WO2019217350A1 - Appareil et procédé de catalyse induite par métal - Google Patents

Appareil et procédé de catalyse induite par métal Download PDF

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Publication number
WO2019217350A1
WO2019217350A1 PCT/US2019/031010 US2019031010W WO2019217350A1 WO 2019217350 A1 WO2019217350 A1 WO 2019217350A1 US 2019031010 W US2019031010 W US 2019031010W WO 2019217350 A1 WO2019217350 A1 WO 2019217350A1
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Prior art keywords
metal
wire
medical device
alloy
prodrug
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PCT/US2019/031010
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English (en)
Inventor
Marja Ter MEER
Alexander N. Zelikin
Jeremy E. Schaffer
Ross DILLION
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Fort Wayne Metals Research Products Corp
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Publication of WO2019217350A1 publication Critical patent/WO2019217350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/06—Titanium or titanium alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/10—Inorganic materials
    • A61L29/106—Inorganic materials other than carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other

Definitions

  • the present disclosure is directed to metallic implants having an ability to mimic enzyme catalysis in the absence of an enzyme, and method for use of the same in conjunction with catalysis targets.
  • metallic wires may be used as a biocatalytic implantable biomaterial to mimic enzyme activation of prodrugs.
  • prodrugs may be provided in conjunction with such metallic wires to provide localized therapy at the site of wire implantation.
  • the catalytic activity enabled by the wire material mimics the activity of an enzyme such that it is able to cleave one or more of the chemical bonds of a promoiety of a prodrug, releasing an acti ve agent - in this instance an antimicrobial agent - locally in the vicinity of the wire material, thereby resulting in a significant zone of inhibition of bacterial proliferation around the metallic wires in vivo.
  • This type of site-specific drug delivery may be used in various applications including cardiovascular, orthopedic and many other implant applications, allowing for extensive flexibility of drug choice and dosing, combination therapies, and other previously unavailable therapy options.
  • the present disclosure is directed to a medical device.
  • the medical device can comprise: a metal material having a first metal adjacent to a second, different metal to form a bimetallic junction, the bimetallic junction configured and positioned to be exposed to body fluid in vivo; and an activatable substance which is activated by the bimetallic junction.
  • the activatable substance may be activated by exposure to the metal material of the medical device.
  • the prodrug may optionally comprise a promoiety bound to a drug via a glycosidic bond.
  • the promoiety may optionally comprise b-galactose, b-glucuronic acid, or a derivative thereof and, in some embodiments, may further comprise a linking group between the b-galactose, b-glucuronic acid, or a derivative thereof and the drug.
  • the linking group is a benzyl acetate moiety.
  • the activatable substance which in some embodiments is a prodrug, may optionally be activated by scission of the glycosidic bond.
  • the present disclosure is directed to a method of administering an activatable substance in vivo.
  • the method comprises: introducing into a subject a metal material having a first metal adjacent to a second, different metal to form a bimetallic junction, the bimetallic junction configured and positioned to be exposed to body fluid in vivo; and administering the activatable substance to the subject; wherein the activatable substance is activated upon exposure to the metal material.
  • the activatable substance may optionally be a prodrug comprising a promoiety bound to a drug via a glycosidic bond
  • the promoiety may optionally comprise b-galactose, b-glucuronic acid, or a derivative thereof.
  • the promoiety can further comprise a linking group between the b-galactose, b-glucuronic acid, or a derivative thereof and the drug which, in one embodiment, is a benzyl acetate moiety.
  • the metal material may optionally activate the prodrug by catalyzing scission of the g!ycosklic bond.
  • FIG. 2 is an enlarged view of a portion of the stent shown in Fig. 1;
  • Fig. 3 is a cross-section view of a wire of the stent of Fig. 1, taken along the line
  • Fig 4A is an enlarged view of a wire surface as shown in Fig. 2, in which a surface coating is substantially intact;
  • Fig. 4B is an enlarged view of the wire surface of Fig 4 A, in which the surface coating has entered early stages of in vivo degradation;
  • Fig. 4C is an enlarged view of the wire surface of Figs. 4A and 4B, in which the surface coating has become substantially degraded;
  • FIG. 5 is a cross-section, perspective view of a multifilament wire made in accordance with the present disclosure, in which a central filament is made from a first metal material and the surrounding peripheral filaments are made from a second, different metal material;
  • Fig. 8A is a schematic view illustrating an exemplary forming process of monolithic wire using a lubricated drawing die
  • Fig. 8B is a schematic view illustrating an exemplary forming process of composite wire using a lubricated drawing die
  • Fig. 8C is an elevation view of a wire in accordance with the present disclosure, before a final cold working process.
  • Fig. 8D is an elevation view of the wire of Fig. 8C, after the final cold working process
  • Fig. 9 is an elevation view 7 of a portion of a laser-cut stent including a himetalized portion in accordance with the present disclosure
  • FIG. 10 is an elevation view of an orthopedic screw including a himetalized portion in accordance with the present disclosure
  • FIG 1 1 is a perspective view of a coiled cerclage cable including a himetalized portion in accordance with the present disclosure, together with a cable crimp;
  • Fig. 12 is an enlarged view of a portion of the coiled cerclage cable of Fig. 1 1 , illustrating the bimetallized portion;
  • Fig. 13 is an elevation view of a Kirschner wire including a himetalized portion in accordance with the present disclosure
  • Fig. 14 is a perspective view of a medical device clip including a himetalized portion in accordance with the present disclosure
  • Fig. 15 is a perspective view of another medical device clip including a bimetaiized portion in accordance with the present disclosure.
  • Fig. 16 is an enlarged view of a portion of the medical device clip of Fig. 15, illustrating the bimetallized portion;
  • Fig. 17 is a perspective view of an electrode including a bimetaiized portion in accordance with the present disclosure
  • Fig. 18 is a perspective view of another electrode including a bimetalized portion in accordance with the present disclosure
  • Fig 19 is a perspective view of an array of electrodes including a bimetalized portion in accordance with the present disclosure
  • Fig. 20 is an enlarged view of a portion of the array of electrodes of Fig. 19, illustrating the bimetaliized portion;
  • Fig. 21 A shows SEM images of the 35N LT grooved wires
  • Fig. 21 B shows results of characterization of the enzymatic mimicry activity revealed by the wires investigated using fluorogenic enzyme substrates, resorufm and fluorescein galactoside and glucuronides;
  • Fig. 21C shows scaling of catalytic activity with wire length
  • Fig 21 D shows prodrug concentration dependence for the biomimetic catalysis by the wire
  • Fig. 2 IE show's continuous production of the fluorescent product via enzymatic reaction recorded over time
  • Fig. 21F is a comparison of diverse metallic wires in terms of their enzyme- mimicry performance
  • Fig. 21G shows catalysis by twisted wire samples containing 35N LT and iron wire
  • Fig. 21H shows substrate conversion by iron(II) chloride
  • Fig. 22B shows conversion of the fluorogenic substrates by wires with varied thickness of the spray coating performed over 24 h in 10 niM PBS;
  • Fig. 22C shows results of the incubation of the Fe or Mg spray-coated wires in 10 mM PBS pH 7.4 in the presence of resorufm glucuronide expressed as fluorescence of the resulting product and the final pH of the surrounding medium;
  • Fig 22D is control experiments illustrating spontaneous, non-catalyzed prodrug conversion at varied pH
  • Fig. 22E show's prodrug conversion and resulting pH in 100 mM PBS, pH 7 4 solutions at the end of the 24 h incubation with spray-coated wires;
  • Fig. 23A shows chemical formulae for ciprofloxacin and moxifloxacin and corresponding HPLC traces illustrating retention times for the products of prodrug
  • Fig. 23B shows“Zone of bacterial growth inhibition” images for 35N S-shaped samples spray-coated with Fe to varied thickness (0.1, 0.5 or 1.5 pm) in the presence of ciprofloxacin (for E.coli) or moxifloxacin (for S. aureus).;
  • Fig. 23 C shows“Zone of bacterial growth inhibition” images for nitinol S-shaped samples spray-coated with Fe to varied thickness (0.1, 0.5 or 1.5 pm) in the presence of ciprofloxacin (for E.coli) or moxifloxacin (for S. aureus).;
  • Fig. 23D shows“Zone of bacterial growth inhibition” images in the presence of the prodrug only
  • Fig 23E shows results from the ciprofloxacin glucuronide prodrug in PBS buffer in conjunction with 35N LT®;
  • Fig. 23F shows results from the ciprofloxacin glucuronide prodrug in PBS buffer in conjunction with Nitinol
  • Fig. 23G shows results from the ciprofloxacin glucuronide prodrug in PBS buffer in conjunction with 35N LT® with magnesium coatings of various thicknesses
  • Fig. 23H shows results from the ciprofloxacin glucuronide prodrug in PBS buffer in conjunction with using Nitinol with magnesium coatings of various thicknesses;
  • Fig. 24 A show's the results from the salicyclie acid glucuronide prodrug in PBS in the presence of 35N LT® coated with magnesium during a one hour experiment;
  • Fig. 24B shows results from the salicyclie acid glucuronide prodrug in PBS in the presence of 35N LT® coated with magnesium of two different thicknesses during experimental run of various time periods;
  • Fig. 24C shows results from the salicyclie acid glucuronide prodrug in PBS in the presence of 35N LT® coated with iron during a one hour experiment;
  • Fig. 24D shows results from the salicyclie acid glucuronide prodrug in PBS in the presence of 35N LT® coated with magnesium of various thicknesses during experimental runs of various time periods;
  • Fig. 25 A shows the results of control experiments using the diclophenac
  • Fig. 25B show-s the results from the diclophenac glucuronide prodrug in PBS in the presence of Nitinol coated with magnesium at various time points:
  • Fig 25C shows the results from the diclophenac glucuronide prodrug in PBS in the presence of Nitinol with variou s coatings
  • Fig. 25D shows the results from the diclophenac glucuronide prodrug in the presence of either Nitinol or 35N LT®.
  • Fig. 26A shows the structure of the MMAE (antineiplastic agent) prodrug
  • Fig. 26B shows the reference peak for the MMAE prodrug
  • Fig. 26C show's results from the MMAE prodrug in the presence of 35N LT® with Mg or Fe coatings
  • the present disclosure is directed to metal materials capable of catalysis.
  • metal materials made in accordance with the present disclosure may exhibit enzyme mimicry, such that substances normally catalyzed by enzymes may instead be catalyzed by- exposure to the metal materials.
  • bimetal materials are configured to expose two different metals or metal alloys to a bodily fluid (e.g., blood) after implantation of a medical device. This exposure creates the conditions for catalysis to occur.
  • a substance e.g., a prodrug
  • a catalyzed substance e.g., an active therapeutic agent
  • the catalyzed substance may then confer a therapeutic benefit in the vicinity of the bimetal material, for example inhibition of bacterial growth.
  • wire or wire product encompasses continuous wire and wire products which may be continuously produced and wound onto a spool for later dispensation and use, such as wire having a round cross section and wire having a non-round cross section, including flat wire or ribbon.
  • Wire or wire product also encompasses other wire-based products such as strands, cables, coil, strips, sheets and tubing, which may be produced at a particular length depending on a particular application.
  • a wire or wire product in accordance with the present disclosure may have a diameter up to 2.5 mm.
  • Exemplary tubing structures may be in wire form or rod form, with inside diameters ranging from 0.5 mm to 4.0 mm, and wall thicknesses ranging from 0.100 mm to 1.00 mm.“Fine wire” refers to a wire having an outer diameter of less than 1 mm.
  • biodegradable As used herein, “biodegradable,” “bioabsorbable” and “bioresorbable” all refer to a material that is able to be chemically broken down in a physiological environment, . ⁇ ?., within the body or inside body tissue, such as by biological processes including resorption and absorption. This process of chemical breakdown will generally result in the complete degradation of the material and/or appliance within a period of weeks to months, such as 18 months or less, 24 months or less, or 36 months or less, for example.
  • Biodegradable metals used herein include nutrient metals, e.g, metals such as iron, magnesium, manganese and alloys thereof, such as those including lithium. These nutrient metals and metal alloys have biological utility in mammalian bodies and are used by, or taken up in, biological pathways.
  • “Degradation-resistant” or permanent materials suitable for implantation over the life of the patient include 35N; Ti 6/4, CP Ti grades 1 through 4; L605; 316L; ASTM F1058; CCM (FI 037); NiTi and related ternary or quaternary alloys; tantalum and alloys thereof, platinum and alloys thereof, titanium beta alloys such as Beta C, Beta III, and TilSMo; and rhodium and alloys thereof.“Degradation-resistant” or permanent materials suitable for temporary use in vivo, i.e., for devices which are not implanted for the life of the patient, include 304V; 316L; 35N; NiTi and related ternary or quaternary alloys: tungsten and alloys thereof, 400 series stainless steels; and other stainless steels
  • 'Nitinol is a trade name for a shape memory alloy comprising approximately 50 atomic % Nickel and balance Titanium, also known as NiTi, commonly used in the medical device industry for highly elastic metallic implants
  • “35N”,“Co/Cr/Ni/Mo” and“ASTM F562” alloys are alloys conforming to the chemical compositional requirements of ASTM F562 (nominally 35 wt.% Co - 35 wt.% Ni - 20 wt.% Cr - 10 wt.% Mo) These alloys include MP35N® and 35N LT® alloy.
  • 35N LT® alloy is a registered trademark of Fort Wayne Metals Research Products Corporation of Fort Wayne, Indiana
  • MP35N® is a registered trademark of SPS Technologies, Inc. of Jenkintown,
  • Resoioy is a magnesium-based alloy described in U.S. Patent No. 9,522,219, the entire disclosure of which is hereby incorporated herein by reference Resoioy® is further described in a paper authored by Adam Griebel, dated March 1, 2017 and entitled“Resoioy®: A Magnesium Alloy for Absorbable Devices,” the entire di sclosure of which is hereby incorporated herein by reference. “Resoioy®” is a registered trademark of the MeKo Corporation of Sarstedt, Germany
  • DFT® is a registered trademark of Fort Wayne Metals Research Products Corp. of Fort Wayne, IN, and refers to a bimetal or poly-metal composite wire product including two or more concentric layers of metals or alloys, typically at least one outer layer disposed over a core filament formed by drawing a tube or multiple tube layers over a solid metallic wire core element.
  • Impurities “incidental impurities” and“trace impurities” are material constituents present in a material at less than 500 parts per million or 0.05 wt. % for any given element.
  • metal materials have been found to be capable of mediating enzyme-free catalysis of materials typically requiring enzymes for catalysis.
  • These metal materials include two metals exposed to the blood stream to form a “bimetal junction,” which may also form a galvanic couple in certain exemplary embodiments.
  • Exemplary materials useable in this way include:
  • Nitinol alloys having a coating of iron (Fe), magnesium (Mg), another biocompatible transition element or a combination thereof.
  • Fe iron
  • Mg magnesium
  • another biocompatible transition element or a combination thereof.
  • the coating may have a designated thickness T (Fig 3) such that the coating can be dissolved by exposure to body fluid to expose the underlying substrate.
  • Iron-based bioabsorbable materials including Fe-Mn alloys described in U.S. Patent Application No. 2017/0360998 entitled BIODEGRADABLE ALLOY WIRE FOR MEDICAL DEVICES, the entire disclosure of which is hereby incorporated herein by reference.
  • Twisted wires including a combination of 35N-based filaments and/or Nitinol-based filaments with iron (Fe)-based filaments and/or magnesium (Mg)-based filaments, or filaments made with or another biocompatible transition element.
  • a“bimetal!ized” wire or other implant material has its bimetal junction configured for exposure to body fluid (e.g , the bloodstream), such that two adjacent and different metal materials are exposed to such body fluid
  • the wire or other implant material can be designed to delay exposure of the bimetal junction until after a period of time in vivo has elapsed, as is the case of metals coated with a bioabsorbable coating.
  • Exposure of the bimetal junction to body fluid creates the conditions for activation of an activatable substance, such as a prodrug, when the substance comes into contact with the bimetal junction.
  • an activatable substance such as a prodrug
  • the bimetal material can be coated with the activatable substance such that the substance is present and ready for activation upon
  • the activatable substance can be delivered separately to the bimetal material by, e.g., intravenous injection such that only the substance which comes into contact with the bimetal junction is activated, while the remaining substance is not activated. Upon activation, the activatable substance is converted into an activated substance.
  • the activatable substance is a prodrug
  • exposure to the bimetal junction causes catalysis (i.e., activation) which converts the prodrug into a drug. Because such a prodaig will only be converted in the vicinity of the present bimetallized materi al, an implant itself can be the catalyst for the prodrug, thereby enabling localized therapy at the implant site.
  • bimetallized material made in accordance with the present disclosure may take the form of medical-grade wire 30, 31, as shown in Figs. 1 -3.
  • This wire 30, 31 may then be formed or integrated into a medical device, such as by braiding into a stent 20 (Fig. 1) having an overall device diameter Ds, for example.
  • wires 30, 31 may be fine wires having an outer wire diameter Dw of less than 1 mm.
  • Other medical device applications including larger wire constructs, twisted wire constructs, and other devices are discussed in additional detail below.
  • An alloy in accordance with the present disclosure may first be formed in bulk, such as by traditional casting methods. This bulk material is then formed into a suitable pre form material (e.g., a rod, plate or hollow' tube) by hot-working the bulk material into the desired pre-form size and shape. For purposes of the present discl osure, hot working is accomplished by heating the material to an elevated temperature above room temperature and performing desired shaping and forming operations while the material is maintained at the elevated temperature.
  • a suitable pre form material e.g., a rod, plate or hollow' tube
  • the resulting pre-form material such an ingot, is then further processed into an intermediate form, such as a rod, wire, tube, sheet or plate product by repetitive cold-forming and annealing cycles
  • This intermediate material may be made by, for example, a schedule of drawing and annealing to create an initial coarse wire structure ready for final processing. Thereafter, wires 30 or 31 may be subjected to a final cold work conditioning step (Figs. 8A-8D), and in some cases also subjected to a final heat treatment step, in order to impart desired mechanical properties to the finished wire product as further described below.
  • a final cold work conditioning step Figs. 8A-8D
  • a final heat treatment step in order to impart desired mechanical properties to the finished wire product as further described below.
  • monolithic wire 31 suitable for use as bimetallized material may be initially produced using conventional methods, including a schedule of drawing and annealing in order to convert the pre-form material (such as an ingot or rod) into a wire of a desired diameter prior to final processing.
  • the pre-form material is drawn through a die 36 (Fig. 8A) to reduce the outer diameter of the intermediate material slightly while also elongating the material, after which the material is annealed to relieve the internal stresses (i.e., retained cold work) imparted to the material by the drawing process.
  • This annealed material is then drawn through a new die 36 with a smaller finish diameter to further reduce the diameter of the material, and to further elongate the material. Further annealing and drawing of the material is iteratively repeated until the material is formed into a wire construct ready for final processing into wire 31.
  • wire 31 may receive a coating 33 as shown in Fig. 3, such that wire 31 includes a drawn wire 35 and a separately applied coating 33 as illustrated.
  • coating 33 of coated wire 31 is applied after drawing or other working of drawn wire 35.
  • coating 33 is applied by sputter deposition, vapor deposition, or any other suitable coating method.
  • coating 33 is an applied material rather than a drawn material. Coating 33 may similarly be applied to composite wire 30, described further below.
  • T o form composite wire 30 such as DFT®
  • core 34 is inserted within shell 32 to form an intermediate construct, and an end of this intermediate construct is then tapered to facilitate placement of the end into a drawing die 36 (Fig 8B).
  • the end protruding through the drawing die 36 is then gripped and pulled through the die 36 to reduce the diameter of the construct and bring the inner surface of shell 32 into firm physical contact with the outer surface of core 34.
  • the initial drawing process reduces the inner diameter of shell 32, such that shell 32 closes upon the outer diameter of core 34 and the inner diameter of shell 32 equals the outer diameter of core 34 whereby, when viewed in section, the inner core 34 will completely fill the outer shell 32 as shown in Fig. 8B.
  • Drawn wire constructs are structurally distinguished from constructs formed by other methods (e.g., casting, machining, coating, etc.) by their characteristic smoothness and high reflectivity.
  • the circularity of the cross-section and the concentricity of the shell and core are substantially finer in a drawn construct as compared to, e.g., a coated construct.
  • the microstructure of a drawn construct may be structurally distinct from other constructs, for example by exhibiting an elongated grain structure (shown in Fig. 8D and further discussed below) or a fine-grain structure after thermal processing.
  • the step of drawing subjects wire 30 or 31 to cold work.
  • cold-working methods effect material deformation at or near room
  • drawing imparts cold work to the material of both shell 32 and core 34, with concomitant reduction in the cross-sectional area of both materials.
  • the total cold w'ork imparted to wire 30 or 31 during a drawing step can be characterized by the following formula (I): cw - ---- 1 ⁇ x 100% (I)
  • wTserein“cw” is cold work defined by reduction of the original material area
  • D 2 is the outer cross-sectional diameter of the wire after the draw ' or draws (shown as D 2 s in Figs. 8 A and 8B)
  • 'TV is the outer cross-sectional diameter of the wire prior to the same draw or draw's (shown as Dis in Figs. 8A and 8B).
  • the cold work step may be performed by the illustrated drawing process.
  • wire 30 or 31 is drawn through a lubricated die 36 having an output diameter D 2 s, which is less than diameter Dis of wire 30 or 31 prior to the drawing step.
  • the outer diameter of wire 30 or 31 is accordingly reduced from pre-drawing diameter Dis to drawn diameter Dis, thereby imparting cold work cw.
  • net cold work may be accumulated in wire 30 or 31 by other processes such as cold-swaging, rolling the wire (e.g., into a flat ribbon or into other shapes), extrusion, bending, flowforming, or pilgering.
  • Cold work may also be imparted by any combination of techniques including the techniques described here, for example, cold-swaging followed by drawing through a lubricated die finished by cold rolling into a ribbon or sheet form or other shaped wire forms.
  • the cold work step by which the diameter of wire 30 is reduced from Dis to D 2 s is performed in a single draw and, in another embodiment, the cold work step by which the diameter of wire 30 is reduced from Dis to Dis is performed in multiple draw's which are performed sequentially without any annealing step therebetween.
  • the cold work step by which the diameter of wire 30 is reduced from Dis to Dis is performed in multiple draw's which are performed sequentially without any annealing step therebetween.
  • each subsequent drawing step further reduces the cross section of wire 30 proportionately, such that the ratio of the sectional area of shell 32 and core 34 to the overall sectional area of wire 30 is nominally preserved as the overall sectional area of wire 30 is reduced.
  • Heating wire 30 to a temperature sufficient to cause recrystallization of grains eliminates accumulated cold work.
  • the cold work imparted by each iterative cold work process is relieved by fully annealing the material between draws, thereby enabling the next iterative cold working process.
  • full annealing the cold-worked material is heated to a temperature sufficient to substantially fully relieve the internal stresses stored in the material, thereby- relieving the stored cold work and“resetting” cold work to zero.
  • wires 30 or 31 subject to drawing or other mechanical processing without a subsequent annealing process retain an amount of cold w ? ork.
  • the amount of retained work depends upon the overall reduction in diameter from Dis to Dis, and may be quantified on the basis of individual grain deformation within the material as a result of the cold work imparted.
  • wire 31 is shown in a post-annealing state, with grains 12 shown substantially equiaxed, i.e , grains 12 define generally spheroid shapes in which a measurement of the overall length Gl of grain 12 is substantially the same regardless of the direction of measurement.
  • equiaxed grains 12 are converted into elongated grains 14 (Fig. 8D), such that grains 14 are longitudinal structures defining an elongated grain length G2 (i .e., the longest dimension defined by grain 14) and a grain width G3 (i.e., the shortest dimension defined by grain 14).
  • G2 i .e., the longest dimension defined by grain 14
  • G3 i.e., the shortest dimension defined by grain 14
  • the retained cold work of wire 31 after drawing can be expressed as the ratio of the elongated grain length G2 to the width G3, such that a larger ratio implies a grain which has been“stretched” farther and therefore implies a greater amount of retained cold work.
  • annealing wire 31 after an intermediate drawing process reerystallizes the material, converting elongated grains 14 back to equiaxed grains 12 and“resetting” the retained cold w >rk ratio to 1 : 1 (i.e , no retained cold work).
  • full annealing may be accomplished at a temperature and time appropriate for the wire material and geometry (e.g., its cross-sectional area). For a given material, a relatively higher temperature annealing process can utilize a relatively shorter time to achieve a full anneal, while a relatively lower temperature will typically utilize a relatively longer time to achieve a full anneal.
  • annealing parameters can be expected to vary for varying wire diameters, with smaller diameters shortening the time of anneal for a given temperature. Whether a full anneal has been accomplished can be verified in a number of ways as well known in the art, such as microstructural examinations using scanning electron microscopy (SEM), mechanical testing for ductility, strength, elasticity, etc , and other methods.
  • SEM scanning electron microscopy
  • the resulting coarse wire material may then be finally processed into a final form, such as a fine wire suitable for integration into a stent or other medical device.
  • a final form such as a fine wire suitable for integration into a stent or other medical device.
  • Exemplary wire constructs are described in further detail herein.
  • Monolithic wire 31 includes a drawn wire 35 with a coating 33 separately applied, e.g., by deposition processes as described above. Similar to composite wire 30 described above, monolithic wire 31 includes two different materials for drawn wire 35 and coating 33, with coating 33 being made from a bioabsorbable material designed to degrade over a desired period of time.
  • FIGs 4A-4C illustrate the degradation process for an outer layer of a bimetallized single wire, whether formed as a coating upon monolithic wire 31 or as shell 32 of composite wire 30.
  • Fig. 4A the outer surface of a substantially intact outer layer 32, 33 is shown. This is the appearance of wire 30 or 31 before or shortly after implantation. At this stage, wire 30, 31 has not yet presented a bimetallic junction to the bloodstream or other body fluid.
  • Fig. 4B illustrates the outer surface of wire 30, 31 after initiation of the degradation process of outer layer 32, 33.
  • the otherwise intact outer layer 32, 33 is interrupted by areas of degradation where the inner layer 34, 35 (in the form of the outer surface of the core 34 or drawn wire 35, respectively) has become exposed to the bloodstream or other body fluid.
  • This exposure causes both the metal of the inner layer 34, 35 and of the outer layer 32, 33 to be simultaneously exposed to the body fluid, thereby creating a series of bimetal junctions across the surface of wire 30, 31.
  • these bimetal j unctions drive catalysis of any activatable substances which come into contact therewith.
  • outer layer 32, 33 will generally increase the delay until the initiation of catalysis by wire 30, 31, and after initiation, will increase the time of catalysis and vice-versa.
  • choosing a slower- degrading material or alloying degradation inhibitors into outer layer 32, 33 will also increase the delay and time of catalysis and vice-versa.
  • Such a delay can be used to create a“time delay” for exposure of the bimetal junction such that conversion of an activatable substance does not initiate until after a desired time period has elapsed after implantation of a bimeta!lized device.
  • the designated thickness T may be as little as 0 001 micron, 0.01 micron and 0.2 micron and as much as 2.5 microns, 15 microns or 25 microns, or may be any thickness within any range defined by any pair of the foregoing values.
  • thickness T may be between 0.001 and 0.01 micron, between 0.001 and 0.2 micron, between 0.001 and 2.5 microns, between 0.001 and 15 microns, between 0.001 and 25 microns, between 0.01 and 0.2 micron, between 0.01 and 2.5 microns, between 0.01 and 15 microns, between 0.01 and 25 microns, between 0.2 and 2.5 microns, between 0.2 and 15 microns, between 0.2 and 25 microns, between 2.5 and 15 microns, between 2.5 and 25 microns, or between 15 and 25 microns.
  • alternative embodiments utilize multifilament strands or cables to present a bimetal junction by varying the material used to form the individual filaments, such that two adjacent filaments can create a bimetal junction along their respective lengths.
  • strand 40 includes a central filament 42 made of one metal material (e.g., NiTi or 35N) and a surrounding set of six peripheral filaments 44 made of a metal material different from central filament 42.
  • filaments 42 and 44 all share a common outer diameter such that strand 40 has a traditional“1x7” configuration.
  • one or more peripheral filaments 44 may be formed from a bioabsorbable material, such that degradation of the peripheral filament(s) 44 causes exposure of the bimetal junction in a. similar fashion to wires 30, 31 described above.
  • FIG. 6 another multifilament strand 50 is illustrated which is generally similar in structure to strand 40, except that a first metal filament 52 is used as a peripheral filament, while the remaining peripheral filaments and the central filament are formed from a second metal filament 54 made of a different metal in this embodiment, the bimetal junction is formed between the two adjacent and abutting peripheral filaments 52, 54 such that strand 50 is ready to initiate catalysis immediately upon exposure to the bloodstream or other body fluid. Similar to strand 40 discussed above, one or both filaments 52, 54 may be made from a bioabsorbable material such that the bimetal junction is created on a non-permanent basis.
  • the respective metals of filaments 52, 54 in strand 50 may both be made from different degradation-resistant (i.e.,“permanent”) materials to create the bimetal junction.
  • the bimetal junction may be substantially permanently in place within the body, unless and until strand 50 is removed.
  • Fig. 7 illustrates yet another multifilament strand 60 similar in design to strand 50 described above, except that a third layer of filaments is provided to create a“1x19”
  • the third layer features alternating filaments 62 and 64, such that each filament 62 is flanked on either side by filaments 64 and vice-versa.
  • This arrangement presents a series (i.e., twelve) of bimetal junctions evenly spaced about the outer periphery of strand 60, each of which is capable of driving catalysis as described herein. Similar to strand 50, these bimetal junctions may be formed from any combination of bioabsorbable and permanent metal materials as required or desired for a particular application.
  • wires 30, 31 and/or strands 40, 50, 60 may be integrated into a medical device, such as stent 20 shown in Fig. 1.
  • Figs 9-19 illustrate various additional medical device applications, each of which includes a bimetallized material made in accordance with the present disclosure.
  • Fig 9 illustrates a portion of a laser-cut stent 70, which is cut from a tubular piece of solid metal material.
  • Stent 70 includes a functionalized area 72, which may be a coating or metal insert made from a different material than the tubing from which stent 70 is cut.
  • the entirety of the material of stent 70 may be coated in a similar fashion as coated monolithic ware 31 described in detail above.
  • the boundaries of the functionalized area 72, and/or boundaries formed during degradation of a coating, creates a bimetal junction suitable for catalysis in the same manner as described above.
  • Fig 10 shows an orthopedic screw 80 which may be used for fixation of hard to soft tissue.
  • Orthopedic screw includes a threaded shank 82 and a screw head 84. Similar to stent 70 described above, screw 80 may include a functionalized area 86 between the shank 82 and head 84 which includes a coating or inset to establish a bimetal junction at the exterior surface of screw 80. As illustrated, functionalized area 86 is located in a position which can remain exposed to the bloodstream around a bone or soft tissue after implantation, such that catalysis of nearby activatable substances (e.g., antimicrobial prodrugs, as described in further detail below) may occur by contact with area 86.
  • activatable substances e.g., antimicrobial prodrugs, as described in further detail below
  • Fig. 11 illustrates orthopedic cerclage cable 90 made in accordance with the present disclosure and including a functionalized area 92 (Fig. 12) on a portion of the twisted- filament strands 94 from which cable 90 is made.
  • cable 90 includes a plurality of strands 94 twisted together, and each of strands 94 in turn includes a plurality of filaments 96 twisted together in the same manner as discussed above with respect to strands 40, 50 and 60 (Figs. 5-7).
  • Functionalized area 92 may be achieved by including different metals among the individual filaments 96, in the same manner that abutting filaments of different metals are created in strands 40, 50 and/or 60.
  • C erclage cable 90 also includes additional structures suitable for a cerclage application, including lead tip 97, head 98 and crimp 99 which are used to encircle cerclage cable 90 around a bone and affix cable 90 in the encircled and tensioned configuration. At this point, strands 94 and filaments 96 are exposed to the bone and the surrounding body fluids, such that the bimetal junction(s) defined within functionalized area 92 can catalyze nearby activatable substances.
  • Fig. 13 illustrates Kirsehner wire 100 adapted for use in orthopedic fixation applications, and including functionalized area 102 similar to other functionalized areas discussed in detail above.
  • Kirsehner wire 100 (which may also be called a K-wire) includes sharpened distal tip 104, smooth metal shank 106, and a hooked proximal end 108. in use, Kirsehner wire 100 can be deployed as an anchor for skeletal traction, or to hold bone fragments together for example.
  • the entire wire 100 or a portion thereof, such as a portion of shank 106 may include a bimetal junction formed using a coating, shell or metal inset at functionalized area 102 in order to induce catalysis of nearby activatable substances.
  • Fig 14 shows clip 1 10 used, e.g., for vascular ligation, aneurysm and anastomosis applications.
  • Clip 110 has spring coil 114 which biases tines 116 into a closed position such that clip 110 can be used to apply a clamping pressure between tines 116
  • Clip 110 includes functionalized area 112 which functions similar to the other functionalized areas discussed above to present a bimetal junction to the body fluids present at the site of the use of clip 110.
  • the wire material from which clip 110 is made may include a bimetal junction formed using a coating, shell or metal inset at functionalized area 112 in order to induce catalysis of nearby activatable substances.
  • a portion of clip 110, such as tines 1 16, or the entire wire length used for clip 110 may be bimetailized in this way.
  • Fig 15 shows another clip 120 configured for use in microvascular applications including an elastically deformed spring portion 124 which biases tines 126 into a closed or clamped position.
  • Clip 120 includes functionalized area 122 (Fig. 16) which functions similar to the other functionalized areas discussed above to present a bimetal junction to the body fluids present at the site of the use of clip 120.
  • the rectangular wire material from which clip 120 is made may include a bimetal junction formed using a coating, shell or metal inset at functionalized area 122 in order to induce catalysis of nearby activatable substances.
  • a portion of clip 120, such as tines 126, or the entire wire length used for clip 120 may be bimetailized in this way.
  • Figs. 17 and 18 illustrate electrical leads 130 and 140, respectively used for cardiac pacing and/or stimulation, neural recording and/or stimulation, and other electrical functions in connection with medical device applications.
  • Leads 130, 140 include electrically conductive, medical-grade wires 134, 144 having functionalized areas 132, 142 respectively. Functionalized areas 132, 142 may be formed using a bimetal junction in the same manner as discussed above with respect to wires 30, 31 or strands 40, 50, 60, for example.
  • leads 130, 140 have fixation features 136, 146 respectively which facilitate placement and retention of leads 130, 140 within tissue.
  • Lead 130 further includes distal end 138 distal of fixation feature 136, which may include a further functionalized area 133 including a bimetal junction made in accordance with the present disclosure.
  • Lead 140 may include an additional functionalized area 143 formed as a part of its fixation feature 146, which is a distal corkscrew- shaped tip as illustrated.
  • Fig 19 illustrates neural array 150 including an array of wires 154 mounted to an electrical substrate 156 and electrically connected to signal cable 158.
  • Some or ail of wires 154 may include functionalized areas 152 made in accordance with the present disclosure. As shown in Fig. 20, functionalized areas 152 may be disposed along the exposed core wire 155 A which protrudes distally from electrical insulation 155B around core wire 155 A.
  • wires 154 each include a sharpened distal tip designed to facilitate penetration into brain tissue for neural recording or simulation, for example, and may cany current and/or electrical signals from the implant site through wire 154 and cable 158. Additional details of an exemplary neural array can be found in International Patent Application Serial No.
  • Other medical devices envisioned for use in connection with the present disclosure include surgical tools, such as biopsy needles, saws, and other stainless surgical steel tools which may include a bimetallized portion or area for activation of, e.g., prodrugs to inhibit infection, inflammation, or other biological responses at the site of tool application.
  • surgical tools such as biopsy needles, saws, and other stainless surgical steel tools which may include a bimetallized portion or area for activation of, e.g., prodrugs to inhibit infection, inflammation, or other biological responses at the site of tool application.
  • guidewires and catheters may include a bimetallized portion for, e.g., intervention at the site of use for anti-clotting and/or anti -coagulant therapies, thereby preventing the need for systemic and/or pre-operative use of antiplatelet drugs and the like.
  • hip stems which may include a bimetallized portion or area to inhibit infection, inflammation, or other biological responses at the site of implantation, and also to improve bone growth.
  • Heart valve frame and leaflets, dialysis ports, lumen introducer sheaths, pacing and defibrillation generators and neurostimulation generators may also include bimetallized portions or areas in accordance with the present disclosure.
  • any metallic implantable device can include one or more bimetallized portions or areas in order to selectively catalyze activatable substances at the in vivo site of implantation or use.
  • metal materials made in accordance with the present disclosure are capable of catalysis.
  • One type of catalysis enabled by the present metal materials is catalysis normally mediated by enzymes.
  • the present metal materials may be said to exhibit“enzyme mimicry,” it being understood that other types of catalysis not normally mediated by enzymes may also be mediated by the present materials.
  • Enzymes are biological entities, typically proteins, capable of catalysing specific chemical reactions by breaking or forming specific chemical bonds.
  • metallic substances which in some embodiments are wires, are used to mimic the catalytic activity of one or more endogenous enzymes.
  • the metallic substances mimic the catalytic activity of the enzymes b-galactosidase and/or b- glucuronidase. Both b-galactosidase and b-glucuronidase function as hydrolases, enzymes capable of breaking chemical bonds in either b-galactose or b-glucuronic acid, respectively, through the addition of water.
  • b-Galactosidase functions by catalyzing the hydrolysis of b-glycosidic bonds.
  • the metallic substances which in some embodiments are metallic wires, described herein mimic the action of these enzymes by catalyzing these same reactions non-enzymatically, without the need for an enzyme to be present.
  • the R, or variable, group of the free alcohol (ROH) can represent any number of chemical moieties that may be attached to b-galactose and/or b-glucuronic acid without negatively impacting the enzyme mimicking activity of the metallic substances.
  • R may be an alkyl group such as a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne (e.g, methyl; ethyls such as ethany!, ethenyf, ethynyi; propyls such as propan- 1-yl, propan-2-yJ, cyclo-propan-1 -yi, prop-1 -en-l-yJ, prop-l-en-2-yl, prop-2-en-l- yl (ally!), etc.; butyls such as butan-l-yl, butan-2-yl, 2 -methyl -propan-l-yl, 2 -methyl -propan-2-yl, etc.; and the like).
  • alkyl group such as a saturated or unsaturated, branched, straight-chain or
  • R may also be a heteroalkyl group such as an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups (e.g.,— O— ,— S— ,— O— O— ,— S— S— ,
  • a prodrug is a pharmaceutical compound that, after administration, is metabolized (i.e., converted within the body, for example by enzyme mimicry demonstrated by the metallic substances provided by the present disclosure) into a pharmacologically active drug.
  • Prodrugs are compounds comprising a promoiety chemically attached to a pharmacologically active drug and, in that respect, are different compounds than the pharmacologically active drugs
  • prodrags are pharmacologically inactive and are metabolized into an active form within the body by removal of the promoiety from the prodrug.
  • Prodrugs may be used to selectively improve how the pharmacologically active drug interacts with tissues that are not its intended target.
  • the wire materials provided by the present disclosure may be used to metabolize a prodrug locally, at the site in which the wire material is present in the body, such that metabolization of the prodrug, and the concomitant release of the
  • pharmacologically active drag occurs only in close proximity to the wire materials. Elsewhere in the body, the prodrug remains intact and pharmacologically inert, thereby minimizing, if not eliminating, the effects of the pharmacologically active drug in those locations in the body where the wire materials are not present. This reduces the effect and/or severity of any adverse or unintended effects of a drag.
  • a promoiety is a form of protecting group that, when used to mask a functional group within a drug molecule, converts the drug into a prodrug. Promoieties usually render the drug pharmacologically inert until such time as the promoiety is removed from the drug.
  • the promoiety will be attached to the drug via one or more bonds that are cleavable under specified conditions of use, for example by enzymatic or non-enzymatic means in vivo
  • bond cleavage may take place in a number of ways.
  • a promoiety may be cleaved from a prodrug due to changes in pH, exposure to light, exposure to heat, exposure to electricity (such as galvanic effects whereby bimetallic contacts create a localized difference in potential), or exposure to a chemical agent.
  • Embodiments provided by the present disclosure take advantage of the galvanic effects created by the metallic substances disclosed herein in order to cleave promoieties from prodrugs locally, in the immediate vicinity of the metallic substances.
  • a promoiety is cleaved from a prodrag upon contact with a metallic substance disclosed herein. In some embodiments, a promoiety is cleaved from a prodrag when in close proximity to a metallic substance provided by the present disclosure. In some embodiments, a promoiety is cleaved from a prodrug when exposed to a galvanic effect produced by one or more of the metal substances provided by the present disclosure. In some embodiments, a promoiety is cleaved from a prodrag when exposed to a galvanic effect produced by one or more wires provided by the present disclosure.
  • antimicrobial prodrugs are capable of being cleaved via enzyme mimicry demonstrated by the metallic substances provided by the present disclosure in order to release an active antimicrobial agent from the prodrug.
  • the promoieties of glucuronide prodrugs of ciprofloxacin and moxifloxacin are capable of being cleaved via exposure to the galvanic effects produced by the metallic substances provided by the present disclosure.
  • the metallic substances provided by the present disclosure catalyze the removal of the promoieties of the glucuronide prodrugs of ciprofloxacin and moxifloxacin via contact with the metallic substances.
  • the metallic substances provided by the present disclosure catalyze the removal of the promoieties of the glucuronide prodrugs of ciprofloxacin and moxifloxacin when such prodrugs are in close proximity to the metallic substances. In some embodiments, the metallic substances provided by the present disclosure catalyze the removal of the promoieties of the glucuronide prodrugs of ciprofloxacin and moxifloxacin when such prodrugs are exposed to a galvanic effect produced by the metallic substances.
  • antimicrobial prodrugs of ciprofloxacin and moxifloxacin suitable for use with the methods and metallic substances provided by the present disclosure are shown below.
  • the prodrugs shown below are not limiting of the types of prodrugs of antimicrobial agents that may be utilized with embodiments of the present disclosure.
  • the promoiety is removed from the prodrugs agents via cleavage of the giycosidic bond present in the promoiety. That is, the metallic substances of the present disclosure are capable of catalyzing the cleavage of the giycosidic bond. Following cleavage of the giycosidic bond, the promoiety further fragments, resulting in the release of carbon dioxide and the free antimicrobial agent, as shown below in Scheme 3. In this Scheme, the dashed line represents the point of hydrolysis of the giycosidic bond in the promoiety.
  • Scheme 3 Release of pharmaceutically active agents
  • fluorogenic enzyme substrates for example resorufin b-D- galactopyranoside and resorufin b-D-glucuronide (shown below, Sigma Aldrich), can also be used as substrates for catalysis by the metallic substances disclosed herein.
  • fluorogenic substrates two such fluorogenic substrates were used to evaluate the effectiveness of the enzyme mimicry demonstrated by the disclosed metallic substances (see Example 2). Again, it is hydrolysis of the glycosidic bond in the promoiety that removes the b-D-glucuronic acid residues from the fluorogenic substrates, resulting in the release of the acti ve, fluorescent compound.
  • fluorogenic enzyme substrate suitable for use with the methods and metallic substances provided by the present disclosure are shown below.
  • the prodrugs shown below are not limiting of the types of fluorogenic enzyme substrates that may be utilized with embodiments of the present disclosure.
  • Metallic substances provided by the present disclosure are capable of catalyzing bond scission.
  • the metallic substances provided by the present disclosure mimic the catalytic activity of the enzymes b-galactosidase and/or b- glucuronidase. Numerous possible mechanism(s) of catalysis are available. Metal ions are known to activate glycosidic linkages and in doing so may facilitate bond scission.
  • the metallic substances provided by the present di sclosure are capable of enzyme mimicry via the presence of metal ions on the surface of the metallic substances.
  • the fluorogenic galactosides and glucuronides described herein, as well as the cipro- and moxi- floxacin prodrugs described herein, are engineered such that a sugar group is attached to a good leaving group/linking moiety, making glycosidic bond scission highly feasible.
  • the good leaving group/linking moiety is a benzyl acetate moiety, as shown in Scheme 3.
  • the metallic substances provided by the present disclosure are capable of hydrolyzing glycosidic bonds. Promoieties containing glycosidic bonds will be susceptible to hydrolysis by the metallic substances disclosed herein, provided that the promoieties are engineered such that a sugar group is atached to a good leaving group.
  • the good leaving group is itself an active compound.
  • the sugar group is itself the promoiety such that, when the glycosidic bond linking the sugar group to the active compound is cleaved, the active compound is released.
  • the good leaving group is a linker group that is bound to an active compound. In that regard, breaking the glycosidic bond in the promoiety not only removes the sugar, but also causes the remainder of the promoiety to self-fragment, releasing the active compound.
  • catalysis and thus enzyme mimicry, is achieved by galvanic effects, whereby bimetallic contacts provided by the metallic substances of the present disclosure create a localized difference in potential.
  • Bimetallic contacts are characterized as“hot” energy spots, and the difference in potential between, e.g., Fe and Ni-Ti is ca 426 mV, which is similar to the energy of glycosidic linkages featuring good leaving groups, such as those described herein.
  • the metallic substances provided by the present disclosure are capable of enzyme mimicry via both the presence of metal ions on the surface of the metallic substances and the galvanic effects created by bimetallic contacts creating a localized difference in potential.
  • the metallic substances provided by the present disclosure are capable of catalyzing bond scission within a promoiety, the promoiety comprising a sugar group bound to a good leaving group/linking moiety via a glycosidic bond, wherein the glycosidic bond is cleaved, causing the linking moiety to self-fragment, releasing an active therapeutic agent.
  • the metallic substances provided by the present disclosure are capable of catalyzing bond scission within a promoiety, the promoiety comprising a sugar group bound to a benzyl acetate moiety via a glycosidic bond, wherein the glycosidic bond is cleaved, causing the benzyl acetate moiety to self-fragment, releasing an active therapeutic agent.
  • bimetallized wires described herein catalyze the reactions shown in Scheme 3. Briefly, a prodrug, comprising a molecule of interest bound to either a b-galactose-containing promoiety or a b-glucuronic acid-containing promoiety, is exposed to a bimetallized wire. Upon exposure to the bimetallized wires, the glycosidic bond present in the promoiety is cleaved.
  • the linker region of the promoiety then undergoes fragmentation to release the molecule of interest.
  • fragmentation results in the release of p-quinone methide, carbon dioxide, and the pharmacologically active form of the drug.
  • glycosidic bond cleavage alone is sufficient to release the molecule of interest from the prodrug.
  • the prodrug and the bimetallized wire catalyst are in close proximity to one another, thereby allowing the reaction to occur locally. Because of this, local concentration of the active agent appears near the wire and increases as the reaction goes to completion.
  • a therapeutically effective quantity of the molecule of interest which in some embodiments is a pharmaceutically active agent, is made available in proximity to the bimetallized wire.
  • a therapeutically effective quantity means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The quantity will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • the therapeuti cally effective quantity takes into account the rate and efficiency at which the prodrug is metabolized into an active drug substance.
  • the therapeutically effective quantity refers to an amount of a pharmacologically active drug that, following prodrug metabolization, is sufficient to effect treatment of a disease in a patient.
  • the metallic substances provided by the present disclosure are therefore capable of catalyzing the scission of a glycosidic bond. Because of that, a large number of prodrugs containing a glycosidic bond within their promoiety will be suitable for use with the disclosed metallic substances.
  • prodrugs provided by the present disclosure comprise b-gaiactose, b-giucuronic acid or a derivative of either bound to a molecule of interest via a glycosidic bond. Cleavage of the glycosidic bond removes the sugar (or sugar derivative), releasing the molecule of interest from the prodrug.
  • promoieties provided by the present disclosure comprise b-galactose, b-glucuronic acid or a derivative of either bound to a linker molecule via a glycosidic bond. Such promoieties may be bound to a molecule of interest. Cleavage of the glycosidic bond removes the sugar (or sugar derivative), causing the linker molecule to self-fragment, thereby releasing the molecule of interest from the prodrug.
  • exemplary bimeta!lized wires in accordance with the present disclosure were produced, tested and characterized, particularly with regard to their ability to effect conversion of prodrugs at the bimetal junction as described in detail below'.
  • Analytical HPLC was performed on a Shimadzu LC-2010A HT equipped with an Ascentis ⁇ Express Peptide ES-C18 column with 2.7 pm particles, a length of 150 mm and an internal diameter of 3.0 mm from Supelco Analytical.
  • Mobile phase A w'as ultrapure HiO supplemented with 0.1 % TEA (v/v) and mobile phase B acetonitrile (MeCN) supplemented with 0.1 % TFA (v/v).
  • C ustom manufactured 35N LT® grooved wire at a diameter of 200 pm was manufactured using conventional and bulk-replicable methods at Fort Wayne Metals Research Products Corp (Fort Wayne, IN USA). In addition, 254pm 316L annealed round wire was processed using similar methods as reported elsewhere. Cold rolled Nitinol and 35N LT® strip w'ere manufactured using standard cold forming methods, and rolled to a thickness of 152pm Strips w ' ere cut using advanced laser cutting techniques performed by MeKo (Sarstedt,
  • Fig. 21 A Alloy fabricated as grooved wire, Fig. 21 A, converted fluorogenic substrates into their fluorescent products, Fig. 2 IB. These substrates were glucuronides and galactosides and as such are widely used as specific substrates to reveal and quantify enzymatic activity of the corresponding enzymes. Enzyme-like activity of the wires scaled with the dimensions (that is, surface area) of the wires, as shown in Fig. 21C Substrate conversion was progressively more pronounced with increasing substrate concentrations, suggesting low affinity between the substrate itself and the surface if the wires (high apparent K m value for the metal lic enzyme mimics), Fig. 21 D Conversion of the fluorogenic substrates was monitored over the course of 5 hours, a gradual increase in fluorescence 'as observed, Fig. 2 IE
  • Another set of wires also demonstrates conversion of the galactosidase substrate: Resoloy (magnesium-based) and Alloy 8 (iron/manganese-based). These alloys are among the newer generation of materials used in the production of“resorbable wires” that are engineered to provide temporary support to body functions and subsequently degrade away. Following observation of enzyme mimicry displayed by the grooved 35N LT®, Resoloy, and Alloy 8, custom-made wire samples based on nitinol or 35N LT® alloys were manufactured. These were chosen because nitinol or 35N LT® alloys are currently in clinical use, and their background enzyme-like activity is close to zero.
  • S -shaped wires were laser-cut and spray coated with either iron (mimicking grooved alloys) or magnesium (to mimic Resoloy) in various thicknesses (0.1, 0.5, 1.5 or 2.5 pm). Both sets of wires displayed significant enzyme-like activity for both giucuronide and galactoside fluorogenic substrates.
  • Figure 22B This result illustrates a successful de novo engineering of enzyme mimicry into readily industrialized metallic wires. Conversion of the giucuronide and galactoside substrates increased with a thicker coating, except for the giucuronide substrate combined with Mg.
  • Figure 22D reveals that non-catalyzed, spontaneous substrate conversion in the absence of metallic wires was significantly lower than that achieved in the presence of wires.
  • the pH of the medium may contribute to some spontaneous hydrolysis, the total amount observed was negligible.
  • the presence of metallic wires as enzyme mimics to catalyze substrate conversion is important to achieve therapeutically relevant levels of hydrolysis.
  • Fe-coated alloys show significant catalytic conversion of the fluoreogenic substrates while revealing minor, if any, increase in the pH of solution. Specifically, the pH remains close to the normal physiological acidity of the human blood, Figure 22E.
  • glucuronide prodrugs of broad-spectrum agents ciprofloxacin and moxifloxacin
  • ciprofloxacin and moxifloxacin were tested (Fig. 23 A).
  • Acyl glucuronides for these drugs are readily available from commercial sources; however, prodrags of this type are notoriously unstable and their use may result in side effects due to acyl migration and other effects.
  • Engineering of a glucuronide prodrug was achieved through seif-immolative linker (SIL) technology using p-hydroxybenzyi alcohol as shown above. SILs of this type are successful academically and also found in marketed therapeutic agents such as Brentuximab vedotin, thereby validating its safety.
  • SIL seif-immolative linker
  • S-shaped wires based on 35N LT® and Nitinol were coated with Fe to a varied thickness and used in the“zone of bacterial inhibition” experiments.
  • E. coli and a clinically relevant pathogen, S. aureus were plated on agar in the presence of the ciprofloxacin or moxifloxacin prodrug, respectively (taken at a concentration corresponding to lOOxMIC (minimal inhibitory concentration), as determined in separate experiments using pristine drugs).
  • FIG. 23E shows results from the ciprofloxacin giucuronide prodrug in PBS buffer in conjunction with 35N LT®
  • Fig. 23F shows results from the same conditions, using Nitinol in place of with 35N LT®.
  • Fig. 23G shows the same conditions, using 35N LT® with magnesium coatings of various thicknesses.
  • Fig. 23H sho 's results from the same conditions, using Nitinol with magnesium coatings of various thicknesses. All experiments were run over a twenty-four hour period.
  • Fig. 24A show's the results from the salicyclic acid giucuronide prodrug in PBS in the presence of 35 N LT® coated with magnesium during a one hour experiment.
  • Fig. 24B shows results from the salicyclic acid giucuronide prodrug in PBS in the presence of 35N LT® coated with magnesium of two different thicknesses during experimental run of various time periods.
  • Fig. 24C show's results from the salicyclic acid giucuronide prodrug in PBS in the presence of 35N LT® coated with iron during a one hour experiment.
  • Fig. 24D shows results from the sa!icyclic acid glucuronide prodrug in PBS in the presence of 35N LT® coated with magnesium of various thicknesses during experimental runs of various time periods.
  • Fig. 25 shows results of similar tests conducted in the presence of a diclophenac glucuronide prodrug (CGP). Specifically, Fig 25A show's results from various control experiments with CGP in PBS buffer. Fig. 25B shows CGP in PBS in conjunction with Nitinol coated with magnesium at various time points, while Fig. 25C show's similar experiments after one hour, using various coatings on the Nitinol wire. Fig. 25D show's results of experiments using CGP in the presence of either Nitinol or 35N LT®.
  • CGP diclophenac glucuronide prodrug
  • Fig. 26 shows results of experiments using a synthesized prodrug of a neoplastic agent.
  • the prodrug w ' as exposed to 35N LT® with various coatings.

Abstract

Cette invention concerne des implants métalliques ayant une aptitude à imiter la catalyse enzymatique en l'absence d'une enzyme, et des procédés d'utilisation de ceux-ci conjointement avec des cibles de catalyse. Par exemple, des fils métalliques peuvent être utilisés comme biomatériau bio-catalytique implantable pour imiter l'activation enzymatique de promédicaments. Lors de l'utilisation, des promédicaments peuvent être fournis conjointement avec de tels fils métalliques pour fournir une thérapie localisée au niveau du site d'implantation des fils. Dans une application antibactérienne, par exemple, l'activité catalytique activée par le matériau de fil métallique imite l'activité d'une enzyme de telle sorte qu'elle est capable de cliver une ou plusieurs des liaisons chimiques d'un pro-fragment d'un promédicament, libérant d'un agent actif - en l'espèce un agent antimicrobien - localement à proximité du matériau de fil métallique, ce qui permet d'obtenir une zone significative d'inhibition de la prolifération bactérienne autour des fils métalliques in vivo.
PCT/US2019/031010 2018-05-07 2019-05-07 Appareil et procédé de catalyse induite par métal WO2019217350A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024035769A1 (fr) 2022-08-10 2024-02-15 Fort Wayne Metals Research Products, Llc Fil composite avec revêtement

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US6716444B1 (en) * 2000-09-28 2004-04-06 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US20070250158A1 (en) * 2006-04-25 2007-10-25 Medtronic Vascular, Inc. Laminated Implantable Medical Device Having a Metallic Coating
US20080243240A1 (en) * 2007-03-26 2008-10-02 Medtronic Vascular, Inc. Biodegradable Metal Barrier Layer for a Drug-Eluting Stent
US8888841B2 (en) * 2010-06-21 2014-11-18 Zorion Medical, Inc. Bioabsorbable implants

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Publication number Priority date Publication date Assignee Title
US6716444B1 (en) * 2000-09-28 2004-04-06 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US20070250158A1 (en) * 2006-04-25 2007-10-25 Medtronic Vascular, Inc. Laminated Implantable Medical Device Having a Metallic Coating
US20080243240A1 (en) * 2007-03-26 2008-10-02 Medtronic Vascular, Inc. Biodegradable Metal Barrier Layer for a Drug-Eluting Stent
US8888841B2 (en) * 2010-06-21 2014-11-18 Zorion Medical, Inc. Bioabsorbable implants

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024035769A1 (fr) 2022-08-10 2024-02-15 Fort Wayne Metals Research Products, Llc Fil composite avec revêtement

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