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WO2009026380A1 - Dispositif médical avec revêtement polymère biofonctionnalisé - Google Patents

Dispositif médical avec revêtement polymère biofonctionnalisé Download PDF

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Publication number
WO2009026380A1
WO2009026380A1 PCT/US2008/073737 US2008073737W WO2009026380A1 WO 2009026380 A1 WO2009026380 A1 WO 2009026380A1 US 2008073737 W US2008073737 W US 2008073737W WO 2009026380 A1 WO2009026380 A1 WO 2009026380A1
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prosthetic
implant
polymer
biofunctionalized
carbon atoms
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Charles V. Rice
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University of Oklahoma
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University of Oklahoma
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
    • C09D133/04—Homopolymers or copolymers of esters
    • C09D133/14—Homopolymers or copolymers of esters of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen

Definitions

  • the present invention relates to the synthesis of biofunctionalized polymers and their uses, for example as coatings on objects such as implants, medical devices, and therapeutic delivery systems, and to the implants, devices, and systems comprising these polymers.
  • Biomaterials are living and synthetic materials which can be used in implantation into human and animal bodies. A primary goal of biomaterials science is to minimize implant rejection or incompatibility and stimulate regeneration of the original physiologic and biomechanical status in the area of the implant.
  • Biomaterials preferably can be introduced into the human or animal body in order to restore the function of the corresponding functionally damaged natural tissue.
  • These include, for example, hip endoprostheses, artificial knee joints, jaw implants, tendon replacements, skin replacements, vascular prostheses, heart pacemakers, artificial heart valves, breast implants, stents, catheters and shunts.
  • Implantable artificial materials and devices such as drug delivery systems, pacemakers, artificial joints, implants and transplants and sensors play an important role in health care today, and have great potential for improving both the quality of care and quality of life of patients and animals.
  • One of the major problems associated with all types of implants is biocompatibility of the implant with the body, and in particular with the tissue adjacent to the site of the implant.
  • tissue integration of the materials often proceeds too slowly and too incompletely in order to produce a mechanical stability of the tissue/biomaterial bonding which is adequate for functionality.
  • the composition of the implant surface which on account of its inadequate interfacial compatibility or biocompatibility prevents an active absorption of surrounding healthy tissue or cells, is often causally responsible for this. This complicates the formation of a stable tissue-implant boundary layer and thus leads to inadequate tissue integration, which in turn can result in loosening, tissue resorption, infections, inflammations, allergies, microthrombi formation (restenosis).
  • revision interventions for the replacement of the implants e.g.
  • hip endoprostheses, jaw implants, catheters or external fixators and thus renewed surgical interventions often become necessary.
  • aseptic implant loosening proves problematical in which bone cells and thus bony tissue do not, as desired, form the direct connection to the biomaterial, but fibroblasts and connective tissue occur as interfering elements.
  • the prosthesis is lined by connective tissue instead of bony tissue, the resulting stability of the prosthesis-connective tissue bond not being adequate to meet the mechanical demands on the force transmission of an artificial hip joint.
  • this can lead to loosening of the prosthesis and likewise necessitates revision.
  • undesirable cell types adhering to implants are blood platelets, which can lead to the formation of microthrombi and thus to impaired implant integration.
  • osteoblasts It is desirable for osteoblasts to rapidly deposit mineralized matrix on the surface of (or in close apposition to) newly implanted prostheses.
  • the swift deposition of bone stabilized the prosthesis and minimizes motion-induced damage to surgically traumatized tissue at the implantation site.
  • Anchorage-dependent cells such as osteoblasts
  • One method of mitigating these problems is to stimulate the tissue integration of biomaterials/implants by coating them with peptides which mediate cell adhesion.
  • peptides which contain the tripeptide amino acid sequence arginine-glycine- aspartic acid (RGD), or cell adhesion-mediating, non-RGD-containing peptides or proteins which contain them e.g. collagen type I, fibronectin, laminin, vitronectin, entactin, osteopontin, thrombospondin
  • non-RGD-containing peptides or proteins which contain them e.g. collagen type I, fibronectin, laminin, vitronectin, entactin, osteopontin, thrombospondin
  • the blood clotting cascade function as central recognition patterns for the adhesion of eukaryotic cells and have been used in coatings. Since the adhesion of cells to the corresponding proteins is mediated by a large number of different integrins, the integrin expression pattern of a cell species is crucial for their adhesion properties to these proteins.
  • the present invention is directed to coating compositions (biofunctionalized polymers and functionalized polymers) and methods of their use, and to the objects coated therewith, for their use as implants and as medical devices.
  • the medical devices and implants of the present invention comprise objects (otherwise referred to herein as biomaterials) which are coated with functionalized polymers having biomolecules conjugated thereto (i.e. biofunctionalized polymers), or with the functionalized polymers to which such biomolecules can be conjugated to form the biofunctionalized polymer.
  • the biomolecules which are attached to the functionalized polymers contemplated herein comprise natural or synthetic chemical compounds which possess an ability to covalently bond to a functional group on the functionalized polymer or to a spacer thereon, preferably via a sulfhydryl group.
  • the spacer molecule may be covalently linked via sulfhydryl binds to the functional group of the functionalized polymer.
  • the biomolecules of the biofunctionalized polymers may be covalenlty linked to the spacers.
  • Examples of the medical devices and implants which may be coated with the functionalized or biofunctonalized polymers of the invention include, for example, medical devices that replace anatomical features or restore a function of the body such as the femoral hip joint, the femoral head, acetabular cup, elbow including stems, wedges, articular inserts, knee, including the femoral and tibial components, stem, wedges, articular inserts or patellar components, shoulders including stem and head, wrist, ankles, hand, fingers, toes, jaw implants, vertebrae, spinal discs, artificial joints, dental implants, ossiculoplasty implants, middle ear implants including incus, malleus, stapes, incus-stapes, malleus-incus, malleus-incus-stapes, cochlear implants, orthopaedic fixation devices such as nails, screws, staples and plates, heart valves, pacemakers, stents, shunts, catheters, vessels,
  • Figure 1 shows chemical formulas of several dithiol acrylates and methacylates for use as functionalizing groups in the present invention.
  • Figure 2 shows a scheme for the formation of a biofunctionalized polyacrylamide copolymer functionalized with RGDC peptides.
  • Figure 4 is an alternate scheme for the formation of the biofunctionalized polyacrylamide copolymer functionalized with RGDC peptides.
  • the present invention is directed to coating compositions (biofunctionalized polymers and functionalized polymers) and methods of their use, and to the objects coated therewith, for their use as implants and as medical devices.
  • the term "functionalized polymer” as used herein refers to a polymeric material containing one or more functional groups (which may be one or more types of functional groups) to which a biomolecule of the present invention can be covalently linked.
  • biofunctionalized polymer refers to a functionalized polymer having biomolecules of the present invention covalently linked thereto.
  • the biomolecules attached to the functionalized polymers contemplated herein may be defined as natural or synthetic chemical compounds which possess an ability to covalently bond to the functional group on the functionalized polymer or a spacer thereon, preferably via a sulfhydryl group thereon.
  • biomaterial is intended to include, but not be limited to, any device intended to be implanted into the body of a vertebrate animal, in particular a mammal such as a human.
  • object is intended to be used interchangeably with “biomaterial”, or “medical device”.
  • Non-limiting examples of such devices are medical devices that replace an anatomical feature or restore a function of the body, such as the femoral hip joint; the femoral head; acetabular cup; elbow including stems, wedges, articular inserts; knee, including the femoral and tibial components, stem, wedges, articular inserts or patellar components; shoulders including stem and head; wrist; ankles; hand; fingers; toes; jaw implants; vertebrae; spinal discs; artificial joints; dental implants; ossiculoplasty implants; middle ear implants including incus, malleus, stapes, incus-stapes, malleus-incus, malleus-incus-stapes; cochlear implants; orthopedic fixation devices such as nails, screws, staples and plates; heart valves; pacemakers; stents; shunts; catheters; vessels; space filling implants; implants for retention of hearing aids; implants for external fixation; insulin pumps or monitors; and also intra
  • a “biomaterial” is any material, natural or synthetic, that comprises all or part of a living structure or biomedical device which performs, auguments, protects, or replaces a natural function and that is substantially compatible with the body.
  • the implants or devices (biomaterials) contemplated herein upon which the functionalized or biofunctionalized polymer coating herein are disposed may have outer surfaces comprising metal, mineral, glass, ceramic, or thermoplastic polymer, or combinations thereof, for example. The outer surfaces may be smooth, rough, or porous.
  • the device of the present invention is a prosthetic femoral hip joint; a prosthetic femoral head; a prosthetic acetabular cup; a prosthetic elbow; a prosthetic knee; a prosthetic shoulder; a prosthetic wrist; a prosthetic ankle; a prosthetic hand; a prosthetic finger; a prosthetic toe; a prosthetic vertebrae; a prosthetic spinal disc; a prosthetic cochlea; a prosthetic vessel; a prosthetic heart valve; an artificial joint, a dental implant, an ossiculoplasty implant, a middle ear implant, a cochlear implant, an orthopaedic fixation device, a pacemaker, a catheter, a space filling implant, an implant for retention of hearing aids, an implant for external fixation, an intrauterine device (IUD), or a bioelectric device.
  • IUD intrauterine device
  • the present invention contemplates in preferred embodiments objects which are coated with functionalized polymers having biomolecules conjugated thereto (i.e. biofunctionalized polymers), or with the functionalized polymers to which such biomolecules can be conjugated to form the biofunctionalized polymer.
  • a spacer is employed between the biomolecule and the functional group of the functionalized polymer to insure that the reactive site of the biomolecule remains active and accessible.
  • spacer refers to a molecule that is covalently attached to, and interposed between, the biomolecule and the functionalized polymer as an alternative to the direct attachment of the biomolecule to the pyridyldithio functional groups of the functionalized polymer.
  • the spacer may, for example, comprise a polyamino acid comprising a cysteine residue at a terminus thereof for linking to the sulfhydryl binding group on the functionalized polymer.
  • the polyamino acid may comprise repeating units of glycine, alanine, valine, isoleucine, lysine, or other amino acids, or combinations thereof.
  • Other examples of spacers include poly(ethylene imine), ⁇ , ⁇ -alkylenediamines, ⁇ -aminoalkanoic acids and other polypeptides.
  • biomolecule may include the spacer used to attach the biomolecule to the functionalized polymer.
  • the term "functionalized polymer” may include the spacers linked to the functional groups on the functionalized polymer.
  • the functionalized or biofunctionalized polymers of the present invention may comprise spacer molecules which are covalently linked via sulfhydryl binds to the functional groups thereof.
  • the biomolecules of the biofunctionalized polymers may be covalenlty linked to the spacers. More than one type of spacer may be used in a single functionalized polymer or biofunctionalized polymer.
  • the biomolecule itself may comprise the spacer, and it may be the biomolecule itself comprising the spacer moiety, which is reacted with the functionalized polymer to form the biofunctionalized polymer.
  • the reactivity for binding the desired biological constituent is retained after immobilization of the biomolecule onto the functionalized polymer support.
  • biomolecules used herein include: acetylcholine receptor proteins, histocompatibility antigens, ribonucleic acids, basement membrane proteins, immunoglobulin classes and subclasses, myeloma protein receptors, complement components, myelin proteins, and various hormones, vitamins and their receptor components as well as genetically engineered proteins, suitable functional moieties of thiol groups in modified nucleic acids and derivatives thereof; such as DNA, RNA or peptide nucleic acids (PNA), e.g.
  • PNA peptide nucleic acids
  • oligonucleotides or aptamers polysaccharides, proteins including glycosidically modified proteins or antibodies, enzymes, cytokines, chemokines, peptidhormones or antibiotics or peptides or labeled derivatives thereof.
  • the thiol containing biomolecule may be selected from the group consisting of natural or synthetic extracellular proteins, antibodies, antibody fragments, cell adhesion molecules, fragments of a cell adhesion molecules, growth factors, cytokines, peptides, sugars, carbohydrates, polysaccharides, lipids, sterols, fatty acids and combinations thereof.
  • Bioadhesives including fibrin; fibroin; Mytilus edulis foot protein (mefpi , "mussel adhesive protein”); other mussel's adhesive proteins; proteins and peptides with glycine-rich blocks; proteins and peptides with poly-alanine blocks; and silks.
  • Cell Attachment Factors biological molecules that mediate attachment and spreading of cells onto biological surfaces or other cells and tissues
  • molecules participating in cell-matrix and cell-cell interaction during vertebrate development, neogenesis, regeneration and repair such as molecules on the outer surface of cells like the CD class of receptors on white blood cells, immunoglobulins and haemagglutinating proteins, and extracellular matrix molecules/ligands that adhere to such cellular molecules, ankyrins; cadherins (Calcium dependent adhesion molecules); connexins; dermatan sulfate; entactin; fibrin; fibronectin; glycolipids; glycophorin; glycoproteins; heparan sulfate; heparin sulfate; hyaluronic acid; immunoglobulins; keratan sulfate; integrins; laminins; N-CAMs (Calcium independent Adhesive Molecules); proteoglycans
  • Biopolymers including parts of the extracellular matrix which participate in providing tissue resilience, strength, rigidity, integrity, such as alginates; amelogenins; cellulose; chitosan; collagen; gelatins; oligosaccharides; and pectin.
  • Blood proteins dissolved or aggregated proteins which normally are present whole blood, which participate in a wide range of biological processes like inflammation, homing of cells, clotting, cell signaling, defence, immune reactions, and metabolism
  • albumin albumen
  • cytokines factor IX; factor V; factor VII; factor VIII; factor X; factor Xl; factor XII; factor XIII; hemoglobins (with or without iron); immunoglobulins (antibodies); fibrin; platelet derived growth factors (PDGFs); plasminogen; thrombospondin; and transferrin.
  • Enzymes any protein or peptide that has a specific catalytic effect on one or more biological substrates, and which are potentially useful for triggering biological responses in the tissue by degradation of matrix molecules, or to activate or release other bioactive compounds in the implant coating
  • Abzymes antibodies with enzymatic capacity
  • adenylate cyclase alkaline phosphatase; carboxylases; collagenases; cyclooxygenase; hydrolases; isomerases; ligases; lyases; metallo-matrix proteases (MMPs); nucleases; oxidoreductases; peptidases; peptide hydrolase; peptidyl transferase; phospholipase; proteases; sucrase-isomaltase; TIMPs; and transferases.
  • Extracellular Matrix Proteins and non-proteins including ameloblastin; amelin; amelogenins; collagens (I to XII); dentin-sialo-protein (DSP); dentin-sialo-phospho-protein (DSPP); elastins; enamelin; fibrins; fibronectins; keratins (1 to 20); laminins; tuftelin; carbohydrates; chondroitin sulphate; heparan sulphate; heparin sulphate; hyaluronic acid; lipids and fatty acids; and lipopolysaccarides.
  • Growth Factors and Hormones molecules that bind to cellular surface structures (receptors) and generate a signal in the target cell to start a specific biological process, such as growth, programmed cell death, release of other molecules (e.g.
  • Activins Activins
  • Amphiregulin AR
  • Angiopoietins Ang 1 to 4
  • Apo3 a weak apoptosis inducer also known as TWEAK, DR3, WSL-1 , TRAMP or LARD
  • Betacellulin BTC
  • Basic Fibroblast Growth Factor bFGF, FGF-b
  • Acidic Fibroblast Growth Factor aFGF, FGF-a
  • 4-1 BB Ligand Brain-derived Neurotrophic Factor (BDNF); Breast and Kidney derived Bolokine (BRAK); Bone Morphogenic Proteins (BMPs); B-Lymphocyte Chemoattractant/B cell Attracting Chemokine 1 (BLC/BCA-1); CD27L (CD27 ligand); CD30L (CD30 ligand); CD40L (CD40 ligand); A Proliferation-inducing Ligand (APRIL); Cardiotrophin-1 (CT)
  • DNA Nucleic Acids including A-DNA; B-DNA; artificial chromosomes carrying mammalian DNA (YACs); chromosomal DNA; circular DNA; cosmids carrying mammalian DNA; DNA; Double-stranded DNA (dsDNA); genomic DNA; hemi-methylated DNA; linear DNA; mammalian cDNA (complimentary DNA; DNA copy of RNA); mammalian DNA; methylated DNA; mitochondrial DNA; phages carrying mammalian DNA; phagemids carrying mammalian DNA; plasmids carrying mammalian DNA; plastids carrying mammalian DNA; recombinant DNA; restriction fragments of mammalian DNA; retroposons carrying mammalian DNA; single-stranded DNA (ssDNA); transposons carrying mammalian DNA; T- DNA; viruses carrying mammalian DNA; and Z-DNA.
  • YACs artificial chromosomes carrying mammalian DNA
  • chromosomal DNA circular DNA;
  • RNA Nucleic Acids including Acetylated transfer RNA (activated tRNA, charged tRNA); circular RNA; linear RNA; mammalian heterogeneous nuclear RNA (hnRNA), mammalian messenger RNA (mRNA); mammalian RNA; mammalian ribosomal RNA (rRNA); mammalian transport RNA (tRNA); mRNA; polyadenylated RNA; ribosomal RNA (rRNA); recombinant RNA; retroposons carrying mammalian RNA; ribozymes; transport
  • hnRNA mammalian heterogeneous nuclear RNA
  • mRNA mammalian messenger RNA
  • rRNA mammalian ribosomal RNA
  • tRNA mammalian transport RNA
  • mRNA polyadenylated RNA
  • ribosomal RNA recombinant RNA
  • retroposons carrying mammalian RNA ribozymes
  • RNA RNA
  • viruses carrying mammalian RNA viruses carrying mammalian RNA
  • siRNA short inhibitory RNA
  • Receptors cell surface biomolecules that bind signals (such as hormone ligands and growth factors, and transmit the signal over the cell membrane and into the internal machinery of cells) including, the CD class of receptors CD; EGF receptors; FGF receptors;
  • VLA-5 Fibronectin receptor
  • IGFBP 1 to 4 IGF Binding Proteins
  • lntegrins including VLA 1-4
  • Laminin receptor PDGF receptors
  • Synthetic Biomolecules such as molecules that are based on, or mimic, naturally occurring biomolecules.
  • Synthetic DNA including A-DNA; antisense DNA; B-DNA; complimentary DNA
  • cDNA chemically modified DNA; chemically stabilized DNA; DNA; DNA analogues ; DNA oligomers; DNA polymers; DNA-RNA hybrids; double-stranded DNA (dsDNA); hemi- methylated DNA; methylated DNA; single-stranded DNA (ssDNA); recombinant DNA; triplex
  • Synthetic RNA including antisense RNA; chemically modified RNA; chemically stabilized RNA; heterogeneous nuclear RNA (hnRNA); messenger RNA (mRNA); ribozymes; RNA; RNA analogues; RNA-DNA hybrids; RNA oligomers; RNA polymers; ribosomal RNA (rRNA); transport RNA (tRNA); and short inhibitory RNA (siRNA).
  • Synthetic Biopolymers including cationic and anionic liposomes; cellulose acetate; hyaluronic acid; polylactic acid; polyglycol alginate; polyglycolic acid; poly-prolines; and polysaccharides.
  • Synthetic Peptides including decapeptides comprising DOPA and/or diDOPA; peptides with sequence "Ala Lys Pro Ser Tyr Pro Pro Thr Tyr Lys" (SEQ ID NO:2); peptides where a Pro is substituted with hydroxyproline; peptides where one or more Pro is substituted with DOPA; peptides where one or more Pro is substituted with di-DOPA; peptides where one or more Tyr is substituted with DOPA; peptide hormones; peptide sequences based on the above listed extracted proteins; and peptides comprising an RGD
  • Recombinant Proteins including all recombinantly prepared peptides and proteins.
  • Synthetic Enzyme Inhibitors including metal ions, that block enzyme activity by binding directly to the enzyme, molecules that mimic the natural substrate of an enzyme and thus compete with the principle substrate, pepstatin; poly-prolines; D-sugars; D-aminocaids;
  • Vitamins Synthetic or Extracted
  • biotin including biotin; calciferol (Vitamin D's; vital for bone mineralisation); citrin; folic acid; niacin; nicotinamide; nicotinamide adenine dinucleotide (NAD, NAD+); nicotinamide adenine dinucleotide phosphate (NADP, NADPH); retinoic acid (vitamin A); riboflavin; vitamin B's; vitamin C (vital for collagen synthesis); vitamin E; and vitamin K's.
  • Bioactive Molecules including adenosine di-phosphate (ADP); adenosine monophosphate (AMP); adenosine tri-phosphate (ATP); amino acids; cyclic AMP (cAMP); 3,4-dihydroxyphenylalanine (DOPA); 5'-di(dihydroxyphenyl-L-alanine (diDOPA); diDOPA quinone; DOPA-like o-diphenols; fatty acids; glucose; hydroxyproline; nucleosides; nucleotides (RNA and DNA bases); prostaglandin; sugars; sphingosine 1 -phosphate; rapamycin; synthetic sex hormones such as estrogen, progesterone or testosterone analogues, e.g.
  • Tamoxifene such as Raloxifene
  • bis-phosphonates such as alendronate, risendronate and etidronate
  • statins such as cerivastatin, lovastatin, simvaststin, pravastatin, fluvastatin, atorvastatin and sodium 3,5- dihydroxy-7-[3-(4-fluorophenyl)-1-(methylethyl)-1 H-indol-2-yl]-hept-6- -enoate, drugs for improving local resistance against invading microbes, local pain control, local inhibition of prostaglandin synthesis; local inflammation regulation, local induction of biomineralisation and local stimulation of tissue growth, antibiotics; cyclooxygenase inhibitors; hormones; inflammation inhibitors; NSAID's (non-steroid antiinflammatory agents); painkillers; prostaglandin synthesis inhibitors; steroids, and tetracycline (also as biomineralizing agent).
  • SERMs estrogen receptor
  • Bioly Active Ions including ions which locally stimulate biological processes like enzyme function, enzyme blocking, cellular uptake of biomolecules, homing of specific cells, biomineralization, apoptosis, cellular secretion of biomolecules, cellular metabolism and cellular defense, such as calcium; chromium; copper; fluoride; gold; iodide; iron; potassium; magnesium; manganese; selenium; sulphur; stannum (tin); silver; sodium; zinc; nitrate; nitrite; phosphate; chloride; sulphate; carbonate; carboxyl; and oxide.
  • Marker Biomolecules (which generate a detectable signal, e.g.
  • radiolabeled peptides and proteins radiolabeled DNA and RNA; immuno-gold complexes (gold particles with antibodies attached); immuno- silver complexes; immuno-magnetite complexes; Green Fluorescent protein (GFP); Red Fluorescent Protein (E5); biotinylated proteins and peptides; biotinylated nucleic acids; biotinylated antibodies; biotinylated carbon-linkers; reporter genes (any gene that generates a signal when expressed); propidium iodide; and diamidino yellow.
  • GFP Green Fluorescent protein
  • E5 Red Fluorescent Protein
  • the biofunctionally-coated biomaterials of the present invention can be used for a number of purposes.
  • purposes include use for: inducing local hard tissue (e.g. bone tissue) formation at the implantation site; controlling microbial growth and/or invasion at the implantation site or systemically; reducing inflammation at the implantation site or systemically; stimulating ligament repair, regeneration or formation; inducing cartilage formation; nucleating, controlling and/or templating biomineralization; improving attachment between implants and tissues; improving osseointegration of implants; improving tissue adherence to an implant; hindering tissue adherence to an (semipermanent or temporary) implant; improving contact between tissues or tissues and implants, improving tissue sealing of a (surgical) wound; inducing apoptosis (cell death) in unwanted cells (e.g.
  • local hard tissue e.g. bone tissue
  • controlling microbial growth and/or invasion at the implantation site or systemically reducing inflammation at the implantation site or systemically
  • stimulating ligament repair, regeneration or formation inducing cartilage
  • cancer cells inducing specific cell differentiation and/or maturation, increasing tissue tensile strength; improving wound healing; speeding up wound healing; templating tissue formation; guiding tissue formation; local gene therapy; stimulating nerve growth; improving vascularisation in tissues adjacent to an implant; stimulating local extracellular matrix synthesis; inhibiting local extracellular matrix breakdown; inducing local growth factor release; increasing local tissue metabolism; improving function of a tissue or body-part; reducing local pain and discomfort.
  • the purpose will depend on the type of medical device or implant as well as the nature and/or concentration of the biomolecule present in the biofunctionalized polymer thereon.
  • biomolecules for use in the biofunctionalized polymers of the present invention include for example biomolecules which stimulate bone healing, such as TGFs, BMPs, amelogenin, and ameloblastic biomolecules which stimulate wound healing, such as VEGFs, PDGF, HGF, KGF, and FGF; biomolecules which stimulate mineral deposition, such as ameloblastic poly-prolines, and collagens; biomolecules which stimulate cell attachment, such as extracellular matrix, CD molecules, integrins, and RGD-peptides; biomolecules which stimulate bone attachment, such as extracellular matrix, CD molecules, integrins, and RGD-peptides; biomolecules which stimulate cell proliferation, such as growth factors; biomolecules which stimulate osteoblastic cell proliferation, such as BMP, TGF, IL-6, osteocalcin, osteoprotegrin, BSP, and cytokines; biomolecules which stimulate cell differentiation, such as amelogenin, and growth factors; and biomolecules which stimulate osteoblastic cell
  • the amount of biomolecule present on or in the biofunctionalized polymer layer of the implant may vary within wide limits, e.g. dependent on the chemical and biological characteristics of the biomolecule substance or substances in question.
  • the biomolecule of the biofunctionalized polymer layer may be present in amounts ranging, for example, from as low from 1 picogram per mm 2 to as high as 100 mg per mm 2 of coated implant surface. However, it is contemplated that most useful biomolecule concentrations will range from 0.1 nanogram to 100 microgram per mm 2 .
  • Other peptides which may comprise the biomolecules which are attached to the functionalized polymers of the present invention include, but are not limited to, those described in U.S. Patent Nos. 6,262,017 and 6,280,760.
  • the present invention more broadly contemplates in one embodiment a process for the production of a functionalized polymer comprising single polymer chains or crosslinked polymer chains, wherein each copolymer chain comprises a sulfhydryl binding group which allows interaction of the polymer chain with a biomolecule as defined herein, comprising, in one embodiment, the steps of: a) use of a radical polymerization initiator molecules, b) initiating polymerization reactions with (a) a first set of identical or non-identical monomers, each of which comprises (1) at least one sulfhydryl binding group which interacts with a biomolecule and (2) at least one C-C double bond, and (b) a monomer containing at least one C-C double bond, and then c) growing copolymer chains from said initiated polymer in the presence of said set of monomers and said monomer by a radical polymerization chain reaction involving reaction of the C-C double bond of said set of monomers and said comonomer; thereby growing of the functional
  • the initiator molecule preferably comprises a group chosen from azo groups, peroxo groups, or a ketone group in conjugation with an aromatic system.
  • the polymers of the present invention can be produced from a wide variety of monomeric units, either as homopolymers or copolymers.
  • monomers which can be used herein include but are not limited to hydroxyethyl methacrylate, acrylates, acrylamide, N-isopropylacrylamide, dimethyl acrylamide, and vinyl pyrrolidone. It is also possible to use monomers that yield at first water insoluble polymers which can then be transferred to water soluble derivatives.
  • a suitable example for this group of polymers is polyvinyl alcohol which can be obtained, for example, by saponification of polyvinyl acetate.
  • the following compounds can be employed for the purposes of the present invention: acrylic or methacrylic acid N-hydroxysuccinimides, N-methacryloyl-6-aminopropanoic acid hydroxysuccinimide ester, N-methacryloyl-6-aminocapronic acid hydroxysuccinimide ester or acrylic or methacryl acid glycidyl esters.
  • alkyl acrylates and alkyl methacrylates include for example: alkyl acrylates and alkyl methacrylates; hydroxyalkyl acrylates and hydroxyalkyl methacrylates, for example, hydroxyethyl acrylate, hydroxypropyl acrylate, and hydroxybutyl methacrylate; epoxy acrylates and epoxy methacrylates, such as, for example, glycidyl methacrylate; amino alkyl acrylates and amino alkyl methacrylates and monomers containing active methylene groups, such as, for example, acetoacetoxyethylacrylate and methacrylate; N- vinyl compounds, such as, for example, N-vinyl pyrrolidone, N-vinyl carbazole, N-vinyl acetamide, and N-vinyl succinimide; amino styrenes; polyvinyl alcohols and polyvinyl amines, which must be made from suitable polymeric precursors; acrylamide
  • Polymers which may be formed herein include functionalized and biofunctionalized versions of, for example, brominated polystyrene, polyacrylic acid, polyacrylonitrile, polyamide, polyacrylamide, polyethylene oxide, and poly(N-isopropylacrylamide), poly(N- isopropylacrylamide), polyacrolein, polybutadiene, polycaprolactone, polycarbonate, polyester, polyethylene, polyethylene terephthalate, polydimethylsiloxane, polyisoprene, polyurethane, polyvinylacetate, polyvinylchloride, polyvinylpyridine, polyvinylbenzylchloride, polyvinyltoluene, polyvinylidene chloride, polydivinylbenzene, polymethylmethacrylate, polylactide, polyglycolide, poly(lactide-co-glycolide), polyanhydride, polyorthoester, polyphosphazene, polyphosophaze
  • Combination polymers include for example poly-(styrene-co-vinylbenzyl chloride-co-acrylic acid) (85:10:5 molar ratio), poly(styrene-co-acrylic acid) (99:1 molar ratio), poly(styrene-co- methacrylic acid) (90:10 molar ratio), poly(styrene-co-acrylic acid-co-m&p-divinylbenzene) (89:10:1 molar ratio), poly-(styrene-co-2-carboxyethyl acrylate) (90:10 molar ratio), poly(methyl methacrylate-co-acrylic acid) (70:30 molar ratio) and poly(styrene-co-butyl aery late-co-methacry lie acid)(45:45: 10 weight ratio).
  • poly-(styrene-co-vinylbenzyl chloride-co-acrylic acid) 85:10
  • suitable polymers may either be regular homopolymers containing substantially no other material in their matrices (other than the sulfhydryl binding unit), or they may be copolymers prepared from two or more appropriate monomers. In certain instances, this type of tailoring of the copolymers with various monomers may enhance the desirable properties of the functionalized polymer support material.
  • hydrogel is utilized herein to describe a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are very absorbent natural or synthetic polymers, and may contain over 99% water. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content.
  • the term "effective amount” refers to an amount of a functionalized polymer or biofunctionalized polymer, or biomolecule thereon, sufficient to exhibit a detectable therapeutic or prophylactic effect without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of the invention.
  • the present invention is directed, in one embodiment, to the use of N-[2-(2- Pyridyldithiol)] ethyl methacrylamide (PDTEMA) as functional groups in a polymerization reaction to incorporate sulfhydryl binding sites into hydrogels or various monomer or polymer groups.
  • PDTEMA or other pyridyldithioacrylates (or methacrylates) or pyridyldithioacrylamides (or methacrylamides) contemplated herein
  • PDTEMA or other pyridyldithioacrylates (or methacrylates) or pyridyldithioacrylamides (or methacrylamides) contemplated herein
  • PDTEMA or other pyridyldithioacrylates (or methacrylates) or pyridyldithioacrylamides (or methacrylamides) contemplated herein
  • acrylamide is used as the polymer repeat unit. Polymerization is initiated with azobisisobutyronitrile (AIBN), although other initiator reagents or ultra-violet light could be used. In this fashion, most any polymer may be coupled to PDTEMA (or other functional moiety contemplated herein).
  • AIBN azobisisobutyronitrile
  • PDTEMA (or other pyridyldithiomethacrylat.es or acrylates or pyridyldithiomethacrylamides or acrylamides contemplated herein) reacts via disulfide bonding and therefore exhibits reactive specificity with sulfur-containing compounds (thiols); in biological setting, often the amino acid cysteine.
  • PDTEMA (or other pyridyldithiomethacrylates or acrylates or pyridyldithiomethacrylamides or acrylamides contemplated herein) may therefore be used to couple various polymer groups (e.g., as shown elsewhere herein) to cysteine-containing polypeptides or proteins.
  • bioactive polypeptides or other biomolecules contemplated herein
  • functionalized polymer which includes PDTEMA (or other pyridyldithiomethacrylates or acrylates or pyridyldithiomethacrylamides or acrylamides contemplated herein) thereby forming biofunctionalized polymers.
  • PDTEMA pyridyldithiomethacrylates or acrylates or pyridyldithiomethacrylamides or acrylamides contemplated herein
  • thiol-containing compounds or biomolecules means that reactions may be carried out with a decreased risk of side-products and undesired reactions.
  • this technology lends itself to uses in attachment of virtually any cysteine (or sulfhydryl-group) containing peptide or protein (or other biomolecule) to a wide ambit of polymers and monomers of non-biological origin.
  • the functionalized polymer of the present invention preferably comprises a copolymer constructed of repeating units of one or more types of monomers as described herein which are intermixed with a plurality of sulfhydryl binding monomers comprising a pyridyldithioacrylate unit (e.g., Compound I, Fig. 1) or pyridyldithioacrylamide unit (e.g., Compound II, Fig. 1 ).
  • a pyridyldithioacrylate unit e.g., Compound I, Fig. 1
  • pyridyldithioacrylamide unit e.g., Compound II, Fig. 1
  • Compound I of Fig. 1 comprises the pyridyldithioacrylate backbone having an R 1 group comprising a 2-pyridine (see Compound III, Fig. 1), a 3-pyridine (see Compound IV, Fig. 1), or a 4-pyridine (see Compound V, Fig. 1).
  • the Compound I further comprises an R 2 group which may be an alkyl chain having one to 12 carbon atoms, or may be an alkoxyalkyl chain having one to 12 carbon atoms and one to four oxygen atoms, or may be hydroxyalkyl chain having one to 12 carbon atoms and one to four hydroxy groups.
  • Compound I of Fig. 1 comprises the pyridyldithioacrylate backbone having an R 1 group comprising a 2-pyridine (see Compound III, Fig. 1), a 3-pyridine (see Compound IV, Fig. 1), or a 4-pyridine (see Compound V, Fig. 1).
  • the Compound I further comprises an R
  • Compound Il of Fig. 1 comprises the pyridyldithioacrylamide backbone having an R 1 group comprising a 2-pyridine (see Compound Vl, Fig. 1), a 3-pyridine (see Compound VII, Fig. 1), or a 4-pyridine (see Compound VIII, Fig. 1).
  • the Compound Il further comprises an R 2 group which may be an alkyl chain having one to 12 carbon atoms, or may be an alkoxyalkyl chain having one to 12 carbon atoms and one to four oxygen atoms, or may be hydroxyalkyl chain having one to 12 carbon atoms and one to four hydroxy groups.
  • R 2 group which may be an alkyl chain having one to 12 carbon atoms, or may be an alkoxyalkyl chain having one to 12 carbon atoms and one to four oxygen atoms, or may be hydroxyalkyl chain having one to 12 carbon atoms and one to four hydroxy groups.
  • Compound Il of Fig. 1 further comprises an R 3 group which may be an H, methyl, ethyl, propyl or isopropyl group.
  • R 4 group attached to the nitrogen atom.
  • R 4 may be H, methyl, ethyl, propyl or isopropyl or may comprise an alkoxyalkyl chain comprising one to six carbon atoms and one to two oxygen atoms, or may comprise a hydroxyalkyl chain comprising one to six carbon atoms and one to two hydroxy groups.
  • the R 1 group is 2-pyridyl or 4-pyridyl
  • R 2 is methyl, ethyl or propyl
  • R 3 is methyl, ethyl or propyl
  • R 4 is H, methyl, ethyl, or propyl.
  • the mole % of functionalizing monomermole % of primary monomer ratio is 0.1 to 15.
  • the biofunctionalized polymer or functionalized polymer contemplated herein can be attached to the surface of the device or implant by any method known in the art for attaching polymeric materials to implant surfaces.
  • the functionalized or biofunctionalized polymer can be attached via cyanoacrylate adhesives, such as methyl 2-cyanoacrylate, ethyl 2-cyanoacrylate, methyl ⁇ -cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, and octylcyanoacrylate.
  • cyanoacrylate adhesives are shown for example in U.S. Patents 2,768,109; 2,776,232, and 2,749,788. Cyanoacrylate glues are commercially known and available as Super Glue TM and Krazy Glue TM.
  • the functionalized polymer or biofunctionalized polymer can be attached to the surface of the biomaterial by introducing charged species (radicals and ions) to the surfaces which allows for subsequent chemical reactions.
  • charged species Radicals and ions
  • the polymer may be altered by exposure to ultraviolet radiation, photolithographic techniques may use conventional UV radiation from a mercury vapor lamp with an emission spectrum in the near- UV wavelength range. Poly(methyl methacrylate) can be for example used, as can derivatives thereof.
  • the carbonyl groups absorb at 215 nm, and this leads to chain scission and degradation. This provides the radical species necessary to undergo free radical reactions with acrylate or vinyl groups.
  • the biofunctionalized monomers (functionalized with biomolecules, such as RGD or other peptides) creates a biofunctional surface on the biomaterial. Examples of plasma coating and other methods involving application of polymers to implant surfaces are shown in U.S. Patent No. 6,939,376 and other U.S. patents cited therein.
  • the functionalized or biofunctionalized polymer may be attached to the surface of the biomaterial for example by the method shown in U.S. Patent No. 6,319,674.
  • the functionalized polymer or biofunctionalized polymer of the present invention also may be attached to the implant of the present invention by disposing the polymerization mixture of the present invention, as contemplated elsewhere herein, upon the outer surface of the implant such that polymerization and crosslinking ocurs upon the surface wherein the functionalized polymer or biofunctionalized polymer which is produced is formed directly upon the implant surface and thus adhered directly thereto.
  • a functionalized copolymer was produced by the copolymerization of PDTEMA monomer with acrylamide monomer.
  • the functionalized copolymer becomes biofunctionalized by a disulfide transfer reaction with a peptide arg-gly-asp-cys (“RGDC”) (SEQ ID NO:1) wherein the thiol group of the cys of the RGDC peptide is conjugated to a sulfur of the PDTEMA group of the copolymer, releasing thiopyridine and providing a biofunctionalized polyacrylamide gel.
  • RGDC peptide arg-gly-asp-cys
  • Deuterated water (D 2 O, 99%) was purchased from Cambridge Isotope Laboratories, Inc. and used as received. [0078] Instrumentation. NMR (Nuclear Magnetic Resonance) measurements were performed on a Varian 300 MHz instrument, and the signals referenced to that of D 2 O (at 4.80 ppm).
  • the resulting thin film was mostly white with a small amount of a yellow solid present.
  • the film was dissolved in D 2 O with constant aggravation for 3 A hr. 1 H NMR spectroscopic analysis of the clear, viscous solution revealed peaks for PDTEMA (ca. 2% abundant relative to NiPAAm) and pNiPAAm.
  • Fig. 3 Shown in Fig. 3 is a proton NMR spectrum which demonstrates the attachment of the RGDC peptides to the polyacrylamide hydrogel.
  • the biofunctionalized polyacrylamide hydrogel was produced by first combining PDTEMA and RGDC peptides to form RGDC-PDTEMA in a disulfide transfer reaction. This functionalized moiety is then combined with an acrylamide in a polymerization reaction to form the biofunctionalized polyacrylamide hydrogel as first described above. [0086] Reagents.
  • Acrylamide (AAm), N-isopropylacrylamide (NiPAAm), N,N'-methylene bisacrylamide (BIS), N,N,N',N'-tetramethylethylenediamine (TEMED), ammonium persulfate (APS) and riboflavin 5'-phosphate were purchased from Aldrich (Milwaukee) and used as received.
  • RGD peptides were obtained from GenScript (Scotch Plains, NJ) and used as received
  • Deuterium Oxide (D 2 O) was obtained from Cambridge Isotopes Laboratories. [0087] Hydrogel Synthesis.
  • Hydrogels were produced by either UV photopolymerization (TEMED and riboflavin) or chemical polymerization (TEMED and APS) of the monomer (acrylamide or N-isopropylacrylamide) and BIS crosslinker. Samples were washed by heating the gel above the LCST, where excess water and unreacted monomers are expelled. This liquid was removed and replaced with double distilled water. NMR samples were prepared by taking a small portion of the gel to occupy the 60 ⁇ L volume of the HRMAS rotor. Heating above LCST aids the transfer of the gel into the rotor. D 2 O is added to rehydrate the sample.
  • UV photopolymerization TEMED and riboflavin
  • TEMED and APS chemical polymerization
  • the pyridyldithioacrylate or pyridyldithioacrylamide functional (sulfhydryl binding) moieties may be attached to an polyacrylate or polyacrylamide polymer or copolymer after the polymer or copolymer has been formed.
  • the pyridyldithio functional group is thus not combined with the primary monomer of the polymer in a polymerization reaction.
  • the disulfide transfer reaction between the pyridyldithio group and the biomolecule may occur after the pyridyldithio group is attached to the polymer, or before the pyridyldithio group, with biomolecule attached thereto, is attached to the polymer.

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Abstract

La présente invention concerne des compositions de revêtement et des procédés pour leur utilisation, et les objets revêtus avec celles-ci, pour leur utilisation comme implants et dispositifs médicaux. En particulier, les dispositifs médicaux et les implants de la présente invention comprennent des biomatériaux qui sont revêtus avec des polymères fonctionnalisés ayant des biomolécules conjuguées à ceux-ci, ou avec les polymères fonctionnalisés auxquels de telles biomolécules peuvent être conjuguées pour former le polymère biofonctionnalisé. Les biomolécules fixées aux polymères fonctionnalisés envisagés ici peuvent être définies comme étant des composés chimiques naturels ou synthétiques qui possèdent une capacité à se lier de manière covalente au groupe fonctionnel sur le polymère fonctionnalisé ou un espaceur sur celui-ci, de préférence par l'intermédiaire d'un groupe sulfhydryle sur celui-ci. Les polymères fonctionnalisés ou biofonctionnalisés de la présente invention peuvent comprendre des molécules d'espaceur qui sont liées de manière covalente via des liaisons sulfhydryle aux groupes fonctionnels de ceux-ci pour liaison aux biomolécules des polymères biofonctionnalisés.
PCT/US2008/073737 2007-08-20 2008-08-20 Dispositif médical avec revêtement polymère biofonctionnalisé Ceased WO2009026380A1 (fr)

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Cited By (7)

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DE102009011991A1 (de) * 2009-03-05 2010-09-09 Peter Hildebrandt Chirurgisches Implantat mit einem Träger in flächiger Form
US20140271771A1 (en) * 2013-03-14 2014-09-18 Biotronik Ag Implantable object comprising selectively degradable copolymers for improved explantability
KR101659697B1 (ko) * 2015-10-02 2016-09-23 경희대학교 산학협력단 의료용 임플란트 및 그의 제조방법
CN107337940A (zh) * 2017-06-28 2017-11-10 常州文诺纺织品有限公司 一种钛白粉悬浮稳定剂的制备方法
WO2019115814A1 (fr) * 2017-12-15 2019-06-20 Cambridge Enterprise Limited Substrats cellulaires ajustables
CN112451748A (zh) * 2020-11-25 2021-03-09 西北有色金属研究院 一种制备丝素蛋白基双金属抗菌涂层的方法
WO2024040169A3 (fr) * 2022-08-18 2024-04-18 The University Of Chicago Procédés et compositions pour le traitement du cancer avec des adjuvants se liant au cancer

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US20030044408A1 (en) * 2001-06-15 2003-03-06 The Children's Hospital Of Philadelphia Surface modification for improving biocompatibility
US20050124724A1 (en) * 2003-12-05 2005-06-09 3M Innovative Properties Company Polymer compositions with bioactive agent, medical articles, and methods
US7087149B1 (en) * 1999-04-15 2006-08-08 Katayanagi Institute Biosensor

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Publication number Priority date Publication date Assignee Title
US5407581A (en) * 1992-03-17 1995-04-18 Asahi Medical Co., Ltd. Filter medium having a limited surface negative charge for treating a blood material
US7087149B1 (en) * 1999-04-15 2006-08-08 Katayanagi Institute Biosensor
US20030044408A1 (en) * 2001-06-15 2003-03-06 The Children's Hospital Of Philadelphia Surface modification for improving biocompatibility
US20050124724A1 (en) * 2003-12-05 2005-06-09 3M Innovative Properties Company Polymer compositions with bioactive agent, medical articles, and methods

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009011991A1 (de) * 2009-03-05 2010-09-09 Peter Hildebrandt Chirurgisches Implantat mit einem Träger in flächiger Form
US20140271771A1 (en) * 2013-03-14 2014-09-18 Biotronik Ag Implantable object comprising selectively degradable copolymers for improved explantability
KR101659697B1 (ko) * 2015-10-02 2016-09-23 경희대학교 산학협력단 의료용 임플란트 및 그의 제조방법
CN107337940A (zh) * 2017-06-28 2017-11-10 常州文诺纺织品有限公司 一种钛白粉悬浮稳定剂的制备方法
CN107337940B (zh) * 2017-06-28 2018-10-02 上海深竹化工科技有限公司 一种钛白粉悬浮稳定剂的制备方法
WO2019115814A1 (fr) * 2017-12-15 2019-06-20 Cambridge Enterprise Limited Substrats cellulaires ajustables
US12378341B2 (en) 2017-12-15 2025-08-05 Cambridge Enterprise Limited Tuneable cell substrates
CN112451748A (zh) * 2020-11-25 2021-03-09 西北有色金属研究院 一种制备丝素蛋白基双金属抗菌涂层的方法
CN112451748B (zh) * 2020-11-25 2022-09-20 西北有色金属研究院 一种制备丝素蛋白基双金属抗菌涂层的方法
WO2024040169A3 (fr) * 2022-08-18 2024-04-18 The University Of Chicago Procédés et compositions pour le traitement du cancer avec des adjuvants se liant au cancer

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