Classifications

• • D—TEXTILES; PAPER
  • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
  • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
  • D01F1/00—General methods for the manufacture of artificial filaments or the like
  • D01F1/02—Addition of substances to the spinning solution or to the melt
  • D01F1/10—Other agents for modifying properties
• • 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
  • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
  • A61L17/005—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
• • 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
  • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
  • A61L17/04—Non-resorbable 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
  • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
  • A61L17/06—At least partially resorbable materials
  • A61L17/10—At least partially resorbable materials containing macromolecular 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
  • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
  • A61L17/06—At least partially resorbable materials
  • A61L17/10—At least partially resorbable materials containing macromolecular materials
  • A61L17/105—Polyesters not covered by A61L17/12
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
  • C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
  • C08L23/10—Homopolymers or copolymers of propene
  • C08L23/12—Polypropene
• • D—TEXTILES; PAPER
  • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
  • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
  • D01D5/00—Formation of filaments, threads, or the like
  • D01D5/12—Stretch-spinning methods
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
  • A61L2300/206—Biguanides, e.g. chlorohexidine
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

• the present invention refers to the field of medical-surgical devices and in particular it refers to a method for producing suture threads with multifunctional properties (antimicrobial and/or antibiotic and/or cicatrizing); the preparation method is based on the melt incorporation of the antimicrobial and/or antibiotic and/or cicatrizing agent and allows the modulation of the release of the amount of the antimicrobic and/or antibiotic and/or cicatrizing component as a function of the preparation conditions.
• Sutures are identified on several criteria that essentially regard the need to remove them, their structure and their composition.
• the sutures can be woven/threaded or made of a single filament.
• the suture thread can be natural or synthetic.
• the threads can be divided into two main categories: absorbable and non-absorbable.
• the typical materials used for producing non-absorbable threads are silk and linen - as far as natural materials are concerned - while nylon, polyester, polypropylene, polytetrafluoroethylene, polyvynilidenefluoride as synthetic materials.
• Polydioxanone, polyglycolic acid, polylactic acid, polycaprolactone and binary or ternary copolymers of the latter three polymers are the main polymeric materials used to produce absorbable suture threads. Moreover, in some cases, polycaprolactone is used as coating to increase some properties like, for instance, the slippage.
• the suture thread is covered by fluids highly rich in proteins like fibrinogen and fibronectin that create the ideal environment for bacterial proliferation.
• the immunitary system activates local disinfection systems, typically driven by granulocytes, that can be ineffective and cause inflammatory reactions that can be more or less severe.
• Providing specific properties to the suture thread can be carried out by different methods and can modify, or less, the polymer structure. In both cases, it must be verified that the introduction of the antimicrobial and/or antibiotic and /or cicatrizing agent does not significantly modify the mechanical properties of the material.
• the additive must therefore be compatible with the polymer and keep its antiseptic properties for the whole period between the production of the thread and its use. Another aspect that must not be underestimated is, as already highlighted, the release rate of the agent.
• the ideal condition is that wherein the most of the antimicrobial and/or antibiotic and /or cicatrizing agent is released during the most delicate phase (i.e. within the first 10 days after the use of the thread), which is when the wound is most likely affected by bacterial contamination and the cicatrized tissue is not yet formed. It can be therefore understood that it is very difficult to find a couple polymer- antimicrobial properties and/or antibiotic and /or cicatrizing agent that is able to satisfy all the requested characteristics.
• the methods currently used for producing threads with antimicrobial properties are essentially three: coating, grafting and melt incorporation.
• the coating method consists in the physical coating of a material, the substrate, by immersing it in a fluid (usually a solution) containing the compound that is desired onto the surface.
• a fluid usually a solution
• the substrate will be covered by a thin film of the agent, with a thickness that depends on several factors such as the viscosity of the solution, the extraction rate, the surface tension and the gravity acceleration.
• the grafting method consists in the introduction of particular chemical moieties onto the polymer surface in order to provide the material with properties initially non possessed. It is usually realized by introducing the polymer in a solution under appropriate temperature and pH conditions to promote the grafting of desired functional groups.
• the grafting extent can be easily controlled by changing the operating variables.
• the melt incorporation method consists in adding the active compound during an extrusion operation.
• the polymer under the form of powder or pellets, is pre- mixed at the solid state with the agent that is preferably under the form of powder.
• the physical mixture is then fed to the extruder hopper and extruded under a certain temperature profile and screw speed, variable and depending on the polymer used.
• the material is finally fed, in a separate step, to a spinning unit thus producing the antimicrobial threads.
• the patent GB 2 410 028 describes an antimicrobial monofilament used as testing device for diabetes neuropathies.
• This monofilament is rigid.
• this monofilament is not single-use and therefore it is necessary to provide it with antimicrobial and/or antifungine properties in order to avoid contamination between different patients.
• the polymers indicated for the fabrication of that monofilament are PBT, PET and nylon while the only example reported of antimicrobial agent is DurabanTM. It must be pointed out that in the patent it is not reported the preparation method unless a very vague and generic mention to the incorporation of the antimicrobial agent in during a melt extrusion, but without any evidence on the real production of the material or of the suture thread.
• WO 0128601 it is described the preparation of suture threads with antimicrobial properties. They are realized by preparing a coating to be applied onto the external surface or by the incorporation of an antimicrobial agent. Although the patent is extremely detailed, there is no explanation on what the authors mean with "incorporation” and on how it is pursued.
• the antimicrobial agents used are water soluble glasses that release Ag, Cu or Zn.
• the patent EP 1157708 A2 describes the preparation of surgical devices like suture threads with antimicrobial properties realized by melt incorporation (extrusion).
• the thread is not realized in a single passage but the material obtained by extrusion is used to feed a second extruder to produce the final item (for instance a suture thread).
• it is not reported the possibility to modulate the mechanical resistance and/or the release of the incorporated compound by changing processing or post-processing variables.
• the patent WO86/02561 reports a method for preparing plastic objects containing chlorhexidine by melt incorporation in hydrophobic polymers like polyethylene or polypropylene. Also in this case there is no mention on the possibility to modulate the quantity released by changing the processing parameters of extrusion, spinning and drawing stages.
• Aim of the present invention is to provide a simplified and economically advantageous method to prepare suture threads with controlled release of antimicrobial properties and/or antibiotic and /or cicatrizing agents.
• the present invention solve the above reported problems by providing a method for the manufacturing of multifunctional suture threads with controlled release of antimicrobial and/or antibiotic and /or cicatrizing agents.
• This method comprising the melt incorporation of one or more of said agents and said melt incorporation followed by an in-line spinning downstream of the extruder by drawing under predetermined drawing conditions so as to impart a controlled release of each incorporated agent according to the following function:
• Q is the amount of agent released per surface unit
• a and b are unique constants which depend on a polymer/agent pair
• c is the weight concentration of the agent incorporated in the polymer
• D 0 the diameter of the extruder nozzle and D f the final fiber diameter.
• the antimicrobial and/or antibiotic and /or cicatrizing agents are incorporated in the melt polymers chosen among those usually adopted for the preparation of suture threads, both absorbable and non-absorbable.
• the combinations polymer/agents are identified on the basis of the possible processing temperature; in particular, the maximum temperature of the thermal profile of the extruder must be at least 10 °C above the melting temperature of the polymer and at least 10 °C below its degradation temperature. Moreover, the maximum temperature must be at least 5 °C lower than the melting temperature of the agent to be incorporated or than its decomposition temperature, if lower.
• the additives are the above described antimicrobial properties and/or antibiotic and /or cicatrizing agents.
• Said material is appropriate for the preparation or coating of medical-surgical devices.
• it is appropriate for preparing surgical suture threads with antimicrobial properties.
• the present invention regards therefore suture threads, characterized by the melt incorporation of an antimicrobial and/or antibiotic and /or cicatrizing agent in a biocompatible polymer, chosen among those known for the fabrication of suture threads.
• suture thread obtained with the method according to the invention, said thread having antimicrobial properties and/or antibiotic and /or cicatrizing properties with controlled release that can be modulated in the space and in the time based on the drawing conditions adopted during their manufacturing.
• the present method introduces a wide range of improvements and advantages both on the methodic and on the final product.
• the most important advantage is the simplicity of preparation of the final product.
• by a single operation it is possible to provide the thread with the properties above described.
• the reduction of the number of operations has an evident advantage not only for time saving but also avoid the use of other products or solvents different from the polymeric matrix and the antimicrobial agent. This has obvious positive implications from an environmental and economic point of view but also as far as the safety of the thread is concerned.
• the use of solvents, necessary for the two other methods has, as a direct consequence, the need to dispose them.
• the incorporation of the antimicrobial agent rather than having it only onto the surface, allows a higher control of its release by modulating parameters such as:
• Figure 1 - shows a scheme of the preparation method according the present invention by using an extruder with a primary input and several secondary inputs.
• Figure 1a - shows, for the suture threads in PCL/CHX prepared with the method according to the invention, the results regarding the release of the antimicrobial agent as a function of the incorporated concentration and of the drawing conditions.
• Figure 3 shows the results of the antibacterial activity of PCL/CHX suture threads prepared according to the method of the invention; the activity is determined with an agar diffusion test against a Gram positive bacterial strain.
• Figure 4 - graphically shows the linear law QCHX - mpcucHx -CCHX for the couple PLC/CHX.
• Figure 5 graphically shows how the constants a and b were determined for the system PCL/CHX.
• Figure 6 shows, for PP/CFX suture threads prepared according to the method of the invention, regarding the release of antimicrobial agent by changing the incorporated concentration and the drawing conditions.
• Figure 8 - shows the results of antimicrobial activity of PP/CFX suture threads prepared according to the method of the invention; the activity is determined with an agar diffusion test against a Gram positive bacterial strain.
• Figure 9 graphically shows the results of antibacterial activity of PP/CFX suture threads prepared according to the method of the invention; the activity is determined with an agar diffusion test against a Gram positive bacterial strain.
• Figure 10 graphically shows how the constants a and b were determined for the system PP/CHX.
• the amount of released agent strongly depends on the concentration of such compound on the surface of the device.
• This surface concentration can be controlled and modulated both by changing the initial amount of agent incorporated and, above all, by changing the drawing ratio adopted during the production of the fibers.
• the surface concentration can be varied and controlled by changing the extension of the lateral surface on which the agent is distributed.
• draw ratio can be rewritten as a function of the diameters according to the following equation:
• D 0 is the diameter of the extruder nozzle and Df the final diameter of the thread.
• the draw ratio it is possible to modulate the surface concentration of the additive and, consequently, to modulate and control the quantity released.
• the antimicrobial and/or antibiotic and/or cicatrizing effect directly depends on the quantity of agent released and this quantity can be controlled, as already said, by changing the concentration of additive incorporated and by changing the draw ratio.
• This concept can be mathematically expressed by two functions that bind the quantity of released additive to the concentration and to the draw ratio.
• m aDR + b where a and b are constants depending on the specific couple polymer/additive and DR the draw ratio.
• antimicrobial or antibiotic agents refer to antibiotics, lantibiotics, bateriostatics, bactericides and antiseptics that are small organic molecules either natural or synthetic and approved for the use as medicaments or for medical-surgical use.
• metallic ions of silver, copper or zinc and their soluble components are excluded.
• organosilanes like 3-(trimethoxysylil)propyldimethylocadecyl ammonium chloride are not included.
• healing agents refer to agents able to accelerate the healing up of wounds, ulcers and burns, removing the residues of the inflammatory process and recovering the integrity of the cutaneous structures.
• Such compounds, natural or synthetic, must be approved for the use as medicaments or for medical-surgical use.
• the polymers that can be used are those normally adopted for the production of suture threads, both absorbable and non-absorbable, and previously listed above: polyamides (nylons), polyesthers, polypropylene, polytetrafluoroethylene, polydioxanone, polyglycolic acid, polylactic acid, polycaprolactone, bynary or ternary copolymers of the last three together with their blends.
• polyamides nylons
• polyesthers polypropylene
• polytetrafluoroethylene polydioxanone
• polyglycolic acid polylactic acid
• polycaprolactone polycaprolactone
• the choice of the agents described above is drastically reduced as the compound must not be toxic or having harmful side effects for the organism.
• the agent must present activity against microorganisms that usually infect a wound such as: Escherichia Coli, Staphylococcus Epidermidis and Staphylococcus Aureus. Last but not least, it must also be compatible with the material that forms the thread.
• in the class of antimicrobial/antibiotics can be preferred, not being the only, chlorhexidine, neomicine, nalidixic acid, nisin and ciprofloxacine.
• cicatrizing agents can be preferred, not being the only, ialuronic acid, Triticum Vulgaris, collagene and catalase.
• the additive can be both under the form of powder and of liquid. It can be fed together with the polymer or by one of the secondary hoppers, places at a well-defined distance from the main hopper. In order to include in a way and appropriate measure, the agent in the polymer already molten (fed to the extruder by the main hopper) and to regulate the residence time inside the extruder of the agent and therefore the final properties of the device ( Figure 1 ).
• the blend is extruded adopting a thermal profile (generally in the range 70 °C - 300 °C) and at a speed (function of the amount of material to be produced and of the residence time) generally in the range 20 sec - 10 min, appropriated for processing the polymeric materials that forms the thread.
• the polymer/additive couples are identified based on the possible processing temperatures.
• the maximum temperature of the thermal profile of the extruder must be at least 10 °C above the melting temperature of the polymer and at least 10 °C below its degradation temperature.
• the maximum temperature must be at least 5 °C lower than the melting temperature of the agent to be incorporated or than its decomposition temperature, if lower.
• an in-line spinning system allows the direct preparation of the threads that are drawn under isothermal or non-isothermal conditions thus modulating, by changing the drawing conditions, the final diameter, the mechanical resistance but, above all, the release of the necessary amount of additive both in the space (i.e. locally in the proximity of the filament) and in the time (i.e. by regulating the duration of the antimicrobial and/or antibiotic and/or cicatrizing action).
• the antimicrobial action of the thread occurs by migration and consequent release of the active agent. It is therefore possible to modulate the duration of the release, also by appropriately choosing the concentration of antimicrobial agent to be incorporated as well as by modifying in an appropriate manner the structure of the polymeric matrix.
• the polymer under the form of pellets, was fed to the main hopper of co-rotating twin-screw extruder while the antimicrobial agent was fed to the extruder by a secondary hopper.
• the blend was then extruded adopting a thermal profile of 40- 50-70-100 °C through a cylindrical nozzle with a diameter of 1 mm.
• the thread was cooled down and contextually drawn using a drawing unit, until the final desired diameter was achieved.
• the initial concentration of chlorhexidine was 1 %, 2% and 4%.
• the antibacterial activity of the threads was investigated by agar diffusion tests.
• the inhibition was studied against of two Gram positive (M. Luteus and B. Subtilis) and a Gram negative (E. Coli) by the evaluation of the inhibition halo around the fibers.
• test for measuring the inhibition of bacterial growth were carried out in a liquid culture.
• the antibacterial activity of the threads prepared is strictly correlated to the release of the incorporated compound and therefore, by modulating this release, it was also possible to modulate the antibacterial action of the threads as shown in Figure 3 where there are reported, as an example, the inhibition tests against a Gram positive (M. Luteus) of both the groups of threads produced.
• QCHX ITIPCUCHX -CCHX
• CCHX is the weight concentration of chlorhexidine incorporated
• tripcucHx has a value depending on the draw ratio applied as shown in Figure 4.
• the method was also applied for the preparation of suture threads of polypropylene (PP) in which the compound added was an antibiotic agent, ciprofloxacine (CFX).
• PP polypropylene
• CFX ciprofloxacine
• the CFX and the PP used in the example are two commercial sample respectively supplied by Sigma Aldrich and Basell.
• the polymer under the form of pellets was fed to the main hopper of a co-rotating twin-screw extruder while the antibiotic agent, under the form of powder, was fed by a secondary hopper.
• the blend was extruded at a thermal profile of 130-180-200 °C through a cylindrical die with a diameter of 1 mm.
• the thread was cooled down and contextually drawn using a drawing unit, until the final desired diameter was achieved.
• the initial concentration of ciprofloxacine was 1 %, 2% and 4%.
• the antibacterial activity of the threads was investigated by agar diffusion tests.
• the inhibition was studied against of two Gram positive (M. Luteus and B. Subtilis) and a Gram negative (E. Coli) by the evaluation of the inhibition halo around the fibers.
• test for measuring the inhibition of bacterial growth were carried out in a liquid culture.
• the antibacterial activity of the threads prepared is strictly correlated to the release of the incorporated compound and therefore, by modulating this release, it was also possible to modulate the antibacterial action of the threads as reported in Figure 8 where there are reported, as an example, the inhibition tests against a Gram positive (M. Luteus) of both the groups of threads produced.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Materials Engineering (AREA)
• Surgery (AREA)
• Vascular Medicine (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Textile Engineering (AREA)
• Medicinal Chemistry (AREA)
• Organic Chemistry (AREA)
• Polymers & Plastics (AREA)
• Biomedical Technology (AREA)
• Molecular Biology (AREA)
• Manufacturing & Machinery (AREA)
• General Chemical & Material Sciences (AREA)
• Mechanical Engineering (AREA)
• Materials For Medical Uses (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=45992780

Family Applications (1)

Country Status (2)

Cited By (5)

Families Citing this family (1)

Citations (12)

• 2012
  • 2012-02-29 IT IT000041A patent/ITFI20120041A1/it unknown
• 2013
  • 2013-02-28 WO PCT/IB2013/051594 patent/WO2013128401A1/fr not_active Ceased

Patent Citations (12)

Also Published As

Similar Documents

Legal Events