TW202339740A - Drug delivery system and methods of using the same - Google Patents

Abstract

A method of preparing an implantable biomaterial includes combining a polymer comprising polydioxanone with a neuro-regenerative agent or an immunosuppressive agent comprising at least one immunophilin ligand, and melting the polymer. The method further includes extruding the combined polymer and the neuro-regenerative agent or immunosuppressive agent to form the implantable biomaterial.

Description

Drug delivery systems and methods of use

The present disclosure relates generally to the fields of tissue repair and medicine. More specifically, the present disclosure relates to biomaterials and drug delivery platforms containing regenerative compounds including neuroregeneration compounds, as well as methods of making biomaterials and drug delivery platforms, and methods of treatment using such biomaterials and drug delivery platforms.

Regardless of its cause, nerve damage can lead to severe, and in some cases profound, disability and functional impairment. Neuropathic injuries, among others, can cause chronic pain, loss of sensation, loss of some or all muscle control, or other adverse effects. Addressing the deleterious effects of peripheral nerve injury is a considerable challenge, especially when nerve repair is delayed or requires axons to reconnect to peripheral targets over large nerve defects or over long distances. In this situation, regenerating axons often do not have the required chemical and physiological signals to effectively regenerate and reinnervate their terminal target organs. For example, relatively long nerve gaps may experience depletion of neurotrophic factors in the proximal nerve stump, and neurotrophic factor concentrations may decrease in the growth-supportive environment of the distal nerve stump. .

Despite recent advances in surgical techniques, the number of patients with peripheral nerve injuries who have regained full function is limited. Therefore, there is a need to develop clinically applicable techniques to treat nerve injury and restore sensory and functional outcomes after nerve injury. To promote effective recovery of function and sensation after nerve injury and repair, intervention or treatment should support axonal regeneration and/or increase the number of neurons that regenerate their axons.

According to the present disclosure, biomaterials may include regenerative agents such as neuroregenerative agents or immunosuppressive agents. Biomaterials can be used for tissue damage and direct repair (e.g., direct nerve repair) or with implants (e.g., nerve grafts), can be attached to implants (e.g., fixed to the surface of the implant), or Can be incorporated as part of the implant. In particular, the biomaterial may include FK506 incorporated into one or more regions or surfaces of a biomaterial suitable for implantation at or near an injured nerve. In this manner, biomaterials can be used to form localized drug delivery systems to promote repair of damaged tissue, such as neural tissue.

In one aspect, a method of preparing an implantable biomaterial can include combining a polymer including an oxycyclohexanone polymer with a neuroregenerative or immunosuppressive agent including at least one immunophilin ligand, melting the polymer, and extruding the combined polymer and the nerve regeneration agent or immunosuppressive agent to form the implantable biomaterial.

In another aspect, a method of preparing an implantable biomaterial can include combining a polymer with FK506, melting the polymer, and extruding the combined polymer and FK506 to form the implantable biomaterial.

In another aspect, the implant may comprise an oxyhexanone polymer and at least one immunophilin ligand bound to the oxyhexanone polymer.

In another aspect, the implant may comprise a biomaterial comprising a polymer and FK506 contained in the polymer. The biomaterial of the implant can be incorporated into the neural implant in the form of one or more of extruded pellets, rods, sheets, springs or fibers.

Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. It is to be understood, however, that the detailed description and embodiments, while indicating exemplary embodiments of the present disclosure, are set forth by way of illustration only, as it will be apparent to one of ordinary skill in the art that this invention is within the spirit and scope of the present invention. Various changes and modifications will become apparent from this detailed description. Note that just because a particular compound belongs to one formula does not mean that it cannot also belong to another formula.

The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. The terms "approximately" and "approximately" mean substantially the same as a reference number or value. As used herein, the terms "about" and "approximately" should generally be understood to encompass ±10% of a specified amount or value. The term "or" is used in the claims and specification to mean "and/or" unless it is expressly stated that only alternatives are intended or that alternatives are mutually exclusive, although this disclosure supports that only alternatives and "and/or" are meant. . As used herein, "another" may mean at least a second or more. As used herein, the terms "implant" and "implant" need not be placed within a subject such that the implant is beneath the skin or other tissue. Conversely, the term "implant" also includes patches for placement on skin tissue, wraps for skin tissue, and devices for placement on or near mucosa or other tissue surfaces.

Embodiments of the present disclosure relate to the use of neuroregenerative agents or immunosuppressive agents. As used herein, the term "nerve regeneration or immunosuppressive agent" refers to a single nerve regeneration that is distinct from one or more nerve regeneration agents in the absence of an immunosuppressive agent, in the absence of one or more nerve regeneration agents and in the presence of an immunosuppressive agent. Reagents and a single immunosuppressive reagent, the presence of a single reagent that is both neuroregenerative and immunosuppressive (such as FK506), multiple neuroregenerative reagents and multiple immunosuppressive reagents, a single neuroregenerative reagent and multiple immunosuppressive reagents, or multiple neuroregenerative agents reagents and single immunosuppressive reagents, regardless of whether the term "neuroregenerative or immunosuppressive reagent" is presented in the singular or plural form, or is simply referred to as "reagent". Additionally, although nerve regeneration agents are described herein for use in nerve repair, it is contemplated that regenerative agents suitable for use in tissues other than nerves can be used.

The foregoing general description and the following detailed description are exemplary and explanatory only, and are not restrictive of the claimed features. As used herein, the terms "comprises," "includes," "contains," "having" or other variations thereof are intended to cover the non-exclusive inclusion such that a process, method, article or apparatus including a list of elements includes more than just such elements , may also include other elements not expressly listed or are inherent in such elements. Additionally, the term "exemplary" is used herein to mean "example," not "ideal." Furthermore, the term "between" when used to describe a numerical range is intended to include both the minimum and maximum values stated herein.

The terms and expressions used are for purposes of description rather than limitation, and in using such terms and expressions it is not intended to exclude any equivalents of the features shown and described, or parts thereof, but it will be understood that in claiming Various modifications can be made within the scope of disclosure.

Biomaterials useful as topical drug delivery devices and implants of the present disclosure may incorporate one or more neuroregenerative or immunosuppressive agents within the polymeric material. The biomaterial may be attached to or included in a neural implant (e.g., nerve wrap, nerve connector, pre-rolled nerve wrap, nerve graft, etc.) or may be implanted separately (e.g., already or at or near the injured site or other location where a neural implant is to be implanted) to form a local drug delivery device. The biomaterial may be of any suitable shape, such as fibers, rods, beads, pellets, spheres, granules, sheets, films of any suitable size (e.g., inner diameter, outer diameter, length, width, overall thickness, wall thickness, etc.) , caps, tubes, etc. In at least some embodiments, the biomaterial can be in injectable form. For example, the biomaterial may include an injectable carrier (eg, an injectable polymer including a hydrogel, a colloidal dispersion such as a colloidal gel, and/or micelle). Injectable biomaterials may incorporate one or more neuroregenerative or immunosuppressive agents. One or more regenerative, eg, neuroregenerative or immunosuppressive, agents may be distributed throughout the biomaterial or located on one or more surfaces or regions of the biomaterial. The biomaterial can be distributed throughout a tissue implant such as a neural implant, it can be located on one or more surfaces or regions of the tissue implant, or it 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, and in some aspects can improve the results of nerve regeneration. Exemplary biomaterials, related methods for their preparation, and related methods of treatment using biomaterials are described in detail below. Although local drug delivery systems, biomaterials, implants, and methods are discussed herein with respect to use at neural sites, local drug delivery systems, biomaterials, implants, and methods may be applied to other types of tissue in a subject and other Location.

Biomaterials may include polymers suitable for use in conjunction with neural implants. The polymer may be compatible with one or more neuroregenerative or immunosuppressive agents. The polymer becomes biodegradable when implanted into humans or non-human animals. Polymers may include homopolymers, copolymers, and/or polymer blends including one or more of the following monomers: glycolide, lactide, caprolactone, dioxanone ), trimethylene carbonate, monomers of cellulose derivatives and monomers that polymerize to form polyester. Polymers may include polydioxanone (PDS), polycaprolactone (PCL), polytrimethylene carbonate, polyglycolide (PGL), poly3-hydroxybutyrate (poly-3-hydroxybutyrate, PHB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (poly(3-hydroxybutyrate-co-3-hydroxyvalerate, PHBV), poly(propylene carbonate) (poly(propylene carbonate, PPC), poly(butylene succinate), PBS), propylene fumarate polymer (poly(propylene fumarate), PPF). The polymer can be made from one of these monomers Two or more formulations. The polymer may be copolymerized with lactide and/or glycolide. The polymer may be a copolymer including dioxanone copolymerized with lactide and/or glycolide. polymer such that the polymerized dioxanone forms the majority of the polymer by weight. The polymer may include polylactic acid (PLA) or poly(lactic-co-glycolic acid) (poly(lactic-co- glycolic acid, PLGA). However, in some aspects, the polymer may be free of either or both PLA and PLGA.

One or more neuroregenerative or immunosuppressive agents may include an immunophilin ligand. One or more neuroregenerative or immunosuppressive agents may include cyclosporine A or FK506 (tacrolimus). In specific examples, one or more neuroregenerative or immunosuppressive agents may include FK506. One or more neuroregenerative or immunosuppressive agents can be hydrophobic and have a melting point below about 120 degrees Celsius or below about 110 degrees Celsius.

One or more neuroregenerative or immunosuppressive agents can be mixed with the polymer at any suitable concentration, as described below. Biomaterials can be manufactured by producing so-called "master batches," also referred to herein as "stock batches" of biomaterials, which contain polymers and materials with respect to which they will ultimately be used for in vivo drug delivery. Higher concentrations of one or more nerve regeneration or immunosuppressive agents (e.g. 10% by weight of nerve regeneration or immunosuppressive agents such as FK506). Additionally, biomaterials can be made by combining polymers with neuroregenerative or immunosuppressive agents without using stock batches (e.g., by combining one or more neuroregenerative or immunosuppressive agents with polymers that do not contain these agents). Combine the formed biomaterials to achieve concentrations that will ultimately be used for local drug delivery). Stock batches may be used to provide customization for specific uses of localized drug delivery such that stock batches of materials may be used for subsequent processing to produce one or more biomaterials in one of a number of possible final forms and Appropriate reagent concentrations are described below. Depending on the needs, the different biomaterials produced can be used as building blocks to create different localized drug delivery systems.

The biomaterial can be provided in a suitable form factor, whether the biomaterial is an intermediate product (e.g. when the biomaterial is part of a stock batch) or a final form (e.g. intended to be contained in or attached to an implant e.g. Neural implants, or products used independently of neural implants). The biomaterial may be formed into one or more pellets (eg, a stock batch of biomaterial) or one or more fibers or sheets (eg, biomaterial for implantation). The diameter of the fiber may be approximately constant, or the diameter may vary (eg, the diameter may vary regularly or irregularly along the length of the fiber). The fibers may be knotted so that the fibers include one or more knots, such as one or more square knots or one or more loops. The fibers may have a helical shape, including many turns. When knots are present, they can be formed in a manner that can control the number, spacing, size, etc. of the knots.

Biological material can be provided in the form of one or more sheets. The sheet may include embedded fibers and/or may be a nonwoven sheet. Biomaterials can be formed via extrusion of a polymer into one or more sheets. If desired, the biomaterial can be in the form of one or more braided sheets containing a plurality of braided polymer fibers. Fibers of biomaterial may include one or more neuroregenerative or immunosuppressive agents. Biomaterials formed into woven or nonwoven sheets may include one or more patches. The patch may include a biomaterial (e.g., a polymer and one or more neuroregenerative or immunosuppressive agents) and may be surrounded by a polymer that does not contain the neuroregenerative or immunosuppressive agent, or the sheet surrounding the patch may include a polymer and nerve regeneration or immunosuppressive agents and the patch includes a polymer that does not contain nerve regeneration or immunosuppressive agents. When the biomaterial is in sheet form, one or more depots, bags, or reservoirs of one or more neuroregenerative or immunosuppressive agents may be included. The bag or reservoir may provide a continuous supply of neuroregenerative or immunosuppressive agents, for example, for localized, sustained release.

The biomaterial may be in the form of one or more rods or pellets, regularly or irregularly shaped particles, beads, spheres, sheets, films, or may have any other suitable shape. When the biomaterial is in the form of beads, rods, or pellets (which may be short rods), the diameter of the biomaterial may be substantially constant (eg, substantially the same diameter along the length of each rod). The lengths of the multiple rods can be substantially the same. Alternatively, the biomaterial may include a plurality of pellets with diameters and/or lengths within a desired range, with each pellet having a different diameter and/or length. Biomaterials may be formed to include a plurality of pellets, spheres, or other shapes of similar or different lengths and/or diameters.

In some aspects, the biomaterial can be integrated with the neural implant (e.g., one or more portions of the implant can be formed from or can be combined with the biomaterial), the biomaterial can be attached to the implant (e.g., the biomaterial can attached to the inside or outside of the implant), or the biomaterial can be implanted in the same area as the neural implant. The biomaterial can be in any suitable form factor, whether integrated with the implant, attached to the implant, or implanted in the same area as the implant. Neural implants can be used for a variety of purposes, including as nerve connectors, nerve wraps, nerve grafts, nerve protectors, and more. In particular, biomaterials may be provided as part of an implant or used with an implant, such as in U.S. Patent Application No. 15/344908, filed on November 7, 2016, granted as U.S. Patent No. 10835253; in August 2016 U.S. Patent Application No. 15/252917, filed on the 31st, and granted U.S. Patent No. 10945737; U.S. Patent Application No. 15/900971, filed on February 21, 2018, and granted U.S. Patent No. 10813643; on April 11, 2019 U.S. Patent Application No. 16/381860, filed as U.S. Patent No. 11166800; U.S. Patent Application No. 16/192261, filed on November 15, 2018, granted as U.S. Patent No. 11477558; filed on September 25, 2013 U.S. Patent Application No. 14/036405, granted as U.S. Patent No. 9,629,997; U.S. Patent Application No. 16/898224, filed on June 10, 2020; or U.S. Patent Application No. 17/451489, filed on October 20, 2021 .

Although the implant may be a neural implant, the implant may be something other than a neural implant. Any of the biomaterials discussed here can be used in implants other than neural implants. In some aspects, biomaterials and/or implants may be used in vascular implants, implants or placement on the skin surface (e.g., as topical patches, transdermal patches, etc.), bone implants, spinal implants, urology ( urological) implants, tendon implants, muscle implants and/or others. One or more neuroregenerative or immunosuppressive agents may be immunosuppressive agents when incorporated into implants other than neural implants. These agents may have other properties that are beneficial to the implantation site, and/or may be provided with additional compounds that provide beneficial properties. For example, an implant intended for vascular implantation may include, in addition to one or more immunosuppressive agents, an anti-proliferative agent that inhibits neointimal hyperplasia, such as paclitaxel.

When the implant is a neural implant, the neural implant may be formed from tissue, such as nerve graft tissue. For example, neural tissue can be coated or impregnated with biomaterials. In one aspect, pellets or fibers of biomaterial can be coated on or impregnated into the tissue graft. Additionally or alternatively, the implant can be administered in dissolved, micronized or powder form with one or more immunosuppressive agents for use as an injectable implant. Nerve graft tissue suitable for treatment according to the methods herein may be natural or synthetic. For example, the tissue may be soft biological tissue obtained from animals, such as mammals, including humans or non-human mammals, or non-mammals, including fish, amphibians, or insects. The tissue may be allogeneic or xenogeneic relative to the subject into which the graft is implanted. The tissue may be neural tissue, including, for example, peripheral nervous tissue or central nervous system tissue. Other types of tissue suitable for use in the present disclosure include, but are not limited to, epithelial tissue, connective tissue, muscle tissue, microvascular tissue, dermal tissue, skeletal tissue, smooth muscle tissue, cardiac tissue, and adipose tissue. As mentioned above, the biological soft tissue may be mammalian tissue, including human tissue and other primate tissue, rodent tissue, equine tissue, canine tissue, rabbit tissue, porcine tissue, or sheep tissue. Additionally, the tissue may be a non-mammalian tissue selected from fish, amphibian or insect tissue. The tissue may be a synthetic tissue, such as, but not limited to, laboratory-grown tissue or 3D-printed tissue. According to some examples, the tissue is neural tissue obtained from an animal, such as a human or non-human mammal. Organizations may obtain and/or process as disclosed in U.S. Patent Application No. 17/411,718 entitled "Nerve Grafts and Methods of Preparation Thereof" filed on August 25, 2021, the entire contents of which are incorporated by reference. In at least some embodiments, an exemplary tissue may be a processed human neural allograph, such as Avance® Nerve Graft from Axogen, Inc. (Alachua, FL, US).

Although embodiments of the present disclosure are described with respect to biomaterials useful in nerve injuries, and particularly with respect to neural implants used in peripheral nerve injuries, it is contemplated that other types of tissue, including any of the materials described above, may be used as described herein. The methods and implants described.

Figure 1 illustrates a process for manufacturing biomaterials such as biomaterial 142 (particles such as spheres, pellets, etc., shown in Figure 1) and/or biomaterial 144 (fibrous biomaterial collected on a spool as shown in Figure 1). Diagram of an exemplary process 100, which may include polymers and immunosuppressive or neuroregenerative agents. Biomaterials 142 and 144 may be suitable for implantation into humans or non-human animals. For example, biomaterials 142 and 144 may be suitable for use with neural implants and/or suitable for implantation in humans or non-human animals. Biological material 132 may also be formed during process 100 . The biomaterial 132 may form a "stock batch" of biomaterial, as described in detail below.

Figure 2 shows a flow diagram of an exemplary process 200 for making a biomaterial including a polymer and one or more immunosuppressive or neuroregenerative agents, such as FK506. As will be understood with reference to FIG. 1 below, although process 200 is described in conjunction with process 100 , process 200 may include fewer steps, additional steps, and/or different steps than process 100 . Additionally, process 200 may include fewer steps, additional steps, and/or different steps, or a specific sequence of steps, than each block shown in FIG. 2 (eg, steps 202, 204, 206, and 208). Can be different.

In step 202 (Fig. 2), polymer 112 (Fig. 1) is obtained. Polymer 112 may include polyester. Polymer 112 may include oxycyclohexanone polymer (PDS), polycaprolactone (PCL), polyglycolide (PGL), poly3-hydroxybutyrate (PHB), poly(3-hydroxybutyrate) -co-3-hydroxyvalerate) (PHBV), poly(propylene carbonate) (PPC), polybutylene succinate (PBS) and propylene fumaric acid polymer (PPF). Polymer 112 may include polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). However, in at least some embodiments, polymer 112 may be free of both PLA and PLGA. Forming polymer 112 that is free of both PLA and PLGA may allow biomaterial 142 to avoid acid generation at the implant site that may occur when PLA or PLGA degrades after implantation.

The obtained polymer 112 may be in any suitable form, especially powder, silk, particles (spheres, pellets, etc.), etc. For example, polymer 112 may be a substantially pure powder suitable for mixing with one or more immunosuppressive or neuroregenerative agents, which may also be in powder form. Step 202 may include synthesizing polymer 112 if desired. For example, when the polymer 112 is PDS, the polymer 112 can be obtained by ring-opening polymerization of p-dioxanone. When polymer 112 is in a form other than a powder, step 202 may include forming another structure from polymer 112 (eg, particles, filaments, etc.) by grinding particles, filaments, pellets, or another structure of polymer 112 . A form of powder to obtain a powder of the polymer 112 with particles and/or particles of suitable size to facilitate homogeneous mixing of the polymer 112 with the immunosuppressive or neuroregenerative agent 110 .

In step 204 (Fig. 2), one or more immunosuppressive or neuroregenerative agents 110 (Fig. 1) may be mixed with polymer 112. Mixing may include physically mixing reagent 110 and polymer 112 . For example, reagent 110 and polymer 112 , one or both of which are in powder form, may be mixed together sufficiently to produce a uniform, homogenously mixed mixture of pellets having the desired properties of reagent 110 relative to polymer 112 Proportion. Although reagent 110 and polymer 112 may be mixed when both are in the solid state, one or both reagent 110 and polymer 112 may be in liquid form during mixing. For example, reagent 110 and polymer 112 may be heated, dissolved in a solvent, etc. to produce a liquid form suitable for mixing with another liquid. In embodiments where the reagent 110 and the polymer 112 are mixed in liquid form, the melting agent 110 and the polymer 112 in step 206 described below may be omitted.

Reagent 110 and polymer 112 may each be provided to a single system or device configured to mix both reagent 110 and polymer 112 and melt polymer 112 (as described below with respect to step 206 of method 200 ). For example, as shown in FIG. 1 , the extruder 114 may include a plurality of feed devices, such as feed hoppers, for respectively receiving the reagent 110 and the polymer 112 in solid form (eg, as a powder). In some aspects, reagent 110 and polymer 112 may be mixed before polymer 112 is supplied to a device for melting polymer 112 (described below with respect to step 206 of method 200). In these examples, one or more devices may facilitate performance of step 204 in which reagent 110 and polymer 112 are mixed, and one or more additional devices may facilitate execution of step 204 in which polymer 112 is melted (e.g., by providing the reagent with The execution of step 206 (homogeneous mixture of polymer 112).

In examples where one or more immunosuppressive or neuroregenerative agents 110 and polymer 112 are supplied to separate feeders for extruder 114 , extruder 114 may be configured to add metered amounts of agent 110 and A metered amount of polymer 112 is supplied to mixing section 118 . This may be performed using feeder devices such as material feed hoppers 115 (two feed hoppers 115 are shown in Figure 1). Feed hopper 115 may be configured to feed reagents 110 and polymer 112 in a controlled manner, where reagents 110 and polymer 112 are drawn into the interior of extruder 114 . The feed hopper 115 or other feed device may be configured to compensate for changes in the reagents 110 and polymer 112 supplied to the extruder 114 such as weight loss as material is depleted in the example of a gravity fed feed device. .

Whether reagent 110 and polymer 112 are mixed before being supplied to extruder 114 or mixed by extruder 114 itself, reagent 110 and polymer 112 can be metered so that the ratio of reagent 110 to polymer 112 is accurately ground control. For example, the concentration of reagent 110 may range from about 0.5% to about 30% by weight of the biological material, from about 1% to about 20% by weight, or from about 2% to about 10% by weight. within the range. In particular, the concentration of reagent 110 may be about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 10% by weight, or about 20% by weight. The concentration of reagent 110 in biomaterials 132, 142, and/or 144 (as described below) output from extruder 114 may be substantially the same as the concentration of reagent 110 received by extruder 114, or may be the same as the concentration of reagent 110 during extrusion. The concentration at any point in the outlet 114 is the same. Regardless, the concentration of reagent 110 within the extruded product may be any of the concentrations described above.

Step 206 (Fig. 2) of step 200 may include melting the polymer 112 (Fig. 1) received in the extruder 114. This may include supplying reagents 110 and polymer 112 to a feed hopper or other input to the extruder 114 . The extruder 114 may be a single-screw or twin-screw extruder, which includes an extruder screw 116 having a conveying part 118 , a kneading part 120 , a conveying part 122 , a shearing part 124 and a metering part 126 . The extruder 114 may be a twin-screw extruder including a pair of co-rotating or counter-rotating screws 116. Screw 116 may be sized suitable for manufacturing biomaterial 132 . For example, the outer diameter of the screw 116 may range from about 9 mm to about 36 mm, with the outer diameter being the maximum diameter of the screw 116 . In particular, the maximum outer diameter of screw 116 may be approximately 18 mm.

The conveying portion 118 of the extruder screw 116 may include threads sized to receive the reagent 110 and polymer 112 and convey both materials downstream. Additionally, the conveying portion 118 may include a region that includes threads with a reduced pitch (threads that are spaced closer together) to generate heat to begin softening the polymer 112 . Kneading portion 120 can receive reagent 110 and polymer 112 . The threads of the kneading portion 120 may have a geometry suitable for generating heat through friction to melt the polymer 112 . The heat generated by kneading portion 120 during step 206 may be sufficient to soften and at least partially melt polymer 112 without adversely affecting the effectiveness of reagent 110 by overheating. For example, the temperature may range from about 80 degrees Celsius to about 150 degrees Celsius. The temperature generated by the extruder 114 may be selected based on the softening and/or melting temperatures of the reagent 110 and polymer 112, or to avoid temperatures at which the reagent 110 may be destroyed or inactivated, such as denatured.

Second delivery portion 122 can receive heated material from kneading portion 120 and supply the material to shearing portion 124 , which includes shearing or kneading configured to further increase the temperature of reagent 110 and polymer 112 thread. The temperature generated using shear section 124 may be the highest temperature generated by extruder 114 . The maximum temperature within the extruder 114 may be above the melting temperature of the reagent 110 and above the melting temperature of the polymer 112 . In the example where reagent 110 is FK506 and polymer 112 is PDS, shear portion 124 may be configured to generate a temperature in the range of about 110 degrees Celsius to about 155 degrees Celsius. For example, shear portion 124 can increase the temperature of reagent 110 and polymer 112 from a temperature of about 100 degrees Celsius to a temperature in the range of about 120 degrees Celsius to about 155 degrees Celsius. In particular, shear portion 124 can increase the temperature of reagent 110 and polymer 112 to approximately 135 degrees Celsius. This temperature may be sufficient to ensure that polymer 112 is in a liquid state before reagent 110 and polymer 112 are received by the die downstream of extruder 114 .

Although the heat generated by the extruder 114 may be generated entirely by friction caused by the rotation of the extruder screw 116, one or more heaters may be affixed to the extruder 114 to assist in generating the desired amount of heat and in One or more locations within the extruder 114 are maintained at the desired temperature. These heaters may be placed at one or more locations along the barrel of the extruder 114 and may partially or completely surround the kneading portion 120 , the shearing portion 124 , and/or any other portion of the extruder 114 . The temperature may be monitored at one or more locations along the length of the extruder 114. For example, one or more temperature sensors may be positioned to detect the temperature within extruder 114. A control system in communication with these temperature sensors can control the heater on the barrel of the extruder 114 to maintain the desired temperature.

For example, step 208 (FIG. 2) may include extruding reagent 110 (FIG. 1) and polymer 112 using extruder 114. The melted and mixed reagent 110 and polymer 112 may be delivered and metered via metering section 126 downstream of shearing section 124 . Metering section 126 may supply homogenized reagent 110 and polymer 112 to an extruder die having an opening with a diameter of about 0.5 mm to about 2 mm, or suitable for extrusion to a final diameter of about 50 mm. Other diameters for fibers from µm to about 200 µm (e.g. using a puller to pull down the diameter of the fiber). In other aspects, the extruder die can have an opening of about 50 µm to about 200 µm in diameter for producing extruded fibers having a final diameter of about 50 µm to about 200 µm. In particular, the extruder die may have an opening with a diameter of approximately 1 mm. The extruded material, including reagent 110 and polymer 112, may be received by a pelletizer or other forming device 128. While metering portion 126 may be formed from a downstream portion of extruder screw 116 , metering portion 126 may include a metering pump (eg, a gear pump) configured to push accurately metered amounts of combined reagent 110 and polymer 112 to The output of the extruder 114.

Metering section 126 is capable of supplying combined reagent 110 and polymer 112 to forming device 128 at a desired rate. Shaping device 128 may be any suitable device or devices configured to modify or otherwise control the shape of the product extruded by extruder 114, allowing for the production of biomaterial 132 having a desired form. In particular, the forming device 128 may include a sheet extrusion system, a textile system (e.g., for making fibers), a device for forming pellets, spheres, etc. instead of or in addition to a pelletizer. Including those mentioned above.

When the forming device 128 is a granulator (eg, as shown in FIG. 1 ), the forming device 128 may be configured to cut the extruded material into a plurality of pellets or rods or other shapes to form the biomaterial 132 . Biomaterial 132 may include reagent 110 and polymer 112 that are homogeneously mixed and solidified after extrusion through extruder 114 . The amount of reagent 110 in biological material 132 may substantially correspond to the ratio of reagent 110 introduced during step 204 relative to polymer 112, and may be equivalent to any of the concentrations or concentration ranges described above. For example, the concentration of reagent 110 may range from about 0.5% to about 30% by weight, from about 1% to about 20% by weight, or from about 2% to about 10% by weight. In particular, the concentration of reagent 110 may be about 2% by weight, about 3% by weight, about 4% by weight, or about 20% by weight.

In at least some embodiments, biomaterial 132 may be formed from a relatively high concentration of agent 110 to form a stockpile of one or more immunosuppressive or neuroregenerative agents integrated with polymer 112 . The concentration of reagent 110 in a stock batch of biological material 132 may range from about 5% to about 30% by weight, or from about 8% to about 20% by weight. In particular, the concentration of reagent 110 in the stock batch of biological material 132 may be about 8% by weight, about 10% by weight, about 15% by weight, or about 20% by weight.

In embodiments where biomaterial 132 is not a stock batch, biomaterial 132 can be formed at a concentration of agent 110 suitable for use in a local drug delivery device, such as an implant. For example, the concentration of reagent 110 within biological material 132 may range from about 0.5% to about 8% by weight, from about 1% to about 6% by weight, or from about 2% to about 4% by weight. In particular, the concentration of reagent 110 within biological material 132 may be about 2% by weight, about 3% by weight, or about 4% by weight.

In examples where biomaterial 132 that is not intended for implantation without further processing is produced in a so-called "stock" batch, this may be achieved, for example, by utilizing the same or different extruders 114 or one or more Other devices process biological material 132 and the process 200 described above is repeated. Examples of preparation of such further biological material are described below with reference to further (eg, a second or subsequent) performance of method 200 (FIG. 2) utilizing biological material 132. This further performance of method 200 may facilitate a controlled reduction of the concentration of reagent 110 within biological material 132 . If desired, further performance of method 200 , as described below, may facilitate the incorporation of one or more second polymers 134 that are different from the polymer 112 used to make biomaterial 132 .

As an alternative to further performance of method 200, biomaterial 132 formed into a stock batch may be used to manufacture an implant including an injectable polymer. For example, stock batches can be processed to produce hydrogels, colloidal gels, and/or to form polymers including microcells. The injectable implant formed by this process can include a desired concentration of agent 110 and can be implanted into a desired location in a subject (eg, an area of peripheral nerve damage) by injection.

When performing method 200 using biological material 132, as shown in the right portion of Figure 1, step 202 (Figure 2) can be repeated by obtaining additional polymer 134. This additional polymer 134 can be obtained as described above with respect to polymer 112. Additional polymer 134 may be the same polymer as polymer 112 (PDS in the example shown in FIG. 1 ), or polymer 134 may be different than polymer 112 . When additional polymer 134 is different from polymer 112, polymer 134 may be selected to be compatible with polymer 112. In certain embodiments, polymer 134 is completely free of reagent 110 and thus may be considered a "pure" polymer. Polymer 134 can be used to reduce the concentration of reagent 110 in products made by repeating method 200, as described below.

Step 204 may be repeated by mixing biomaterial 132 with additional polymer 134 . For example, rods or pellets of biomaterial 132 may be mixed with pellets, spheres, powder, or another form of polymer 134 . In some aspects, the biomaterial 132 may be structurally modified (e.g., ground into powder form, melted, etc.) prior to being mixed together with the polymer 134. Additionally, although FIG. 1 shows a pair of feeders in the form of a hopper, biomaterial 132 and polymer 134 may be mixed together outside extruder 114 and introduced together into extruder 114 in a manner similar to that described above with respect to reagents. 110 and polymer 112.

The ratio of mixed biomaterial 132 to polymer 134 may be based on the desired concentration of agent 110 in the final product formed from the mixed biomaterial 132 and polymer 134 (e.g., biomaterial 142 or 144, as described below) to choose. For example, step 204 may include mixing biological material 132 and polymer 134 in a 1:5 ratio to dilute biological material 132 having a concentration of reagent 110 of 10% by weight to having a concentration of reagent 110 of approximately 1% by weight. The final product (biomaterial 142 or 144) is about 2% by weight of reagent 110, about 3% by weight of reagent 110, or about 4% by weight of reagent 110. As described above with respect to previous executions of step 204, the biomaterial 132 and the polymer 134 may be mixed prior to being introduced into the feed device of the extruder 114, or the mixing of the biomaterial 132 and the polymer 134 may be controlled by using Feeding device for mixing.

Step 206 may be repeated by introducing the mixed biomaterial 132 and polymer 134 into the extruder 114 . As noted above, step 206 may be performed using the same extruder 114 as described above or a different extruder. The extruder used to mix biomaterial 132 and polymer 134 may include a pair of screws 116 having the same features and portions as described above (eg, portions 118, 120, 122, 124, and 126). Alternatively, the extruder may have different sections and/or a different number of sections. During step 206, extruder 114 may melt and homogenize biomaterial 132 and polymer 134.

Step 208 may be repeated by extruding the melted and mixed biomaterial 132 and polymer 134 through an extruder die. The extruder die may have an opening with a diameter of about 0.5 mm to about 2.00 mm. In particular, the extruder die may have an opening with a diameter of approximately 1.00 mm. The extruder die may have other diameters suitable for extruding fibers having a final diameter of about 50 µm to about 200 µm or may have openings having a diameter of about 50 µm to about 200 µm to produce fibers having a final diameter of about 50 µm to about 200 µm. 200 µm extruded fiber. The extrusion of the mixed material may be facilitated by the shaping device 130 configured to modify the shape of the extruded material. In particular, the forming device 130 may include a puller capable of controlling the diameter of the extruded material by stretching the extrudate under tension to draw down the diameter. For example, when the mixed biomaterial 132 and polymer 134 are in the form of fibrous biomaterial 144, their diameters may range from about 50 µm to about 600 µm, from about 100 µm to about 400 µm, or from about 150 µm to about 150 µm. µm to approximately 300 µm. In particular, the material drawn using the forming device 130 (eg, a puller) may have a diameter of about 150 µm, about 200 µm, about 250 µm, or about 300 µm. The forming device 130 may be used in conjunction with a take-up device or coiler 136 when forming biomaterials having a fibrous form. The coiler 136 may be configured to collect the extruded and appropriately shaped fibrous biomaterial 144.

Step 208 may further include one or more processing steps to produce the biomaterial 142 in a desired form or shape, such as biomaterial 142 in the shape of a rod or pellet (pellets shown for biomaterial 142 ), or Biomaterial 144 is formed into the shape of one or more fibers collected on coiler 136. Although specific examples are described below, step 208 may include forming the biomaterial as fibers (including knotted, knotless, spiral forms, straight, including one or more bends, etc.), sheets, rods, pellets, Cylindrical, granular, spherical or other shaped reagents 110 and polymers 112. The agent 110 can be incorporated into the polymer 112 without coating the agent 110 so that the core of the agent is surrounded by a shell of the polymer. Coating can be avoided, for example, by a homogeneous combination of reagent 110 and polymer 112 . Reagent 110 can be incorporated into polymer 112 in crystalline form. This crystalline form of agent 110 may be present in the biomaterial having any of the shapes described herein (eg, fibers, sheets, rods, pellets, cylinders, granules, spheres, etc.). However, if desired, reagent 110 can be provided entirely in amorphous form, or as a mixture of amorphous and crystalline forms.

3A illustrates an exemplary biomaterial 302, which may be in the form of fibers produced by fiber extrusion, for example, where the biomaterial 302 is collected on a spool 304 (eg, by a reel 136). The fibers of biomaterial 302 may have a desired diameter (e.g., a diameter determined by extruder 114 and/or shaping device 130, e.g., in the range of about 50 µm to about 3 mm, about 100 µm to about 2.5 mm, or diameter in the range of about 250 µm to about 2 mm. In some aspects, the forming device 130 can reduce the diameter of the fibers of the biomaterial 302 such that the final diameter of the fibers ranges from about 50 µm to about 600 µm, about 100 µm to about 400 µm, or about 150 µm to about 300 µm). The concentration of agent 110 in the fibers may range from about 0.5% to about 30% by weight, from about 1% to about 20% by weight, or from about 2% to about 10% by weight. In particular, the concentration of reagent 110 may be about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 10% by weight, or about 20% by weight.

3B illustrates an exemplary biomaterial assembly 350, which may be formed from biomaterial 144 or 302, for example. Biomaterial component 350 may be formed from one or more fibers 352 secured within one or more layers 354 of biocompatible material, such as natural material. Materials for layer 354 may include, for example, porcine small intestine submucosa (“SIS”), amniotic membrane-based tissue (eg, amnion/chorion), or reconstituted denatured collagen. If desired, layer 354 may include one or more synthetic materials in place of or in addition to natural materials such as SIS. Suitable synthetic materials for use as or included in layer 354 may include resorbable polymers formed as one or more layers in a nonwoven or woven structure, including homopolymers, copolymers of one or more of the following monomers: Materials and/or polymer blends (polymeric blend): monomers of glycolide, lactide, caprolactone, dioxanone, trimethylene carbonate, cellulose derivatives, and polymerization to form poly Monomer of ester. Additional synthetic materials that may be included in layer 354 in place of or in addition to natural materials include: polysilicone membrane, expanded-polytetrafluoroethylene (ePTFE), polyterephthalene Ethylene formate (Dacron), polyurethane aliphatic polyester, poly(amino acid), poly(propylene fumaric acid), copoly(ether-ester), polyacetylenic grass Polyalkylenes oxalates, polyamides, polycarbonates derived from tyrosine acid, poly(iminocarbonates), polyorthoesters, polyoxaesters , polyamide esters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes and their mixtures. Natural polymers suitable for use as or included in material layer 354 may include collagen, elastin, thrombin, reticulin, starch, poly(amino acids), gelatin, alginates, pectin, Fibrin, oxidized cellulose, chitin, chitosan, tropoelastin, hyaluronic acid, fibrin-based materials, collagen-based materials, hyaluronic acid-based materials, glycoprotein-based materials, cellulose-based materials , silk and combinations thereof.

Biomaterial 352 and layer 354 of biomaterial component 350 can be formed in one of a variety of form factors. For example, biomaterial 352 may be in the form of fibers of suitable diameter and length. Although FIG. 3B illustrates a single fibrous biomaterial sandwiched between multiple layers of material 354 , multiple biomaterials 352 having the same shape or different shapes (eg, multiple individual fibers) may be provided between one or more layers of material 354 . , pellets, balls, springs, etc.).

Biomaterial 302 and/or biomaterial 352 of biomaterial component 350 may have been formed using one or more of biomaterials 132 , 142 , and 144 . For example, biomaterial 132 may be manufactured as a stock batch for use in a universal localized delivery system. The local delivery system may be formed by diluting biomaterial 132 (eg, by mixing biomaterial 132 with polymer 134 as described above) and forming biomaterial 142 and/or 144, or the biomaterial in any other suitable form factor. Accordingly, these biomaterials may enable modularized local drug delivery systems that can be used in implants 400, 420, 440, and/or 460 as described below.

Exemplary form factors and uses of biomaterial 352 are described below with respect to implants 400, 420, 440, and 460, as shown in Figures 4A-4D. Although Figures 4A-4D illustrate fibrous biomaterials 402, 422, 442, and 462, it is understood that each biomaterial in Figures 4A-4D can have any of the shapes described above, or can be in any of these shapes. Combinations are offered as a variety of biomaterials. Biomaterials 402, 422, 442, and 462 may be attached to implants 400, 420, 440, and 460 by wrapping one or more sheets of material, such as layer 354, around the structure of the corresponding implant. The implant may have a cylindrical or generally tubular shape to attach the biomaterial 402, 422, 442, 462 to the implant. Alternatively, layer 354 may form the structure of corresponding implants such as implants 400, 420, and 440. For example, implants 400, 420, and 440 may include a SIS material, as described above with respect to biomaterial component 350, which constitutes the body of the implant. As will be appreciated, any of the materials described above with respect to material layer 354 may be employed in place of or in addition to the SIS material. Implant 460 (Fig. 4D) is an example of an implant formed from neural graft material, such as decellularized tissue from human or non-human sources, other natural materials, and/or synthetic materials.

Figure 4A illustrates an exemplary implant 400 that may be adapted to be implanted in a subject. In some aspects, the implant 400 may be used as a nerve wrap configured to be implanted at the site of a peripheral nerve injury in a subject. Implant 400 may be formed by attaching or embedding one or more biomaterials 402, such as fibers, at one or more locations on implant 400. For example, one or more biomaterials 402 may be attached to and/or embedded throughout the implant 400 . Implant 400 may be in the form of a generally rectangular sheet (as shown in Figure 4A), a circular sheet, or a sheet having other regular or irregular shapes. Although one sheet of material is shown in Figure 4A, implant 400 may include multiple layers of sheets stacked and secured together. The proximal and distal ends 404 and 406 of the implant 400 may be adapted to be secured (eg, with sutures) to soft tissue to form a barrier that protects the neural tissue during healing.

In some aspects, implant 400 may be rectangular, with a length measured from proximal end 404 to distal end 406 that is longer than the width of implant 400 measured in a direction perpendicular to the length. In particular, the length of the implant 440, measured from the proximal end 404 to the distal end 406, ranges from about 5 mm to about 60 mm, from about 10 mm to about 50 mm, or from about 20 mm to about 40 mm. In particular, the length of cylinder 444 may be about 20 mm or about 40 mm.

The biomaterial 402 of the implant 400 may be provided at various locations throughout the implant 400. In some aspects, a higher concentration of biomaterial 402 may be provided at a location where the implant 400 is expected to be positioned adjacent to an injured nerve, such as a nerve terminal. In this case, a higher concentration of agent 110 such as FK 506 may be provided at the proximal end 404, the distal end 406, and/or the axial central portion including the midpoint between ends 404 and 406. This may be accomplished by placing a higher concentration of biomaterial 402 at the proximal end 404, distal end 406, and/or the axially central portion of the implant 400. Alternatively, biomaterial 402 may be distributed substantially uniformly and regularly throughout implant 400 . In some aspects, biomaterial 402 can include fibers oriented in a desired manner. For example, as shown in Figure 4A, the fibers may extend so as to be generally parallel to each other. Other distributions may also be used in implant 400, as described below with respect to implants 420, 440, and 460. Additionally, although biomaterial 402 may include neuroregenerative or immunosuppressive agents, biomaterial 402 of implant 400 may include one or more growth-inhibiting agents that may, for example, prevent or reduce neuroma formation.

Figure 4B illustrates an exemplary implant 420 that may be adapted for implantation into a subject. In some aspects, implant 420 may function as a neural connector configured to be implanted at the site of a peripheral nerve injury in a subject. Implant 420 may include a cylinder 424 defining a proximal end 428 and a distal end 426 configured for attachment (eg, by suture) to proximal and distal nerve ends, respectively. In some aspects, cylinder 424 may define a diameter ranging from 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. In particular, the diameter of cylinder 424 may 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 cylinder 424 of the implant 420 may range from about 5 mm to about 20 mm, or from about 10 mm to about 15 mm. In particular, the length of cylinder 424 may be equal to approximately 10 mm or equal to approximately 15 mm.

As shown in Figure 4B, biomaterial 422 of implant 420 may be in the form of fibers, where the fibers extend in different directions. Alternatively, implant 420 may include fibrous biomaterial 422 that is generally aligned or parallel, or distributed in one or more of the manners described herein with respect to implants 400, 440, and/or 460. Although the distribution of biomaterial 422 can be generally uniform, if desired, higher concentrations of biomaterial 422 and therefore higher concentrations of FK 506 can be present at the proximal and distal ends 428 and 426 of implant 420, or Present in the central region of implant 420. This provides localized concentrations of FK506 at the subject's proximal and distal nerve terminals. Although implant 420 is shown as a tube, in some aspects, implant 420 may begin as a flat sheet, such as a rectangular sheet, and may then be wrapped around one or more nerves during implantation to form the tube. .

Figure 4C illustrates an exemplary implant 440 that may be adapted for implantation into a subject. In some aspects, implant 440 can extend from proximal end 448 to distal end 446 to define a rod or cylinder (eg, implant 420) with a hollow interior that can be used as a nerve protector. Implant 440 may be a pre-rolled version of implant 400. Implant 440 may be configured to be implanted at a site of peripheral nerve injury in a subject. In particular, implant 440 may be configured for attachment at a site of peripheral nerve injury to provide a structural barrier for protecting one or more peripheral nerves or nerve terminals, and for supporting structural reinforcement of peripheral nerve reconstruction and healing. . Implant 440 may include a cylinder 444 formed into a rod or tube. In some aspects, the length of implant 440 may be longer than the length of implant 420 . In particular, the length of cylinder 444 of implant 440, measured from end 446 to end 448, may range from about 5 mm to about 60 mm, from about 10 mm to about 50 mm, or from about 20 mm to about 50 mm. Within about 40 mm. In particular, the length of cylinder 444 may be about 20 mm or about 40 mm. The diameter of the cylinder 444 of the implant 440 may range from about 1.0 mm to about 20 mm, from about 1.5 mm to about 15 mm, or from about 2 mm to about 10 mm. In particular, the diameter of cylinder 444 may be about 2 mm, about 3.5 mm, about 5 mm, about 7 mm, or about 10 mm.

When biomaterial 422 is attached to or incorporated within implant 440, biomaterial 422 may be provided at various locations throughout cylindrical portion 444. In some aspects, a higher concentration of biomaterial 442 may be provided at the distal end 446 and the proximal end 448 compared to the axially central portion of the implant 440 . Alternatively, biomaterial 402 may be distributed substantially uniformly and regularly throughout implant 440 . In some aspects, biomaterial 402 may include fibers oriented in a desired manner. For example, as shown in Figure 4C, the fibrous biomaterials 442 may extend so as to be generally parallel to each other and thus extend along the circumference of the implant 440.

Figure 4C provides an example of a plurality of biomaterials 442 formed as fibers extending generally parallel to each other. Biomaterial 442 may be fibers extending along the circumference of cylinder 444. Additionally or alternatively, implant 440 may include biomaterial 442 extending in a direction parallel to the axial direction of implant 440 . If desired, biomaterial 442 can also extend in different directions. Additionally or alternatively, biomaterial 442 may include helically extending fibers and/or other suitable fiber orientations. For example, as described with respect to implants 400, 420, and 460, any other orientation or arrangement may be used in implant 440.

Figure 4D illustrates an exemplary implant 460 that may be adapted to be implanted in a subject. In some aspects, implant 460 can be used as a nerve graft formed from decellularized material that can be implanted in a subject at the site of peripheral nerve injury. Although implants 400, 420, and 440 may have hollow interiors, implant 460 may include an interior that includes decellularized epineurium, decellularized perineurium, and/or decellularized endoneurium. Biomaterial 462 of implant 460 may generally extend along the length of implant 460, as shown in Figure 4D. Additionally or alternatively, biomaterial 462 may extend along the circumference of implant 460 . Similar to implants 400 , 420 and 440 , biomaterial 462 may provide relatively high concentrations at one or more locations, such as the proximal and distal ends of implant 460 .

Each of the above-described embodiments, including biomaterials 132, 142, 144, 302, 350, 402, 422, 442, and 462, and each implant 400, 420, 440, and 460, may be configured to perform localized, sustained, and The reagent is delivered 110 in a controlled manner. Although fibrous biomaterials are described above, any suitable form factor or combination of form factors may be used. In particular, biomaterials may be provided as fibers, pellets, spheres, springs or other shapes, alone or in combination. For example, these biomaterials and implants can precisely deliver active ingredients, such as one or more neuroregenerative or immunosuppressive agents, into a polymer matrix to achieve controlled release of the agent when combined with other devices or implants. .

Specifically, incorporation of FK506 into a polymeric delivery system formed from one or more of the biomaterials described above may allow for localized release of FK506 while axons regenerate toward the target terminal tissue or organ. Local delivery of one or more neuroregenerative or immunosuppressive agents may be required to increase the number of neurons capable of regenerating their axons, as well as to increase the rate of axonal regeneration. The fabrication of biomaterials containing FK506 can be used as a universal or modular delivery system that can form implants and devices that release FK506 in a variety of different form factors. These form factors can be used for different types of injuries, especially Different types of peripheral nerve injuries. The biomaterials described above can also be used to incorporate active ingredients, such as one or more neuroregenerative or immunosuppressive agents, without the need to add these agents after the delivery device (e.g., implant) is formed. These biomaterials can be used with one or more neuroregenerative or immunosuppressive agents such as FK506, which have a molecular weight of less than about 1200 g/mol, or less than about 1000 g/mol. The above biomaterials can also be used with hydrophobic nerve regeneration or immunosuppressive agents such as FK506.

One or more of the above biomaterials and/or implants may be used together. For example, fibrous biomaterials (eg, biomaterial 302 ) or components including fibrous biomaterials (eg, biomaterial component 350 ) can be wrapped directly around neural tissue and then covered with implants 400 , 420 , or 440 . In such examples, the implant 400, 420, or 440 may not contain any active ingredients, such that all of the agent 110 at the implantation site is delivered via the implanted biomaterial. Additionally or alternatively, the fibrous biomaterial may be coated along the surface of and/or adhered to a suitable material, such as one or more layers of SIS, which is implanted independently of implant 400, 420 or 440. The SIS with adhesively adhered biomaterial can be fixed directly to the neural tissue or to the implant 400, 420, 440 as desired. Example

The present disclosure may be further understood by the following non-limiting examples. The examples are intended to illustrate the above-disclosed embodiments and should not be construed to narrow their scope. Those of ordinary skill in the art will readily appreciate that these examples suggest many other ways in which embodiments of the disclosure may be practiced. It will be understood that many changes and modifications may be made within the scope of this disclosure. Example 1 , Part A : FK506 incorporated into fibers of oxycyclohexanone polymer

The biomaterial was prepared using a two-stage process, including a first stage in which a stock batch of biomaterial containing oxycyclohexanone polymer (PDS) and 10% FK506 was prepared. This stock batch is then used in a second stage to prepare biological material with a target concentration. Biomaterials were produced with two different target concentrations, one with a concentration of 2% by weight of FK506 and a second with a concentration of 4% by weight of FK506.

To prepare a stock batch, mix FK506 with PDS. This mixture of FK506 and PDS contains 10% by weight of FK506 and has a coarse pellet form after mixing. The coarse pellet mixture was introduced into the feed hopper of a twin-screw extruder manufactured by Leistritz Group of Nuremberg, Germany. The extruder includes a pair of 18 mm screws, each of which consists of metering, kneading and shearing parts. The rotation of a pair of screws in the extruder heats the mixture of FK506 and PDS to a maximum temperature of 135 degrees Celsius, which melts the PDS into a liquid form. The intrinsic viscosity of PDS is 2.13 dL/gram. The extruded FK506 and PDS were received by the granulator through a die with an opening with a diameter of 1 mm. The pelletizer breaks the extrudate initially formed into rods into multiple pellets (i.e., shortened rods).

Pellets from the pelletizer to form a stock batch of biomaterial containing homogeneously mixed PDS and FK506 were supplied to the twin-screw extruder. The extruder is also available in pure polymer without FK506. The stock batch of pellet biomaterial and FK506-free polymer is mixed and melted in the manner described above during preparation of the stock batch to form a final concentration of 2 wt% FK506 or 4 wt% FK506 polymer. The polymer is drawn to a diameter of about 250 µm using a coiler with a system including a puller manufactured by Killion to form a fibrous biomaterial that is received by a spool. Example 1 , Part B : Release Analysis of FK506 from Fibers

Biomaterial samples prepared according to Example 1, Part A, included a first set of fiber samples having 2 wt% FK506 and a second set of fiber samples having 4 wt% FK506. Two sets of samples were evaluated to determine the kinetics of FK506 release from fibrous biomaterials. To prepare both groups, separate individual fibers from the spool and place into vials containing 1 mL of saline buffer solution. Two different weights of fiber were collected, resulting in four different sample groups: 2 wt% FK506 per 10 mg sample, 4 wt% FK506 per 10 mg sample, and 4 wt% FK506 per 20 mg sample. 2 wt% FK506, and 4 wt% FK506 per 20 mg sample.

Each vial containing the biomaterial was placed in a bath maintained at 37 degrees Celsius to simulate human body temperature. While maintaining the temperature of each biomaterial at approximately 37 degrees Celsius, 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, replace the saline buffer in each vial with 1 mL of fresh saline buffer.

Buffer solution samples collected from each vial were analyzed by LC-MS/MS to determine release from fibers at 1 minute, 1 hour, 3 hours, 1 day, 3 days, 7 days, 14 days, 21 days, and 28 days The amount of FK506. The final concentration of FK506 released from the fibers is shown in Figure 5. In Figure 5, each circle drawn represents the average concentration of FK506 in the collected saline buffer from six measurements of a sample with an initial FK506 concentration of 2% by weight. Each square drawn represents the average concentration of FK506 in the collected saline buffer from six measurements of a sample with an initial FK506 concentration of 4% by weight.

In some aspects, it may be desirable to release one or more neuroregenerative or immunosuppressive agents such as FK506 for a specific period of time. In particular, it may be desirable to achieve a release period of FK506 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 effective concentrations of FK506 and/or other agents remain within the therapeutic window. Additionally, it may be desirable to avoid burst release of one or more neuroregenerative or immunosuppressive agents such as FK506. Avoiding burst release may be desirable, for example, to achieve a longer overall duration of FK506 release and/or to avoid the possibility of local concentrations exceeding the upper limit of the therapeutic window.

As can be seen in Figure 5, the effective concentration of FK506 remained at or above the therapeutic window of approximately 0.1 µg/mL and below the toxic dose of approximately 5 mg/mL in every sample measured over the 28-day period. . In particular, mean concentrations of FK506 between approximately 5 µg/mL and approximately 20 µg/mL were observed throughout the 28-day period for each of the two groups of nerve grafts. Additionally, no significant burst release was observed. Example 2 : Release Analysis of FK506 from Fibers Clamped by SIS

Biomaterial samples were prepared according to Example 1, Part A, including a first set of fiber samples with 2 wt% FK506 and a second set of fiber samples with 4 wt% FK506. These samples were sandwiched between multiple layers of SIS to evaluate the effect of SIS on the release kinetics of FK506 in fiber samples belonging to the two groups.

The amount of FK506 released from each sample was analyzed by LC-MS/MS in the manner described for Example 2. The final concentration of FK506 released from SIS-clamped fibers is shown in Figure 6, where each circle represents the average concentration of FK506 from three measurements of a sample with an initial concentration of 2 wt% FK506 in the collected saline buffer. Each square drawn represents the average concentration of FK506 in the collected saline buffer from six measurements of a sample with an initial FK506 concentration of 4% by weight.

It can be seen that the effective concentration of FK506 remained at or above approximately 0.1 µg/mL and below the toxic dose of approximately 5 mg/mL in each measured sample for at least 21 days. Furthermore, for the biomaterial with a higher concentration of 4 wt% FK506, the concentration of FK506 remained within the therapeutic window throughout the 28-day period.

It should be understood that, although this disclosure has been made with reference to preferred embodiments, exemplary embodiments, and optional features, modifications and variations of the concepts disclosed herein may be employed by those of ordinary skill in the art, and that such modifications and Variations are deemed to be within the scope of the present disclosure as defined by the appended claims. The specific embodiments and examples provided herein are illustrative and non-limiting of useful implementations of the disclosure, and are illustrative only. It will be apparent to one of ordinary skill in the art that numerous variations of the apparatus, apparatus components, methods and steps set forth in this specification may be used to carry out the present disclosure. As one of ordinary skill in the art will appreciate, the means and apparatus useful in the present methods may include a wide variety of optional compositions and processing elements and steps.

100:Process 110:Reagent 112:Polymer 114:Extruder 115: Feed hopper 116:Screw 118:Conveying part 120: Kneading part 122: Second conveying part 124: Cut part 126:Measurement part 128:Forming device 130: Forming device 132:Biological materials 134:Polymer 136: Coiler 142:Biological materials 144:Biological materials 200:Method 202:Step 204:Step 206:Step 208:Step 302:Biological materials 304:Spool 350:Biomaterial components 352:Fiber 354:Layer 400:Implant 402:Biological materials 404: Near end 406:Remote 420:Implant 422:Biological materials 424:Cylinder 426:Remote 428: Near end 440:Implant 442:Biological materials 444:Cylinder 446:Remote 448: Near end 460:Implant 462:Biological materials

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

In accordance with aspects of the present disclosure, Figure 1 shows a schematic diagram of an exemplary process for incorporating one or more neuroregenerative or immunosuppressive agents into a polymer.

Figure 2 illustrates a flow diagram of an exemplary process for incorporating one or more neuroregenerative or immunosuppressive agents into a polymer, in accordance with aspects of the present disclosure.

Figure 3A illustrates an exemplary biomaterial comprising one or more neuroregenerative or immunosuppressive agents, in accordance with aspects of the present disclosure.

Figure 3B illustrates an exemplary biomaterial comprising one or more neuroregenerative or immunosuppressive agents, in accordance with aspects of the present disclosure.

Figure 4A illustrates an exemplary nerve encapsulation implant comprising a biomaterial with one or more nerve regeneration or immunosuppressive agents, in accordance with aspects of the present disclosure.

Figure 4B illustrates an exemplary neural connector implant comprising biomaterial with one or more neuroregenerative or immunosuppressive agents, in accordance with aspects of the present disclosure.

Figure 4C illustrates an exemplary pre-rolled nerve-covered implant comprising biomaterial with one or more nerve regeneration or immunosuppressive agents, in accordance with aspects of the present disclosure.

In accordance with aspects of the present disclosure, Figure 4D illustrates an implant comprising biomaterial having one or more neuroregenerative or immunosuppressive agents.

Figure 5 is a graph depicting the release of an exemplary neuroregenerative or immunosuppressive agent from a biological material, in accordance with aspects of the present disclosure.

Figure 6 is a graph depicting the release of an exemplary neuroregenerative or immunosuppressive agent from a biological material, in accordance with aspects of the present disclosure.

100:Process

110:Reagent

112:Polymer

114:Extruder

115: Feed hopper

116:Screw

118:Conveying part

120: Kneading part

122: Second conveying part

124: Cut part

126:Measurement part

128:Forming device

130: Forming device

132:Biological materials

134:Polymer

136: Coiler

142:Biological materials

144:Biological materials

Claims (68)

A method for preparing implantable biomaterials, characterized by including: combining a polymer comprising an oxycyclohexanone polymer with a nerve regeneration agent or an immunosuppressive agent comprising at least one immunophilin ligand; melting the polymer; and The combined polymer and the nerve regeneration agent or the immunosuppressive agent are extruded to form the implantable biomaterial. The method of claim 1, wherein the at least one immunophilin ligand includes cyclosporine A or FK506. The method of claim 1 or 2, wherein the combined polymer and the at least one immunophilin ligand are extruded to form pellets. The method as claimed in any one of claims 1 to 3, wherein the combined polymer and the at least one immunophilin ligand are extruded to form a sheet. The method according to any one of claims 1 to 3, wherein the combined polymer and the at least one immunophilin ligand are extruded to form a spring-shaped biological material. The method as claimed in any one of claims 1 to 3, wherein the polymer and the at least one immunophilin ligand are extruded to form fibers. The method of claim 6, wherein the fiber contains one or more knots. The method of claim 6, wherein the fiber has a diameter of about 50 µm to about 600 µm. The method of claim 6, wherein the fiber has a diameter of about 100 µm to about 400 µm. The method according to any one of claims 1 to 9, wherein the implantable biomaterial is included in an implant. The method of claim 10, wherein the implant is a nerve wrap. The method of claim 10, wherein the implant is a neural connector. The method of claim 10, wherein the implant is a pre-rolled nerve wrap. The method of claim 10, wherein the implant is a nerve graft. The method of claim 14, wherein the nerve graft contains decellularized material. The method according to any one of claims 1 to 15, wherein the implantable biomaterial includes small intestinal submucosa. The method according to any one of claims 1 to 16, wherein the at least one immunophilin ligand includes FK506, and the content of FK506 in the extruded implantable biomaterial is from about 1% to about 1% by weight. About 20%. The method according to any one of claims 1 to 17, wherein the nerve regeneration reagent or the immunosuppression reagent includes a plurality of nerve regeneration reagents, a plurality of immunosuppression reagents, or at least one nerve regeneration reagent and at least one immunosuppression reagent. The method according to any one of claims 1 to 18, wherein the nerve regeneration reagent or the immunosuppressive reagent includes at least one reagent, which simultaneously serves as a nerve regeneration reagent and an immunosuppressive reagent. A method for preparing implantable biomaterials, characterized by including: Combine the polymer with FK506; melting the polymer; and The combined polymer and FK506 are extruded to form the implantable biomaterial. The method of claim 20, wherein the combined polymer and FK506 are extruded to form pellets. The method of claim 20, wherein the combined polymer and FK506 are extruded to form a sheet. The method of claim 20, wherein the combined polymer and FK506 are extruded to form a spring-shaped biomaterial. The method of claim 20, wherein the combined polymer and FK506 are extruded to form fibers. The method of claim 24, wherein said fiber includes one or more knots. The method of claim 24, wherein the fiber has a diameter of about 50 µm to about 600 µm. The method of claim 24, wherein the fiber has a diameter of about 150 µm to about 400 µm. The method according to any one of claims 20 to 27, wherein the implantable biomaterial is contained in an implant. The method of claim 28, wherein the implant is a nerve wrap. The method of claim 28, wherein the implant is a neural connector. The method of claim 28, wherein the implant is a pre-rolled nerve wrap. The method of claim 28, wherein the implant is a nerve graft. The method of claim 32, wherein the nerve graft includes decellularized material. The method of any one of claims 20 to 33, wherein the implantable biomaterial includes small intestinal submucosa. The method according to any one of claims 20 to 34, wherein the content of FK506 in the extruded implantable biomaterial is from about 1% to about 20% by weight. The method according to any one of claims 20 to 35, wherein the polymer is a homopolymer, a copolymer and/or a polymer blend, including one or more of the following monomers: glycolide, lactide Esters, caprolactone, dioxanone, trimethylene carbonate, monomers of cellulose derivatives, and monomers that polymerize to form polyesters. An implant, characterized in that it includes: Oxycyclohexanone polymer; and At least one immunophilin ligand bound to the oxycyclohexanone polymer. The implant of claim 37, wherein the at least one immunophilin ligand comprises cyclosporin A or FK506. The implant according to claim 37, wherein the oxycyclohexanone polymer and the at least one immunophilin ligand are formed into one or more of pellets, sheets, springs or fibers. The implant of claim 37, wherein the oxycyclohexanone polymer and the at least one immunophilin ligand are contained in one or more fibers with a diameter of about 50 µm to about 600 µm. The implant of claim 37, wherein the oxycyclohexanone polymer and the at least one immunophilin ligand are contained in one or more fibers with a diameter of about 150 µm to about 400 µm. The implant according to any one of claims 37 to 41, wherein the implant is a nerve covering. The implant according to any one of claims 37 to 41, wherein the implant is a neural connector. The implant according to any one of claims 37 to 41, wherein the implant is a pre-rolled nerve wrap. The implant according to any one of claims 37 to 41, wherein the implant is a nerve graft. The implant of claim 45, wherein the nerve graft includes decellularized material. The implant of claim 37, wherein said oxycyclohexanone polymer and said at least one immunophilin ligand are sandwiched between multiple layers of material. The implant as claimed in claim 47, wherein the material layer is the submucosa of the small intestine. An implant, characterized in that it includes: Biological material, wherein said biological material includes: polymers; and FK506, which binds to said polymer; wherein the biomaterial is incorporated into the implant in one or more forms of extruded pellets, rods, sheets, springs or fibers. The implant as described in claim 49, wherein the polymer is a homopolymer, a copolymer and/or a polymer blend, including one or more of the following monomers: glycolide, lactide, caprolactide esters, dioxanone, trimethylene carbonate, monomers of cellulose derivatives, and monomers that polymerize to form polyesters. The implant of claim 49, wherein the biomaterial includes fibers. The implant of claim 51, wherein the fiber has a diameter of about 50 µm to about 600 µm. The implant of claim 51, wherein the fiber has a diameter of about 100 µm to about 400 µm. The implant according to any one of claims 49 to 53, wherein the implant is a nerve wrap. The implant according to any one of claims 49 to 53, wherein the implant is a neural connector. The implant of any one of claims 49 to 53, wherein the implant is a pre-rolled nerve wrap. The implant according to any one of claims 49 to 53, wherein the implant is a nerve graft. The implant of claim 57, wherein the nerve graft includes decellularized material. The implant of claim 49, wherein said biomaterial is sandwiched between multiple layers of material. The implant as claimed in claim 59, wherein the material layer is the submucosa of the small intestine. The implant according to any one of claims 49 to 60, wherein the polymer is an injectable polymer. The implant of claim 61, wherein the injectable polymer comprises a hydrogel. The implant of claim 61, wherein the injectable polymer comprises a colloidal gel. The implant of claim 61, wherein the injectable polymer comprises microcells. A method of treating a subject, characterized by including implanting the implant described in any one of claims 37 to 64 into the subject. The method of claim 65, wherein the implant is implanted into a peripheral nerve of the subject. The method as described in claim 65 or 66, wherein the subject is a mammal. The method described in claim 67, wherein the object is a human.