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WO1996039202A1 - Preparations biocompatibles d'hydroxyapatite et leurs utilisations - Google Patents

Preparations biocompatibles d'hydroxyapatite et leurs utilisations Download PDF

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Publication number
WO1996039202A1
WO1996039202A1 PCT/US1996/008652 US9608652W WO9639202A1 WO 1996039202 A1 WO1996039202 A1 WO 1996039202A1 US 9608652 W US9608652 W US 9608652W WO 9639202 A1 WO9639202 A1 WO 9639202A1
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WO
WIPO (PCT)
Prior art keywords
liquid phase
biocompatible
calcium phosphate
phosphate salts
formulation
Prior art date
Application number
PCT/US1996/008652
Other languages
English (en)
Inventor
Peter D. Constantino
Craig D. Friedman
Arup Sen
Original Assignee
Osteogenics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Osteogenics Inc. filed Critical Osteogenics Inc.
Priority to JP9501179A priority Critical patent/JPH11506659A/ja
Priority to EP96919055A priority patent/EP0830149A1/fr
Priority to BR9608344A priority patent/BR9608344A/pt
Priority to AU61496/96A priority patent/AU723740B2/en
Publication of WO1996039202A1 publication Critical patent/WO1996039202A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00796—Coating or prosthesis-covering structure made of a phosphorus-containing compound, e.g. hydroxy(l)apatite

Definitions

  • This invention generally relates to certain combinations of sparingly soluble calcium phosphates and applications thereof. More specifically, certain calcium phosphates may be combined with a liquid to form a paste or slurry of hydroxyapatite, which has a variety of medical, dental and other uses. Various biocompatible additives may be incorporated into the paste or slurry for various applications.
  • Hydroxyapatite is a calcium phosphate mineral and is the primary constituent of human bones and teeth. Hydroxyapatite is only one of a number of such calcium phosphate minerals, which have differing calcium-to-phosphate ratios, crystal structures, and physical characteristics.
  • Apatite is a general term for a wide range of compounds represented by the general formula M 2+ ⁇ 0 (ZO 4 3 ") 6 Y" 2 , where M is a metal atom, particularly alkali or an alkaline earth metal atom, and ZO 4 is an acid radical, where Z may be phosphorous, arsenic, vanadium, sulfur or silicon, or may be substituted in whole or part with carbonate (CO 3 2 ).
  • Y is an anion, usually halide, hydroxy or carbonate.
  • a combination of sparingly soluble calcium phosphate salts, especially tetracalcium phosphate and another sparingly soluble calcium phosphate salt, bom in their solid state, in equilibrium or quasi equilibrium in an aqueous or non-aqueous liquid phase such that both salts are in excess, can precipitate hydroxyapatite, s,., Ca 5 (PO 4 ) 3 OH. If both calcium phosphate salts are near equilibrium with the same saturated solution which additionally is supersaturated witii respect to hydroxyapatite, then the composition will continue to precipitate hydroxyapatite.
  • the precipitated hydroxyapatite can be formed either in vivo or ex vivo (in vitro) and may possess varying mechanical and biological features including, e.g.. hardness, flexibility, porosity, dissolution, bioresorption, biodegradation, tissue adhesion, and replacement by soft and hard tissues.
  • Hydroxyapatite is a naturally occurring material in bone, teeth and some invertebrate skeletons. Crystals of hydroxyapatite are embedded in the matrices of bone and tooth together with cells and tissue matrix materials including fibrous proteins such as cross-linked collagen and mineral binding proteins such as certain gla proteins, dentin and enamel. All vertebrate and dentulous animals are capable of causing mineralization of bone and tooth matrices through the precipitation of hydroxyapatite crystals under suitable physiological conditions of pH, temperature and ionic conditions. The resulting tissues are not highly cellular and display certain unique properties, such as significant mechanical strength, flexibility, physiological activity, and continual self-remodeling.
  • hydroxyapatite is a highly biocompatible material. These unique properties of hydroxyapatite present in bone have prompted efforts to develop implants made of hydroxyapatite, ceramics and other similar hard calcium phosphate materials such as - and ⁇ - tricalcium phosphates. These implants have been used to fill a wide range of bony defects in orthopedic and reconstructive surgeries and in the anchoring of tooth to bone (e.g.. in periodontal, dental and orthognathic applications).
  • Hydroxyapatite has other known applications, such as bone repair and remineralization of teeth. Such uses are shown in, for example, U.S. Patent Nos. Re. 33,221 and Re. 33,161 to Brown et al.
  • One specific example is the repair of tooth lesions or cavities. When an incipient lesion or cavity develops on the surface of a tooth, the dentist traditionally fills the cavity that forms. This procedure may prevent the decay from spreading further, but does not restore the tooth to its original state.
  • a considerable amount of research has been directed to the mineralization of incipient dental lesions.
  • the object of remineralization is to deposit hydroxyapatite on the carie lesion such that the dental enamel incorporates the hydroxyapatite into its structure at the point of lesion.
  • remineralization prevents further tooth decay and restores the tooth.
  • the supersaturated solutions or slurries used for remineralization have been prepared from a single form of calcium phosphate.
  • these solutions or slurries have been unsatisfactory for a variety of reasons.
  • the amount of calcium and phosphate ions available for remineralization in these supersaturated solutions is relatively low, thereby requiring both an excessive volume of fluid and an excessive number of applications.
  • 4,795,467; 4,865,602; 4,992,226; 5,123,925; and 5,246,457 disclose mineral- collagen mixture preparations, including methods of sterilization, for bone repair wherein the mineral component can be selected from a group of tricalcium phosphates or hydroxyapatites with preferred particle size of between 100-2000 ⁇ m and the collagen is either mixed to provide a moldable formulation or applied to coat the porous interstices within the ceramic particles.
  • U.S. Patent No. 5,204,382 and International Application WO 93/16657 disclose injectable compositions comprising particulate ceramic materials with sizes between 50-250 ⁇ m and collagen or another biocompatible organic polymer.
  • All of these disclosures relate to materials wherein the hydroxyapatite is preformed (as octacalcium phosphate or ⁇ -tricalcium phosphate salts) and is substantially composed of or manufactured from one essentially homogeneous form of calcium phosphate salt with contaminants or impurities present due to or arising from the raw material source or the manufacturing method.
  • JP 1,111,762 discloses a powder or a powder mixture containing tetracalcium phosphate and a kneading solution to produce a hardening composition which produces hydroxyapatite on contact with water.
  • EP 436,499 provides a process for producing a calcium phosphate-type powder, as a highly active powder, as a component in calcium phosphate-type hardening materials. These materials may be used to obtain a highly plastic, moldable material that hardens under mild conditions.
  • U.S. Patent No. 5,068,122 Kokubo et al.
  • calcium phosphate cements comprising the various precursor calcium phosphate salts and capable of precipitating hydroxyapatite provide the option of incorporation with bioactive substances such as proteins to produce implants that induce active regeneration of tissues such as bone.
  • bioactive substances such as proteins
  • tissue matrix proteins such as collagen
  • these references only concern incorporation of bioactive or biocompatible proteins and related substances as a means to improve the properties of hydroxyapatite as an implant material for tissue repair applications.
  • the available technologies and products, which utilize hydroxyapatite suffer from other conceptual as well as practical limitations.
  • One of the major conceptual limitations arises from the focus on using hydroxyapatite for tissue replacement as described above.
  • the implant is intended to either fill a tissue void and provide structural support or to be incorporated into newly formed tissue developed during the process of repair or regeneration.
  • hydroxyapatite technology is limited by harsh production methodology. Most hydroxyapatite implants are produced under extreme physical and chemical conditions resulting in hard implants comprised of large, fused, macro-crystals with random pores and gaps, unlike material formed naturally in bone or other skeletal structures encountered in nature.
  • typical hydroxyapatite formulations are characterized by limited tissue compatibility and resorbabilit . For instance, the hardness and the nature of the crystal structure frequently make them incompatible for application in repairing soft tissues. These shortcomings are caused not only by the physical characteristics of the formulations, but are also due to the body's inability to completely resorb the material over an acceptable time period.
  • known formulations also suffer from limited coformulation capability.
  • Biocompatible or bioactive materials applied to coat a hydroxyapatite implant surface may be rapidly washed away in a physiological milieu resulting in a rapid rise in local concentration of the substance with little or no material remaining available for the long term action required for most of these substances.
  • biocompatibility of hydroxyapatite and the ability to precipitate hydroxyapatite crystals under ambient conditions leads to the production of novel biomaterials wherein biologically active substances may be incorporated.
  • biomaterials are also amenable to coformulation with or coating of other polymeric (e_£,., dacron, nylon, vinyl, teflon, acrylic), elemental (e.g.. carbon, titanium), or alloy (£__&,., steel) implants.
  • Novel biomaterials selected based on mechanical and biological properties have utility in providing structural support for tissue filling or covering, or the stabilization of other mechanical devices; in promoting or supporting tissue formation for repair, regeneration or augmentation of tissues; in delivering or releasing antigenic materials for vaccination or genetic materials for gene therapy; in facilitating local, extended or controlled delivery of pharmaceutically active agents such as antibiotics or chemotherapeutics or hormonal substances for enhanced therapeutic effect; and in providing a piezoelectric field to deliver or amplify direct or pulsed electromagnetic stimulation to enhance healing or to generate controlled mechanical motion.
  • These are merely examples of applications of a biocompatible hydroxyapatite formulation.
  • the formulations and methods of this invention will be amenable to different means of administration (£_&., injection, implantation, arthroscopic application, packing, etc.) in different medical applications.
  • the molecular composition of hydroxyapatite makes it highly biocompatible.
  • a significant portion of an adult vertebrate animal's body weight is comprised of calcium phosphate.
  • bone is an actively remodeling tissue, there is a substantial turnover of calcium phosphate in a continuous manner.
  • the body's major organs are capable of withstanding physiological calcium phosphate turnover, and the excretory system, primarily the kidney, is capable of processing the released calcium phosphate.
  • Formulations based on such biocompatible materials are preferable over synthetic polymers such as polymethylmediacrylate, polyglycolic acid, poly lactic acid and copolymers of these substances that are not found in nature. Although many of these polymers are available in a range of consistencies, the processes of polymerization and depolymerization of these materials are frequently accompanied by unacceptable changes in pH or temperature, may require the use of toxic organic solvents, or lead to undesirable inflammatory reactions in animals and humans.
  • Hydroxyapatite crystals also possess unique piezoelectric characteristics which can be exploited in modulating the growth and metabolic activities of cells. Therefore, the use of electrical and electromagnetic stimulation approaches for tissue healing or the generation of controlled mechanical motion may be significantly enhanced through the use of implants made of hydroxyapatite crystals. Such implants may also be enhanced by incorporation of other biocompatible or bioactive substances involved in cell manipulation.
  • the present invention provides formulations of certain sparingly soluble calcium phosphate salt combinations, having the ability to precipitate hydroxyapatite under physiological and/or ambient conditions, wherein a biocompatible or a bioactive material is incorporated during the precipitation process such that the incorporated material is retained at the site of application of the formulation for extended time periods or gradually released into the surrounding physiological milieu.
  • the composition of the salt combination used in a formulation of the present invention is chosen such that the physical properties (porosity, tensile and flexural strength, consistency, etc.) and the resorption/biodegradation properties of the resulting hydroxyapatite precipitate enable the formulation to enhance the function of the incorporated biocompatible or bioactive material.
  • a biocompatible hydroxyapatite formulation in which hydroxyapatite precipitates under physiological conditions (including pH, temperature, ionic strength, etc.) or under conditions that (i) preserve the activity of an added biocompatible or bioactive substance and (ii) allow the substance to be impregnated reasonably uniformly throughout the precipitated composite.
  • physiological conditions including pH, temperature, ionic strength, etc.
  • One aspect of this embodiment concerns formulations containing biologically compatible materials that support the growth or formation of different cells or tissues and biologically active substances that cause or induce the formation of such cells or tissues.
  • Another aspect contemplates formulations containing biologically active substances that kill diseased or undesirable cells or tissues, or activate certain cells or tissues wherein the activity may produce a therapeutic benefit.
  • the biocompatible hydroxyapatite formulations may be used in products and structures with other technologies to create novel combined medical devices.
  • a method for preparing a biocompatible hydroxyapatite formulation.
  • a base combination of calcium phosphate salts is prepared.
  • a liquid phase is prepared.
  • a biocompatible additive is provided. These components are then combined to form a mixture. Then, a biocompatible hydroxyapatite formulation is precipitated from this mixture.
  • any two of the components may be combined first by suitable methods and then combined with the third component. Alternately, the three ingredients may be simultaneously combined.
  • the biocompatible additive may be any of several additives including, without limitation, growth factors, adhesive agents, immunogens, vaccines, genes, recombinant cells, antibiotics, pharmaceutical agents, hormones, fibers, gels, space occupying particles, and electrical stimulus enhancers.
  • a formulation prepared according to this method may also incorporate a pharmaceutically acceptable carrier.
  • a method for treating a patient in another embodiment, is provided.
  • a biocompatible hydroxyapatite formulation is prepared as before. Then, the formulation is administered to the patient.
  • Fig. 1 is a plot of the solubility isotherms of Ca 4 (PO 4 ) 2 O; CaHPO 4 «2H 2 O; CaHPO 4 ; Ca 8 H 2 (PO 4 ) 6 -5H 2 O; ⁇ -Ca 3 (PO 4 ) 2 ; and Ca 5 (PO 4 ) 3 OH at 25°C in the ternary system of Ca(OH) 2 ; H 3 PO 4 ; and H 2 O.
  • the present invention is generally directed to selected mixtures of calcium phosphate salts formed as powders, slurries or pastes and having various mechanical properties, porousness, piezoelectric features and bioresorption characteristics. These materials serve as novel delivery vehicles for various chemical agents used as traditional pharmaceutical drugs and for biological agents including glycoproteins, polymeric hydrocarbons, lipids, glycolipids, carbohydrates, proteins and nucleic acids. Additionally, these materials enhance the effects of electrical or electromagnetic stimulation in tissue healing.
  • the resulting novel compositions have utility in a broad range of medical applications such as immunization or vaccination, gene therapy, therapeutic modalities mediated through selective elimination or modification of cells or removal of substances from a physiological milieu, repair or regeneration of biological structural material (e.g.. bone, muscle, skin, tendon, and ligament) anchoring of tooth to bone, anchoring of prosthetic devices, or augmentation of soft tissues such as breast tissue.
  • biological structural material e.g. bone, muscle, skin, tendon, and ligament
  • Other uses are envisioned and certain specific applications contemplated for the various compositions are discussed in detail below.
  • the major components for the biocompatible hydroxyapatite formulation comprise sparingly soluble calcium phosphate salts.
  • two salts are combined, one of which is preferably tetracalcium phosphate.
  • the other salt may be selected from the group consisting of CaHPO 4 »2H 2 O; CaHPO 4 ; Ca 8 H 2 (PO 4 ) 6 »5H 2 O; ⁇ -Ca 3 (PO 4 ) 2 ; ⁇ -Ca 3 (PO 4 ) 2 ; and modified Ca 3 (PO 4 ) 2 , e.g.. tri-calcium phosphate modified by protons or up to approximately 10wt% magnesium.
  • each of these calcium phosphate salts has a characteristic solubility behavior that may be represented by a plot of the total concentration of calcium ions at the point of saturation versus the pH of the solution at a constant temperature.
  • a plot of the total concentration of phosphate ions versus pH would be equivalent for the purposes of the present invention because the concentrations of phosphate and calcium ions in solution are linked. The resulting curve is called an isotherm.
  • Fig. 1 is a plot of the solubility isotherms for six calcium phosphate salts in the ternary system comprising Ca(OH) 2 , H 3 PO 4 and H 2 O at 25 °C.
  • the y-axis of Fig. 1 represents the total concentration of calcium ions in solution in moles per liter, while the x-axis represents pH.
  • the isotherm for Ca 8 H 2 (PO 4 ) 6 -5H 2 O is based on the solubility product disclosed in Moreno et al., "Stability of Dicalcium Phosphate Dihydrate in Aqueous Solutions and Solubility of Octacalcium Phosphate," Soil Sci. Soc. Am. Proc. 21: 99-102 (1960).
  • the isotherm of Ca 4 (PO 4 ) 2 O is based on the approximate value of the solubility product calculated by Brown and Chow as referred to, for example, in Re. 33,221 and Re. 33,161.
  • the ratio of tetracalcium phosphate to the other salt as well as the relative particle sizes are varied in the different contemplated formulations in order to obtain the ones that meet the mechanical criteria and resorption and degradation profiles desired for the particular bioactive or biocompatible substance incorporated as an additive.
  • the relative amount of a liquid phase preferably chosen from the group consisting of water, saline, a weakly acidic solution, a biocompatible buffer solution, serum, plasma, and other bodily fluids
  • the amount of the salt combination may be varied in order to alter setting time and the consistency of the resulting precipitated biocompatible hydroxyapatite formulation.
  • the biocompatible or the bioactive additive is preferably dissolved or essentially uniformly mixed in the liquid phase prior to adding the liquid phase to the dry salts combination and initiating the hydroxyapatite precipitation reaction.
  • the liquid phase may be first combined with the calcium phosphate salts, followed by incorporation of the additive into the mixture.
  • the bioactive additive is first combined with the salts, and then the liquid phase is added.
  • the salts, additives and liquids may be simultaneously combined.
  • the liquid phase may additionally contain setting reaction or hydroxyapatite crystal growth modifiers such as a proteoglycan (e.g.. hyaluronic acid), a protein (e.g.. serum albumin), a carbohydrate (e.g.. granular sugar), a synthetic material (e.g.. polyethylene glycol), certain other ionic agents, and the like. Many additional representative examples of such materials may be found in U.S. Patent Nos. Re. 33,161 and Re. 33,221.
  • the tetracalcium phosphate component may be produced by any of various suitable methods.
  • the tetracalcium phosphate is produced by a solid state reaction catalyzed by high temperature treatment (e.g.. 1500°C to 1700°C) of an equimolar mixture of dicalcium phosphate and calcium carbonate.
  • high temperature treatment e.g. 1500°C to 1700°C
  • the tetracalcium phosphate thus produced is then mixed with a desired amount of another sparingly soluble calcium phosphate salt selected from the group recited above.
  • a mixture of ⁇ -Ca 3 (PO 4 ) 2 and tetracalcium phosphate may be produced by calcining a hydroxyapatite preparation having a molar ratio of Ca/P of between 1.5 and 1.8 at 1150°C to 1450°C under reduced pressure.
  • This mixture is further adjusted by the addition of a suitable sparingly soluble calcium phosphate salt in order to provide the desired setting properties and consistency of the hydroxyapatite formulation produced by precipitation upon mixing with the augmented liquid phase containing a bioactive or a biocompatible additive.
  • the calcium phosphate salts and their combinations are preferably produced and stored under substantially anhydrous conditions in order to precipitate hydroxyapatite formulations of consistent and superior quality upon addition of the liquid phase.
  • the following embodiments include methods of producing formulations comprising the calcium phosphate salt combinations mentioned above and various bioactive or biocompatible additives, formulations thus obtained, and uses therefor.
  • representative bioactive or biocompatible substances intended for certain medical applications are described.
  • a person of ordinary skill in the art will be able to produce such materials as described in these embodiments and will also be able (where appropriate or desirable) to substitute or add bioactive or biocompatible substances with properties similar to the ones cited in any particular embodiment.
  • the foregoing discussion relates to calcium phosphate salt combinations such as those described by Brown and Chow, the technology herein is not so limited.
  • the embodiments, features and aspects of the present invention can be applied to otiier calcium phosphate salt combinations.
  • the characteristics of the biocompatible hydroxyapatite formulations allow precipitation in vivo, ex vivo, or partially ex vivo and partially in vivo. Also, the hydroxyapatite may be resorbed or degraded in vivo. 1. Incorporation of Growth Factors For Wound Healing And Soft Tissue Repair
  • a first embodiment is directed to wound healing and soft tissue repair, and addresses a major need which exists for materials that can be applied to wounded soft tissues (SL&., skin, muscle, fascia, gum, periodontium, etc.) in order to cause or promote (as distinct from support) healing of the damaged tissue.
  • SL&. wounded soft tissues
  • Various biological factors have the potential for inducing growth of desired cells or formation of such cells from uncommitted precursor cells in the area of the damaged site. Systemic application of such materials would require substantial quantities, making such an approach both cost prohibitive and impractical due to limitations on the availability of the materials.
  • a first embodiment of the present invention which is directed to this medical application of augmentation or guided tissue regeneration, relates to a biocompatible hydroxyapatite formulation that incorporates one or more growth factors.
  • the growth factor may be selected from the group consisting of epidermal growth factor (EGF), transforming growth factor alpha (TGF- ⁇ ), transforming growth factor beta (TGF- ⁇ ), vaccinia growth factor (VGF), acidic or basic fibroblast growth factor (FGF), insulin-like growth factor (IGF) (e.g.. IGF-I and IGF-IJ), platelet-derived growth factor (PDGF), cartilage-derived growth factor (CDGF), interleukin-2, nerve cell growth factor (NCGF), hemopoietic cell growth factor (HCGF), lymphocyte growth factor (LGF), bone morphogenic protein (BMP) and other members of the growing family of wound healing factors.
  • EGF epidermal growth factor
  • TGF- ⁇ transforming growth factor alpha
  • TGF- ⁇ transforming growth factor beta
  • VGF vaccinia growth factor
  • FGF acidic or basic fibroblast growth factor
  • IGF insulin-like growth factor
  • PDGF platelet-derived growth factor
  • CDGF cartilage-derived growth factor
  • the hemopoietic cell growth factor may be selected from the group consisting of interleukin-3, granulocyte-macrophage colony stimulating factor, angiogenesis factors, macrophage colony stimulating factor, granulocyte colony stimulating factor and erythropoietin.
  • the lymphocyte growth factor may be selected from the group consisting of B cell growth factor, T cell growth factor, interleukin-4, interleukin-5, and interleukin-6.
  • the formulation preferably displays mechanical properties of a paste, a hydrogel, a film, or the like. The formulation preferably releases less than about 20% of the growth factor in about 1 day and greater than about 90% of the growth factor in about 30 days.
  • the release rate equals less than 20% in about 2 days and greater than 90% in about 5 days.
  • the amount of the growth factor is preferably from about 0.1 ⁇ g to about 10 ⁇ g per cubic centimeter volume of the formulation, and is more preferably in the range of from about 3 ⁇ g to about 6 ⁇ g per cubic centimeter volume.
  • the biocompatible hydroxyapatite formulation may be prepared according to the following steps.
  • a base combination of calcium phosphate salts is prepared. This step is preferably accomplished by performing the following procedure.
  • One or more calcium phosphate salt combinations are prepared as described above.
  • a liquid phase is formed by supplementing a liquid, such as sterile water, saline or a physiologically compatible buffer with a crystal growth modifier, such as hyaluronic acid, non-cross-linked collagen, ethylene glycol, polyethylene glycol, glycerin, polylysine, or the like.
  • the crystal growth modifier permits changes to the setting time and allows achievement of a desirable consistency, which depends on the method of administration.
  • the resulting liquid phase is added to the one or more salt combinations, respectively, preferably at a weight-to- weight solid-to-liquid ratio of between about 1 : 1 and about 5:1.
  • the solid-to-liquid ratio is more preferably between about 1.5:1 and about 4:1, and most preferably between about 2.5:1 and about 3.5:1.
  • Respective hydroxyapatite samples are precipitated from these mixtures, which are each evaluated for its setting property as well as its consistency.
  • Each respective sample then, is allowed to harden to a sheet, each sheet preferably having a thickness ranging between about 1 mm and about 7 mm. More preferably, the thickness ranges from about 3mm to about 5mm.
  • Pieces of the respective hardened materials are implanted subcutaneously and intramuscularly into test animals, e.g.. rats, guinea pigs, rabbits or pigs.
  • test animals e.g.. rats, guinea pigs, rabbits or pigs.
  • a base hydroxyapatite formulation which permits the desired release rates, is then selected.
  • the base combination of calcium phosphate salts is that combination which can precipitate this base hydroxyapatite formulation.
  • a liquid phase is augmented by the addition of a selected growth factor.
  • a growth factor is selected, preferably from those already described.
  • EGF, TGF-a, TGF- ⁇ or VGF may be produced by recombinant DNA technology from a transformed host cell substrate (e.g.. mammalian, microbial, or insect cell culture), by chemical synthesis, or from cultured cell sources that elaborate these materials. Purified preparations are assayed in cell culture systems to determine the potency to promote cell growth and the specificity for binding to the receptor (EGF R ), and are stored as lyophilized powders.
  • wound healing factors may be produced by recombinant or synthetic means, and are characterized for potency and specificity using cell culture stimulation assays and specific receptor binding assays, respectively.
  • One or more varying amounts of the selected growm factor then are added to the supplemented liquid phase described in the above first step to provide one or more augmented liquid phases, respectively, having a range of final concentrations of the selected growth factor.
  • the respective augmented liquid phases are each mixed with the above-described base salt combination to precipitate respective augmented hydroxyapatite samples.
  • this mixing results in a solid-to-liquid weight ratio between about 1:1 and about 5:1 (more preferably between 1.5:1 and 4:1; most preferably between 2.5:1 and 3.5:1).
  • These respective augmented hydroxyapatite samples then are allowed to harden in sheets having thicknesses preferably ranging from about 1 mm to about 7 mm (more preferably between 3mm and 5mm). Alternatively, the samples may be allowed to harden into test blocks. Test portions of the respective hardened samples are then immersed in water, saline, or other physiological fluids, such as serum or plasma, under sterile conditions at a temperature from about 25 °C to about 42 °C and the respective test portions are gently agitated. The test portions from the liquid medium are then tested at various times, by immunological techniques, for amounts of growth factor released. A release kinetics diagram may be plotted from these testing results. Formulations which display about 30% or less release within about 5 days are chosen for subsequent in vivo testing.
  • the chosen formulations are implanted subcutaneously and intramuscularly at vascularized sites in test animals. Release rates of the growth factor in the respective samples are determined by collecting serum samples as well as by collecting, via aspiration, local fluid surrounding the implant. Then a final augmented hydroxyapatite formulation is selected, which permits the aforementioned desired release rates.
  • the augmented liquid phase is that which permits precipitation of this final augmented hydroxyapatite formulation.
  • the augmented liquid phase is mixed with the base combination of calcium phosphate salts.
  • the biocompatible hydroxyapatite formulation is precipitated from this mixture.
  • an immunogen e.g. a purified protein, glycoprotein, lipoprotein or the like
  • a biocompatible implant that resorbs and releases the immunogen over several weeks has several advantages over known technology. These include, without limitation, avoiding the need for multiple booster injections that require multiple visits to the clinic by the subject, and enabling the elicitation of a more potent immune response with less immunogen material than is required when such immunogens are admixed with various adjuvants and administered by various conventional methods.
  • the implant may be formulated to produce low grade local inflammatory response, thereby enhancing the potency of the immunogen.
  • a slow release approach may also enable immunization against materials that are moderately toxic and thus not amenable to the development of an effective immune response by traditional immunization protocols.
  • the second embodiment of the present invention thus relates to a biocompatible hydroxyapatite formulation which incorporates an immunogen.
  • the immunogen may be selected from the group consisting of viral antigens, bacterial antigens, fungal antigens, and parasitic antigens.
  • the immunogen may also be any malignancy-specific marker including without limitation, tumor antigens, peptide fragments of tumor antigens, and metastatic- specific antigens.
  • the immunogen may be a subunit vaccine.
  • the immunogen may be incorporated in a vaccine, which can be active or passive.
  • the vaccine may be a synthetic vaccine which can be organically made or recombinantly made.
  • the formulation displays mechanical properties of a granule or plug.
  • the formulation releases about 20% or less of the immunogen in about 1 day and 90% or greater in about 30 days. More preferably, the release rates are 20% or less in about 2 days and 90% or more in about 5 days.
  • the amount of the immunogen in the formulation is preferably between about 50 ⁇ g to about 500 ⁇ g per cubic centimeter packed volume. This amount is more preferably between about 100 ⁇ g to about 400 ⁇ g per cubic centimeter, and most preferably between about 150 ⁇ g to about 300 ⁇ g per centimeter.
  • a formulation according to this embodiment is preferably prepared according to the following steps.
  • a base combination of calcium phosphate salts is prepared.
  • This first step is preferably accomplished according to the following procedure.
  • First, one or more combinations of sparingly soluble calcium phosphate salts is prepared as previously described.
  • a liquid phase is formed as previously described to have a solid-to-liquid ratio as previously described.
  • the liquid phases are mixed with the salt combinations to precipitate hydroxyapatite formulations which are each tested as described in connection with the first embodiment. Formulations that provide the desired resorption rates indicated above are selected. These formulations should permit the desired release rates of the immunogen.
  • a liquid phase is augmented by the addition of a selected immunogen.
  • This step is preferably accomplished according to the following procedure. First, an immunogen is selected. The immunogen may be any of those already described. Next, one or more varying amounts of the selected immunogen are added to the liquid phase described in the above first step to provide one or more augmented liquid phases, respectively, having a range of final densities of the selected immunogen. The respective augmented liquid phases then are each mixed with the above-described base salt combination to precipitate respective augmented hydroxyapatite samples. In subsequent steps, these samples are tested as described in connection with the first embodiment. A final augmented hydroxyapatite formulation is selected which permits the desired release rates. The augmented liquid phase for the second embodiment is that which permits precipitation of this selected final augmented hydroxyapatite formulation.
  • the augmented liquid phase is mixed with the base combination of calcium phosphate salts.
  • the biocompatible hydroxyapatite formulation is precipitate from this mixture.
  • a third embodiment of the present invention relates to gene therapy.
  • the genetic material of humans and other animals which is comprised of deoxyribonucleic acid (DNA), is amenable to direct transfer into recipient cells across species barriers.
  • DNA deoxyribonucleic acid
  • tissue culture used a method of complexing DNA with calcium phosphate and applying this complex to the intended recipient cells.
  • a major obstacle in delivering genes in the form of naked DNA into intact organisms (animals or humans) is the susceptibility of DNA to degrading enzymes in bodily fluids and the propensity of DNA delivered at target tissue sites, such as muscle tissue, to be washed away prior to the ability of the exposed cells to take up a reasonable amount.
  • Some attempts at solving these problems have involved the attachment of genetic sequences derived from certain viruses whereby the desired piece of DNA, even if taken up by only a few cells, would be sufficient since the attached viral sequences would allow reproduction of the piece of DNA in the recipient cells. It was expected that progenies of the recipient cells and cell-to-cell transfer would amplify the delivered DNA dose in the animal (or human) in order to lead to a desired clinical outcome.
  • a biocompatible hydroxyapatite formulation for gene therapy, wherein the formulation incorporates a genetic material.
  • the genetic material may comprise nucleic acids such as DNA or RNA (e.g.. antisense), proteins or modified proteins (e.g.. enzymes, transcription factors or translation factors), or cells that express a desired protein or nucleic acid.
  • the genetic material e.g.
  • the formulation of the third embodiment incorporates purified DNA molecules (e.g.. concatenated, circular or linear form) representing a coding sequence operably linked to regulatory and promoter sequences that allow favorable expression of a desired gene product in one or more types of mammalian cells.
  • the formulation preferably displays mechanical properties of a soft paste or a slurry, and should deliver 20% or less of the genetic material about 1 day and 90% or greater in about 30 days. More preferably, the delivery rates are 20% or less in about 2 days and 90% or greater in about 5 days.
  • the level of DNA is preferably in the range of from about 10 ⁇ g to about 100 ⁇ g per cubic centimeter of the delivery vehicle produced according to this embodiment. More preferably, the level of DNA is preferably between 10 ⁇ g and 50 ⁇ g.
  • the biocompatible hydroxyapatite formulation of this embodiment is preferably prepared according to the following steps.
  • a base combination of calcium phosphate salts is prepared. This may be accomplished according to the following procedure, which is similar to that of previous embodiments.
  • one or more combinations of calcium phosphate salts are prepared as previously described.
  • a liquid phase is prepared, also as previously described. Mixtures of these components, preferably having solid-to- liquid ratios as discussed in connection with previously described embodiments, liquid ratios as discussed in connection with previously described embodiments, are tested as discussed above.
  • a liquid phase is augmented by addition of the desired genetic material.
  • This step may be accomplished according to the following procedure.
  • a desired gene (“coding sequence") may be selected which encodes the product intended to be expressed in the host.
  • the gene may be cloned, propagated in a microbial host, and edited for expression either in a broad variety of recipient host cells or in a tissue-specific manner.
  • Required regulatory elements necessary for expression include general or tissue-specific promoter sequences, splice signals, polyadenylation signals and enhancer sequences.
  • the genetic construct to be incorporated in the hydroxyapatite formulation may be derived by combining the coding sequence with an appropriate set of regulatory elements in an operable linkage.
  • the construct may then be propagated in a microbial host in order to avoid the risks of contaminating potentially hazardous genetic sequences from a mammalian cell or a human cell-directed virus.
  • all parts of the genetic construct are cloned from normal human cellular genetic material and then modified or edited and propagated in microbial host systems.
  • the coding sequence may be derived from the appropriate virus or tumor cells.
  • the coding sequence may be created by deleting "introns" from the original chromosome-derived material or through the creation of a DNA copy of the functional messenger RNA by a process called reverse transcription.
  • the coding sequence for such a protein or altered forms of such a protein with predetermined changes may be produced by chemical gene synthesis.
  • editing of the coding sequence may involve predetermined addition of new splice signals, transcription/translation start sites, or the like, in order to facilitate the production of the product encoded by the coding sequence in the recipient cells.
  • Purified DNA for the biocompatible hydroxyapatite formulation of this embodiment preferably comprises the functional gene construct produced as described herein in a linear or circular form, in a single copy or tandemly linked multiple copy form, or in a composite of these forms.
  • the desired gene may be encompassed in a cell, which may be a recombinant cell.
  • the cell may be a myeloid-derived cell or a lymphoid-derived cell.
  • the cell may express a recombinant product including, without limitation, those selected from the group consisting of insulin, nucleic acid, viral antigens, bacterial antigens, fungal antigens, parasitic antigens, cytokines, growth factors, hormones, cell surface proteins, and enzymes. It is also envisioned that a protein or a nucleic acid may be directly added to the liquid phase.
  • augmented liquid phases are mixed with the base salt combination to provide augmented hydroxyapatite samples which are tested as described previously.
  • a final augmented hydroxyapatite formulation is selected, which permits the desired delivery rates.
  • the augmented liquid phase is that which leads to this final augmented hydroxyapatite test formulation.
  • the augmented liquid phase is mixed with the base combination of calcium phosphate salts.
  • the biocompatible hydroxyapatite formulation is precipitated from this mixture. 4. Extended Or Controlled Delivery Of Pharmaceutical Agents
  • Traditional pharmaceutical agents typically comprise small chemical molecules that are cleared from the circulatory system relatively rapidly.
  • the fourth embodiment relates to a biocompatible hydroxyapatite formulation that incorporates a pharmaceutical agent.
  • the agent is a biocide selected from the group consisting of anti- neoplastic agents, anti-bacterial agents, and anti-parasitic agents.
  • An anti- neoplastic agent may be selected from the group consisting of cyclophosphamides, alkylating agents, purine analogs, pyrimidine analogs, vinca and vinca-like alkaloids, etoposides and etoposide-like drugs, antibiotics, corticosteroids, nitrosoureas, antimetabolites, platinum-based cytotoxic drugs, hormonal antagonists, antiestrogens, tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amsacrine, procarbazine, hexamethylmelamine and mitoxantrone.
  • An anti-bacterial agent may comprise a heavy metal, an antibiotic, or another anti-bacterial agent.
  • the pharmaceutical agent may also be an inflammatory agent, an analgesic, or a chemotherapeutic substance.
  • Other pharmaceutical agents envisioned are known to those having ordinary skill in the art.
  • the biocompatible hydroxyapatite formulation should display the mechanical properties of granules or a soft paste.
  • the formulation should be capable of releasing 20% or less of the agent within 1 day and 90% or greater with about 30 days. More preferably, the release rates are 20% or less within about 2 days and 90% or greater within about 10 days.
  • the level of the agent preferably comprises from about 10% to about 50% of the total dosage conventionally prescribed for a full course of a specific treatment.
  • the biocompatible hydroxyapatite formulation according to the fourth embodiment is preferably produced by the following steps.
  • a base combination of calcium phosphate salts is prepared by following a procedure similar to that in the previous embodiments.
  • a liquid phase is augmented by adding a desired pharmaceutical agent.
  • the desired agent is selected from among the agents already described.
  • one or more liquid phases, which are prepared as in previous embodiments, are augmented by adding varying amounts of the pharmaceutical agent.
  • Each of the augmented liquid phases then are respectively mixed with the base salt combination preferably at a solid-to-liquid ratio as previously described, to form an augmented formulation.
  • Test samples of the respective augmented formulations (having varying amounts of the pharmaceutical compound) are implanted subcutaneously, intramuscularly or intraperitoneally into test animals and characteristics such as serum levels of the pharmaceutical agent compound and resorption rate of the implanted formulation are monitored.
  • a final augmented formulation which displays mechanical properties of granules or a paste, which permits the desired release rates of the agent, and which has a level of the agent of about 10% to about 50% of the total dosage currently prescribed for a full course of treatment.
  • the augmented liquid phase is that which leads to this final augmented test formulation.
  • a third step the base combination of calcium phosphate salts is mixed with the augmented liquid phase. And, in a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step.
  • antibiotics and anti-inflammatory compounds are incorporated into a hydroxyapatite formulation, wherein a final augmented formulation is selected that provides a suitable dosage for about 7 to about 14 days.
  • a chemotherapeutic substance (or a combination thereof with other substances) is incorporated into a hydroxyapatite formulation to produce an augmented formulation capable of delivering the chemotherapeutic substance over a period of about 20 to about 30 days.
  • Small peptide hormones or their derivatives are believed to exert their physiological action on specific target cells by binding to specific membrane receptors on such cells. As in the case of small chemical molecules that are incorporated in conventional pharmaceutical agents, the small peptides have only a limited circulating half-life. This characteristic can be significantly improved by incorporating such molecules in a biodegradable hydroxyapatite material.
  • a biocompatible hydroxyapatite formulation is provided as a delivery vehicle for hormones including peptide hormones and hormone-like agents.
  • the formulation comprises a hormone or peptide factor such as a regulatory-type hormone selected from the group consisting of insulin, atrial natriuretic factor (ANF), calcitonin, vasopressin, relaxin and the like.
  • the hormone may also be a sex hormone selected from the group consisting of estrogenic hormones, progestational hormones, androgenic hormones and any active derivative of these.
  • the formulation should display mechanical properties of a paste suitable for subcutaneous placement and percutaneous application.
  • the formulation is capable of delivering the hormone at a rate of about 20% or less in about 1 day and about 90% or greater in about 30 days. More preferably, the delivery rates are 20% or less in about 2 days and 90% or greater in about 7 days.
  • the concentration of the active material in the formulation is preferably from about 10% to about 50% (per cubic centimeter of the administered formulation) of the conventional recommended cumulative dosage for a conventional treatment period of about 5 to about 30 days.
  • the biocompatible hydroxyapatite formulation may be accomplished by the following steps.
  • a base combination of calcium phosphate salts is prepared preferably by following the procedure described in the fourth embodiment (i.e.. the embodiment incorporating a pharmaceutical agent) or steps similar thereto.
  • a liquid phase such as that described in the previous embodiments, is augmented by adding the desired hormone (or peptide factor or hormone-like agent). This is preferably accomplished by following the procedure describe in the fourth embodiment.
  • the base salt combination is mixed with the augmented liquid phase.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. 6.
  • Bone Replacement, Repair and Regeneration Bone is unique in its ability to fully regenerate among the complex tissues in higher organisms such as vertebrates. Due to the complex nature of bone tissue and the varied functions performed by the skeleton at different locations within the body, different approaches for intervention may provide greater therapeutic benefits in different locations. The respective roles played by the cellular component, the matrix component, and the interaction between these two phases of bone, contribute to the regenerative process and the functioning of the tissue. Certain proteins that are unique to bone have been identified witii respect to their structural and mineral binding properties. Thus, a sixth embodiment of the present invention relates to bone replacement, repair and regeneration.
  • a biocompatible hydroxyapatite formulation which represents the major mineral component of bone in the presence of the major structural and mineral binding proteins found in bone, may be provided which has utility as a filler of bone voids with a matrix resembling that of normal bone.
  • Such a formulation is compatible with bone and capable of undergoing resorption to be replaced by new bone that remodels along natural processes.
  • This novel formulation is useful in filling various damaged sites and is also useful in filling gaps between prosthetic devices and surrounding bony tissue, thus providing a better attachment for orthopedic, periodontal and dental applications.
  • the formulation is also useful as an extender of autografts or allografts where the amounts normally available are not sufficient.
  • a biocompatible hydroxyapatite formulation which is capable of supporting bone growth.
  • a formulation according to this aspect contains one or more adhesive agents.
  • the adhesive agent may be chosen from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins, bone gla protein, and matrix gla protein.
  • the biocompatible hydroxyapatite formulation should display mechanical properties of a paste that hardens into an implant.
  • the implant preferably has a compressive strength greater than 10 MPa, which is more preferably greater than about 50 MPa, and most preferably greater than about 100 MPa.
  • the implant should be about 45% porous with an average pore size of from about 15 microns to about 30 microns. More preferably the average pore size is from about 20 microns to about 25 microns. Most preferably, the average pore size equals about 23 microns. The maximum pore size should be less than 100 microns, preferably less than 50 microns.
  • the formulation is preferably resorbable within about 60 days to about 2 years. More preferably, the formulation is resorbable within about 60 to about 90 days.
  • the amount of the osteogenic protein should be from about 10% to about 40% of the total weight of the formulation, and the relative amount of the proteins to each other (if more than one is incorporated) should be similar to that found in the bony tissues at the site of application.
  • the biocompatible hydroxyapatite formulation may additionally contain (a) an antibiotic substance that is locally released from the formulation during the repair process and prevents infections that could hinder regeneration; or (b) a hormone, e.g.. calcitonin, that may be locally released during the repair process to inhibit bone loss due to an underlying metabolic disease such as osteoporosis.
  • an antibiotic substance that is locally released from the formulation during the repair process and prevents infections that could hinder regeneration
  • a hormone e.g.. calcitonin
  • the augmented hydroxyapatite formulation of this aspect of the sixth embodiment is preferably formed according to the following method.
  • a base combination of calcium phosphate salts is prepared. This may be accomplished according to a procedure similar to that of previous embodiments.
  • a liquid phase is augmented by adding an osteogenic adhesive-type protein.
  • an osteogenic adhesive-type protein This may be accomplished by the following procedure. First, one or more proteins are selected from those already described. For example, human bone gla protein, human matrix gla protein and human osteonectin may be produced by recombinant means and purified. Then, a liquid phase is formed as described previously. The liquid phase may be supplemented (or additionally supplemented) with granular sugar, such that upon mixing with the base salt combination the final formulation will contain up to about 20% by weight of sugar. The selected proteins are then uniformly dissolved in the supplemented liquid phase to form an augmented liquid phase.
  • the base salt combination is mixed with the augmented liquid phase.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step.
  • the paste thus formed is preferably allowed to harden under pressure (e.g.. from about 40,000 psi to about 80,000 psi) in vitro in desirable mold conformations for a period of about 12 hours to about 48 hours.
  • the hardened formulation is then subjected to treatment with warm water at temperatures in the range from about 50°C to about 70°C, more preferably about 50°-55°C. This treatment should last for about 4 to about 10 hours, more preferably from 4 to 5 hours, to remove most of the granular sugar, thus creating a highly porous material.
  • the material may then be implanted into a body, for example, at a selected bone void.
  • Another aspect of the sixth embodiment deals with osteoinduction.
  • Hydroxyapatite implants including the porous forms, frequently allow ingrowth of newly developed bony tissue at bone defect sites.
  • the hydroxyapatite implant is incorporated into the newly formed bone which remodels naturally.
  • a hydroxyapatite implant that can actively effect the differentiation process that causes the pluripotent stem cells at the site of a trauma to follow the path of bone formation - "osteogenesis" - will provide improved therapeutic benefits.
  • a group of factors generally called osteogenic factors, bone morphogenic protein, or chondrogenic factors, have been shown to mediate such phenomenon in animals and humans.
  • this aspect of the sixth embodiment of the present invention provides a biocompatible hydroxyapatite formulation, which may cause active ingrowth of bone into implants.
  • the formulation is capable of causing induction of new bone formation and comprises one or more growth factors selected from the group consisting of osteogenic factors, bone morphogenic, proteins, and chondrogenic factors.
  • growth factors may be included either alone or in combination with one or more adhesive agents, which may be selected from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins, bone gla protein, and matrix gla protein.
  • the formulation should display mechanical properties of a paste that hardens into an implant having a tensile strength of at least 20 MPa. More preferably, the tensile strength is greater than 60 MPa, and most preferably greater than about 70MPa.
  • the formulation is preferably porous with average and maximum pore sizes as described above.
  • the level of the active growth factor should be in the range of from about 10 ⁇ g to about 100 ⁇ g for every cubic centimeter of a delivery vehicle containing the selected growth factor alone, or of a delivery vehicle containing up to about 40 wt% of the one or more adhesive agents.
  • the final formulation may additionally contain a heparanase. This term is generically intended to mean an enzyme that either degrades heparin sulphate or causes the release of molecules in vivo that bind to heparin or heparin sulphate.
  • the final formulation may also contain an antibiotic substance.
  • the formulation of this aspect of the sixth embodiment may be prepared according to the following method.
  • a base combination of sparingly soluble calcium phosphate salts is prepared as before.
  • a liquid phase is augmented by adding the appropriate one or more growth factors and the desired adhesive agents.
  • growth factors and the desired adhesive agents Various suitable factors, including those already mentioned as examples, have been described in the art along with recombinant means of production either in genetically engineered mammalian cells or microbial host cells.
  • the augmented liquid phase is mixed with the base salt combination. Preferably, this mixture has a solid-to- liquid ratio as described previously.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step.
  • the formulation preferably has the above described characteristics.
  • the final formulation may be hardened ex vivo or rapidly in vivo when applied in an open fracture as an implant or a grouting material in conjunction with other implants.
  • Still another aspect of the sixth embodiment focuses on bone regeneration. Bone defects at different skeletal sites may require different balances between bone regeneration and short term biomechanical support.
  • the formulations described in the previous aspect of the sixth embodiment can provide modest mechanical support and allow efficient bone ingrowth such that the implant is rapidly incorporated into newly formed bone for long term mechanical support. Yet, these formulations also provide reasonable stress bearing capability within a short time post-operatively by virtue of their biomechanical strength. In other applications, where short term load bearing is not an important factor (e.g. spinal fixation, radial and ulnar non-union fracture, and the like), there is a need to be able to cause rapid formation of new bone for long term benefit with short term support being provided by other fixation devices.
  • a biocompatible hydroxyapatite formulation which is capable of actively inducing bone repair in small defects.
  • the formulation preferably comprises a growth factor selected from the group consisting of osteogenic factors, bone morphogenic proteins, and chondrogenic factors.
  • the formulation may also comprise one or more adhesive agents, which may be selected from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins, bone gla protein, and matrix gla protein.
  • the formulation should be in the form of a soft paste or slurry that can be applied percutaneously.
  • the formulation is characterized by the resorbability described in connection with the previous aspects and preferably contains between about 50 ⁇ g and about 500 ⁇ g of the selected growth factor for every cubic centimeter of the formulation. If incorporated, the adhesive agent should be at a level of up to 40 wt% of the final formulation.
  • the formulation additionally may contain heparanase, which is generically intended to mean an enzyme that either degrades heparin sulphate or induces the release of molecules in vivo which bind to heparin or heparin sulphate.
  • the formulation may additionally contain an antibiotic substance. Compared to the formulation described in the previous aspects of this embodiment, this formulation is not intended to have significant mechanical strength and is intended to provide a more rapid, local delivery of growth factors for a shorter duration.
  • the formulation of this aspect of the sixth embodiment may be prepared according to the following method.
  • a base combination of sparingly soluble calcium phosphate salts is prepared as before.
  • a liquid phase is augmented by adding the appropriate one or more growth factors and the desired adhesive agents.
  • the augmented liquid phase is mixed with the base salt combination.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step.
  • the formulation preferably has the above-mentioned characteristics. Also, this mixture should have a solid-to-liquid ratio as previously described.
  • the final formulation is applied percutaneously and hardens in vivo.
  • Examples of this and the previous aspects of this embodiment include: (a) a formulation that incorporates a homodimer of BMP-2 produced in Chinese hamster ovary (CHO) cells; (b) a formulation that uses molecules designated COP5 or COP7 or Vgl produced in E coli cells; and (c) a formulation that incorporates a heterodimer of BMP-4 and BMP-5 produced in a genetically engineered mammalian host cell. 7. Enhancement Of Electrical Or Electromagnetic Stimulation Of Bone Growth
  • a seventh embodiment of the present invention relates to the enhancement of osteogenesis around and into hydroxyapatite implants in response to electromagnetic stimulation.
  • Electromagnetic stimulation has been reported to be effective in stimulating bone healing and bone ingrowth into hydroxyapatite implants when the implants have an average pore size preferably in the range of from about 15 microns to about 30 microns (more preferably between 20 microns and 25 microns; most preferably equal to about 23 microns).
  • the incorporation of paramagnetic, diamagnetic, conductive, and insulating material into an implant can intensify or attenuate the electrical and magnetic fields proximal to the implant when it is subjected to electromagnetic stimulation.
  • This improved formulation can increase the rate of bone healing and reduce the field intensity required for electromagnetic stimulation.
  • This embodiment of the present invention relates to an augmented hydroxyapatite formulation with altered magnetic and conductive properties which enhance the effects of electromagnetic field-induced bone repair and bone formation.
  • the seventh embodiment of the present invention provides a biocompatible hydroxyapatite formulation, which incorporates an electrical stimulus enhancer.
  • the stimulus enhancer may be one or more of a paramagnetic material, a diamagnetic material, a conductive material, or an insulator.
  • the paramagnetic material may be selected from the roup consisting of iron, iron ammonium alum, uranium, platinum, and aluminum.
  • the diamagnetic material may be selected from the group consisting of bismuth, mercury, silver, carbon (diamond), lead, and copper.
  • the conductive material may be selected from the group consisting of silver, copper, aluminum, and tungsten.
  • the insulator may be selected from the group consisting of glass, lucite, mica, quartz, and polytetrafluoroethylene (PTFE).
  • the formulation is capable of causing new bone ingrowth and promoting osteogenesis in the tissue surrounding the implant.
  • the formulation should display mechanical properties of a paste that hardens into an implant having a tensile strength greater than 20 MPa (more preferably greater than 60 MPa; most preferably greater than 70 MPa).
  • the formulation should be porous with average and maximum pore sizes as described above.
  • the formulation preferably has the resorbability already described (i,e.. 60 days to 2 years; preferably 60-90 days).
  • the hydroxyapatite formulation of the seventh embodiment may be prepared according to the following method.
  • a base combination of sparingly soluble calcium phosphate salts is prepared as before.
  • a liquid phase is augmented by adding one or more electromagnetic enhancers selected from those already described. In the cases where the material is toxic, it can be encased in glass or PTFE.
  • the augmented liquid phase is mixed with the base salt combination.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step.
  • the hydroxyapatite formulation may be hardened in vitro and used as a bone replacement.
  • an implant formed from the formulation may be implanted in a human body.
  • the implant is stimulated electrically or magnetically to induce bone growth within and around the implant.
  • hydroxyapatite formulation for the delivery of a bioreactive substance.
  • Application of an electromagnetic field can stimulate bone and tissue growth and vascularization in and around a hydroxyapatite implant.
  • Electromagnetically stimulating a hydroxyapatite implant or implanted hydroxyapatite formulation can also regulate the delivery of bioreactive substances. Electric fields have been shown to cause desorption of factors from a matrix which is exposed to the field. In addition to causing direct release, electromagnetic stimulation will also stimulate tissue ingrowth into the implant, thus increasing contact between the bioreactive substance and the tissue.
  • the eighth embodiment of the present invention relates to a biocompatible hydroxyapatite formulation which is subjected to electrical or electromagnetic stimulation after being inserted into a human or animal.
  • the hydroxyapatite formulation is preferably prepared according to the following method.
  • a base combination of calcium phosphate salts is prepared as before.
  • a liquid phase is augmented by adding one or more bioreactive substances.
  • the bioreactive substance can be any of the biocompatible additives described herein.
  • the augmented liquid phase is mixed with the base salt combination.
  • the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The precipitation can be in vivo.
  • the precipitation can be ex vivo.
  • an additional step is required in which the precipitated hydroxyapatite formulation is implanted into a human or animal.
  • the implant is stimulated electrically or electromagnetically to induce bone and tissue growth and vascularization within and around the hydroxyapatite implant and to induce release of the bioreactive substance from the hydroxyapatite formulation.
  • the devices interface with both the soft tissue of the gum and the underlying bony structure.
  • a desirable device should have one surface compatible with bone and another compatible with cartilage. It will be readily apparent to one of ordinary skill that other examples could be easily identified with application throughout the human body, as well as animals.
  • the ninth embodiment which may be used for such dual tissue interface applications, provides a layered device having a first layer comprising a synthetic polymer (e ⁇ , a glycolide/lactide/acrylic material selected for compatibility with soft tissues or cartilage) and a second layer of a biocompatible hydroxyapatite formulation which is compatible with bone.
  • the second layer may be created by the application of a paste formed from a sparingly calcium phosphate salt mixture, such as those previously described.
  • This embodiment further contemplates the incorporation of one class of pharmaceutically active or biocompatible material in the first layer to facilitate the regeneration of soft tissue or cartilage while the hydroxyapatite layer incorporates one or more biologically active or biocompatible substances, which facilitate bone repair as described in previous embodiments.
  • a significant advantage of the layered devices of this embodiment is that biologically or pharmaceutically active substances that negate the formation of selected tissues may be incorporated into one layer while other substances which encourage such formation can be incorporated into the other layer.
  • biologically or pharmaceutically active substances that negate the formation of selected tissues may be incorporated into one layer while other substances which encourage such formation can be incorporated into the other layer.
  • This allows clear delineation of the dual tissue interface created in the guided tissue regeneration process.
  • the synthetic polymer layer that is made to be compatible with cartilage may contain an anti-angiogenic factor to prevent migration of bone tissue into this layer from the bony tissue being regenerated at the hydroxyapatite layer.
  • the synthetic polymer layer is impregnated with Type II collagen and hyaluronic acid to allow better cartilage compatibility, while the hydroxyapatite layer is impregnated with Type I collagen, bone gla protein, osteonectin and the like, for the facilitation of bone regeneration. 10.
  • Other Features and Aspects The embodiments thus described are merely intended as examples of the present invention, which is not limited thereto.
  • many of the embodiments described herein involve a process wherein a liquid phase is augmented with a biocompatible additive. Then, the augmented liquid phase is mixed with a base combination of calcium phosphate salts.
  • the components of the mixture, which precipitates hydroxyapatite can be combined in different orders or simultaneously.
  • various release rates are described, those having ordinary skill will recognize that the components of the hydroxyapatite formulations may be manipulated to achieve different release rates which may be more suitable for a given application.
  • a package comprises a kit having three vials.
  • a first vial preferably contains a measured amount of the base calcium phosphate salt combination.
  • a second vial preferably contains the selected additive, which may be any of the additives already described (e.g.. a growth factor).
  • the additive may be in any of several forms.
  • a growth factor might be provided in a lyophilized state.
  • the third vial contains the liquid phase.
  • the kit could contain two vials.
  • one vial would contain the calcium phosphate salts and the other would contain a mixture of the liquid phase and the additive.
  • one vial contains a combination of the additive and the salts, while the other vial contains the liquid phase.
  • the contents of the vials may be combined to produce a paste of the biocompatible hydroxyapatite material.
  • the resulting paste may be administered by itself in a surgical site or may be used to augment sutures, staples, membranes (resorbable or nonresorbable) or the like that are in widespread use for wound stabilization and closure.
  • the paste may also be used to augment artificial skin and membranes used to cover major burn wounds.
  • pre- impregnated hardened sheets of a precipitated biocompatible hydroxyapatite formulation incorporating an additive may be provided in sterile form.
  • these sheets are capable of being cut into desired shapes and applied to cover wound sites or to pack deep wounds.
  • the sheets thus applied may be stabilized using known surgical closure techniques.
  • Various processes of producing the sheets or similar structures are contemplated in this embodiment.
  • the embodiments described above may also incorporate an antibiotic substance that prevents infection of the augmented hydroxyapatite material.
  • the antibiotic substance may also be released at the wound site in order to prevent infection of the wound site while the material is in place.
  • Some of the types of antibiotics which may be used include, without limitation, aminoglycosides, amphenicols (e.g.. chloramphenicol), ⁇ -Lactams antibiotics, penicillins (e.g.. ampicillin), peptide antibiotics, and tetracycline antibiotics (e.g.. tetracycline).
  • two or more formulations are independently prepared.
  • an implant may be prepared ex vivo by mixing the salts, additives and liquid phase as described above to produce a paste.
  • the paste may be allowed to harden into a component which is more slowly resorbable than a separately prepared formulation.
  • This paste may be extruded through an appropriate aperture to produce granules of such a size that may be applied through a large gauge hypodermic needle or other acceptable injector mechanism.
  • a second formulation may be freshly prepared at the time of administration (e.g.. by adding a liquid phase containing approximately one third of the total intended dosage of the additive to the base salt combination at a ratio that produces a softer paste, which can harden in situ into a more rapidly biodegradable implant.
  • Adequate amounts of the granules can be mixed uniformly with the base salt combination prior to adding the augmented liquid phase, such that the granules contribute about three times as much of the immunogen as contributed by the softer paste.
  • a system comprising a paste with admixed granules and a freshly prepared paste provides a two-component system wherein the freshly prepared paste releases a first dose of the selected additive relatively rapidly and the admixture of paste and granules delivers booster amounts more slowly over an extended time period.
  • a layered composite may be produced wherein the central core contains a more slowly resorbable formulation that is surrounded by a more rapidly resorbable formulation.
  • the formulation may be administered intramuscularly, intravenously, subcutaneously or percutaneously (depending on the desired target tissue) where the additive (e.g.. DNA) is to be delivered.
  • the additive e.g.. DNA
  • the solid-to-liquid ratio and the amounts of supplements recited herein for the liquid phase are selected based on results of animal evaluations where various test formulations are a ⁇ ninistered, and the release of the additive and the biodegradation of hydroxyapatite are monitored.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une préparation biocompatible d'hydroxyapatite obtenue par précipitation d'un mélange d'une phase liquide, d'un additif biocompatible ou bioactif, qui peut être choisi parmi différents bioréacteurs ou d'autres substances, et une combinaison basique de sels phosphocalciques. La phase liquide et l'additif peuvent être combinés pour produire une phase liquide plus importante qui est ensuite mélangée avec la combinaison de sels basiques. L'additif est choisi pour permettre d'obtenir l'effet désiré lors de l'administration de la préparation à un végétal ou à un animal. L'additif est libéré dans le milieu physiologique environnant et l'hydroxyapatite est résorbée.
PCT/US1996/008652 1995-06-06 1996-06-03 Preparations biocompatibles d'hydroxyapatite et leurs utilisations WO1996039202A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9501179A JPH11506659A (ja) 1995-06-06 1996-06-03 生物学的互換ヒドロキシアパタイト製剤及びその使用
EP96919055A EP0830149A1 (fr) 1995-06-06 1996-06-03 Preparations biocompatibles d'hydroxyapatite et leurs utilisations
BR9608344A BR9608344A (pt) 1995-06-06 1996-06-03 Formulações de hidroxiapatita biocompatível e usos das mesmas
AU61496/96A AU723740B2 (en) 1995-06-06 1996-06-03 Biocompatible hydroxyapatite formulations and uses therefor

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US47121695A 1995-06-06 1995-06-06
US46990995A 1995-06-06 1995-06-06
US46808495A 1995-06-06 1995-06-06
US08/468,084 1995-06-06
US08/469,909 1995-06-06
US08/471,216 1995-06-06

Publications (1)

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WO1996039202A1 true WO1996039202A1 (fr) 1996-12-12

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EP (1) EP0830149A1 (fr)
JP (1) JPH11506659A (fr)
AU (1) AU723740B2 (fr)
BR (1) BR9608344A (fr)
CA (1) CA2223596A1 (fr)
WO (1) WO1996039202A1 (fr)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022154A3 (fr) * 1996-11-21 1998-10-22 Tissue Eng Inc Mousses de biopolymere pour la reparation et la reconstruction de tissus
WO1998047485A3 (fr) * 1997-04-24 1999-04-01 Takeda Chemical Industries Ltd Composition solide recouverte d'apatite
WO1999020319A1 (fr) * 1997-10-21 1999-04-29 Augmentec Aktiengesellschaft Implantologie-Epithetik Implant constitue d'un materiau ceramique pouvant se resorber
NL1008582C2 (nl) * 1998-01-05 1999-07-06 Vrije Universiteit Botmateriaal.
WO1999052542A1 (fr) * 1998-04-09 1999-10-21 Roche Diagnostics Gmbh Utilisation de l'erythropoietine pour le traitement des hemochromatoses
WO2000001427A1 (fr) * 1998-07-02 2000-01-13 Stichting Skeletal Tissue Engineering Group Amsterdam Ciment a base d'os, contenant des peptides antimicrobiens
US6069295A (en) * 1996-05-10 2000-05-30 Isotis B.V. Implant material
US6123925A (en) * 1998-07-27 2000-09-26 Healthshield Technologies L.L.C. Antibiotic toothpaste
US6143948A (en) * 1996-05-10 2000-11-07 Isotis B.V. Device for incorporation and release of biologically active agents
WO2001041821A1 (fr) * 1999-12-09 2001-06-14 Biosyntech Canada Inc. Composition hybride mineral-polymere
WO2001076649A1 (fr) * 2000-04-11 2001-10-18 Bone Support Ab Materiau de substitution du mineral osseux injectable
EP1228772A1 (fr) * 2001-02-01 2002-08-07 AM-Pharma B.V. Nouveau ciment osseux contenant des principes actifs
WO2004043495A1 (fr) * 2002-11-12 2004-05-27 The Circle For The Promotion Of Science And Engineering Agent d'administration, procede d'administration d'une substance cible dans des cellules, procedes d'obtention d'un agent d'administration, composition d'obtention d'un agent d'administration et kit d'obtention d'un agent d'administration
WO2004060425A3 (fr) * 2002-12-27 2005-01-06 Angiotech Pharm Inc Compositions et procedes d'utilisation de collajolie
WO2007010512A1 (fr) * 2005-07-19 2007-01-25 University Of Limerick Implants
EP1714622A4 (fr) * 2003-12-09 2007-10-24 Pentax Corp Materiau d'enrichissement osseux
US7341756B2 (en) 2003-06-04 2008-03-11 Chemat Technology, Inc. Coated implants and methods of coating
EP1952829A2 (fr) 2003-12-18 2008-08-06 Warsaw Orthopedic, Inc. Dégradation composite conçue pour implants spinaux
US7417077B2 (en) 2000-07-17 2008-08-26 Bone Support Ab Composition for an injectable bone mineral substitute material
EP2077126A1 (fr) * 2008-01-07 2009-07-08 Graftys Ciment calcium-phosphate apatitique analgésique
WO2008148878A3 (fr) * 2007-06-06 2009-11-26 Innotere Gmbh Matériau d'implant à base de ciment hydraulique et utilisation de celui-ci
KR100973470B1 (ko) * 2008-06-16 2010-08-02 인제대학교 산학협력단 칼시토닌-폴리포스페이트의 복합체 및 그의 제조방법
US7935121B2 (en) 2003-11-11 2011-05-03 Bone Support Ab Device for providing spongy bone with bone substitute and/or bone reinforcing material, bone substitute and/or bone reinforcing material and method
US7938572B2 (en) 2004-06-22 2011-05-10 Bone Support Ab Device for producing a hardenable mass
JP4778143B2 (ja) * 1998-07-28 2011-09-21 アルツケム トロストベルク ゲゼルシャフト ミット ベシュレンクテル ハフツング 骨または軟骨細胞および組織の治療用クレアチン化合物の使用
US8158752B2 (en) * 2003-09-09 2012-04-17 Two Cells Co., Ltd. Therapeutic agent and therapeutic method for periodontal diseases and pulpal diseases
EP2529764A1 (fr) 2011-05-31 2012-12-05 Curasan AG Matériau composite biodégradable
WO2014040061A1 (fr) * 2012-09-10 2014-03-13 Ortho Transmission, Llc Implant transcutané pour une fixation squelettique de dispositifs prothétiques externes
US8852672B2 (en) 2008-01-28 2014-10-07 Biomet 3I, Llc Implant surface with increased hydrophilicity
US8920842B2 (en) 1999-11-15 2014-12-30 Piramal Healthcare (Canada) Ltd. Temperature controlled and pH dependent self gelling biopolymeric aqueous solution
US9034201B2 (en) 2010-03-29 2015-05-19 Biomet 3I, Llc Titanium nano-scale etching on an implant surface
US9131995B2 (en) 2012-03-20 2015-09-15 Biomet 3I, Llc Surface treatment for an implant surface
US9180137B2 (en) 2010-02-09 2015-11-10 Bone Support Ab Preparation of bone cement compositions
US9763751B2 (en) 2005-11-14 2017-09-19 Biomet 3I, Llc Deposition of discrete nanoparticles on an implant surface
US10294107B2 (en) 2013-02-20 2019-05-21 Bone Support Ab Setting of hardenable bone substitute
CN112891639A (zh) * 2021-01-21 2021-06-04 西北工业大学 一种超薄碳质皮肤修复材料及制备方法
CN113913805A (zh) * 2021-10-20 2022-01-11 中南大学湘雅医院 一种冷喷涂改性层及其应用

Families Citing this family (6)

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JP4654427B2 (ja) * 2002-11-22 2011-03-23 独立行政法人産業技術総合研究所 骨形成を促進する水溶性タンパク質−リン酸カルシウム複合体およびその製造方法
FR2849436B1 (fr) * 2002-12-27 2007-01-05 Patrick Frayssinet Particules et ceramiques de phosphates de calcium pour transfection in vivo et in vitro
JP4604238B2 (ja) * 2003-09-19 2011-01-05 独立行政法人産業技術総合研究所 燐酸カルシウムと生理活性物質を含有する高分子複合体、その製造方法及びそれを用いた医療用材料
JP4569946B2 (ja) * 2003-10-21 2010-10-27 セルメディシン株式会社 リン酸カルシウム微粒子
FR2885525B1 (fr) * 2005-05-13 2009-09-18 Urodelia Sa Medicament notamment anti-cancereux, destine a des traitements par immunotherapie, en particulier autologue

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323632A1 (fr) * 1987-12-28 1989-07-12 Asahi Kogaku Kogyo Kabushiki Kaisha Composition pour la fabrication d'un matériau durcissable du type phosphate de calcium et procédé pour la production d'un tel matériau
USRE33221E (en) * 1982-04-29 1990-05-22 American Dental Association Health Foundation Dental restorative cement pastes
EP0389629A1 (fr) * 1988-08-10 1990-10-03 Nitta Gelatin Inc. Substance durcissante pour utilisations dentaires et medicales
GB2248232A (en) * 1990-09-27 1992-04-01 Mitsubishi Materials Corp Cement compositions
US5149368A (en) * 1991-01-10 1992-09-22 Liu Sung Tsuen Resorbable bioactive calcium phosphate cement
WO1994020064A1 (fr) * 1993-03-12 1994-09-15 American Dental Association Health Foundation Phosphate de calcium utilise comme precurseur de l'hydroxyapatite et procedes pour leur preparation et leur utilisation
JPH0731673A (ja) * 1993-07-19 1995-02-03 Asahi Optical Co Ltd 生体吸収性高分子含有硬化型骨補填材

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE33221E (en) * 1982-04-29 1990-05-22 American Dental Association Health Foundation Dental restorative cement pastes
EP0323632A1 (fr) * 1987-12-28 1989-07-12 Asahi Kogaku Kogyo Kabushiki Kaisha Composition pour la fabrication d'un matériau durcissable du type phosphate de calcium et procédé pour la production d'un tel matériau
EP0389629A1 (fr) * 1988-08-10 1990-10-03 Nitta Gelatin Inc. Substance durcissante pour utilisations dentaires et medicales
EP0538913A1 (fr) * 1988-08-10 1993-04-28 Nitta Gelatin Inc. Matériau durcissant pour usage médical et dentaire
GB2248232A (en) * 1990-09-27 1992-04-01 Mitsubishi Materials Corp Cement compositions
US5149368A (en) * 1991-01-10 1992-09-22 Liu Sung Tsuen Resorbable bioactive calcium phosphate cement
WO1994020064A1 (fr) * 1993-03-12 1994-09-15 American Dental Association Health Foundation Phosphate de calcium utilise comme precurseur de l'hydroxyapatite et procedes pour leur preparation et leur utilisation
JPH0731673A (ja) * 1993-07-19 1995-02-03 Asahi Optical Co Ltd 生体吸収性高分子含有硬化型骨補填材

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 9515, Derwent World Patents Index; AN 95-109588, XP002016014 *

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US6069295A (en) * 1996-05-10 2000-05-30 Isotis B.V. Implant material
US6143948A (en) * 1996-05-10 2000-11-07 Isotis B.V. Device for incorporation and release of biologically active agents
WO1998022154A3 (fr) * 1996-11-21 1998-10-22 Tissue Eng Inc Mousses de biopolymere pour la reparation et la reconstruction de tissus
WO1998047485A3 (fr) * 1997-04-24 1999-04-01 Takeda Chemical Industries Ltd Composition solide recouverte d'apatite
US6344209B1 (en) * 1997-04-24 2002-02-05 Takeda Chemical Industries, Ltd. Apatite-coated solid composition
US6811570B1 (en) 1997-10-21 2004-11-02 Augmentec Ag Implant made of a reabsorbable ceramic material
WO1999020319A1 (fr) * 1997-10-21 1999-04-29 Augmentec Aktiengesellschaft Implantologie-Epithetik Implant constitue d'un materiau ceramique pouvant se resorber
WO1999034844A1 (fr) * 1998-01-05 1999-07-15 Vrije Universiteit Matiere osseuse
NL1008582C2 (nl) * 1998-01-05 1999-07-06 Vrije Universiteit Botmateriaal.
WO1999052542A1 (fr) * 1998-04-09 1999-10-21 Roche Diagnostics Gmbh Utilisation de l'erythropoietine pour le traitement des hemochromatoses
US6676947B1 (en) * 1998-04-09 2004-01-13 Roche Diagnostics Gmbh Use of erythropoietin for the treatment of haemochromatoses
AU762262B2 (en) * 1998-07-02 2003-06-19 Stichting Skeletal Tissue Engineering Group Amsterdam Bone cement with antimicrobial peptides
WO2000001427A1 (fr) * 1998-07-02 2000-01-13 Stichting Skeletal Tissue Engineering Group Amsterdam Ciment a base d'os, contenant des peptides antimicrobiens
JP2002519155A (ja) * 1998-07-02 2002-07-02 スティヒティング・スケルトル・ティシュー・エンジニアリング・グループ・アムステルダム 抗微生物性ペプチドを有する骨セメント
US6123925A (en) * 1998-07-27 2000-09-26 Healthshield Technologies L.L.C. Antibiotic toothpaste
JP4778143B2 (ja) * 1998-07-28 2011-09-21 アルツケム トロストベルク ゲゼルシャフト ミット ベシュレンクテル ハフツング 骨または軟骨細胞および組織の治療用クレアチン化合物の使用
US8920842B2 (en) 1999-11-15 2014-12-30 Piramal Healthcare (Canada) Ltd. Temperature controlled and pH dependent self gelling biopolymeric aqueous solution
WO2001041821A1 (fr) * 1999-12-09 2001-06-14 Biosyntech Canada Inc. Composition hybride mineral-polymere
WO2001076649A1 (fr) * 2000-04-11 2001-10-18 Bone Support Ab Materiau de substitution du mineral osseux injectable
US7417077B2 (en) 2000-07-17 2008-08-26 Bone Support Ab Composition for an injectable bone mineral substitute material
WO2002060503A1 (fr) * 2001-02-01 2002-08-08 Am-Pharma B.V. Ciment d'os bioresorbable contenant des agents actifs
EP1228772A1 (fr) * 2001-02-01 2002-08-07 AM-Pharma B.V. Nouveau ciment osseux contenant des principes actifs
WO2004043495A1 (fr) * 2002-11-12 2004-05-27 The Circle For The Promotion Of Science And Engineering Agent d'administration, procede d'administration d'une substance cible dans des cellules, procedes d'obtention d'un agent d'administration, composition d'obtention d'un agent d'administration et kit d'obtention d'un agent d'administration
WO2004060425A3 (fr) * 2002-12-27 2005-01-06 Angiotech Pharm Inc Compositions et procedes d'utilisation de collajolie
US7648726B2 (en) 2003-06-04 2010-01-19 Chemat Technology, Inc. Coated implants and methods of coating
US7341756B2 (en) 2003-06-04 2008-03-11 Chemat Technology, Inc. Coated implants and methods of coating
US9089606B2 (en) 2003-09-09 2015-07-28 Two Cells Co., Ltd. Brain-derived neurotrophic factor or neurotrophin-4/5 to treat periodontal diseases and pulpal diseases
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US7935121B2 (en) 2003-11-11 2011-05-03 Bone Support Ab Device for providing spongy bone with bone substitute and/or bone reinforcing material, bone substitute and/or bone reinforcing material and method
US8034117B2 (en) 2003-12-09 2011-10-11 Hoya Corporation Bone replacement material
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WO2009087148A3 (fr) * 2008-01-07 2009-09-11 Graftys Ciment analgésique-phosphate de calcium apatitique
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Also Published As

Publication number Publication date
MX9709904A (es) 1998-08-30
JPH11506659A (ja) 1999-06-15
AU6149696A (en) 1996-12-24
AU723740B2 (en) 2000-09-07
EP0830149A1 (fr) 1998-03-25
CA2223596A1 (fr) 1996-12-12
BR9608344A (pt) 1999-01-05

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