WO2002082973A2 - Biomateriaux osteotropes, leurs methodes d'utilisation et systemes d'implant comportant de tels composes - Google Patents

Biomateriaux osteotropes, leurs methodes d'utilisation et systemes d'implant comportant de tels composes Download PDF

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WO2002082973A2
WO2002082973A2 PCT/US2002/011519 US0211519W WO02082973A2 WO 2002082973 A2 WO2002082973 A2 WO 2002082973A2 US 0211519 W US0211519 W US 0211519W WO 02082973 A2 WO02082973 A2 WO 02082973A2
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group
scaffold
osteotropic
poly
bone
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PCT/US2002/011519
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WO2002082973A3 (fr
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Kyumin Whang
Neera Satsangi
Barry K. Norling
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Board Of Regents, The University Of Texas System
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Publication of WO2002082973A3 publication Critical patent/WO2002082973A3/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3821Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A61L27/3843Connective tissue
    • A61L27/3847Bones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41Anti-inflammatory agents, e.g. NSAIDs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602Type of release, e.g. controlled, sustained, slow
    • A61L2300/604Biodegradation

Definitions

  • the present invention concerns compounds, materials, systems and methods for stimulating the production of bone growth in a subject in need thereof.
  • Statins Science 286, 1946-1949 (1999), describes the stimulation of bone formation by statins in vitro and in vivo. Particular delivery systems are neither suggested nor described.
  • Patent No. 6,080,779 describes, among other things, a variety of different statin analogs that have activity in enhancing bone.
  • a variety of different delivery techniques are described, and the patent states that "for local administration, the delivery vehicle preferably provides a matrix for the growing bone or cartilage, and more preferably is a vehicle that can be absorbed by the subject without adverse effects.” (Column 6, lines 48-52).
  • the polymers include poly (lactic acid), poly (glycolic acid), and copolymers thereof (page 8, lines 15-20).
  • the conjugation linkage is described as being, among other things, an ester or amide bond (page 9, lines 3-7).
  • the conjugation technique is described as being the coupling of the active molecule to a carboxyl or hydroxyl group in the polymer (page 14 line 25 to page 15 line 9).
  • Drugs to be coupled are, in general, peptides or therapeutic agents (page 6, lines 4-21).
  • the compositions are described as being formed into microspheres, nanoparticles or films (page 10, lines 13-15). Techniques for bone implantation and treatment are neither suggested nor described.
  • a first aspect of the present invention is an osteoinductive protein synthesizing implant system.
  • the system comprises a porous scaffold or support structure, the porous scaffold formed from (i) a biodegradable polymer in combination with (ii) a 3- hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor.
  • Bone cells e.g., bone marrow cells
  • the HMG Co-A reductase inhibitor included in the scaffold in an amount effective to stimulate the formation of bone tissue from the bone cells (e.g., when the scaffold is implanted in a subject as described below).
  • the HMG Co-A reductase inhibitor is included in the scaffold in an amount effective to stimulate the production of bone morphogenetic protein-2 (BMP-2) from the bone cells, which in turn stimulates the formation of bone tissue from the bone cells.
  • BMP-2 bone morphogenetic protein-2
  • the HMG Co-A reductase inliibitor is covalently coupled to the biodegradable polymer (as described in greater detail below).
  • Such covalent coupling of the HMG Co-A reductase inhibitor to the biodegradable polymer advantageously serves to control the release of the HMG Co-A reductase inhibitor to the bone cells within the scaffold.
  • a second aspect of the present invention is a method of stimulating bone growth in a subject in need of such treatment, comprising implanting an implant system as described above into the subject (e.g., in, on or adjacent a broken bone or a bone or region requiring the growth of bone tissue).
  • a third aspect of the present invention is an implantable porous scaffold formed from an osteotropic compound of the Formula:
  • P is a biodegradable polymer (preferably a polyester polymer);
  • L is a linking group;
  • S is an osteotropic group, and preferably an osteotropic group according to Formula I or Formula II:
  • X in each of formulas (I) and (II) represents an alkylene, alkenylene, or alkynylene linker
  • Y represents one or more carbocyclic or heterocyclic rings wherein, when Y comprises two or more rings, the rings may be fused
  • R' represents a cation, H or a substituted or unsubstituted alkyl group
  • the dotted lines represent optional ⁇ bonds.
  • a still further aspect of the present invention is an osteotropic compound of the Formula:
  • P is a biodegradable polymer (preferably a polyester polymer such as poly(lactic acid), poly(glycolic acid), or copolymer thereof);
  • L is a linking group; and
  • S is an osteotropic group (preferably as described above).
  • Figure 1 shows a simplified schematic diagram of an illustrative osteogenic- poly(lactide) (PLG-STAT) synthesis.
  • FIG. 2 shows a UN spectra of simvastatin (Sim) dissolved in methanol (MeOH), simvastatin in methylene chloride (MC), simvastatin in Dulbecco's Modified Eagle's Media (DMEM), simvastatin and PLG in MC and Osteogenic-PLG (OG-PLG) in MC. All have simvastatin concentrations of 50 ⁇ g/mL.
  • Figure 3 shows a concentration curve for simvastatin in MeOH.
  • Figure 4 shows in vitro release curves of PLG + Simvastatin (4 mg/g PLG) and OG-PLG (100% w/w PLG). Note the quicker initial release and the more gradual continued release by OG-PLG.
  • Figure 5 shows an Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) spectrum of OG-PLG. Peaks to note are at 2958, 2919, 2851, and 1022 cm “1 .
  • ATR-FTIR Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy
  • Figure 6 shows H&E stained sections of clavarial cross-sectioned bone. Large arrow point to the position of films and the small arrows point to areas of new bone formation.
  • the present invention is intended for use on human subjects or patients, but may also be used on animal subjects (particularly dogs, cats, pigs, and other mammalian species) for veterinary purposes or for the purpose of medical product screening and development.
  • Biodegradable polymers e.g., biocompatible and bioabsorbable polymers
  • Biodegradable polymers that may be used to carry out the present invention include, but are not limited to, poly(hydroxybutyrate), polycarbonates, polyacrylates, polyanhydrides, poly(ortho esters), polytjphosphoesters), polyesters, polyamides (such as polyamides derived from D-glucose), polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, and copolymers thereof, erodable hydrogels, natural polymers such as collagen and chitosan, etc.. See, e.g., U.S. Patent No.
  • biodegradable polymers include, but are not limited to, aliphatic polyester polymers such as poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly (D,L- lactic-co-glycolic acid), poly(caprolactone), poly(valerolactone), poly(hydroxy butyrate) (inlcuding poly(hydroxy butyrate valerate)), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), etc., including copolymers thereof such as polylactic acid-polyethylene glycol block copolymer, and poly(ethyleneoxide)- poly(butylenetetraphthalate), poly(lactic acid-c ⁇ -lysine), etc..
  • aliphatic polyester polymers such as poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic
  • the molecular weight (that is, average molecular weight) of the polymer may be from 1,000, 10,000, 100,000 or 500,000 to 2,000,000 or 4,000,000 Daltons, or more. Currently, average molecular weights of about 1 ,000,000 Daltons are preferred.
  • HMG Co-A reductase inhibitors Any suitable HMG Co-A reductase inhibitor may be used to carry out the present invention (e.g., to form osteotropic groups on the compounds herein).
  • Any suitable HMG Co-A reductase inhibitor may be used to carry out the present invention (e.g., to form osteotropic groups on the compounds herein).
  • Numerous statins that are HMG Co-A reductase inhibitors are known; examples are disclosed, for example, in U.S. Patent No. 6,022,887 to Gasper et al, and in B. Roth et al., J Med. Chem. 34, 463-466 (1991). Examples of a variety of statins that may be used to carry out the present invention are provided in conjunction with the description of polymers below (where hydroxyl groups are removed from the statins and replaced with bonds to the linking groups).
  • statins that may be used to carry out the present invention include, but are not limited to, atorvastatin (Merck Index monograph number 897; 12 th Edition 1996), fluvastatin, (Merck Index monograph number 4250), lovastatin (Merck Index monograph number 5616), mevastatin (Merck Index monograph number 6251), pravastatin (Merck Index monograph number 7894 for pravastatin sodium), and simvastatin (Merck Index monograph number 8686).
  • atorvastatin Merck Index monograph number 897; 12 th Edition 1996)
  • fluvastatin (Merck Index monograph number 4250)
  • lovastatin Merck Index monograph number 5616
  • mevastatin Merck Index monograph number 6251
  • pravastatin Merck Index monograph number 7894 for pravastatin sodium
  • simvastatin Merck Index monograph number 8686.
  • compounds of the invention formed with statins as the osteotropic group or HMG Co-A reductase inhibitor are those in which S is an osteotropic group according to Formula I or Formula II:
  • X in each of formulas (I) and (II) represents an unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6 C;
  • Y represents one or more carbocyclic or heterocyclic rings wherein, when Y comprises two or more rings, said rings may be fused;
  • R' represents a cation, H or a substituted or unsubstituted alkyl group of 1-6 C; the dotted lines represent optional ⁇ bonds;
  • P is a polymer as described herein;
  • L is a linking group as described herein.
  • S is based upon mevastatin, lovastatin or simvastatin
  • S is an osteotropic group of the formula:
  • R is H or CH 3 and R 1 is H or CH 3 (for mevastatin R and R 1 are H, for lovastatin R is H and R 1 is CH 3 , and for simvastatin R is H and R 1 is CH 3 ).
  • S is based upon fluvastatin
  • S is an osteotropic group of the formula:
  • S is based upon pravastatin
  • S is an osteotropic group of the formula:
  • S is based upon pravastatin sodium
  • S is an osteotropic group of the formula:
  • S is based upon atorvastatin
  • S is an osteotropic group of the formula:
  • linking group Any suitable linking group may be used to link the osteotropic group to the polymer to carry out the present invention.
  • the linking group may represent a linkage by an ester bond, amide bond, anhydride bond, carbonate bond, urea bond, urethane bond, thioester bond, disulfide bond, imine bond, carbonate bond, etc.
  • the linking group may be a direct covalent bond between the polymer and the osteotropic group.
  • a spacer group such as a C1-C6 alkylene group may be included in the linking group. See, e.g., J. Oh et al, PCT Application WO99/59548 at page 15.
  • linking group L may be a covalent bond or any group having a valence of at least two and covering a linear distance of from about 1.5 to about 15 Angstroms, including those that contain cyclic moieties, that meet this spatial requirement.
  • Useful linkers include, for example, flexible non-conjugating linkers and flexible conjugating linkers.
  • Flexible non-conjugating linkers are those that link only one position of the polymer to one position of the osteotropic group, and provide only a single covalent bond or a single chain therebetween.
  • the chain may contain branches or cyclic portions in the chain.
  • linker atoms in the chain itself rotate freely around single covalent bonds, and thus the linker has more than two degrees of freedom.
  • Example non-conjugating linkers, besides a covalent bond are those of the formulae: — NR — , — CR 2 — , — S — , or — O — , wherein R is H or alkyl (1-6C), more preferably H or lower alkyl (1-4C) and more preferably H.
  • NRCO— CONR— , — CR 2 S— , — SCR 2 — , — OCR 2 — , — CR 2 O— , — NRNR— , — CR 2 CR 2 — , — NRSO 2 — , — SO 2 NR— , — CR 2 CO— , — €OCR 2 — , and — NR—NR— CO— CR 2 — and its complement — CR 2 — CO — NR — NR — — — — — , including the isosteres thereof.
  • Example flexible conjugating linkers are those that link only one position of the polymer to one position of the osteotropic group, but incorporate at least one double or triple bond or one or more cyclic systems and thus have only two degrees of freedom.
  • a flexible conjugating linker may form a completely conjugated ⁇ -bond linking system between S and P, thus providing for co-planarity of S and P.
  • Scaffold body production and use may be formed from polymers as described above, where the polymers are either covalently linked to an osteotropic group such as a statin as described above, or where the scaffold bodies are simply impregnated with osteotropic compounds such as statins as described above, in accordance with known techniques.
  • the scaffold bodies are formed from polymers covalently linked to an osteotropic group, as described above.
  • the scaffold bodies are formed by emulsion freeze dry casting, such as described in U.S. Patent No.
  • the resulting body is then freeze-dried to partially or completely convert the body to a porous solid.
  • the process can then optionally be repeated until the body is entirely a porous open-celled body.
  • Once completed the body may be sterilized and packaged in a sterile aspect package or container for subsequent use, in accordance with standard techniques.
  • the scaffold body described above may be used in a variety of ways, such as described in U.S. Patent No. 5,723,508 to Healy et al.
  • the body is impregnated with bone cells, prior to implantation.
  • the bone cells may in general be bone marrow cells, and more particularly may be osteoblasts, stem cells, progenitor cells, or combinations or mixtures thereof.
  • the bone cells may be autologous or non- autologous cells, but in a preferred embodiment the bone cells are withdrawn from the subject into which the implant system is to be implanted prior to implantation (e.g., immediately prior to implantation, or withdrawn and stored, processed, etc. for subsequent use).
  • the bone cells (in a physiologically acceptable media such as sterile saline solution) are then inserted into the scaffold by any suitable technique, such as pumping, use of vacuum systems, soaking, absorption, injection (e.g., by injection into multiple points therein with a syringe), or combinations thereof.
  • a physiologically acceptable media such as sterile saline solution
  • injection e.g., by injection into multiple points therein with a syringe
  • the scaffold may then implanted into the subject.
  • the scaffold body may be used in a preformed shape, or may be cut to the appropriate size at the time of use.
  • Such scaffold implants may be used for any of a variety of different procedures, including but not limited to the repair of non union defects, treatment of osteonecrosis, repair of bone cysts, bone regeneration in large bone defects, periodontal bone regeneration, sinus lifts, alveolar ridge augmentation, acute fracture healing, etc.
  • the present invention is explained in greater detail in the following non- limiting Examples.
  • Emulsion freeze-dried (EFD) scaffolds with 30- ⁇ m median pore size were seeded with 10 4 fetal rat calvarial cells in 24-well plates by injection into the scaffold at six evenly distributed sites around the periphery and also in the center of the scaffold, and the scaffolds then cultured in vitro.
  • the capillary pressure generated by pores less than 50 ⁇ m absorbed the cell suspension, and the high porosity allowed even distribution of the suspension.
  • EFD scaffolds with a median pore size of 145 ⁇ m were loaded with lovastatin by dissolving into the organic phase with the poly(lactide-co-glycolide) (PLG) before homogenization.
  • Efficiency of lovastatin loading was determined by dissolving the scaffold in methylene chloride and extracting lovastatin with methanol.
  • High-pressure liquid chromatography (HPLC) showed over 90% recovery from scaffolds, and a HMG Co-A reductase assay showed full activity of the recovered lovastatin. Scaffolds were immersed in culture media for eight days to determine release kinetics.
  • HPLC showed that the kinetics of lovastatin release was zero-order, with about 2.5 ⁇ g/day being released from 30-mg scaffolds loaded with 64 or 222 ⁇ g of lovastatin.
  • EXAMPLE 3 The Osteoinductive Protein Synthesizing Implant System (OPSIS) An osteoinductive protein synthesizing implant system (OPSIS) has been developed to further amplify bone formation by making better use of the scaffold as a substrate. Bone marrow cells are seeded into scaffolds made with an osteotropic biomaterial, Osteogenic-PLG (OG-PLG). The OPSIS may enhance bone formation via three methods. First, bone marrow cells will be induced to produce BMP-2 and attract cells to migrate into the scaffolds to form bone; second, the bone marrow cells will themselves be induced to form bone; and third, the scaffold microarchitecture will further enhance bone formation.
  • OPSIS Osteoinductive Protein Synthesizing Implant System
  • the osteotropic biomaterial is produced by grafting statins to the end of PLG.
  • Figure 1 shows a schematic of the synthesis.
  • the terminal carboxyl group of the polymer whether glycolide or lactide, was activated as its acid chloride with oxalyl chloride, which was then esterified with the alcoholic functionality in simvastatin (Cal Biochem Corp., San Diego, CA).
  • PLG (2.64 g, 85:15 molar ratio, inherent viscosity 0.78 dL/g, Birmingham Polymers, Birmingham, AL) was dissolved in methylene chloride (MC, 10 mL, Aldrich, Milwaukee, WI) and oxalyl chloride (3 mL added slowly, Aldrich, Milwaukee, WI) and stirred at room temperature for 24 hours. Then, the solvent and excess oxalyl chloride was distilled off on a rotary evaporator at room temperature.
  • MC methylene chloride
  • oxalyl chloride 3 mL added slowly, Aldrich, Milwaukee, WI
  • DMEM was used in the following studies because the in vitro release study was performed in media, a more accurate representation of what the cells would be seeing in in vitro cell studies.
  • the OG-PLG was further characterized using contact angle measurements, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR; Southwest Research Institute (San Antonio, TX)), and UN/Nis.
  • ATR-FTIR Attenuated Total Reflectance Fourier Transform Infrared spectroscopy
  • UX National Research Institute
  • UN/Nis Attenuated Total Reflectance Fourier Transform Infrared spectroscopy
  • PLG, PLG and simvastatin (PLG+Sim, 4 mg/g PLG) and OG-PLG were dissolved into MC at 20% w/v and cast onto glass slides to form films.
  • ATR-FTIR spectroscopy revealed a change in the spectrum between PLG, PLG+Sim and OG-PLG. There were three distinct peaks at 2958, 2919 and 2851 cm “1 for stock simvastatin powder (Figure 5). Neither PLG nor PLG+Sim spectra contained those peaks but OG-PLG contained them, though they were weak peaks ( Figure 5). These peaks represent the -CH 2 and -CH 3 groups on simvastatin. Another notable peak was one at 1022 cm "1 representing an ester group that did not exist in the other spectra. It is believed that this peak represents the ester group that was formed during the reaction and either the simvastatin or the PLG lost an -OH group.
  • EXAMPLE 4 In Vitro Controlled Release of Simvastatin Films of PLG, PLG+Sim and OG-PLG were cast into scintillation vials and an in vitro release study in DMEM was conducted. The release was measured using UN/N is at 248 nm.
  • Figure 4 shows the cumulative release curves of simvastatin from PLG+Sim, and OG-PLG fragments from OG-PLG. It appears that there was no simvastatin release from PLG+Sim until almost 20 days. This was probably >ecause the simvastatin in PLG+Sim was not showing at the surface.
  • UV-Nis assay was developed to measure in vitro release and have shown that degradation-controlled release allows for a quicker initial release with a more gradual prolonged release as compared to diffusion- controlled release. It is expected that the OPSIS would continually synthesize in situ BMP-2 by stimulating seeded bone marrow cells via the OG-PLG. It is also expected that the scaffold microarchitecture would further enhance the mass and speed of new bone formation. Clinically, the clinician can cut the scaffold into the appropriate shape and size, draw the patient's bone marrow, inject it into the scaffold, and implant the OPSIS into the patient.
  • Figure 6 shows that most of the new bone was formed near the suture lines next to the edge of the films along with periodic pockets of new bone below the films. Note that there is bone formation in negative controls (PLG) in this model. Histomorphometry suggests that there is more new bone in the OG-PLG group than negative controls (19038 ⁇ 7803 vs. 14624 ⁇ 5568 pixels of new bone area) suggesting that the released OG-PLG is osteotropic.

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Abstract

L'invention concerne une composé ostéotrope de formule P-L-S, dans laquelle P est un polymère biodégradable tel qu'un polymère de polyester, L est un groupe de liaison tel qu'une liaison covalente ou un carbonyle, et S est un groupe ostéotrope tel qu'une statine. L'invention concerne en outre des corps squelette constitués à partir de tels composés, lesdits corps comportant des cellules osseuses telles que des cellules de moelle osseuse, ainsi que leurs méthodes d'utilisation.
PCT/US2002/011519 2001-04-16 2002-04-15 Biomateriaux osteotropes, leurs methodes d'utilisation et systemes d'implant comportant de tels composes WO2002082973A2 (fr)

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AU2002256190A AU2002256190A1 (en) 2001-04-16 2002-04-15 Osteotropic biomaterials, methods of use thereof and implant systems incorporating the same

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US28410701P 2001-04-16 2001-04-16
US60/284,107 2001-04-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007837A1 (fr) * 2003-07-14 2005-01-27 Cellfactors Plc Substance extracellulaire osteo-inductive irradiee
EP1591133A1 (fr) * 2004-04-30 2005-11-02 Synthes Implants ayant une activité biologique
NL1026712C2 (nl) * 2004-07-23 2006-01-24 Technologiestichting Stw Bioresorbeerbaar botimplantaat.

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5990194A (en) * 1988-10-03 1999-11-23 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5990194A (en) * 1988-10-03 1999-11-23 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007837A1 (fr) * 2003-07-14 2005-01-27 Cellfactors Plc Substance extracellulaire osteo-inductive irradiee
EP1591133A1 (fr) * 2004-04-30 2005-11-02 Synthes Implants ayant une activité biologique
WO2005105168A1 (fr) * 2004-04-30 2005-11-10 Synthes Gmbh Implants biologiquement actifs
NL1026712C2 (nl) * 2004-07-23 2006-01-24 Technologiestichting Stw Bioresorbeerbaar botimplantaat.

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AU2002256190A1 (en) 2002-10-28

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