ANTIMICROBIAL ARTICLES PRODUCED BY ADDITIVE MANUFACTURING

Abstract

An antibiotic-eluting article for implantation into a mammalian subject, produced by an additive manufacturing process wherein a polymeric material is concurrently deposited with a selected antibiotic. The additive manufacturing process may be a selective laser sintering process or a selective laser melting process or a selective heat sintering process or an electron beam melting process. The antibiotic-eluting article may be temporary or permanent orthopaedic skeletal component, an orthopaedic articulating joint replacement component, and/or an external hard-shell casing for an implantable device. One or more bone-growth-promoting compositions may be concurrently deposited with the polymeric material. The implantable device may be a cardiac pacemaker, a spinal cord stimulator, a neurostimulation system, an intrathecal drug pump for delivery of medicants into the spinal fluid, and infusion pump for delivery of chemotherapeutics and/or anti-spasmodics, an insulin pump, an osmotic pump, and a heparin pump.

Claims

1. An antibiotic-eluting article for implantation into a mammalian subject, said antibiotic-eluting article produced from a dry antibiotic-containing polymeric granular powder blend by one of a selective laser sintering process, a selective laser melting process, a selective heat sintering process, and an electron beam melting process, said article having a structural matrix, a surface, and an antibiotic compound homogeneously distributed throughout the structural matrix and across the surface, wherein said dry antibiotic-containing polymeric granular powder blend consists of: a polymeric granular powder; and at least about 1% w/w of at least one antibiotic powder.

2. The antibiotic-eluting article of claim 1, wherein the polymer is selected from a group consisting of poly(methyl methacrylates), acrylonitrile butadiene styrenes, polycarbonates, blends of acrylonitrile butadiene styrene(s) and polycarbonate(s), polyether ether ketones, polyethylenes, polyamides, polylactic acids, polyphenylsulfones, polystyrenes, nylons, methylmethacrylates, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, block copolymers, multi-block co-polymers, multi-block co-polymers with polyethylene glycol (PEG), polyols, terpolymers, and mixtures thereof.

3. The antibiotic-eluting article of claim 1, wherein the at least one antibiotic is selected from a group consisting of an aminoglycoside, an azole, a -lactam antibiotic, a -lactamase inhibitor, a cephalosporin, chloramphenicol, clindamycin, fusidic acid, a glycopeptide, a macrolide, metronidazole, mupirocin, a penicillin, a polyene, a quinolone, a rifamycin, a sufonamide, a tetracycline, trimethoprim, and combinations thereof.

4. The antibiotic-eluting article of claim 1, wherein the at least one antibiotic is tobramycin and/or gentamicin and/or vancomycin.

5. The antibiotic-eluting article of claim 1, where the article is provided with an outer coat comprising a biocidal composition selected from a group consisting of silver nanoparticles, zinc pyrithione, cationic polymeric biocides, and mixtures thereof.

6. The antibiotic-eluting article of claim 1, wherein the article is an orthopaedic skeletal component.

7. The antibiotic-eluting article of claim 6, wherein the article is an orthopaedic articulating joint replacement component.

8. The antibiotic-eluting article of claim 6, wherein the article is an orthopaedic bone replacement component.

9. The antibiotic-eluting article of claim 6, wherein the dry antibiotic-containing polymeric granular powder blend additionally comprises a bone-growth-promoting composition.

10. The antibiotic-eluting article of claim 9, wherein the bone-growth-promoting composition is selected from a group consisting of hyaluronic acid, -TCP compositions, SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, and 7-{[2-(3,5-dichloro-phenoxyl)-ethyl]-methanesulfonyl-amino}-heptanoic acid and its analogs, 3-benzothiepin derivatives.

11. The antibiotic-eluting article of claim 6, wherein the antibiotic-eluting article is provided with an outer coat comprising a bone-growth-promoting composition.

12. The antibiotic-eluting article of claim 11, wherein the bone-growth-promoting composition is selected from a group consisting of hyaluronic acid, -TCP compositions, SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, and 7-{[2-(3,5-dichloro-phenoxyl)-ethyl]-methanesulfonyl-amino}-heptanoic acid and its analogs, and 3-benzothiepin derivatives.

13. The antibiotic-eluting article of claim 1, wherein the article is an external hard-shell casing for an implantable device.

14. The antibiotic-eluting article of claim 13, wherein the article is one of a cardiac pacemaker, a spinal cord stimulator, a neurostimulation system, an intrathecal drug pump for delivery of medicants into the spinal fluid, and infusion pump for delivery of chemotherapeutics and/or anti-spasmodics, an insulin pump, an osmotic pump, and a heparin pump.

15. The antibiotic-eluting article of claim 1, wherein the article is an implantable dental prosthesis or an oral device or a replacement tooth component.

16. The antibiotic-eluting article of claim 1, wherein the article is a transcutaneous skin surface treatment device or a wound treatment device.

17. A method for producing an antibiotic-eluting article for implantation into a mammalian subject, said article having a structural matrix, a surface, and an antibiotic compound homogeneously distributed throughout the structural matrix and across the surface, wherein said article is produced from a dry antibiotic-containing polymeric granular powder blend by any one of a selective laser sintering machine, a selective laser liquefying machine, a selective heat sintering machine, and an electron beam liquefying machine, and wherein the dry antibiotic-containing polymeric granular powder blend consists of: a polymeric granular powder; and at least about 1% w/w of at least one antibiotic powder.

18. The method of claim 17, wherein the polymer is selected from a group consisting of poly(methyl methacrylates), acrylonitrile butadiene styrenes, polycarbonates, blends of acrylonitrile butadiene styrene(s) and polycarbonate(s), polyether ether ketones, polyethylenes, polyamides, polylactic acids, polyphenylsulfones, polystyrenes, nylons, methylmethacrylates, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, and copolymers, block copolymers, multi-block co-polymers, multi-block co-polymers with polyethylene glycol (PEG), polyols, terpolymers, and mixtures thereof.

19. The method of claim 17, wherein the antibiotic is selected from a group consisting of an aminoglycoside, an azole, a -lactam antibiotic, a -lactamase inhibitor, a cephalosporin, chloramphenicol, clindamycin, fusidic acid, a glycopeptide, a macrolide, metronidazole, mupirocin, a penicillin, a polyene, a quinolone, a rifamycin, a sufonamide, a tetracycline, trimethoprim, and combinations thereof.

20. The method of claim 17, wherein the dry antibiotic-containing polymeric granular powder blend additionally comprises a bone growth promoter selected from a group consisting of hyaluronic acid SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, and 7-{[2-(3,5-dichloro-phenoxyl)-ethyl]-methanesulfonyl-amino}-heptanoic acid and its analogs, and 3-benzothiepin derivatives.

21. The method of claim 17, additionally comprising a step of coating the article with a bone growth promoter selected from a group consisting of hyaluronic acid SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, and 7-{[2-(3,5-dichloro-phenoxyl)-ethyl]-methanesulfonyl-amino}-heptanoic acid and its analogs, and 3-benzothiepin derivatives.

22. The method of claim 17, additionally comprising a step of coating the article with a biocidal composition selected from a group consisting of silver nanoparticles, zinc pyrithione, cationic polymeric biocides, and mixtures thereof.

Description

DETAILED DESCRIPTION

[0008] The present disclosure pertains to methods for producing implantable antibiotic-eluting polymeric medical devices having antimicrobial compounds and/or bactericidal compounds homogenously distributed and sequestered throughout their structural matrix and across their surfaces. The present disclosure also pertains to implantable antibiotic-sequestering and eluting medical devices produced by the exemplary methods disclosed herein.

[0009] The exemplary methods of the present disclosure are particularly useful for producing substantially rigid articles that are suitable for surgical implantation into mammalian bodies, for example humans, primates, livestock, ruminants, equines, canines, felines, and the like.

[0010] The exemplary methods are also useful for producing external hard-shell casings for implantable devices such as cardiac pacemakers, spinal cord stimulators, neurostimulation systems, intrathecal drug pumps for delivery of medicants into the spinal fluid, infusion pumps for delivery of chemotherapeutics and/or anti-spasmodics, insulin pumps, osmotic pumps, heparin pumps, and the like. The exemplary methods are also useful for producing dental prosthesis, dental implants comprising one or more replacement tooth components, and the like. The exemplary methods are also useful for producing transcutaneous skin surface treatment devices exemplified by devices for providing transcutaneous electrical nerve stimulation and by devices for providing long-term percutaneous access. The exemplary methods are also useful for producing wound treatment surface devices exemplified by staples and sutures, and the like. The exemplary methods are particularly useful for producing three-dimensional intricate orthopaedic skeletal components including but not limited to articulating joint replacements, hip joint spacers, knee joint spacers, shoulder joint spacers, and the like. The three-dimensional intricate orthopaedic skeletal components may be temporary structures or alternatively, permanent structures.

[0011] The exemplary methods generally incorporate into manufacturing processes using additive manufacturing technologies, the concurrent deposition of one or more antimicrobial and/or biocidal compositions with the base feedstock materials to form the three-dimensional physical structures comprising the implantable antimicrobial articles of the present disclosure. The articles may be formed into solid and dense non-porous three-dimensional structures. Alternatively, the structures may be formed into heterogenous three-dimensional structures comprising solid regions and porous regions. Alternatively, the structures may comprise inner cores having heterogenous three-dimensional structures that are overlaid with outer coverings comprising one or more solid dense layers. One or more selected antimicrobial compositions may be incorporated into the inner cores and/or into the outer coverings. Alternatively, the structures may comprise inner cores comprising a first heterogenous three dimensional structure with a first degree of porosity, overlaid with one or more layers of a second heterogenous three dimensional structure with a second degree of porosity. One or more selected antibiotic compositions may be incorporated into the inner cores and/or into the outer layers. If so desired, the articles can be formed having more than three zones of porosity ranging from the inner cores to the outer surfaces.

[0012] Suitable additive manufacturing technologies include molten polymer deposition exemplified by selective laser sintering, selective laser melting, selective heat sintering, electron beam melting, and the like. One or more antibiotic compositions are concurrently deposited with the polymeric materials resulting in sequestration of the antibiotic compositions within and about the matrix formed by the polymeric materials. The antibiotic compositions are deposited at rates that will provide in the articles of the present disclosure, from about 0.01% w/w to about 25% w/w of the antibiotic active ingredient by weight of the total weight of an antimicrobial article. For example, about 0.01% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.75% w/w, about 1.0% w/w, about 1.25% w/w, about 1.5% w/w, about 1.75% w/w, about 2.0% w/w, about 2.25% w/w, about 2.5% w/w, about 2.75% w/w, about 3.0% w/w, about 3.25% w/w, about 3.5% w/w, about 3.75% w/w, about 4.0% w/w, about 4.25% w/w, about 4.5% w/w, about 4.75% w/w, about 5.0% w/w, about 5.25% w/w, about 5.5% w/w, about 5.75% w/w, about 6.0% w/w, about 7.0% w/w, about 8.0% w/w, about 9.0% w/w, about 10.0% w/w, about 15.0% w/w, about 20.0% w/w, about 25.0% w/w, and therebetween.

[0013] The term antimicrobial as used herein means antibiotic, antiseptic, disinfectant. Classes of antibiotic compositions that may be useful for in the methods of the present disclosure for producing antimicrobial implantable medical devices include aminoglycosides exemplified by tobramycin, gentamicin, neomycin, streptomycin, and the like; azoles exemplified by fluconazole, itraconazole, and the like; -lactam antibiotics exemplified by penams, cephems, carbapenems, monobactams, -lactamase inhibitors, and the like; cephalosporins exemplified by cefacetrile, cefadroxyl, cephalexin, cephazolin, cefproxil, cefbuperazone, and the like; chloramphenicol; clindamycin; fusidic acid; glycopeptides exemplified by vancomycin, teicoplanin, ramoplanin, and the like; macrolides exemplified by azithromycin, clarithromycin, dirithromysin, erythromycin, spiramycin, tylosin, and the like; metronidazole; mupirocin; penicillins exemplified by benzylpenicillin, procaine benzylpenicillin, benzathine benzylpenicillin, phenoxymethylpenicillin, and the like; polyenes exemplified by amphotericin B, nystatin, natamycin, and the like; quinolones exemplified by ciprofloxacin, ofloxacin, danofloxacin, and the like; rifamycins exemplified by rifampicin, rifabutin, rifapentine, rifaximin, and the like; sufonamides exemplified by sulfacetamine, sulfadoxine, and the like; tetracyclines exemplified by doxycycline, minocycline, tigecycline, and the like; and trimethoprim, among others. It is expected that tobramycin and/or gentamicin and/or neomycin and/or vancomycin are particularly suitable for concurrent deposition with polymeric materials for additive manufacturing of the antimicrobial medical devices of the present disclosure.

[0014] Various thermoplastic polymers and/or free radical polymers and/or cross-linked polymers may be used for concurrent deposition with antibiotic compositions to produce the antimicrobial articles disclosed herein. For example poly(methyl methacrylates), acrylonitrile butadiene styrenes, polycarbonates, blends of acrylonitrile butadiene styrene(s) and polycarbonate(s), polyether ether ketones, polyethylenes, polyamides, polylactic acids, polyphenylsulfones, polystyrenes, nylon particularly nylon 12, among others. Also useful are methylmethacrylates, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, and copolymers, block copolymers, multi-block co-polymers, multi-block co-polymers with polyethylene glycol (PEG), polyols, terpolymers and mixtures thereof Also useful is incorporation of glass fibres during deposition of selected polymers and antibiotic compositions.

[0015] If so desired for manufacture of the three-dimensional intricate orthopaedic skeletal components disclosed herein, one or more bone-growth-promoting compositions may be deposited concurrently with the polymeric materials and the antibiotic compositions resulting in sequestration of the antibiotic compositions and bone-growth-promoting compositions within and about the matrix formed by the polymeric materials. Suitable bone-growth-promoting compositions are exemplified by hyaluronic acid, -TCP compositions, SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, 7-{[2-(3,5-dichloro-phenoxyl)-ethyl]-methanesulfonyl-amino}-heptanoic acid and its analogs, 3-benzothiepin derivatives, and the like.

[0016] Granular materials binding processes exemplified by selective laser sintering, selective laser liquefying, selective heat sintering and electron beam liquefying (all referred to herein as SLS), comprise selective fusing of print media in a granular bed. In this type of method, a high power laser is used to fuse small particles of plastic, metal, ceramic, or glass powders into a mass that has a desired three-dimensional shape. The laser selectively fuses powdered material by scanning cross-sections generated from a 3-D digital description of the part (for example from a CAD file or scan data) on the surface of a powder bed. After each cross-section is scanned, the powder bed is lowered by one layer thickness, a new layer of material is applied on top, and the process is repeated until the part is completed. Because finished part density depends on peak laser power rather than laser duration, a SLS machine typically uses a pulsed laser. A suitable SLS machine preheats the bulk powder material in the powder bed somewhat below its melting point, to make it easier for the laser to raise the temperature of the selected regions the rest of the way to the melting point.

[0017] Accordingly, the exemplary implantable polymeric antimicrobial devices disclosed herein may also be produced by SLS 3D printing machines by providing powdered blends of one or more selected granular polymers with one or more selected antibiotic compositions and/or one or more bone-growth-promoting composition. Suitable SLS 3D printing machines are manufactured by EOS GmbH (Munich, Fed. Rep. Germany) and are available in North America from EOS of North America Inc. (Novi, Mich., USA). Suitable EOS SLS 3D printing machines include their FORMIGA P 110, EOSINT P 395, EOSINT P 760, and EOSINT P 800 equipment (FORMIGA and EOSINT are registered trademarks of EOS GmbH Electro Optical Systems Co., Krailling, Fed. Rep. Germany). Suitable SLS 3D printing machines are also manufactured and supplied by 3D Systems Inc. (Rock Hill, S.C., USA) and are exemplified by their SPRO line of equipment (SPRO is a registered trademark of 3D Systems Inc.). Suitable electron beam melting (also referred to as EBM) 3D printing machines are manufactured by Arcam AB (Molndal, Sweden) and are available in North America from their office in Chicago, Ill. Suitable Arcam EBM 3D printing machines include their Q10 and A2 equipment.

[0018] Suitable exemplary powdered antibiotic/polymer compositions for SLS 3D printing may comprise granules of one or more of poly(methyl methacrylates), acrylonitrile butadiene styrenes, polycarbonates, blends of acrylonitrile butadiene styrene(s) and polycarbonate(s), polyether ether ketones, polyethylenes, polyamides, polylactic acids, polyphenylsulfones, polystyrenes, nylon particularly nylon 12, among others. Also useful are methylmethacrylates, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, and copolymers, block copolymers, multi-block co-polymers, multi-block co-polymers with polyethylene glycol (PEG), polyols, terpolymers and mixtures thereof.

[0019] Suitable powdered antibiotic/polymer compositions for SLS 3D printing may comprise one or more of aminoglycosides exemplified by tobramycin, gentamicin, neomycin, streptomycin, and the like; azoles exemplified by fluconazole, itraconazole, and the like; -lactam antibiotics exemplified by penams, cephems, carbapenems, monobactams, -lactamase inhibitors, and the like; cephalosporins exemplified by cefacetrile, cefadroxyl, cephalexin, cephazolin, cefproxil, cefbuperazone, and the like; chloramphenicol; clindamycin; fusidic acid; glycopeptides exemplified by vancomycin, teicoplanin, ramoplanin, and the like; macrolides exemplified by azithromycin, clarithromycin, dirithromysin, erythromycin, spiramycin, tylosin, and the like; metronidazole; mupirocin; penicillins exemplified by benzylpenicillin, procaine benzylpenicillin, benzathine benzylpenicillin, phenoxymethylpenicillin, and the like; polyenes exemplified by amphotericin B, nystatin, natamycin, and the like; quinolones exemplified by ciprofloxacin, ofloxacin, danofloxacin, and the like; rifamycins exemplified by rifampicin, rifabutin, rifapentine, rifaximin, and the like; sufonamides exemplified by sulfacetamine, sulfadoxine, and the like; tetracyclines exemplified by doxycycline, minocycline, tigecycline, and the like; and trimethoprim, among others. The antibiotic content of exemplary powdered antibiotic/polymer compositions for SLS 3D printing may comprise about 0.01% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.75% w/w, about 1.0% w/w, about 1.25% w/w, about 1.5% w/w, about 1.75% w/w, about 2.0% w/w, about 2.25% w/w, about 2.5% w/w, about 2.75% w/w, about 3.0% w/w, about 3.25% w/w, about 3.5% w/w, about 3.75% w/w, about 4.0% w/w, about 4.25% w/w, about 4.5% w/w, about 4.75% w/w, about 5.0% w/w, about 5.25% w/w, about 5.5% w/w, about 5.75% w/w, about 6.0% w/w, about 7.0% w/w, about 8.0% w/w, about 9.0% w/w, about 10.0% w/w, about 15.0% w/w, about 20.0% w/w, about 25.0% w/w, and therebetween.

[0020] Suitable powdered antibiotic/polymer compositions for SLS 3D printing may comprise one or more of hyaluronic acid, -TCP compositions, SOST(sclerostin) antagonists for modulating the Wnt signaling pathway, Wise antagonists for modulating the Wnt signaling pathway, LRP antagonists for modulating the Wnt signaling pathway, (3(4-tert-butyl-b enzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic-acid and its analogs, 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its analogs, 7-{[2-(3,5-dichloro-phenoxyl)-ethyl] -methanesulfonyl -amino}-heptanoic acid and its analogs, 3-benzothiepin derivatives, and the like. The bone-growth-promoting composition content of exemplary powdered antibiotic/polymer compositions for SLS 3D printing may comprise about 0.01% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.75% w/w, about 1.0% w/w, about 1.25% w/w, about 1.5% w/w, about 1.75% w/w, about 2.0% w/w, about 2.25% w/w, about 2.5% w/w, about 2.75% w/w, about 3.0% w/w, about 3.25% w/w, about 3.5% w/w, about 3.75% w/w, about 4.0% w/w, about 4.25% w/w, about 4.5% w/w, about 4.75% w/w, about 5.0% w/w, about 5.25% w/w, about 5.5% w/w, about 5.75% w/w, about 6.0% w/w, about 7.0% w/w, about 8.0% w/w, about 9.0% w/w, about 10.0% w/w, about 15.0% w/w, about 20.0% w/w, about 25.0% w/w, and therebetween.

[0021] The 3D printing methods of the present disclosure may additionally include additionally or alternatively comprise steps of concurrent deposition of a first antibiotic composition or mixture of antibiotic compositions and/or a first bone-growth-promoting composition with a selected polymeric material in several layers to form the core of a three-dimensional antimicrobial article, followed by concurrent deposition of a second first antibiotic composition or mixture of antibiotic compositions and/or a second bone-growth-promoting composition with the selected polymeric material to form the outer regions and surfaces of the antimicrobial article. The methods may additionally comprise concurrent deposition of additional layers of a third antibiotic composition or mixture of antibiotic compositions and/or a third bone-growth-promoting composition if so desired. It is optional to provide a final outer surface layer to which is added a biocidal composition exemplified by silver nanoparticles, zinc pyrithione, cationic polymeric biocides, and the like. It is optional to provide a final outer surface layer to which is added a bone-growth-promoting composition exemplified by hyaluronic acid, -TCP compositions, 3-benzothiepin derivatives, and the like.

[0022] It is also optional to provide a final outer surface layer to which is added mixture of a biocidal composition and a bone-growth-promoting composition. The outer surface layer comprising the biocidal coating and/or the bone-growth-promoting composition may be applied by the same additive manufacturing process used to produce the core structural matrix of the three-dimensional antimicrobial article. Alternatively, the outer surface layer may be applied as a coating over the core structural matrix of the three-dimensional antimicrobial article. The outer coating may be applied by processes exemplified by dipping, spraying, soaking, infusing, powder-coating, sputter-coating, arc depositing, and the like.

[0023] The antibiotic-eluting articles of the present disclosure are exemplified by orthopaedic skeletal components, orthopaedic articulating joint replacement components, and bone spacers. Also included are temporary orthopaedic components for short-term implantation while the permanent replacement orthopaedic components are being produced. The term short-term as used herein means three hundred and sixty five (365) days and less. The antibiotic-eluting articles of the present disclosure are also exemplified by external hard-shell casings for implantable devices such as cardiac pacemakers, spinal cord stimulators, neurostimulation systems, intrathecal drug pumps for delivery of medicants into the spinal fluid, infusion pumps for delivery of chemotherapeutics and/or anti-spasmodics, insulin pumps, osmotic pumps, heparin pumps, and the like. The antibiotic-eluting articles of the present disclosure are also exemplified by implantable dental prosthesis, dental implants comprising one or more replacement tooth components, and the like. The antibiotic-eluting articles of the present disclosure are also exemplified by transcutaneous skin surface treatment devices for providing transcutaneous electrical nerve stimulation and by devices for providing long-term percutaneous access. The antibiotic-eluting articles of the present disclosure are also exemplified by wound treatment surface devices exemplified by staples and sutures, and the like.

EXAMPLES

Example 1

[0024] Polylactide (PLA) granules were sourced from NatureWorks LLC (Blair, Nev. USA). Polycaprolactone (PCL) granules (CAPA 6500) were sourced from Plastics Systems Inc. (Lakewood, Wash., USA). Vancomycin and Gentamicin were sourced from Gold Biotechnology (St. Louis, Mont., USA). 0.28 kg of Vancomycin was dry-blended together with a 5.8 Kg batch of PLA granules to produce a PLA blend comprising about 5% Vancomycin. 0.122 kg of Vancomycin was dry-blended together with a 5.8 Kg batch of PLA granules to produce a PLA blend comprising about 2% Vancomycin. 0.125 Kg of Gentamicin was dry-blended together with a 2.5 Kg batch of PCL granules to produce a PCL blend comprising about 5% Gentamicin. A PCL blend comprising about 2% Gentamicin was prepared by dry-blending a PCL blend comprising about 5% Gentamicin with additional PCL to adjust the Gentamicin content to about 2%.

[0025] A SINTERSTATION HiQ SLS system (SINTERSTATION and SLS are registered trademarks of 3D Systems Inc., Valencia, Calif., USA) was used to print round discs having about diameter of about 1 inch (2.54 cm) and a thickness of about 0.125 inch (0.3175 cm) from each batch of polymer/antibiotic blends. Control discs were printed from pure PLA granules and PCL granules. About 4 inches of a polymer/antibiotic blend was placed into the machine's feed cylinders, and a powder bed was then generated by depositing powder onto the part cylinder. A warm up cycle was then used to warm both the feed cylinder and part cylinder, after which, the discs printed according to STL CAD software files loaded into 3D System's Build Setup Version 3.602 software. A portion of each polymer/antibiotic blend was used for SLS printing of discs for assessment of their antibiotic-eluting performance, and the remainder of the polymer/antibiotic blend was used for printing Type IV dumb-bell-shaped test specimens for tensile testing.

[0026] The system operating conditions for SLS printing of discs and Type IV dumb-bell-shaped specimens from PCL/Vancomycin blends and from PCL/Gentamicin blends were:

TABLE-US-00001 Particle bed temperature: 48 C. Feed temperature: ambient Smart feed gain: 1.3 Fill laser power (W): 49 Fill scan speed (inches/sec): 500 Fill scan spacing (inches): 0.01 Outline laser power (W): 14 Outline scan speed (inches/sec): 70

[0027] The system operating conditions for SLS printing of the discs from PLA/Vancomycin blends and from PLA/Gentamicin blends were:

TABLE-US-00002 Particle bed temperature: 75 C. Feed temperature: 40 C. Smart feed gain: 1.3 Fill laser power (W): 67 Fill scan speed (inches/sec): 500 Fill scan spacing (inches): 0.01 Outline laser power (W): 14 Outline scan speed (inches/sec): 70

Example 2

[0028] Selected physical properties of the antibiotic-containing plastic Type IV dumb-bell-shaped test specimens were determined following the test methods set out in ASTM D638-08 document titled Standard Test Method for Tensile Properties of Plastics published by ASTM International and publicly available from their website: http://www.astm.org/Standards/D638.htm. The physical properties of the SLS-printed antibiotic-containing plastic discs are listed in Tables 1-4.

TABLE-US-00003 TABLE 1 Physical properties of Type IV dumb-bell-shaped specimens printed with PCL/Gentamicin dry blends*. Gentamicin content in PCL discs Physical parameter 0 2% 5% Thickness (in) 0.134 0.134 0.001 0.138 0.001 Modulus (lbf/in.sup.2) 53200 47700 1700 314000 4330 0.2% Offset yield 1970 1150 67 1210 191 strength (lbf/in.sup.2) Ultimate strength 3090 1990 26 1830 13 (lbf/in.sup.2) % elongation at 407 4032.72 0.96 1.23 0.68 offset yield (%) break *data are means of three replicates SD

TABLE-US-00004 TABLE 2 Physical properties of Type IV dumb-bell-shaped specimens printed with PCL/Vancomycin dry blends. Vancomycin content in PCL discs Physical parameter 0 2% 5% Thickness (in) 0.134 0.128 0.001 0.129 0.001 Modulus (lbf/in.sup.2) 53200 94200 3720 65900 4750 0.2% Offset yield 1970 1150 67 1130 71 strength (lbf/in.sup.2) Ultimate strength 3090 1430 130 1930 167 (lbf/in.sup.2) % elongation at 407 1.41 0.25 1.76 0.28 offset yield (%) break *data are means of three replicates SD

TABLE-US-00005 TABLE 3 Physical properties of Type IV dumb-bell-shaped specimens printed with PLA/Gentamicin dry blends*. Gentamicin content in PCL discs Physical parameter 0** 2% 5% Thickness (in) 0.156 0.001 0.158 0.001 Modulus (lbf/in.sup.2) 155000 5680 164000 7010 0.2% Offset yield 919 45 980 191 strength (lbf/in.sup.2) Ultimate strength 1130 75 1170 104 (lbf/in.sup.2) % elongation at 0.569 0.2 0.66 0.13 offset yield (%) break *data are means of three replicates SD **the control PLA granules did not sinter well and did not hold its structure

TABLE-US-00006 TABLE 4 Physical properties of Type IV dumb-bell-shaped specimens printed with PLA/Vancomycin dry blends*. Vancomycin content in PCL discs Physical parameter 0** 2% 5% Thickness (in) 0.152 0.001 0.156 0.001 Modulus (lbf/in.sup.2) 161000 7950 124000 1930 0.2% Offset yield 903 190 849 111 strength (lbf/in.sup.2) Ultimate strength 1090 69 962 67 (lbf/in.sup.2) % elongation at 0.538 0.14 0.545 0.12 offset yield (%) break *data are means of three replicates SD **the control PLA granules did not sinter well and none of the control Type IV dumb-bell-shaped specimens held their structures

Example 3

[0029] The elution of antibiotics from the discs produced in Example 1 was assessed by the inhibition of the growth of Staphylococcus aureus on the surfaces of Meuller Hinton agar contained within Petri dishes onto which test coupons placed. S. aureus cultures were grown on TSA amended with 5% sheep blood. A sufficient amount of S. aureus culture was transferred from the TSA culture plates to a 0.85% sterile saline solution to provide a uniform suspension that fell within a 0.5-2.0 McFarland turbidity standard. Aliquots of the S. aureus culture were plated onto Meuller Hinton agar in Petri dishes after which, two test coupons/dish (or alternatively, control coupons) were placed on the agar; one with its shiny side up and the other with its matte side up. The Meuller Hinton agar-containing Petri dishes were then incubated for about 72 hrs at temperatures in the range of about 35 C. to about 37 C. The zones of inhibition around each coupon were then measured and recorded (in mm). A clear zone around a test coupon indicates the inhibition of growth of S. aureus. The diameter of the PLA/Antibiotic blend coupons were 25 mm and 26 mm for the PCL/Antibiotic coupons. The diameters of the PLA control coupon were 25 mm and 26 mm respectively, and considered as the 0 points. If no inhibition occurred, then the value 25 was recorded and indicates that no inhibition of microbial growth occurred. The data shown in Table 5 confirm that the antibiotics were eluted from articles printed from each polymer/antibiotic blend.

TABLE-US-00007 TABLE 5 Elution of antibiotics from 3d-printed articles comprising PCL or PLA*. Antibiotic concentration Polymer/antibiotic blend 0 2% 5% PCL/Gentamicin 25 43.7 45.0 PCL/Vancomycin 25 42.0 41.7 PLA/Gentamicin 32 41.7 43.7 PLA/Vancomycin 32 40.3 43.7 *data are means of three replicates SD