Antimicrobial filaments and methods of making the same

Abstract

An antimicrobial filament containing a filament resorbable material and an antimicrobial agent in which the antimicrobial agent is incorporated throughout the body of the filament. The antimicrobial agent is broad spectrum and fast acting, and the filament retains antimicrobial activity throughout the life of the filament. Also provided is a method of manufacturing an antimicrobial filament including the steps of obtaining raw filament material, obtaining raw antimicrobial agent, grinding the raw filament material and the raw antimicrobial agent to form a mixture, compounding the mixture, and extruding the compounded mixture to form an antimicrobial filament. A surgical suturing kit is disclosed that includes the antimicrobial filament and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 764,207, filed on Feb. 27, 2025. The entire disclosure of that application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Surgical site infections (“SSIs”) are common nosocomial infections that, in 2016, accounted for at least 20% of all hospital-acquired infections in the United States. SSIs are associated with up to an 11-fold increase in the risk of mortality, and the annual cost in the US of dealing with SSI-related complications is estimated between 3.5 and 10 billion dollars.

[0003] There are a variety of factors that contribute to SSIs, among them being wound closure methods. Sutures have been developed with the goal of reducing SSIs related to wound closure.

[0004] For example, barbed sutures immediately maintain tension once engaged in the tissue and can eliminate the need to tie knots. Eliminating suture knot tying can reduce closure time by up to 50%, not only reducing exposure time to bacteria, but also saving on operating room costs. On the other hand, barbs provide an ideal location for bacterial colonization.

[0005] Antibiotic-coated sutures for wound closure have been developed and approved for use. One drawback of such sutures is that the antibiotic released from the coated surface of the suture only provides an initial burst of protection against pathogens. Further, the coating process typically employs volatile solvents, thus increasing the cost and reducing consistency of the product.

[0006] Triclosan, the antibiotic typically used to coat sutures, has been shown to be ineffective against Pseudomonas spp, and Enterococcus spp. isolates, crucial causative agents of post-operative SSIs. Moreover, some studies have concluded that environmental triclosan impairs thyroid homeostasis and could be associated with neurodevelopment impairment, metabolic disorders, cardiotoxicity, and increased cancer risk.

[0007] Chlorhexidine likewise may undergo hydrolytic degradation above about 100 C and has other undesirable properties such as its potential to act as an allergen and its high cellular toxicity relative to its antimicrobial effectiveness (e.g., a biocompatibility index of about 1).

[0008] There is a need to develop improved antibiotic- and antimicrobial-releasing resorbable filaments, including ones that allow for uniform distribution of an effective and safe antimicrobial agent within the filament while maintaining filament strength and antimicrobial efficacy, without the drawbacks mentioned above.SUMMARY OF THE INVENTION

[0009] To meet the need set forth above, an antimicrobial filament is provided that comprises a filament resorbable material and an antimicrobial agent in which the antimicrobial agent is incorporated throughout the body of the filament.

[0010] The antimicrobial agent, which is broad spectrum and fast acting, may be present at 0.1% to 5% by weight of the filament, and the filament retains antimicrobial activity throughout the life of the filament. In some embodiments, the filament resorbable material comprises polydioxanone (“PDO”) or a blend of polyglycolic acid and ε-caprolactone (“PGCL,” e.g., 75% by weight polyglycolic acid and 25% by weight ε-caprolactone). In some embodiments, the antimicrobial agent comprises an antimicrobial peptide. In some embodiments, the antimicrobial agent comprises voxvoganan. In some embodiments, the antimicrobial agent has a biocompatibility index of at least above 2, 3, 4, 5, 6, 7, 8, 10, 20, 30 or 40. In some embodiments, the filament includes a plurality of barbs formed of the filament resorbable material, and in some instances, each barb contains the antimicrobial agent. In other embodiments, the filament does not include any barbs.

[0011] The filament may retain tensile strength post implantation, e.g., 60-90% tensile strength up to 14 days post implantation, 60-80% tensile strength up to 28 days post implantation, and / or 40-70% tensile strength up to 42 days post implantation. The filament may be essentially absorbed by a subject between 180 and 220 days post implantation. In alternative aspects, the filament retains 42-76% tensile strength up to 7 days post implantation and / or 36-52% tensile strength up to 14 days post implantation. In some embodiments, the filament is essentially absorbed by a subject at 90 days post implantation. The filament may be used in general surgery, orthopedic surgery, or dermatology.

[0012] Also provided is a method of manufacturing an antimicrobial suture including the steps of obtaining raw filament material, obtaining raw antimicrobial agent, grinding the raw filament material and the raw antimicrobial agent to form a mixture, compounding the mixture, and extruding the compounded mixture to form an antimicrobial filament. In some embodiments, steps occur under low moisture or conditions including the steps of grinding and / or compounding the components.

[0013] Further, a surgical suturing kit is disclosed that comprises the antimicrobial filament set out, supra, and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments.

[0014] A medical device or component thereof formed of the antimicrobial filament is also described.

[0015] The details of one or more embodiments of the invention are set forth in the drawings and description below. Other features, objects, and advantages of the invention will be apparent from the description, from the drawings, and from the claims. All references cited herein are hereby incorporated by reference in their entirety.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The invention description below refers to the accompanying drawings.

[0017] FIG. 1 shows a diagram of a barbed filament of an embodiment of the invention.

[0018] FIG. 2 shows an exemplary device for providing barbs on a filament of the invention. The device is described in U.S. Pat. No. 7,913,365.

[0019] FIG. 3A shows the zones of inhibition of Escherichia coli growth surrounding two lengths of PDO filament material coated with the antibiotic voxvoganan.

[0020] FIG. 3B shows the zones of inhibition of Escherichia coli growth surrounding two lengths of barbed PDO filament material compounded with the antibiotic voxvoganan such that the antibiotic is incorporated uniformly throughout the filament and the barbs.DETAILED DESCRIPTION OF THE INVENTION

[0021] Disclosed herein are antimicrobial filaments composed of a filament resorbable material and an antimicrobial agent. The antimicrobial filament provides an alternative to existing triclosan-coated filaments without the drawbacks of that antibiotic.

[0022] The filament resorbable material may be any resorbable material suitable for in vivo use that is capable of combination with an antimicrobial agent as discussed herein, e.g., in a mixing and extrusion process. Examples of suitable filament resorbable materials include biocompatible resorbable, moldable, and meltable materials, e.g., synthetic biodegradable polymers such as resorbable and extrudable synthetic aliphatic polyesters. Examples of filament resorbable materials include polydioxanone (PDO), polyglycolic acid and ε-caprolactone (PGCL), polyglycolic acid (PGA), and / or polyglycolide-Co-Lactide (PGLA) including combinations thereof. In some embodiments, the filament resorbable material is polydioxanone (PDO) or a blend of polyglycolic acid and s-caprolactone (PGCL). In an embodiment, the filament resorbable material is 75% by weight polyglycolic acid and 25% by weight ε-caprolactone. Other examples of suitable resorbable filament materials suitable for hot-melt extrusion are discussed in Khalid and Bilal, Drug-Eluting Sutures by Hot-Melt Extrusion: Current Trends and Future Potentials, Materials 2023, 16, 7245.

[0023] The antimicrobial agent is an active agent that, e.g., kills or inhibits the growth of microbes including bacteria, viruses, and fungi. The antimicrobial agent has chemical and physical properties that make it suitable for mixing with the filament resorbable material such that an extruded filament incorporating the antimicrobial agent may be produced. For example, the selected antimicrobial agent is able to withstand hot-melt extrusion and is thermally stable at and above the filament resorbable material's melt processing temperature. The antimicrobial agent is miscible with the polymer matrix such that it is able to disperse homogenously or uniformly and, preferably, without acting as disruptive plasticizer that compromises the filament's crystallinity, tensile strength, or mechanical integrity. The antimicrobial agent, in combination with the filament resorbable material, is physically and chemically stable for downstream use and processing. As discussed below, in some embodiments, hydrophilic antimicrobial agents are preferred.

[0024] The antimicrobial agent may be incorporated uniformly throughout the body of the filament. In some embodiments, the antimicrobial agent is fast acting, i.e., it is effective starting minutes to hours after administration (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 90, 120 minutes) and broad spectrum, being effective against, e.g., Staphylococcus aureus, Pseudomonas Spp., and Enterococcus Spp. A particular antimicrobial filament includes 0.1% to 5% by weight of the antimicrobial agent. In some aspects, the filament retains antimicrobial activity throughout the life of the filament. In some aspects, the antimicrobial agent does not significantly degrade, sublimate, or produce toxic byproducts during its residence in an extruder or at elevated temperatures, but rather maintains its efficacy during the production process.

[0025] In some embodiments, the antimicrobial agent has a high therapeutic index (antimicrobial effectiveness) while exhibiting low cellular toxicity. For example, the antimicrobial agent may have a relatively high biocompatibility index, for example, by measuring the antibacterial activity against the test organisms Escherichia coli and Staphylococcus aureus. See Muller et al, Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity, J. Antimicrobial Chemotherapy (2008) 61, 1281-1287. In some embodiments, the biocompatibility index of the antimicrobial agent is at least above about 2, 3, 4, 5, 6, 7, 8, 10, 20, 30, or 40.

[0026] In some embodiments, the antimicrobial agent is an antimicrobial peptide comprising from 2 to 30, 2 to 20, 2 to 10, 2 to 8, or 2 to 5 amino acids. The amino acids may be natural, meaning that they are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, or synthetic, for example selected from the group consisting of 2,5,7-tri-tert-butyl-tryptophan, (4-(2′-naphtyl))phenylalanine, and (4-4′-biphenyl)phenylalanine.

[0027] In some embodiments, the antimicrobial peptide comprises at least one cationic amino acid. The at least one cationic amino acid may be natural, e.g. selected from the group consisting of arginine and lysine, or synthetic.

[0028] An exemplary antimicrobial agent is voxvoganan (IUPAC name: L-arginyl-2,5,7-tri-tert-butyl-L-tryptophyl-N-(2-phenylethyl)-L-argininamide), also known as LTX-109 and Lytixar. Voxvoganan is a peptide comprising three amino acids, two natural arginine, and a synthetic amino acid, 2,5,7-tri-tert-butyl-tryptophan.

[0029] Voxvoganan is a broad-spectrum, fast-acting bactericidal antimicrobial agent that binds to negatively charged membrane components on the bacterial cell wall, which leads to membrane disruption and rapid cell lysis. This agent is a peptidomimetic that is stable in vivo, not harmful to human cells, and does not induce bacterial resistance. Further, voxvoganan is hydrophilic and, as such does not accumulate in lipid tissue in the body, as do hydrophobic antimicrobials, e.g., triclosan. Voxvoganan also has a favorable biocompatibility index, e.g., at least above 2 and preferably at least above 4.

[0030] Other examples of suitable antimicrobial agents are described in WO 2009 / 081152, US2023 / 0338609, and in Table 4 of WO2021250286A1, which are hereby incorporated by reference. For example, the antimicrobial agent may have the general compound formula Arg-AA2-Arg-XY, where, e.g., AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is NHCH(CH3)2, AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is NH(CH2)5CH3, AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is OCH3, and / or AA2 is (4-(2′-napthtyl))phenylalanine and XY is NH(CH2)2Ph.

[0031] The presence of the antimicrobial agent does not significantly influence the resorption time of the filament. For example, the filament that comprises PDO or other filament resorbable material may retain 60-90% (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90%) tensile strength up to 14 days post implantation. Up to 28 days post implantation, the filament may retain 60-80% (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82%) tensile strength. Further, the filament may retain 40-60% (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60%) tensile strength up to 42 days post implantation. The PDO-containing filament, or other filaments comprising filament resorbable material, may essentially be absorbed by a subject between 180 and 220 days (e.g., 180, 185, 190, 195, 200, 205, 210, 215, and 220 days) post implantation.

[0032] As mentioned above, in an embodiment, the filament can also be formed of 75% by weight polyglycolic acid and 25% by weight-caprolactone. Again, the presence of the antimicrobial agent does not alter the resorption time of this filament. Up to 7 days post implantation, the filament may retain 42-76% (e.g., 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, and 76%) tensile strength, up to 14 days post implantation, it may retain 36-52% (e.g., 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52%) tensile strength, and at 90 days post implantation, the filament may be essentially absorbed.

[0033] In certain embodiments, the filament includes a plurality of barbs formed of the filament resorbable material. The barbs maintain tension in tissue once the filament is applied, thereby eliminating the need for tying knots to secure the filament. The barbs can be (i) uni-directional in which all of the barbs are oriented in the same direction along the major axis of the filament and (ii) bi-directional in which the barbs on either side of the filament midpoint have opposite orientations. The barbs on a filament may serve as a site of bacterial colonization. To lessen or prevent bacterial colonization, each barb may contain one or more antimicrobial agents, such as those described herein. In other embodiments, the filament is free of barbs. Filaments that include barbs can be used as a tissue-closing device for use in soft tissue approximation where use of a resorbable filament is appropriate or when a physician wishes to avoid tying knots to secure the filament.

[0034] The filaments described above can be used for a variety of applications, including, but not limited to, general surgery, orthopedic surgery, and dermatology.

[0035] Also disclosed herein is a method of manufacturing an antimicrobial filament including the steps of obtaining raw filament material, obtaining raw antimicrobial agent, grinding the raw filament material and the raw antimicrobial agent to form a mixture, compounding the mixture, and extruding the compounded mixture to form an antimicrobial filament including, e.g., an antimicrobial filament in which the antimicrobial is incorporated uniformly throughout the filament. Uniform distribution of the antimicrobial agent within the filament advantageously allows for steady, consistent, and safe release of the antimicrobial agent over time.

[0036] In some embodiments, moisture control is employed in the manufacturing method and the method is undertaken in a low moisture or dry environment, e.g., under sealed nitrogen or desiccant circulated air environment. This facilitates stabilizing the moisture content of the base polymer and / or the antimicrobial agent during processing. For example, the steps of grinding, compounding, and / or mixing the materials occur under dry or low moisture conditions. As another example, the method may entail minimizing moisture in steps occurring under ordinary or ambient conditions to the extent possible.

[0037] In an embodiment, the method of manufacturing includes the following steps:

[0038] 1 Mixing of Polymer resin, i.e., raw filament material such as base polymer resin granules, colorant and antimicrobial agent. In some embodiments, a mixture of granules are mixed into a semi-uniform distribution or mixture of powders to form a more uniform feedstock.

[0039] 2. Extruding the compounded polymer mix

[0040] 3. Dry Storage

[0041] 4. Winding into large bobbins

[0042] 5. Annealing

[0043] 6. Dry Storage

[0044] 7. Vacuum dry, including at ambient and elevated temperatures (e.g., above 60 C)

[0045] 8. Final package with moisture barrier

[0046] 9. QA Mechanical properties testing

[0047] In some embodiments, the raw filament material contains a filament resorbable material that can be PDO or a blend of polyglycolic acid and ε-caprolactone. In an embodiment, the filament resorbable material is 75% by weight polyglycolic acid and 25% by weight ε-caprolactone.

[0048] In some embodiments, the amount of raw antimicrobial agent employed in the method is such that the antimicrobial filament includes 0.1% to 5% by weight of the antimicrobial agent. In some embodiments, the amount of raw antimicrobial agent employed is about 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5% by weight. In other embodiments, the amount of raw antimicrobial agent is about 0.1% by weight, 0.1 to 4% by weight, 0.1 to 3% by weight, 0.1 to 2% by weight, 0.5 to 4% by weight, 1 to 4% by weight, 0.5 to 3% by weight, or 0.5 to 2% by weight. The amount employed may depend on the efficacy of the agent and the intended size of the final filament. Moreover, consideration is given to the upper limit of concentration that an extruded polymer can support for additive loading without deviation from the intended strength and degradation profile. In some aspects, the filament retains antimicrobial activity throughout the life of the filament.

[0049] The antimicrobial agent has the same properties described above, i.e., it is fast acting and broad spectrum. In an exemplary method, the raw antimicrobial agent is voxvoganan.

[0050] Carrying out the method produces an antimicrobial filament having the resorption characteristics detailed above. For example, the filament that comprises PDO retains 60-90% tensile strength up to 14 days post implantation, 60-80% tensile strength up to 28 days post implantation, and 40-60% tensile strength up to 42 days post implantation. The PDO-containing filament is essentially absorbed by a subject between 180 and 220 days.

[0051] For the filament containing 75% by weight polyglycolic acid and 25% by weight-caprolactone, the resorption times are those set forth above. Briefly, up to 7 days post implantation, the filament retains 42-76% tensile strength, up to 14 days post implantation, it retains 36-52% tensile strength, and at 90 days post implantation, the filament is essentially absorbed.

[0052] The method can also include a step of forming barbs. The barbs can be formed oriented in one direction along the major axis of the filament or in a bi-directional manner in which the barbs have the opposite orientation on either side of the midpoint of the filament. See FIG. 1. An exemplary method and device for forming barbs is shown in U.S. Pat. No. 7,913,365, the content of which is incorporated herein by reference in its entirety. FIG. 2, reproduced from U.S. Pat. No. 7,913,365, shows a diagram of an exemplary device for providing barbs to the filament described herein. As set forth in the patent and referring to FIG. 2, reciprocating blade assembly 250 includes blade 8 connected via arm 225 to a linear reciprocating solenoid, which reciprocates in direction (2) and (42). Cutting bed vise 63 is synchronized with reciprocating blade assembly 250 and the indexing mechanism such that the vise closes to hold suture 6 in place during cutting and opens to allow suture 6 to be advanced by the indexer to the next cutting position.

[0053] Also within the scope of the invention in some embodiments is a surgical suturing kit comprising the antimicrobial filament described in detail above, and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments. The suture needle is preferably pre-attached to the filament such that the filament is ready to use upon opening the sterilizable package. The discrete compartments can each hold an individual filament / suture needle assembly.

[0054] The antimicrobial filament described above may also be used in other applications. For example, the use of the antimicrobial filament described above in additive manufacturing methods, for example three-dimensional (3D) printing, is provided. In one aspect, the antimicrobial filament may be used to manufacture a medical device or a component thereof, in particular using additive manufacturing techniques such as 3D printing. Moldable and meltable materials, such as PDO, are suitable to be used in additive manufacturing techniques, wherein the material is heated and deposited on a support material according to a defined pattern. Once the material cools, it forms a three-dimensional structure that may be used as a medical device or as part of one. Additive manufacturing thus allows the production of medical devices or components thereof with a higher degree of complexity than techniques such as extrusion.

[0055] The antimicrobial filament as described above may be used in such methods allowing for the production of a medical device with an antimicrobial agent distributed throughout the device or component. For example, biodegradable polymer filaments in 3D printing can enable patient-specific, temporary implants, scaffolds, and drug-delivery devices that safely resorb in the body after fulfilling their therapeutic or structural function. Thus, in one aspect, a method of manufacturing a medical device or component thereof is provided, the method comprising: a) obtaining raw filament material; b) obtaining raw antimicrobial agent; c) forming a mixture with the raw filament material and the raw antimicrobial agent, e.g., as discussed above; d) producing the antimicrobial filament as described above, and e) processing the antimicrobial filaments in an additive manufacturing device, thereby producing a medical device or component thereof, wherein the device or component includes the antimicrobial agent incorporated throughout the body of the device or component.

[0056] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications, including patent documents, cited herein are incorporated by reference in their entirety.EXAMPLESExample 1: Method for Producing Anti-Microbial Filament

[0057] The first step in producing the antimicrobial filament is to dry the starting raw materials under a nitrogen vacuum (−1000 mbar) and ambient temperatures (~25° C.). The N2 gas is cycled until the water content of the materials falls below 100 ppm. As soon as the vacuum is achieved the system moves to the next cycle so there is no processing time beyond the time required by the pump to achieve the target vacuum.

[0058] The second step is the size reduction of the antimicrobial agent. The antimicrobial agent is placed in a laboratory ball mill together with silica or ceramic balls. The antimicrobial material is then sieved until it can pass comfortably through a 425 micron square mesh. The size reduction requires approximately 30 minutes of processing time. In one embodiment, the antimicrobial agent has a particle size of less than about 100 microns, e.g., between about 60-100 microns.

[0059] In the third step, the polymers, dyes, if using, and size-reduced antimicrobial agent are mixed in a dry atmosphere (nitrogen glove box) at ambient conditions (~21° C.) manually for 2-3 minutes and then by a tumbler machine for 30 minutes.

[0060] In the fourth step, filaments are formed by extrusion at temperatures of 150-185° C. for the range. The pressure of the barrel and extrusion head ranges from 60 to 80 bars. The quenching of the extrusion is performed in a water bath that is kept below 8° C. In some embodiments, the extrusion residence time is 1 to 5 minutes. In other embodiments, extrusion temperatures are above 100° C. and below 270° C. In some embodiments, depending on the polymer used and the intended size of the filament, filaments are formed by extrusion at temperatures of about 120-140° C., 130-150° C., 150-185° C., 175-200° C., 200-230° C., 215-235° C., 230-260° C., and 250-275° C. In some examples, pressures may be between about 40 to 80 or 90 bar or between about 20 to 40 bar.

[0061] In the fourth, i.e., extrusion, step, stretching speeds and stretching temperatures depend on the diameter of the extrusion and the final diameter expected for the filament. Typically, the speed ranges between 20 to 30 meters / minute and the stretching temperatures range from 100 to 130° C.Example 2: Zone of Inhibition of Antibiotic-Containing Filaments

[0062] A standard assay was performed to assess the ability of the antibiotic to elute from the filament and inhibit the growth of E. coli on an agar plate. The results are shown in FIGS. 3A and 3B. In the study shown in FIG. 3A, PDO filaments coated with the antibiotic voxvoganan were placed on an agar plate after spreading an E. coli culture uniformly on the plate surface. The clear areas show the zone of inhibition after one day of incubation.

[0063] FIG. 3B shows the zones of inhibition of barbed PDO filaments compounded with the antibiotic voxvoganan in a method of the invention such that the antibiotic is incorporated uniformly throughout the filament and the barbs. The zones of inhibition extend out from the filament body and clearly extend out from the barbs.Other Embodiments

[0064] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0065] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Examples

example 1

Method for Producing Anti-Microbial Filament

[0057]The first step in producing the antimicrobial filament is to dry the starting raw materials under a nitrogen vacuum (−1000 mbar) and ambient temperatures (~25° C.). The N2 gas is cycled until the water content of the materials falls below 100 ppm. As soon as the vacuum is achieved the system moves to the next cycle so there is no processing time beyond the time required by the pump to achieve the target vacuum.

[0058]The second step is the size reduction of the antimicrobial agent. The antimicrobial agent is placed in a laboratory ball mill together with silica or ceramic balls. The antimicrobial material is then sieved until it can pass comfortably through a 425 micron square mesh. The size reduction requires approximately 30 minutes of processing time. In one embodiment, the antimicrobial agent has a particle size of less than about 100 microns, e.g., between about 60-100 microns.

[0059]In the third step, the polymers, dyes, if using...

example 2

Zone of Inhibition of Antibiotic-Containing Filaments

[0062]A standard assay was performed to assess the ability of the antibiotic to elute from the filament and inhibit the growth of E. coli on an agar plate. The results are shown in FIGS. 3A and 3B. In the study shown in FIG. 3A, PDO filaments coated with the antibiotic voxvoganan were placed on an agar plate after spreading an E. coli culture uniformly on the plate surface. The clear areas show the zone of inhibition after one day of incubation.

[0063]FIG. 3B shows the zones of inhibition of barbed PDO filaments compounded with the antibiotic voxvoganan in a method of the invention such that the antibiotic is incorporated uniformly throughout the filament and the barbs. The zones of inhibition extend out from the filament body and clearly extend out from the barbs.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 764,207, filed on Feb. 27, 2025. The entire disclosure of that application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Surgical site infections (“SSIs”) are common nosocomial infections that, in 2016, accounted for at least 20% of all hospital-acquired infections in the United States. SSIs are associated with up to an 11-fold increase in the risk of mortality, and the annual cost in the US of dealing with SSI-related complications is estimated between 3.5 and 10 billion dollars.

[0003] There are a variety of factors that contribute to SSIs, among them being wound closure methods. Sutures have been developed with the goal of reducing SSIs related to wound closure.

[0004] For example, barbed sutures immediately maintain tension once engaged in the tissue and can eliminate the need to tie knots. Eliminating suture knot tying can reduce closure time by up to 50%, not only reducing exposure time to bacteria, but also saving on operating room costs. On the other hand, barbs provide an ideal location for bacterial colonization.

[0005] Antibiotic-coated sutures for wound closure have been developed and approved for use. One drawback of such sutures is that the antibiotic released from the coated surface of the suture only provides an initial burst of protection against pathogens. Further, the coating process typically employs volatile solvents, thus increasing the cost and reducing consistency of the product.

[0006] Triclosan, the antibiotic typically used to coat sutures, has been shown to be ineffective against Pseudomonas spp, and Enterococcus spp. isolates, crucial causative agents of post-operative SSIs. Moreover, some studies have concluded that environmental triclosan impairs thyroid homeostasis and could be associated with neurodevelopment impairment, metabolic disorders, cardiotoxicity, and increased cancer risk.

[0007] Chlorhexidine likewise may undergo hydrolytic degradation above about 100 C and has other undesirable properties such as its potential to act as an allergen and its high cellular toxicity relative to its antimicrobial effectiveness (e.g., a biocompatibility index of about 1).

[0008] There is a need to develop improved antibiotic- and antimicrobial-releasing resorbable filaments, including ones that allow for uniform distribution of an effective and safe antimicrobial agent within the filament while maintaining filament strength and antimicrobial efficacy, without the drawbacks mentioned above.SUMMARY OF THE INVENTION

[0009] To meet the need set forth above, an antimicrobial filament is provided that comprises a filament resorbable material and an antimicrobial agent in which the antimicrobial agent is incorporated throughout the body of the filament.

[0010] The antimicrobial agent, which is broad spectrum and fast acting, may be present at 0.1% to 5% by weight of the filament, and the filament retains antimicrobial activity throughout the life of the filament. In some embodiments, the filament resorbable material comprises polydioxanone (“PDO”) or a blend of polyglycolic acid and ε-caprolactone (“PGCL,” e.g., 75% by weight polyglycolic acid and 25% by weight ε-caprolactone). In some embodiments, the antimicrobial agent comprises an antimicrobial peptide. In some embodiments, the antimicrobial agent comprises voxvoganan. In some embodiments, the antimicrobial agent has a biocompatibility index of at least above 2, 3, 4, 5, 6, 7, 8, 10, 20, 30 or 40. In some embodiments, the filament includes a plurality of barbs formed of the filament resorbable material, and in some instances, each barb contains the antimicrobial agent. In other embodiments, the filament does not include any barbs.

[0011] The filament may retain tensile strength post implantation, e.g., 60-90% tensile strength up to 14 days post implantation, 60-80% tensile strength up to 28 days post implantation, and / or 40-70% tensile strength up to 42 days post implantation. The filament may be essentially absorbed by a subject between 180 and 220 days post implantation. In alternative aspects, the filament retains 42-76% tensile strength up to 7 days post implantation and / or 36-52% tensile strength up to 14 days post implantation. In some embodiments, the filament is essentially absorbed by a subject at 90 days post implantation. The filament may be used in general surgery, orthopedic surgery, or dermatology.

[0012] Also provided is a method of manufacturing an antimicrobial suture including the steps of obtaining raw filament material, obtaining raw antimicrobial agent, grinding the raw filament material and the raw antimicrobial agent to form a mixture, compounding the mixture, and extruding the compounded mixture to form an antimicrobial filament. In some embodiments, steps occur under low moisture or conditions including the steps of grinding and / or compounding the components.

[0013] Further, a surgical suturing kit is disclosed that comprises the antimicrobial filament set out, supra, and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments.

[0014] A medical device or component thereof formed of the antimicrobial filament is also described.

[0015] The details of one or more embodiments of the invention are set forth in the drawings and description below. Other features, objects, and advantages of the invention will be apparent from the description, from the drawings, and from the claims. All references cited herein are hereby incorporated by reference in their entirety.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The invention description below refers to the accompanying drawings.

[0017] FIG. 1 shows a diagram of a barbed filament of an embodiment of the invention.

[0018] FIG. 2 shows an exemplary device for providing barbs on a filament of the invention. The device is described in U.S. Pat. No. 7,913,365.

[0019] FIG. 3A shows the zones of inhibition of Escherichia coli growth surrounding two lengths of PDO filament material coated with the antibiotic voxvoganan.

[0020] FIG. 3B shows the zones of inhibition of Escherichia coli growth surrounding two lengths of barbed PDO filament material compounded with the antibiotic voxvoganan such that the antibiotic is incorporated uniformly throughout the filament and the barbs.DETAILED DESCRIPTION OF THE INVENTION

[0021] Disclosed herein are antimicrobial filaments composed of a filament resorbable material and an antimicrobial agent. The antimicrobial filament provides an alternative to existing triclosan-coated filaments without the drawbacks of that antibiotic.

[0022] The filament resorbable material may be any resorbable material suitable for in vivo use that is capable of combination with an antimicrobial agent as discussed herein, e.g., in a mixing and extrusion process. Examples of suitable filament resorbable materials include biocompatible resorbable, moldable, and meltable materials, e.g., synthetic biodegradable polymers such as resorbable and extrudable synthetic aliphatic polyesters. Examples of filament resorbable materials include polydioxanone (PDO), polyglycolic acid and ε-caprolactone (PGCL), polyglycolic acid (PGA), and / or polyglycolide-Co-Lactide (PGLA) including combinations thereof. In some embodiments, the filament resorbable material is polydioxanone (PDO) or a blend of polyglycolic acid and s-caprolactone (PGCL). In an embodiment, the filament resorbable material is 75% by weight polyglycolic acid and 25% by weight ε-caprolactone. Other examples of suitable resorbable filament materials suitable for hot-melt extrusion are discussed in Khalid and Bilal, Drug-Eluting Sutures by Hot-Melt Extrusion: Current Trends and Future Potentials, Materials 2023, 16, 7245.

[0023] The antimicrobial agent is an active agent that, e.g., kills or inhibits the growth of microbes including bacteria, viruses, and fungi. The antimicrobial agent has chemical and physical properties that make it suitable for mixing with the filament resorbable material such that an extruded filament incorporating the antimicrobial agent may be produced. For example, the selected antimicrobial agent is able to withstand hot-melt extrusion and is thermally stable at and above the filament resorbable material's melt processing temperature. The antimicrobial agent is miscible with the polymer matrix such that it is able to disperse homogenously or uniformly and, preferably, without acting as disruptive plasticizer that compromises the filament's crystallinity, tensile strength, or mechanical integrity. The antimicrobial agent, in combination with the filament resorbable material, is physically and chemically stable for downstream use and processing. As discussed below, in some embodiments, hydrophilic antimicrobial agents are preferred.

[0024] The antimicrobial agent may be incorporated uniformly throughout the body of the filament. In some embodiments, the antimicrobial agent is fast acting, i.e., it is effective starting minutes to hours after administration (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 90, 120 minutes) and broad spectrum, being effective against, e.g., Staphylococcus aureus, Pseudomonas Spp., and Enterococcus Spp. A particular antimicrobial filament includes 0.1% to 5% by weight of the antimicrobial agent. In some aspects, the filament retains antimicrobial activity throughout the life of the filament. In some aspects, the antimicrobial agent does not significantly degrade, sublimate, or produce toxic byproducts during its residence in an extruder or at elevated temperatures, but rather maintains its efficacy during the production process.

[0025] In some embodiments, the antimicrobial agent has a high therapeutic index (antimicrobial effectiveness) while exhibiting low cellular toxicity. For example, the antimicrobial agent may have a relatively high biocompatibility index, for example, by measuring the antibacterial activity against the test organisms Escherichia coli and Staphylococcus aureus. See Muller et al, Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity, J. Antimicrobial Chemotherapy (2008) 61, 1281-1287. In some embodiments, the biocompatibility index of the antimicrobial agent is at least above about 2, 3, 4, 5, 6, 7, 8, 10, 20, 30, or 40.

[0026] In some embodiments, the antimicrobial agent is an antimicrobial peptide comprising from 2 to 30, 2 to 20, 2 to 10, 2 to 8, or 2 to 5 amino acids. The amino acids may be natural, meaning that they are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, or synthetic, for example selected from the group consisting of 2,5,7-tri-tert-butyl-tryptophan, (4-(2′-naphtyl))phenylalanine, and (4-4′-biphenyl)phenylalanine.

[0027] In some embodiments, the antimicrobial peptide comprises at least one cationic amino acid. The at least one cationic amino acid may be natural, e.g. selected from the group consisting of arginine and lysine, or synthetic.

[0028] An exemplary antimicrobial agent is voxvoganan (IUPAC name: L-arginyl-2,5,7-tri-tert-butyl-L-tryptophyl-N-(2-phenylethyl)-L-argininamide), also known as LTX-109 and Lytixar. Voxvoganan is a peptide comprising three amino acids, two natural arginine, and a synthetic amino acid, 2,5,7-tri-tert-butyl-tryptophan.

[0029] Voxvoganan is a broad-spectrum, fast-acting bactericidal antimicrobial agent that binds to negatively charged membrane components on the bacterial cell wall, which leads to membrane disruption and rapid cell lysis. This agent is a peptidomimetic that is stable in vivo, not harmful to human cells, and does not induce bacterial resistance. Further, voxvoganan is hydrophilic and, as such does not accumulate in lipid tissue in the body, as do hydrophobic antimicrobials, e.g., triclosan. Voxvoganan also has a favorable biocompatibility index, e.g., at least above 2 and preferably at least above 4.

[0030] Other examples of suitable antimicrobial agents are described in WO 2009 / 081152, US2023 / 0338609, and in Table 4 of WO2021250286A1, which are hereby incorporated by reference. For example, the antimicrobial agent may have the general compound formula Arg-AA2-Arg-XY, where, e.g., AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is NHCH(CH3)2, AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is NH(CH2)5CH3, AA2 is 2,5,7-tri-tert-butyltryphtophan and XY is OCH3, and / or AA2 is (4-(2′-napthtyl))phenylalanine and XY is NH(CH2)2Ph.

[0031] The presence of the antimicrobial agent does not significantly influence the resorption time of the filament. For example, the filament that comprises PDO or other filament resorbable material may retain 60-90% (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90%) tensile strength up to 14 days post implantation. Up to 28 days post implantation, the filament may retain 60-80% (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82%) tensile strength. Further, the filament may retain 40-60% (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60%) tensile strength up to 42 days post implantation. The PDO-containing filament, or other filaments comprising filament resorbable material, may essentially be absorbed by a subject between 180 and 220 days (e.g., 180, 185, 190, 195, 200, 205, 210, 215, and 220 days) post implantation.

[0032] As mentioned above, in an embodiment, the filament can also be formed of 75% by weight polyglycolic acid and 25% by weight-caprolactone. Again, the presence of the antimicrobial agent does not alter the resorption time of this filament. Up to 7 days post implantation, the filament may retain 42-76% (e.g., 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, and 76%) tensile strength, up to 14 days post implantation, it may retain 36-52% (e.g., 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52%) tensile strength, and at 90 days post implantation, the filament may be essentially absorbed.

[0033] In certain embodiments, the filament includes a plurality of barbs formed of the filament resorbable material. The barbs maintain tension in tissue once the filament is applied, thereby eliminating the need for tying knots to secure the filament. The barbs can be (i) uni-directional in which all of the barbs are oriented in the same direction along the major axis of the filament and (ii) bi-directional in which the barbs on either side of the filament midpoint have opposite orientations. The barbs on a filament may serve as a site of bacterial colonization. To lessen or prevent bacterial colonization, each barb may contain one or more antimicrobial agents, such as those described herein. In other embodiments, the filament is free of barbs. Filaments that include barbs can be used as a tissue-closing device for use in soft tissue approximation where use of a resorbable filament is appropriate or when a physician wishes to avoid tying knots to secure the filament.

[0034] The filaments described above can be used for a variety of applications, including, but not limited to, general surgery, orthopedic surgery, and dermatology.

[0035] Also disclosed herein is a method of manufacturing an antimicrobial filament including the steps of obtaining raw filament material, obtaining raw antimicrobial agent, grinding the raw filament material and the raw antimicrobial agent to form a mixture, compounding the mixture, and extruding the compounded mixture to form an antimicrobial filament including, e.g., an antimicrobial filament in which the antimicrobial is incorporated uniformly throughout the filament. Uniform distribution of the antimicrobial agent within the filament advantageously allows for steady, consistent, and safe release of the antimicrobial agent over time.

[0036] In some embodiments, moisture control is employed in the manufacturing method and the method is undertaken in a low moisture or dry environment, e.g., under sealed nitrogen or desiccant circulated air environment. This facilitates stabilizing the moisture content of the base polymer and / or the antimicrobial agent during processing. For example, the steps of grinding, compounding, and / or mixing the materials occur under dry or low moisture conditions. As another example, the method may entail minimizing moisture in steps occurring under ordinary or ambient conditions to the extent possible.

[0037] In an embodiment, the method of manufacturing includes the following steps:

[0038] 1 Mixing of Polymer resin, i.e., raw filament material such as base polymer resin granules, colorant and antimicrobial agent. In some embodiments, a mixture of granules are mixed into a semi-uniform distribution or mixture of powders to form a more uniform feedstock.

[0039] 2. Extruding the compounded polymer mix

[0040] 3. Dry Storage

[0041] 4. Winding into large bobbins

[0042] 5. Annealing

[0043] 6. Dry Storage

[0044] 7. Vacuum dry, including at ambient and elevated temperatures (e.g., above 60 C)

[0045] 8. Final package with moisture barrier

[0046] 9. QA Mechanical properties testing

[0047] In some embodiments, the raw filament material contains a filament resorbable material that can be PDO or a blend of polyglycolic acid and ε-caprolactone. In an embodiment, the filament resorbable material is 75% by weight polyglycolic acid and 25% by weight ε-caprolactone.

[0048] In some embodiments, the amount of raw antimicrobial agent employed in the method is such that the antimicrobial filament includes 0.1% to 5% by weight of the antimicrobial agent. In some embodiments, the amount of raw antimicrobial agent employed is about 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5% by weight. In other embodiments, the amount of raw antimicrobial agent is about 0.1% by weight, 0.1 to 4% by weight, 0.1 to 3% by weight, 0.1 to 2% by weight, 0.5 to 4% by weight, 1 to 4% by weight, 0.5 to 3% by weight, or 0.5 to 2% by weight. The amount employed may depend on the efficacy of the agent and the intended size of the final filament. Moreover, consideration is given to the upper limit of concentration that an extruded polymer can support for additive loading without deviation from the intended strength and degradation profile. In some aspects, the filament retains antimicrobial activity throughout the life of the filament.

[0049] The antimicrobial agent has the same properties described above, i.e., it is fast acting and broad spectrum. In an exemplary method, the raw antimicrobial agent is voxvoganan.

[0050] Carrying out the method produces an antimicrobial filament having the resorption characteristics detailed above. For example, the filament that comprises PDO retains 60-90% tensile strength up to 14 days post implantation, 60-80% tensile strength up to 28 days post implantation, and 40-60% tensile strength up to 42 days post implantation. The PDO-containing filament is essentially absorbed by a subject between 180 and 220 days.

[0051] For the filament containing 75% by weight polyglycolic acid and 25% by weight-caprolactone, the resorption times are those set forth above. Briefly, up to 7 days post implantation, the filament retains 42-76% tensile strength, up to 14 days post implantation, it retains 36-52% tensile strength, and at 90 days post implantation, the filament is essentially absorbed.

[0052] The method can also include a step of forming barbs. The barbs can be formed oriented in one direction along the major axis of the filament or in a bi-directional manner in which the barbs have the opposite orientation on either side of the midpoint of the filament. See FIG. 1. An exemplary method and device for forming barbs is shown in U.S. Pat. No. 7,913,365, the content of which is incorporated herein by reference in its entirety. FIG. 2, reproduced from U.S. Pat. No. 7,913,365, shows a diagram of an exemplary device for providing barbs to the filament described herein. As set forth in the patent and referring to FIG. 2, reciprocating blade assembly 250 includes blade 8 connected via arm 225 to a linear reciprocating solenoid, which reciprocates in direction (2) and (42). Cutting bed vise 63 is synchronized with reciprocating blade assembly 250 and the indexing mechanism such that the vise closes to hold suture 6 in place during cutting and opens to allow suture 6 to be advanced by the indexer to the next cutting position.

[0053] Also within the scope of the invention in some embodiments is a surgical suturing kit comprising the antimicrobial filament described in detail above, and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments. The suture needle is preferably pre-attached to the filament such that the filament is ready to use upon opening the sterilizable package. The discrete compartments can each hold an individual filament / suture needle assembly.

[0054] The antimicrobial filament described above may also be used in other applications. For example, the use of the antimicrobial filament described above in additive manufacturing methods, for example three-dimensional (3D) printing, is provided. In one aspect, the antimicrobial filament may be used to manufacture a medical device or a component thereof, in particular using additive manufacturing techniques such as 3D printing. Moldable and meltable materials, such as PDO, are suitable to be used in additive manufacturing techniques, wherein the material is heated and deposited on a support material according to a defined pattern. Once the material cools, it forms a three-dimensional structure that may be used as a medical device or as part of one. Additive manufacturing thus allows the production of medical devices or components thereof with a higher degree of complexity than techniques such as extrusion.

[0055] The antimicrobial filament as described above may be used in such methods allowing for the production of a medical device with an antimicrobial agent distributed throughout the device or component. For example, biodegradable polymer filaments in 3D printing can enable patient-specific, temporary implants, scaffolds, and drug-delivery devices that safely resorb in the body after fulfilling their therapeutic or structural function. Thus, in one aspect, a method of manufacturing a medical device or component thereof is provided, the method comprising: a) obtaining raw filament material; b) obtaining raw antimicrobial agent; c) forming a mixture with the raw filament material and the raw antimicrobial agent, e.g., as discussed above; d) producing the antimicrobial filament as described above, and e) processing the antimicrobial filaments in an additive manufacturing device, thereby producing a medical device or component thereof, wherein the device or component includes the antimicrobial agent incorporated throughout the body of the device or component.

[0056] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications, including patent documents, cited herein are incorporated by reference in their entirety.EXAMPLESExample 1: Method for Producing Anti-Microbial Filament

[0057] The first step in producing the antimicrobial filament is to dry the starting raw materials under a nitrogen vacuum (−1000 mbar) and ambient temperatures (~25° C.). The N2 gas is cycled until the water content of the materials falls below 100 ppm. As soon as the vacuum is achieved the system moves to the next cycle so there is no processing time beyond the time required by the pump to achieve the target vacuum.

[0058] The second step is the size reduction of the antimicrobial agent. The antimicrobial agent is placed in a laboratory ball mill together with silica or ceramic balls. The antimicrobial material is then sieved until it can pass comfortably through a 425 micron square mesh. The size reduction requires approximately 30 minutes of processing time. In one embodiment, the antimicrobial agent has a particle size of less than about 100 microns, e.g., between about 60-100 microns.

[0059] In the third step, the polymers, dyes, if using, and size-reduced antimicrobial agent are mixed in a dry atmosphere (nitrogen glove box) at ambient conditions (~21° C.) manually for 2-3 minutes and then by a tumbler machine for 30 minutes.

[0060] In the fourth step, filaments are formed by extrusion at temperatures of 150-185° C. for the range. The pressure of the barrel and extrusion head ranges from 60 to 80 bars. The quenching of the extrusion is performed in a water bath that is kept below 8° C. In some embodiments, the extrusion residence time is 1 to 5 minutes. In other embodiments, extrusion temperatures are above 100° C. and below 270° C. In some embodiments, depending on the polymer used and the intended size of the filament, filaments are formed by extrusion at temperatures of about 120-140° C., 130-150° C., 150-185° C., 175-200° C., 200-230° C., 215-235° C., 230-260° C., and 250-275° C. In some examples, pressures may be between about 40 to 80 or 90 bar or between about 20 to 40 bar.

[0061] In the fourth, i.e., extrusion, step, stretching speeds and stretching temperatures depend on the diameter of the extrusion and the final diameter expected for the filament. Typically, the speed ranges between 20 to 30 meters / minute and the stretching temperatures range from 100 to 130° C.Example 2: Zone of Inhibition of Antibiotic-Containing Filaments

[0062] A standard assay was performed to assess the ability of the antibiotic to elute from the filament and inhibit the growth of E. coli on an agar plate. The results are shown in FIGS. 3A and 3B. In the study shown in FIG. 3A, PDO filaments coated with the antibiotic voxvoganan were placed on an agar plate after spreading an E. coli culture uniformly on the plate surface. The clear areas show the zone of inhibition after one day of incubation.

[0063] FIG. 3B shows the zones of inhibition of barbed PDO filaments compounded with the antibiotic voxvoganan in a method of the invention such that the antibiotic is incorporated uniformly throughout the filament and the barbs. The zones of inhibition extend out from the filament body and clearly extend out from the barbs.Other Embodiments

[0064] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0065] From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Examples

example 1

Method for Producing Anti-Microbial Filament

[0057]The first step in producing the antimicrobial filament is to dry the starting raw materials under a nitrogen vacuum (−1000 mbar) and ambient temperatures (~25° C.). The N2 gas is cycled until the water content of the materials falls below 100 ppm. As soon as the vacuum is achieved the system moves to the next cycle so there is no processing time beyond the time required by the pump to achieve the target vacuum.

[0058]The second step is the size reduction of the antimicrobial agent. The antimicrobial agent is placed in a laboratory ball mill together with silica or ceramic balls. The antimicrobial material is then sieved until it can pass comfortably through a 425 micron square mesh. The size reduction requires approximately 30 minutes of processing time. In one embodiment, the antimicrobial agent has a particle size of less than about 100 microns, e.g., between about 60-100 microns.

[0059]In the third step, the polymers, dyes, if using...

example 2

Zone of Inhibition of Antibiotic-Containing Filaments

[0062]A standard assay was performed to assess the ability of the antibiotic to elute from the filament and inhibit the growth of E. coli on an agar plate. The results are shown in FIGS. 3A and 3B. In the study shown in FIG. 3A, PDO filaments coated with the antibiotic voxvoganan were placed on an agar plate after spreading an E. coli culture uniformly on the plate surface. The clear areas show the zone of inhibition after one day of incubation.

[0063]FIG. 3B shows the zones of inhibition of barbed PDO filaments compounded with the antibiotic voxvoganan in a method of the invention such that the antibiotic is incorporated uniformly throughout the filament and the barbs. The zones of inhibition extend out from the filament body and clearly extend out from the barbs.

Claims

1. An extruded antimicrobial filament comprising a filament resorbable material and an antimicrobial agent, wherein the antimicrobial agent is incorporated uniformly throughout the body of the filament.

2. The antimicrobial filament of claim 1, wherein the filament resorbable material comprises polydioxanone.

3. The antimicrobial filament of claim 1, wherein the filament resorbable material comprises a blend of polyglycolic acid and ε-caprolactone.

4. The antimicrobial filament of claim 1, wherein the antimicrobial agent comprises an antimicrobial peptide.

5. The antimicrobial filament of claim 1, wherein the antimicrobial agent has a biocompatibility index of at least about 2 or at least about 4.

6. The antimicrobial filament of claim 1, wherein the antimicrobial agent comprises voxvoganan.

7. The antimicrobial filament of claim 1, wherein the filament comprises 0.1% to 5% by weight of the antimicrobial agent.

8. The antimicrobial filament of claim 1, wherein the filament retains 60-90% tensile strength up to 14 days post implantation.

9. The antimicrobial filament of claim 1, wherein the filament retains 60-80% tensile strength up to 28 days post implantation.

10. The antimicrobial filament of claim 1, wherein the filament retains 40-60% tensile strength up to 42 days post implantation.

11. The antimicrobial filament of claim 1, wherein the filament is essentially absorbed by a subject between 180 and 220 days post implantation.

12. The antimicrobial filament of claim 1, wherein the filament retains 42-76% tensile strength up to 7 days post implantation.

13. The antimicrobial filament of claim 1, wherein the filament retains 36-52% tensile strength up to 14 days post implantation.

14. The antimicrobial filament of claim 1, wherein the filament is essentially absorbed by a subject at 90 days post implantation.

15. The antimicrobial filament of claim 1, wherein the filament retains antimicrobial activity throughout the life of the filament.

16. The antimicrobial filament of claim 1, wherein the filament includes a plurality of barbs formed of the filament resorbable material.

17. The antimicrobial filament of claim 16, wherein each barb contains the antimicrobial agent.

18. The antimicrobial filament of claim 1, wherein the filament is free of barbs.

19. The antimicrobial filament of claim 1, wherein the filament is for use in general surgery, orthopedic surgery, or dermatology.

20. A method of manufacturing an antimicrobial filament comprising:a) obtaining raw filament material;b) obtaining raw antimicrobial agent;c) grinding the raw filament material and the raw antimicrobial agent to form a mixture;d) compounding the mixture; ande) extruding the compounded mixture to form an antimicrobial filament.

21. The method of claim 20, wherein the raw filament material comprises a filament resorbable material.

22. The method of claim 21, wherein the filament resorbable material comprises polydioxanone.

23. The method of claim 21, wherein the filament resorbable material comprises a blend of polyglycolic acid and ¿-caprolactone.

24. The method of claim 20, wherein the particle size of the raw antimicrobial agent is less than 100 microns.

25. The method of claim 20, wherein the raw antimicrobial agent comprises voxvoganan.

26. The method of claim 20, wherein the antimicrobial filament comprises 0.1% to 5% by weight of the antimicrobial agent.

27. The method of claim 20, wherein the grinding and compounding steps occur under low moisture or dry conditions.

28. The method of claim 20, wherein the antimicrobial filament retains 60-90% tensile strength up to 14 days post implantation, or wherein the antimicrobial filament retains 60-80% tensile strength up to 28 days post implantation, or wherein the antimicrobial filament retains 47-79% tensile strength up to 42 days post implantation.

29. The method of claim 20, wherein the antimicrobial filament is essentially absorbed between 180 and 220 days post implantation.

30. The method of claim 20, wherein the filament retains 42-76% tensile strength up to 7 days post implantation or wherein the filament retains 36-52% tensile strength up to 14 days post implantation.

31. The method of claim 20, wherein the filament is essentially absorbed 90 days post implantation.

32. The method of claim 20, wherein the antimicrobial filament retains antimicrobial activity throughout the life of the filament.

33. The method of claim 20, further comprising forming a plurality of barbs in the antimicrobial filament.

34. The method of claim 20, wherein each barb contains the antimicrobial agent.

35. A surgical suturing kit comprising the antimicrobial filament of claim 1 and one or more suture needles or other medical devices in a sterilizable package having a plurality of discrete compartments.

36. A medical device formed from the antimicrobial filament of claim 1.

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