS / MS to determine the amount of FK506 released from the fibers at 1 day, 3 days, 7 days, 14 days, 21 days, and 28 days. Figure 6 The resulting concentration of FK506 released from the fibers is shown. In Figure 6 , each plotted point (i.e., circle, square, and rectangle) represents the average concentration of FK506 in the saline buffer collected when measuring six samples, with an initial concentration of 2 wt% FK506 for each sample. Each plotted circle represents the average concentration of FK506 in the saline buffer collected when measuring samples with a thickness of 30 μm to 60 μm at 610. Each plotted square represents the average concentration of FK506 in the saline buffer collected when measuring six samples with a thickness of 50 μm to 110 μm at 620. Each plotted triangle represents the average concentration of FK506 in the saline buffer collected when measuring six samples with a thickness of 90 μm to 120 μm at 630.

[0129] In some aspects, it may be desirable for the release of one or more neuroregenerative agents or immunosuppressive agents (such as FK506) to continue for a specific period of time. Specifically, it may be desirable for the release of FK506 to continue for a period of at least 7 days, at least 14 days, or at least 28 days, during which the release of FK506 is sufficient to ensure that the effective concentration of FK506 and / or other agents remains within the therapeutic window. Additionally, it may be desirable to avoid the burst release of one or more neuroregenerative agents or immunosuppressive agents (such as FK506). It may be desirable to avoid burst release, for example, in order to make the total duration of FK506 release longer and / or to avoid the possibility of local concentrations exceeding the upper limit of the therapeutic window.

[0130] As Figure 6 can be seen, during the 28-day measurement period, the effective concentration of FK 506 in each measured sample remained within the therapeutic window of approximately 2.1 μg / mL or above, and was far below the toxic dose of approximately 5 mg / mL. Specifically, for each of the three groups of films, the average concentration of FK506 observed over the entire 28-day period was between approximately 2.1 μg / mL and approximately 20 μg / mL. Additionally, no significant burst release was observed.

[0131] Example 2: In Vitro Analysis of Enhanced Neuroregeneration in the Presence of FK506-Containing Films

[0132] Eight biomaterial films were prepared according to Parts A and B of Example 1. These biomaterial films each contained 2 wt% of FK506 and had a thickness of 30 μm to 60 μm. Blank films containing only PDS and no FK506 (and no other neuroregenerative agents or immunosuppressive agents) were made for comparison.

[0133] Four treatment groups were prepared, each with eight samples. In each group, a cluster of dorsal root ganglion cells was processed to obtain isolated sensory neurons. These isolated neurons were placed in wells containing culture medium, and the wells were subsequently covered with a laminin-coated coverslip. The cells were cultured at 37 degrees Celsius for 48 hours. After culturing, the coverslips were stained, and a visual analysis of the stained sensory neuron cells was performed to evaluate the presence of extended neurites.

[0134] Figure 7 is a bar graph showing the observed neurite growth. Figure 7 The values shown in

[0135] In Figure 7Among them, the negative control corresponded to the sensory neurons cultured as described above in the absence of the film and in the absence of FK506. As described above, the blank film results corresponded to the sensory neurons cultured in the presence of a PDS film with a thickness of 30 μm to 60 μm and without FK506. The film containing FK506 corresponded to the sensory neurons cultured in the presence of a biomaterial film (with a thickness of 30 μm to 60 μm) containing 2% by weight of FK506. The positive control corresponded to the sensory neurons cultured in the presence of a FK506 solution and without a film.

[0136] Figures 8A to 8D Representative images of each of the above four treatment groups were provided. In Figures 8A to 8D it, the light color indicates the presence of neurite outgrowth, which is related to the ability of nerve regeneration. The dark part indicates the absence of neurite outgrowth. Figure 8A The image 810 in Figure 8B corresponded to the negative control, Figure 8C the image 820 in Figure 8D corresponded to the blank film,

[0137] As Figure 7 and Figures 8A to 8D could be seen, the presence of FK506 significantly increased the neurite outgrowth. No statistically significant difference was observed between the film containing FK506 and the use of the solution containing FK506. This indicates that the film containing FK506 is suitable for in vivo use, while the solution containing FK506 may not be suitable for in vivo use or is not practical for in vivo use (e.g., due to the inability to control the migration of the solution).

[0138] ***

[0139] It should be understood that although the present disclosure has been described with reference to preferred embodiments, exemplary embodiments, and optional features, those skilled in the art can make modifications and variations to the concepts disclosed herein, and such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims. The specific embodiments and examples provided herein are examples of the available embodiments of the present disclosure and are only non - restrictive and illustrative. It will be apparent to those skilled in the art that a large number of variations of the devices, device components, methods, and steps described in this specification can be used to implement the present disclosure. Those skilled in the art will recognize that the methods and devices that can be used for the present disclosure can include a large variety of alternative compositions and processing elements and steps.

Claims

1. A method for preparing an implantable biomaterial film, comprising: feeding a combination of a polymer and a nerve regenerator or an immunosuppressant into an extruder; melting the polymer within the extruder; and extruding the combined polymer and the nerve regenerator or the immunosuppressant to form the implantable biomaterial film.

2. The method according to claim 1, wherein the nerve regenerator or the immunosuppressant comprises FK506, rapamycin or nimodipine.

3. The method according to claim 1 or claim 2, wherein the implantable biomaterial film has a thickness of about 10 μm to about 200 μm.

4. The method according to any one of the preceding claims, wherein the implantable biomaterial film has a width of about 100 mm to about 6.4 mm.

5. The method according to any one of the preceding claims, further comprising incorporating the implantable biomaterial film as part of an implant.

6. The method according to claim 1, further comprising incorporating the implantable biomaterial film into one of a nerve connector, a pre-rolled nerve wrap, a sheet-shaped nerve wrap or a nerve graft.

7. The method according to claim 5, wherein the implant is a multi-layer implant.

8. The method according to claim 5 or claim 6, wherein the implantable biomaterial film is attached to the inner surface of the implant.

9. The method according to claim 5 or claim 6, wherein the implantable biomaterial film is attached to the outer surface of the implant.

10. The method according to any one of the preceding claims, wherein the nerve regenerator or the immunosuppressant comprises FK506, and the combination of the polymer and the KF506 fed into the extruder comprises about 1% to about 20% of FK506 by weight measurement.

11. The method according to any one of the preceding claims, wherein the nerve regenerator or the immunosuppressant comprises multiple nerve regenerators, multiple immunosuppressants, or at least one nerve regenerator and at least one immunosuppressant.

12. The method according to any one of the preceding claims, wherein the nerve regenerator or the immunosuppressant comprises at least one agent that is both nerve-regenerating and immunosuppressive.

13. The method according to any one of the preceding claims, further comprising reducing the thickness of the extruded implantable biomaterial film by compressing and / or stretching the extruded implantable biomaterial film using a film removal unit.

14. The method according to claim 13, wherein the film removal unit comprises a pair of pressure rollers having a gap spaced apart by about 10 μm to about 60 μm, about 20 μm to about 50 μm or about 30 μm to about 40 μm.

15. The method according to claim 13 or claim 14, further comprising operating the film removal unit at a substantially constant speed to facilitate the formation of the implantable biomaterial film having a substantially constant thickness.

16. The method according to any one of claims 13 to 15, further comprising operating the film removal unit at a speed about 2 to about 5 times faster than the speed at which the polymer is extruded.

17. The method according to any one of claims 13 to 16, wherein the film take-out unit operates at a certain speed such that the speed of the film immediately downstream of the roller of the film take-out unit is about 0.3 m / min to about 6.1 m / min, about 1.5 m / min to about 4.6 m / min, or about 2.1 m / min to about 3.0 m / min.

18. The method according to any one of claims 13 to 17, further comprising collecting the implantable biomaterial film with the film take-out unit.

19. The method according to any one of claims 13 to 18, wherein the roller of the film take-out unit is cooled with a liquid coolant.

20. The method according to any one of the preceding claims, further comprising cutting the implantable biomaterial film into a plurality of sheets.

21. The method according to any one of the preceding claims, wherein the polymer is a homopolymer, copolymer, and / or polymer blend comprising one or more of the following monomers: glycolide, lactide, caprolactone, p-dioxanone, trimethylene carbonate, cellulose derivative monomers, and monomers that can be polymerized to form a polyester.

22. The method according to any one of claims 1 to 20, wherein the polymer comprises poly(p-dioxanone).

23. The method according to any one of claims 1 to 20, wherein the polymer comprises poly(p-dioxanone) and a second polymer copolymerized with the poly(p-dioxanone).

24. The method according to any one of claims 1 to 20, wherein the polymer comprises poly(p-dioxanone) (PDS) and at least one of poly(trimethylene carbonate), poly(glycolide), poly(d,l-lactide), poly(l-lactide), or poly(caprolactone) as a copolymer with the PDS.

25. The method according to claim 24, wherein the copolymer is a random copolymer, and the polymer comprises about 40% to about 90% PDS by molecular weight, or about 50% to about 80% PDS.

26. The method according to claim 24, wherein the copolymer is a block copolymer, and the polymer comprises about 45% to about 85% PDS by molecular weight, or about 55% to about 75% PDS.

27. The method according to any one of claims 1 to 20, wherein the polymer comprises poly(p-dioxanone) (PDS) and at least one of poly(glycolide), poly(l-lactide), or poly(d,l-lactide) as a copolymer with the PDS.

28. The method according to claim 27, wherein the polymer is surface-treated with polyethylene glycol.

29. The method according to claim 27 or claim 28, wherein the polymer contains a basic salt, and the basic salt accounts for about 0.5% to about 10% of the polymer by molecular weight.

30. A method for preparing an implantable biomaterial film, comprising: feeding a combination of a polymer and FK506 into an extruder; melting the polymer; extruding the polymer and the FK506 using a film die to form an implantable biomaterial film; cooling the implantable biomaterial film; and Collect the implantable biomaterial film comprising the polymer and FK506 of the combination.

31. The method according to claim 30, wherein the implantable biomaterial film has a thickness of about 10 μm to about 200 μm.

32. The method according to claim 30 or claim 31, wherein the implantable biomaterial film has a width of about 100 mm to about 6.4 mm.

33. The method according to any one of claims 30 to 32, further comprising incorporating the implantable biomaterial film as part of an implant.

34. The method according to claim 30, further comprising incorporating the implantable biomaterial film into one of a nerve connector, a pre-rolled nerve wrap, a sheet-shaped nerve wrap, or a nerve graft.

35. The method according to claim 33, wherein the implant is a multi-layer implant.

36. The method according to claim 35, wherein the layers of the implant comprise small intestinal submucosa, amniotic tissue, or recombinant denatured collagen.

37. The method according to claim 35, wherein the layers of the implant further comprise a synthetic material in addition to the film.

38. The method according to any one of claims 33 to 37, wherein the implantable biomaterial film is attached to the inner surface of the implant.

39. The method according to any one of claims 33 to 37, wherein the implantable biomaterial film is attached to the outer surface of the implant.

40. The method according to any one of claims 30 to 39, further comprising reducing the thickness of the extruded implantable biomaterial film by compressing and / or stretching the extruded implantable biomaterial film using a film take-out unit.

41. The method according to claim 40, wherein the take-out unit comprises a pair of pressure rollers spaced apart by a gap of about 10 μm to about 60 μm, about 20 μm to about 50 μm, or about 30 μm to about 40 μm.

42. The method according to claim 40 or claim 41, further comprising operating the film take-out unit at a substantially constant speed to facilitate the formation of the implantable biomaterial film having a substantially constant thickness.

43. The method according to any one of claims 40 to 42, further comprising operating the film take-out unit at a speed about 2 times to about 5 times faster than the speed at which the polymer is extruded from the film die.

44. The method according to any one of claims 40 to 43, wherein the film take-out unit is operated at a speed such that the speed of the film immediately downstream of the rollers of the film take-out unit is about 0.3 m / min to about 6.1 m / min, about 1.5 m / min to about 4.6 m / min, or about 2.1 m / min to about 3.0 m / min.

45. The method according to any one of claims 40 to 44, further comprising collecting the implantable biomaterial film with the film take-out unit.

46. The method according to any one of claims 40 to 45, wherein the rollers of the take-out unit are cooled with a liquid coolant.

47. The method according to any one of claims 40 to 46, wherein collecting the implantable biomaterial film comprises winding the implantable biomaterial film onto a collecting roller of the retrieving unit.

48. The method according to any one of claims 30 to 47, further comprising cutting the implantable biomaterial film into a plurality of sheets.

49. The method according to any one of claims 30 to 48, wherein the combination of the polymer and the KF506 input into the extruder comprises about 1% to about 20% of FK506 by weight measurement.

50. The method according to any one of claims 30 to 49, wherein the polymer is a homopolymer, copolymer, and / or polymer blend comprising one or more of the following monomers: glycolide, lactide, caprolactone, p-dioxanone, trimethylene carbonate, cellulose derivative monomers, and monomers polymerizable to form polyesters.

51. The method according to any one of claims 30 to 49, wherein the polymer comprises poly(p-dioxanone) and a second polymer copolymerized with the poly(p-dioxanone).

52. The method according to any one of claims 30 to 49, wherein the polymer comprises poly(p-dioxanone) (PDS) and poly(trimethylene carbonate), poly(l-lactide), or poly(caprolactone) as a copolymer with the PDS.

53. The method according to claim 52, wherein the copolymer is a random copolymer, and the polymer comprises about 50% to about 90% PDS, or about 60% to about 80% PDS by molecular weight.

54. The method according to claim 52, wherein the copolymer is a block copolymer, and the polymer comprises about 45% to about 85% PDS, or about 55% to about 75% PDS by molecular weight.

55. The method according to any one of claims 30 to 49, wherein the polymer comprises poly(p-dioxanone) (PDS) and at least one of poly(glycolide), poly(l-lactide), or poly(d,l-lactide) as a copolymer with the PDS.

56. The method according to any one of claims 50 to 55, wherein the polymer is surface-treated with polyethylene glycol.

57. The method according to any one of claims 50 to 55, wherein the polymer contains a basic salt, and the basic salt accounts for about 0.5% to about 10% of the polymer by molecular weight.

58. An implant, comprising: An extruded film, the extruded film comprising: Poly(p-dioxanone) (PDS); and FK506, rapamycin, or nimodipine.

59. The implant according to claim 58, wherein the implant is a nerve wrap or forms part of a nerve wrap.

60. The implant according to claim 58, wherein the implant forms part of a nerve connector.

61. The implant according to claim 58, wherein the implant forms part of a pre-rolled nerve wrap.

62. The implant according to claim 58, wherein the implant forms part of a nerve graft.

63. The implant according to claim 62, wherein the nerve graft comprises acellular material.

64. The implant according to claim 58, wherein the film is attached to the outer surface of the implant.

65. The implant according to claim 58, wherein the film is attached to the inner surface of the implant.

66. The implant according to any one of claims 58 to 65, wherein the implant is a multi-layer implant.

67. The implant according to claim 66, wherein the layers of the implant comprise small intestinal submucosa, amniotic basement tissue, or recombinant denatured collagen.

68. The implant according to claim 66, wherein the layers of the implant further comprise a synthetic material in addition to the film.

69. The implant according to any one of claims 58 to 68, wherein the film has a thickness of about 10 μm to about 200 μm.

70. The implant according to any one of claims 58 to 69, wherein the film has a width of about 100 mm to about 6.4 mm.

71. The implant according to any one of claims 58 to 70, wherein the extruded film comprises a polymer that contains, in addition to the PDS, poly(glycolide), poly(l-lactide), or poly(d,l-lactide) as a copolymer with the PDS.

72. The implant according to claim 71, wherein the polymer is surface-treated with polyethylene glycol.

73. The implant according to claim 71 or claim 72, wherein the polymer contains a basic salt, and the basic salt accounts for about 0.5% to about 10% of the polymer by molecular weight.

74. The implant according to any one of claims 58 to 73, wherein the extruded film comprises rapamycin or nimodipine.

75. A method of treating a subject, comprising implanting an implant according to any one of claims 58 to 74 into the subject.

76. The method according to claim 75, wherein the implant is implanted at a peripheral nerve of the subject.

77. The method according to claim 75 or claim 76, wherein the subject is a mammal.

78. The method according to claim 77, wherein the subject is a human.

Images