Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
  • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
  • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
  • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
  • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
  • A61K47/6937—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
  • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
  • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
• • 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
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

• the present invention relates generally to the field of medical implants and in particular to providing medical implants with improved biocompatibility.
• Medical implants and devices play an important role in the practice of contemporary medicine. Unfortunately, following introduction into an organism, many implants and devices trigger a series of biologic reactions, many of which are deleterious to the body. Such adverse biologic reactions include inflammation, fibrosis, thrombosis, and infections that may lead to implant rejection.
• Implant-mediated protein "denaturation” a biologic process that appears to occur via protein adsorption onto the surface of an implant. The adsorption is led by a chaotic layer of spontaneously adsorbed, partially 'denatured' host proteins, including fibrinogen.
• fibrinogen mediates acute inflammatory responses to biomaterials. J Exp Med 1993;178:2147-56; Hu et al. Molecular basis of biomaterial-mediated foreign body reactions. Blood 2001;98: 1231-38; incorporated herein by reference).
• the denatured proteins such as fibrinogen
• fibrinogen are thus involved in promoting adverse biologic reactions to an implant, by, in part, attracting inflammatory cells to implants after their adsorption.
• it remains to be understood how to prevent the denaturation and adsorption processes. Indeed, there remains a need for implants and devices that do not promote such adverse biologic reactions. This is likely to occur by identifying implants and surfaces that are compatible with the body (e.g., biocompatible) and do not promote protein denaturation and/or protein adsorption onto the implant surface.
• biocompatible implants and devices have yielded materials with hydrophilic surfaces thought to prevent protein (e.g., fibrinogen) denaturation. Disappointingly, even the most hydrophilic of these materials, including polyethylene glycol, when placed on the surface of an implant or device is found to prompt protein conformational changes and adverse biologic reactions.
• Most if not all medical implants when introduced into an organism trigger a series of biologic reactions, referred to herein as foreign body reactions.
• the biologic reactions are generally accompanied by an accumulation of inflammatory and fibrotic cells that collect and/or adhere to the implant surface. It is this accumulation of cells, their by-products and the associated immune responses that lead to the failure of medical implants or devices.
• Prior art coating techniques have been developed to improve the biocompatibility of the implant. These techniques, however, have been designed to change material surface chemistries in an attempt to reduce protein denaturation and protein/cell accumulation. Prior art techniques generally fail to significantly reduce surface-induced protein denaturation and subsequent adverse reactions. Therefore, there still remains a need for improved implants with surfaces that prevent protein denaturation and subsequent adverse reactions in the organism.
• the present invention solves many problems associated with adverse reactions occurring upon introduction of an implant or device into an organism.
• the present invention provides for a preparation that prevents protein denaturation (e.g., unfolding) and subsequent adverse reactions upon its introduction into an organism.
• the present invention is a nanoparticle preparation that reduces or prevents protein unfolding as well as subsequence adverse reactions from occurring in an organism.
• Adverse reactions may include biologic processes and/or cell surface interactions such as inflammatory cell accumulation, protein unfolding, protein denaturation, fibrotic tissue formation, thrombosis and device-centered infection.
• the nanoparticle preparation comprises nanoparticles less than or equal to 500 nanometer (nm) in diameter and an implant surface capable of receiving the nanoparticles.
• the invention provides for a biocompatible coating on an implant that prevents adverse reactions in the body upon its introduction into an organism.
• the present invention is a nanoparticle preparation for coating an implant surface comprising nanoparticles of less than or equal to 500 nanometers, wherein the nanoparticles promote characteristics on the implant surface after implantation into an organism in need thereof, the characteristics selected from the group consisting of reducing protein unfolding, reducing protein denaturation, preventing accumulation of inflammatory cells, preventing the accumulation of fibrotic cells, preventing fibrotic tissue formation, preventing thrombosis or device-centered infection, reducing the number of cell attachment sites, reducing adverse biological reactions and combinations thereof.
• the present invention is a nanoparticle preparation for coating an implant surface comprising one or more nanoparticles of less than or equal to 500 nanometers and coating the surface of an implant with nanoparticles, wherein the nanoparticles promote characteristics on the implant surface selected from the group consisting of reducing protein unfolding, reducing protein denaturation, preventing accumulation of inflammatory cells, preventing the accumulation of fibrotic cells, preventing fibrotic tissue formation, preventing thrombosis or device-centered infection, reducing the number of cell attachment sites, reducing adverse biological reactions and combinations thereof.
• the method may include coating an implant or device with such a nanoparticle preparation that prevents protein unfolding or denaturation upon introduction of the implant into an organism.
• Advantages of the present invention include findings that the reduction or prevention of protein unfolding, adverse biologic reactions, protein adsorption and protein denaturation that occur via the present invention appear regardless or independent of nanoparticle composition.
• the nanoparticle preparation of the present invention does not adversely affect surface properties or function of an implant.
• FIGURE 1 depicts a schematic of a nanoparticle in accordance with one aspect of the present invention
• FIGURE 2A depicts a lack of foreign body reactions in mice following contact with 100 nrn NIPA particles of the present invention
• FIGURE 2B illustrates one example of inflammatory and fibrotic reactions in mice following contact with 10 micrometer NIPA particles
• FIGURE 2C illustrates a lack of foreign body reactions in hypofibrinogenic mice following contact with microparticles of the present invention
• FIGURE 2D illustrates "normal" foreign body reactions in hyperfibrinogenemic mice following contact with 10 micrometer microparticles preincubated with fibrinogen;
• FIGURE 2E illustrates the extent of foreign body reactions (as number of cells associated with a particle implants) in mice following contact with various coated and uncoated implants;
• FIGURE 3 shows fibrinogen accumulation in untreated Balb/C mice following subcutaneous implantation of (FIGURE 3A) 10 micrometer microparticles or (FIGURE 3C) 100 nm nanoparticles as it compares with ancrod-treated Balb/C mice following subcutaneous implantation of (FIGURE 3B) 10 micrometer microparticles or (FIGURE 3D) 100 nm nanoparticles;
• FIGURE 4 exemplifies an inflammatory response following implantation of 10 micrometer NIPA particles for views of (FIGURE 4A) X200 and (FIGURE 4B) X600 as it compares with the absence of such a response following implantation of 100 nm NIPA nanoparticles for views Of (FIGURE 4C) X200 and (FIGURE 4D) X600;
• FIGURE 5A shows an absence of an adverse or foreign body reaction seven days after implantation of poly-L-lactic acid fibers covalently coated with 100 nm nanoparticles of the present invention
• FIGURE 5B depicts an adverse or foreign body reaction seven days after implantation of "uncoated" poly-L-lactic fibers
• FIGURE 6 depicts fibrinogen P2 epitope exposure on fibrinogen adsorbed to (FIGURE 6A) 10 micrometer microparticles preincubated with human fibrinogen as it compares with (FIGURE 6B) 100 nanometer nanoparticles preincubated with human fibrinogen, (FIGURE 6C) fibrinogen-free 10 micrometer microparticles (FIGURE 6D) and fibrinogen-free 100 nanometer nanoparticles; and
• FIGURE 7 depicts a schematic of potential nanoparticle coatings.
• the present invention provides for a surface on an implant, similar to a surface "coating,” that reduces and/or prevents adverse foreign body reactions, such as protein adsorption to the implant surface.
• the present invention improves the biocompatibility and blood compatibility of an implant by using a coating of nanoparticles, wherein each particle is generally less than 500 nm in diameter.
• nanoparticles of the present invention reduce protein "denaturation" as well as subsequent foreign body reactions.
• nanoparticle coating of implants provides for improved biocompatibility and, subsequently, therapeutic efficacy of the implant and hence with an organism in need of such an implant.
• compositions comprising one or more degradable polymers, nondegradable polymers, metals, proteins, nucleic acids, micro-organisms (bacteria and viruses) and similar combinations may be used to improve the biocompatibility of implants introduced to organisms.
• medical implants or devices include any material with a surface to which a "coating" may be applied.
• the implant "material” as used herein may be any organic or inorganic used with medical implants or devices.
• the "coating" applied to the material surface includes “nanoparticles,” “nanoparticles-like objects,” “microscopic particles” or “functionalized particles.”
• the material surface may be treated to create particle-like structures on the surface by performing surface modification procedures, such as plasma polymerization, spot coating, etc.
• Such particles are generally a few micrometers in size to few millimeters in size or submicroscopic (less than one micrometer) and solid colloidal objects that may be cylindrical or spherical in shape with a semipermeable shell or shaped like a permeable nano-ball.
• One or more drugs or other relevant materials may be included with the nanoparticles of the present invention. Inclusion may be via entrapment, encapsulation, absorption, adsorption, covalent linkage, or other attachment. Nanoparticles of the present invention may be, themselves, further coated as required.
• Nanoparticles of the present invention are generally provided as a metal particle, carbon particle, inorganic chemical particle, organic chemical particle, ceramic particle, graphite particle, polymer particle, protein particle, peptide particle, DNA particle, RNA particle, bacteria/virus particle, hydrogel particle, liquid particle or porous particle.
• the nanoparticles may be, for example, metal, carbon, graphite, polymer, protein, peptide, DNA/RNA, microorganisms (bacteria and viruses) and polyelectrolyte, and may be loaded with a light or color absorbing dye, an isotope, a radioactive species, a tag, or be porous having gas-filled pores.
• hydrogel refers to a solution of polymers, sometimes referred to as a sol, converted into gel state by small ions or polymers of the opposite charge or by chemical crosslinking.
• Suitable polymers of the present invention include copolymers of water soluble polymers, including, but not limited to, dextran, derivatives of poly-methacrylamide, PEG, maleic acid, malic acid, and maleic acid anhydride and may include these polymers and a suitable coupling agent, including l-ethyl-3 (3-dimethylaminopropyl)-carbodiimide, also referred to as carbodiimide.
• Polymers may be degradable or nondegradable or of a polyelectrolyte material.
• Degradable polymer materials include poly-L-glycolic acid (PLGA), poly-DL-glycolic, poly-L-lactic acid (PLLA), PLLA-PLGA copolymers, poly(DL-lactide)-block-methoxy polyethylene glycol, polycaprolacton, poly(caprolacton)- block-methoxy polyethylene glycol (PCL-MePEG), poly(DL-lactide-co-caprolactone)- block-methoxy polyethylene glycol (PDLLACL-MePEG), some polysaccharide (e.g., hyaluronic acid, polyglycan, chitoson), proteins (e.g., fibrinogen, albumin, collagen, extracellular matrix), peptides (e.g., RGD, polyhistidine), nucleic acids (e.g., RNA, DNA, single or double stranded), viruses, bacteria, cells and cell fragments, organic or carbon- containing materials, as examples.
• PLGA
• Nondegradable materials include natural or synthetic polymeric materials (e.g., polystyrene, polypropylene, polyethylene teraphthalate, polyether urethane, polyvinyl chloride, silica, polydimethyl siloxane, acrylates, arcylamides, poly (vinylpyridine), polyacroleine, polyglutaraldehyde), some polysaccharides (e.g., hydroxypropyl cellulose, cellulose derivatives, dextran ® , dextrose, sucrose, ficoll ® , percoll ® , arabinogalactan, starch), and hydrogels (e.g., polyethylene glycol, ethylene vinyl acetate, N-isopropylacrylamide, polyamine, polyethyleneimine, poly-aluminum chloride).
• polystyrene polypropylene, polyethylene teraphthalate, polyether urethane
• polyvinyl chloride silica, polydi
• typical suitable layers include, as examples, surfactants such as those including fatty acid esters of glycerols, sorbitol and other multifunctional alcohols (e.g., glycerol monostearate, sorbitan monolaurate, sorbitan monoleate), polysorbates, poloxamers, poloxamines, polyoxyethylene ethers and polyoxyethylene esters, ethoxylated triglycerides, ethoxylated phenols and ethoxylated diphenols, surfactants of the Genapol TM and Bauki series, metal salts of fatty acids, metal salts of fatty alcohol sulfates, sodium lauryl sulfate, and metal salts of sulfosuccinates.
• surfactants such as those including fatty acid esters of glycerols, sorbitol and other multifunctional alcohols (e.g., glycerol monostearate, sorbitan monolaurate, sorbit
• the particles of the present invention are produced by conventional methods known to those of ordinary skill in the art. Techniques include emulsion polymerization in a continuous aqueous phase, emulsion polymerization in continuous organic phase, interfacial polymerization, solvent deposition, solvent evaporation, dissolvation of an organic polymer solution, cross-linking of water-soluble polymers in emulsion, dissolvation of macromolecules, and carbohydrate cross-linking. These fabrication methods can be performed with a wide range of polymer materials as described above. Removal of any solvent or emulsifier as required may include a number of methods well known to one of ordinary skill in the art. Examples of materials and fabrication methods for making nanoparticles have been published. (See Kreuter, J.
• Nanocoatings may be made to specifically accumulate certain cells, proteins, growth factors, peptides, biological substances and chemicals.
• nanoparticles may be "tagged” to have a high affinity to specific biological component(s).
• a coating made of such cell/protein-affinity particles or “tags” may increase the specific accumulation of cells and proteins.
• a “tag” When a "tag” is in contact with a nanoparticle of the present invention, it may be adsorbed or absorbed to a premade nanoparticle, or incorporated into the nanoparticle during the manufacturing process. Methods of absorption, adsorption, and incorporation are of common knowledge to those skilled in the art.
• the choice of the monomer and/or polymer, the solvent, the emulsifier, the tag and other auxiliary substances used herein will be dictated by the nanoparticle being fabricated and is chosen, without limitation and difficulty, by those skilled in the art.
• the ratio of tag to nanoparticle may be varied as required.
• a "tag” includes an addition to the nanoparticle that has an ability to modify the nanoparticle.
• tags may include drugs, molecular ligands (e.g., molecules/compounds) that recognize a material, cell, organ or tissue of interest, such as antibodies, antigens, proteins, peptides, nucleic acid sequences, fatty acid or carbohydrate moieties, chemicals, as examples. They may also be modified compounds or polymers that mimic recognition sites on cells, organs, or tissues.
• the tags may recognize a portion of a material, cell, organ, or tissue, including but not limited to a cell surface marker, cell surface receptor, immune complex, antibody, MHC, extracellular matrix protein, plasma, cell membrane, extracellular protein, polypeptide, cofactor, growth factor, fatty acid, lipid, carbohydrate chain, gene sequence, cytokine or other polymer.
• Nanoparticles of the present invention may be applied to the surface of an implant by methods known to one of ordinary skill in the art, including by physical adsorption or chemical conjugation.
• the techniques described in accordance with the present invention may be used in vivo and in vitro.
• nanoparticles can be used for coating blood bags and/or blood tubes. Techniques for making particles and coating implants in accordance with the present invention are further described by examples presented below.
• NIPA N-isopropylacrylamide
• HPC hydro-propyl cellulose
• the particles were implanted in a subcutaneous space of Balb/C mice. After implantation for periods ranging from 3 days to 21 days, it was determined that adverse and foreign body reactions, such as inflammatory and fibrotic responses, were absent or less evident when smaller particles were implanted. Such size-dependence related to adverse tissue responses was independent of the material (i.e., particle) composition. In general, particles with sizes less than 500 nm showed the least adverse responses as shown in FIGURE 2A and B.
• FIGURES 2, 2A and 2B are photos taken at 200X and show the absence or presence of adverse or foreign body reactions to NIPA nanoparticles of the present invention seven days after implantation in the subcutaneous space of Balb/C mice.
• NIPA particles 100 nanometers in diameter were found to illicit minimal foreign body reactions (e.g., inflammation) as compared with NIPA particles that were 10 micrometers in diameter, as shown in FIGURE 2B.
• Fibronogen-depleted mice also referred to a hypofibrinogenemic mice
• a hypofibrinogenemic mice were generated by repeat administering ancrod (a snake venom) to the mice 3 days prior to implantation.
• These hypofibrinogenemic mice failed to illicit adverse or foreign body reactions to particles that were 10 micrometers in diameter, as shown in FIGURE 2C, because of the depletion of fibrinogen.
• fibrinogen supplied with fibrinogen
• FIGURE 4A 100X
• FIGURE 4B 100X
• FIGURE 4C and 4D are enlarged views (400X) of the dashed boxes FIGURES 4A and 4B, respectively
• the extent of the inflammatory response to particle implants was assessed using immunohistochemical staining against CDl lb-positive inflammatory cells
• FIGURE 5A shows that fibers coated with such nanoparticles did not produce adverse biologic responses such as inflammation and inflammatory cell accumulation or protein adhesion This was contrasted to fibers that were not coated or that were coated with larger particles (micrometer in diameter) With uncoated or larger- coated fibers, adverse responses and foreign body reactions were elicited (FIGURE 5B)
• adverse reactions were not apparent when implanting PET films coated with 100 nm diameter nanoparticles using the subcutaneous implant model, while reactions were apparent when implanting PET films coated with larger particles (micrometer m diameter) (Data not shown)
• coating with nanoparticles, with diameters less than 500 nm significantly reduced the accumulation of phagocytic cells by greater than 70% and reduced fibrotic tissue formation by greater than
• FIGURE 6A demonstrated that there was an increase in P2 exposure with larger particles (A) trigger much more P2 exposure than did nanoparticles (C).
• the fibrinogen-free microparticles (C) and nanoparticles (D) have very low affinity to P2 antibody. Similar results have also been obtained from studies using HPC particles (not shown).
• Nanoparticles of the present invention provide for a coating on an implant surface to be implanted into an organism in need thereof.
• the coating may be applied to any material via physical and/or chemical binding, including techniques such as plasma polymerization or spot coating.
• the coating of the present invention when applied to an implant surface is used for purposes that may be cosmetic, therapeutic, preventative, reconstructive, monitoring and replacement.
• the coating of the present invention may be used for in vitro purposes.
• FIGURE 7 illustrates that such a coating is generally at least one layer thick, may include particle-like structures (e.g., using plasma polymerization, spot coating, laser deposition, and related technologies) and may also be used on implant surfaces such as small 2mm rods or microparticles.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Genetics & Genomics (AREA)
• Pharmacology & Pharmacy (AREA)
• Nanotechnology (AREA)
• Biomedical Technology (AREA)
• Physics & Mathematics (AREA)
• Biotechnology (AREA)
• Molecular Biology (AREA)
• General Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Zoology (AREA)
• Wood Science & Technology (AREA)
• Optics & Photonics (AREA)
• Immunology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Plant Pathology (AREA)
• Microbiology (AREA)
• Biophysics (AREA)
• Dermatology (AREA)
• Biochemistry (AREA)
• Transplantation (AREA)
• Heart & Thoracic Surgery (AREA)
• Materials For Medical Uses (AREA)
• Medicinal Preparation (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=35967825

Family Applications (1)

Country Status (6)

Cited By (2)

Families Citing this family (21)

Citations (1)

Family Cites Families (17)

• 2004
  • 2004-07-21 US US10/896,376 patent/US20050084513A1/en not_active Abandoned
• 2005
  • 2005-04-20 CN CNA2005800288126A patent/CN101010073A/zh active Pending
  • 2005-04-20 CA CA002574463A patent/CA2574463A1/en not_active Abandoned
  • 2005-04-20 WO PCT/US2005/013380 patent/WO2006022887A1/en not_active Ceased
  • 2005-04-20 EP EP05746566A patent/EP1778200A1/en not_active Withdrawn
  • 2005-04-20 JP JP2007522487A patent/JP2008507326A/ja active Pending

Patent Citations (1)

Also Published As

Similar Documents

Legal Events