US20130309275A1 - Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers - Google Patents

Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers Download PDF

Info

Publication number
US20130309275A1
US20130309275A1 US13/793,858 US201313793858A US2013309275A1 US 20130309275 A1 US20130309275 A1 US 20130309275A1 US 201313793858 A US201313793858 A US 201313793858A US 2013309275 A1 US2013309275 A1 US 2013309275A1
Authority
US
United States
Prior art keywords
composition
copolymer
poly
polymer
bioceramic
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US13/793,858
Inventor
Andrew J. Carter
Said Rizk
David P. Martin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tepha Inc
Original Assignee
Tepha 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 Tepha Inc filed Critical Tepha Inc
Priority to US13/793,858 priority Critical patent/US20130309275A1/en
Assigned to TEPHA, INC. reassignment TEPHA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARTER, ANDREW J., MARTIN, DAVID P., RIZK, SAID
Publication of US20130309275A1 publication Critical patent/US20130309275A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/127Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing fillers of phosphorus-containing inorganic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/128Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C45/00Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
    • B29C45/0053Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor combined with a final operation, e.g. shaping
    • B29C45/0055Shaping
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids

Definitions

  • “Blend” as generally used herein means a physical combination of different polymers, as opposed to a copolymer comprised of two or more different monomers.
  • poly-4-hydroxybutyrate P4HB
  • Copolymers include P4HB with another hydroxyacid, such as 3-hydroxybutyrate, and P4HB with glycolic acid or lactic acid monomer.
  • P4HB and copolymers thereof can be obtained from Tepha, Inc. of Lexington, Mass.
  • the polymer may comprise P4HB blended with other absorbable polymers such as homopolymers or copolymers of glycolic acid, lactic acid, p-dioxanone, trimethylene carbonate, ⁇ -caprolactone or copolymers containing 4HB.
  • the P4HB formulation comprise up to 70% by weight or 50% by volume of the composition.
  • compositions prepared with P4HB and copolymers thereof are less brittle than those prepared, for example, with PLLA.
  • Improved toughness of an implant is particularly important to prevent breakage of the implant either during implantation or prior to the conclusion of healing.
  • a DSM XploreTM 15 cm 3 Twin Screw Microcompounder was used to compound P4HB with 44 weight % of Calcium Carbonate at a temperature of 220° C.
  • the Calcium Carbonate had a nominal particle size of 10 microns.
  • Tacks of this design were also produced from PHA material without ceramic filler. Tacks of this design are suitable for use in plastic surgery procedures such as brow lifts to attach mesh to the skull.
  • TCP in a P4HB/TCP pellet and a P4HB/TCP pin was characterized by energy dispersive spectroscopy (EDS).
  • EDS energy dispersive spectroscopy
  • Each test sample was embedded in paraffin and cross-sectioned using a microtome. Cross sections in the transverse and longitudinal directions were obtained from each article.
  • the test articles were analyzed by EDS to verify the absence of foreign material, and to map the locations of TCP particles in the polymer medium.
  • Backscatter electron micrographs at 75 ⁇ and 500 ⁇ magnification were collected from each test article to examine the general distribution pattern of the TCP particles.
  • the TCP particles of both test samples were found to be evenly distributed through the polymer medium.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Composite Materials (AREA)
  • Materials Engineering (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Manufacturing & Machinery (AREA)
  • Mechanical Engineering (AREA)
  • Materials For Medical Uses (AREA)
  • Injection Moulding Of Plastics Or The Like (AREA)

Abstract

Compositions for making implants comprising high levels of resorbable bioceramics have been developed. These compositions comprise P4HB and copolymers thereof filled with bioceramics, and can be prepared with high levels of bioceramic without the compositions becoming too brittle for the intended application. A preferred embodiment comprises P4HB filled with β-TCP.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims benefit of U.S. Provisional Application No. 61/713,139 filed Oct. 12, 2012, and 61/649,506, filed May 21, 2012, both of which are herein incorporated by reference in their entirety.
  • FIELD OF THE INVENTION
  • The present invention generally relates to compositions and implants comprising resorbable bioceramics and poly-4-hydroxybutyrate and copolymers thereof. The compositions can be used in many types of implant applications including orthopedic, craniomaxillofacial, and dental applications, as well as in oral surgery, plastic and reconstructive surgery, ear, nose and throat surgery, and general surgery.
  • BACKGROUND OF THE INVENTION
  • Poly-4-hydroxybutyrate (P4HB) and copolymers thereof can be produced using transgenic fermentation methods, see, for example, U.S. Pat. No. 6,548,569 to Williams et al., and are produced commercially, for example, by Tepha, Inc. (Lexington, Mass.). Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is a strong, pliable thermoplastic polyester that, despite its biosynthetic route, has a relatively simple structure.
  • Figure US20130309275A1-20131121-C00001
  • The polymer belongs to a larger class of materials called polyhydroxyalkanoates (PHAs) that are produced by numerous microorganisms (see, for example, Steinbiichel A., et al. Diversity of Bacterial Polyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228 (1995)). In nature these polyesters are produced as storage granules inside cells, and serve to regulate energy metabolism. They are also of commercial interest because of their thermoplastic properties, biodegradability and relative ease of production. Several biosynthetic routes are currently known to produce P4HB as shown in FIG. 1.
  • Chemical synthesis of P4HB has been attempted, but it has been impossible to produce the polymer with a sufficiently high molecular weight that is necessary for most applications (see Hori, et al., Polymer 36:4703-4705 (1995); Houk, et al., J. Org. Chem., 73 (7):2674-2678 (2008); and Moore, T., et al., Biomaterials 26:3771-3782 (2005)). In fact, it has been calculated to be thermodynamically impossible to chemically synthesize a high molecular weight homopolymer under normal conditions (Moore, et al., Biomaterials 26:3771-3782 (2005)). Examples of high molecular weight P4HB and copolymers thereof with weight average molecular weights in the region of 50,000 to 1,000,000 Da are produced by Tepha, Inc. of Cambridge, Mass., using transgenic fermentation methods.
  • U.S. Pat. Nos. 6,245,537, 6,623,748 and 7,244,442 describe methods of making PHAs with little to no endotoxin, which are suitable for medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493, 6,867,247, 7,268,205, 7,179,883, 7,943,683, WO 09/085,823 to Ho et al., and WO 11/159,784 to Cahil et al. describe the use of PHAs to make medical devices. Copolymers of P4HB including 4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid are described in U.S. patent application No. 20030211131 by Martin and Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No. 6,323,010 to Skraly et al. Methods to control the molecular weight of PHA polymers produced by biosynthetic methods have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.
  • PHAs with controlled degradation and degradation in vivo of less than one year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764, 6,828,357, 6,867,248, and 6,878,758 to Williams et al. and WO 99/32536 to Martin et al. Applications of P4HB have been reviewed in Williams, S. F., et al., Polyesters, III, 4:91-127 (2002), and by Martin, D. et al. Medical Applications of Poly-4-hydroxybutyrate: A Strong Flexible Absorbable Biomaterial, Biochem. Eng. J. 16:97-105 (2003). Medical devices and applications of P4HB have also been disclosed by WO 00/56376 to Williams et al. Several patents including U.S. Pat. Nos. 6,555,123, 6,585,994, and 7,025,980 describe the use of PHAs in tissue repair and engineering.
  • Morbidities associated with the use of metallic implants have stimulated interest in the development of resorbable ceramic implants that can provide structural support for a variety of clinical applications (including load-bearing and non load-bearing applications), and provide osteointegration over time. Resorbable bioceramic compositions filled with tricalcium phosphate (TCP), calcium sulfate, and other calcium phosphate salt-based bioceramics have previously been developed. These include resorbable bioceramic compositions derived from high modulus resorbable polymers such as PLLA (poly-l-lactic acid), PDLLA (poly-DL-lactic acid) and PLGA (polylactic-co-glycolic acid) that have been filled with TCP in order to improve osteointegration of the implant, and to tailor the resorption rate of the implant. Typically, these implants are limited to 30 vol-% or less of TCP in the composition.
  • In order to further improve the osteointegration of resorbable bioceramic filled implants it would be desirable to identify degradable polymers that can be filled with bioceramics at higher levels. It would also be desirable to identify bioceramic filled implants incorporating higher levels of bioceramics to provide a range of compositions such that the resorption rate of the implant can be tailored to the tissue healing. In addition, it would be desirable to identify degradable polymers that can be filled with bioceramics that resorb faster than PLLA, are tougher and less brittle, and that do not break down to yield highly acidic metabolites in vivo that can cause inflammatory responses.
  • It is an object of the present invention to provide compositions of bioceramics with P4HB and copolymers thereof with enhanced osteointegration, enhanced mechanical properties, and controlled degradation profiles, that can be used in medical applications.
  • It is another object of the present invention to provide methods for manufacturing biocompatible implants derived from resorbable bioceramics with P4HB and copolymers thereof.
  • It is still another object of the present invention to provide devices manufactured from bioceramic compositions with P4HB and copolymers thereof.
  • SUMMARY OF THE INVENTION
  • Compositions for making implants comprising high levels of resorbable bioceramics have been developed. These compositions comprise P4HB and copolymers thereof filled with bioceramics. A preferred embodiment comprises P4HB filled with TCP.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a diagram of pathways leading to the biosynthesis of poly-4-hydroxybutyrate. Pathway enzymes are: 1. Succinic semialdehyde dehydrogenase, 2. 4-hydroxybutyrate dehydrogenase, 3. diol oxidoreductase, 4. aldehyde dehydrogenase, 5. Coenzyme A transferase and 6. PHA synthetase.
  • FIG. 2 is a prospective view of a tack made with the P4HB-bioceramic filled material of example 3.
  • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • “Poly-4-hydroxybutyrate” as generally used herein means a homopolymer comprising 4-hydroxybutyrate units. It may be referred to herein as P4HB or TephaFLEX® biomaterial (manufactured by Tepha, Inc., Lexington, Mass.).
  • “Copolymers of poly-4-hydroxybutyrate” as generally used herein means any polymer comprising 4-hydroxybutyrate with one or more different hydroxy acid units.
  • “Bioactive agent” is used herein to refer to therapeutic, prophylactic, and/or diagnostic agents. A biologically active agent is a substance used for, for example, the treatment, prevention, diagnosis, cure, or mitigation of a disease or disorder, a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. Bioactive agents include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body. Examples can include, but are not limited to, small-molecule drugs, peptides, proteins, antibodies, sugars, polysaccharides, nucleotides, oligonucleotides, hyaluronic acid and derivatives thereof, aptamers, siRNA, nucleic acids, and combinations thereof. “Bioactive agent” includes a single such agent and is also intended to include a plurality.
  • “Bioceramic” means a ceramic suitable for use or replacement in the human body.
  • “Biocompatible” as generally used herein means the biological response to the material or device being appropriate for the device's intended application in vivo. Any metabolites of these materials should also be biocompatible.
  • “Blend” as generally used herein means a physical combination of different polymers, as opposed to a copolymer comprised of two or more different monomers.
  • “Ceramic” means an inorganic, nonmetallic solid prepared by the action of heat and subsequent cooling.
  • “Molecular weight” as used herein, unless otherwise specified, refers to the weight average molecular weight (Mw), not the number average molecular weight (Mn), and is measured by GPC relative to polystyrene.
  • “Resorbable” as generally used herein means the material is broken down in the body and eventually eliminated from the body.
  • “Resorbable bioceramic” means a bioceramic that is used to replace or repair damaged tissue in the body, and is eventually resorbed such that the host replaces the implant. Examples include tricalcium phosphate (TCP), biphasic calcium phosphate (BCP), hydroxylapatite, calcium sulfate, calcium carbonate, and other calcium phosphate salt-based bioceramics, including bioactive glasses composed of SiO2, Na2O, CaO and P2O5 in specific proportions.
  • I. Compositions
  • Methods have been developed to produce bioceramic compositions comprising P4HB and copolymers thereof containing bioceramics at loadings up to 72% by weight and 50% by volume. These bioceramic compositions may be processed into biocompatible implants.
  • A. P4HB Polymer and Copolymers
  • The processes described herein can typically be used with poly-4-hydroxybutyrate (P4HB) or a copolymer thereof. Copolymers include P4HB with another hydroxyacid, such as 3-hydroxybutyrate, and P4HB with glycolic acid or lactic acid monomer. P4HB and copolymers thereof can be obtained from Tepha, Inc. of Lexington, Mass. The polymer may comprise P4HB blended with other absorbable polymers such as homopolymers or copolymers of glycolic acid, lactic acid, p-dioxanone, trimethylene carbonate, ε-caprolactone or copolymers containing 4HB.
  • The P4HB polymers or copolymers polymers typically have a molecular weight over 300, for example between 300 and 107. In some embodiments, the P4HB copolymers or copolymers have a molecular between 10,000 to 10,000,000 Daltons, preferably, a weight average molecular weight ranges from 1,000 to 800,000 Da. In some embodiments, the a weight average molecular weight between of the P4HB polymer or copolymer is between 50,000 and 1,000,000 Da, 50,000 and 1,000,000 Da, included.
  • In a preferred embodiment, the starting P4HB homopolymer and/or copolymers thereof are compounded with the bioceramic by metering in the desired ratio into a single or twin screw extruder wherein they are mixed prior to being extruded into pellets. These pellets can then be used to produce medical devices by existing processes used for thermoplastic polymers such as molding or extrusion.
  • B. Resorbable Bioceramics
  • Resorbable bioceramics that can be used in the processes described herein must be: (i) biocompatible, (ii) eventually be resorbed by the body, and (iii) permit the replacement or repair of damaged tissues in the body. Examples of resorbable bioceramics include tricalcium phosphate (α and β forms of tricalcium phosphate (TCP)—with a nominal composition of Ca3(PO4)2), biphasic calcium phosphate (BCP), hydroxylapatite, calcium sulfate, calcium carbonate, and other calcium phosphate salt-based bioceramics. Bio-active glasses may also be used. Bioactive glasses include bioactive glasses composed of SiO2, Na2O, CaO and P2O5 in specific proportions. The choice of bioceramic and particle size of the bioceramic will depend in part on the desired rate of resorption for the implant. In a preferred embodiment, P4HB polymer is filled with β-TCP, α-TCP or a combination thereof with a nominal particle size of 20 microns. In further embodiments, the particles may have a size or distribution between 0.1 and 500 microns.
  • P4HB polymers and copolymers may also be blended with other polymers or materials to improve polymer properties, and filled with resorbable bioceramics. The P4HB polymer and copolymers filled with bioceramics may also contain other additives including contrast agents, radiopaque markers or radioactive substances.
  • II. Methods of Manufacturing P4HB Polymer and Copolymer Devices Filled with Resorbable Bioceramics
  • A. Compounding of P4HB Polymer and Copolymers
  • Compositions of P4HB polymers and copolymers filled with resorbable bioceramics can be prepared by compounding using a single or twin screw extruder. Alternatively, the P4HB polymer and copolymers may be dissolved in a solvent, the bioceramic is then dispersed in the solvent solution, and the solvent removed by evaporation. Preferred solvents include acetone and chlorinated solvents such as methylene chloride and chloroform.
  • The P4HB formulation comprise up to 70% by weight or 50% by volume of the composition.
  • B. Processing of Composition into Medical Devices
  • The P4HB polymer and copolymers filled with resorbable bioceramics may be melt-processed into medical devices. In a preferred embodiment the devices may be injection molded or extruded.
  • The P4HB polymer and copolymer compositions filled with resorbable bioceramic have tensile or compressive modulus values higher than for the polymers alone. A particular advantage of using P4HB polymer or a copolymer thereof is the ability to prepare compositions with high percentages of bioceramic filler that are not brittle. In contrast to other degradable polymers such as PLLA, poly-3-hydroxybutyrate (P3HB, also denoted PHB), and polyhydroxybutyrate-co-valerate (PHBV), which are relatively brittle materials, P4HB polymer and copolymers thereof can help to toughen the resulting bioceramic composition. This means that at the same loading of bioceramic, compositions prepared with P4HB and copolymers thereof are less brittle than those prepared, for example, with PLLA. Improved toughness of an implant is particularly important to prevent breakage of the implant either during implantation or prior to the conclusion of healing.
  • Implants made from P4HB polymer and copolymers thereof filled with resorbable bioceramics have substantially improved properties for many medical applications relative to the same compositions made from brittle degradable thermoplastics.
  • If desired, implants made from P4HB polymer and copolymer compositions filled with resorbable bioceramics may incorporate bioactive agents. These may be added during the formulation process, during the processing into molded parts or by coating/impregnating implants.
  • Implants made from P4HB polymer and copolymer compositions filled with resorbable bioceramics may be used in the following medical devices, including, but not limited to, suture anchors, screws, pins, bone plates, interference screws, tacks, fasteners, rivets, staples, tissue engineering scaffolds, rotator cuff repair device, meniscus repair device, guided tissue repair/regeneration device, articular cartilage repair device, tendon repair device, plastic surgery devices (including devices for fixation of facial and breast cosmetic and reconstructive devices), spinal fusion devices, imaging devices, and bone graft substitutes.
  • Method of manufacturing are demonstrated by reference to the following non-limiting examples.
  • Example 1 Compounding of P4HB and β-TCP
  • P4HB (Mw 350 kDa) was compounded with β-TCP using a Leistritz twin screw extruder with β-TCP loadings on a weight basis (wt-%) of 8.5%, 38%, and 69% (corresponding to loadings on a volume basis, (vol-%) of 3.4%, 19%, and 45%).
  • The β-TCP had a mean particle size of 20±5 microns with 98% of the particles with a diameter of less than 75 microns. It conformed to ASTM F1088 with a purity, as measured by x-ray diffraction of >99%. The barrel temperature of the extruder increased from 100° C. at the feed zone to 190° C. at the die. The screws were rotated at 135 rpm. The extruded strands were cooled in a water bath before being pelletized. The ash contents of the compounded compositions, including pure P4HB, are shown in Table 1.
  • TABLE 1
    Ash contents of P4HB compounded with β-TCP
    Nominal wt- P4HB Actual β-TCP - Actual
    % β-TCP wt-% vol-% wt-% vol-%
    0 100 100 0 0
    10 91.5 96.6 8.5 3.4
    40 62 81 38 19
    72 31 55 69 45
  • Example 2 Injection Molding of P4HB Compounded with β-TCP
  • Two inch dog bone test pieces were injection molded using an Arburg model 221 injection molder from the four samples shown in Table 1 of Example 1 after the samples were dried in a vacuum oven at room temperature for 48 hours. The barrel temperature increased from 170° C. at the feed zone to 200° C. at the end of the barrel. The mold temperature was maintained at 32° C. Dog bone samples for each composition were tested for tensile properties in at least triplicate using an MTS test machine with a 2 inch/min cross head speed.
  • The tensile properties for each composition are shown in Table 2. Notably, the modulus of the compounded composition increases as the percentage of β-TCP in the composition increases.
  • TABLE 2
    Tensile test results for dog bones of P4HB filled at different levels
    with β-TCP
    Yield Break Strain at
    Modulus Stress Strain at Stress Break
    vol % Wt % (psi) (psi) Yield (%) (psi) (%)
    PHA 0 0  48,600 3,070 15 5,200 230
    Extruded
    PHA
    4 3.4 8.5  54,000 3,170 12 4,800 190
    PHA 20 19 38  81,900 3,000 14 3,300 92
    PHA 50 45 69 193,500 2,170 1 4
  • Example 3 Injection Molding of Interference Screws of P4HB Compounded with β-TCP
  • P4HB was compounded with β-TCP to provide a composition with 53 wt % β-TCP.
  • The intrinsic viscosity of the formulation prior to injection molding was 1.79 dL/g. Interference screws with a diameter of 7 mm and length of 20 mm were injection molded. After injection molding of the screws the intrinsic viscosity of the composition was essentially identical, indicating little loss of molecular weight during the injection molding process. For comparative testing, screws of the same design were molded from the P4HB alone.
  • The torsional strength of the screws was determined by embedding the tip of the screw in epoxy resin and measuring the maximum torque achieved by the screwdriver before failure. For the biocomposite screw, the average of three screws tested gave a value of 14.0 Ncm. For the P4HB screw, the average of three tests gave 7.3 Ncm. For comparison, an Arthrex Biointerference screw composed of PLLA was also tested. This gave an average failure torque of 12.1 Ncm.
  • Example 4 Compounding of P4HB with Calcium Carbonate
  • A DSM Xplore™ 15 cm3 Twin Screw Microcompounder was used to compound P4HB with 44 weight % of Calcium Carbonate at a temperature of 220° C. The Calcium Carbonate had a nominal particle size of 10 microns.
  • The rod of material extruded from the Microcompounder was collected and tensile testing showed it to have a modulus of 130 MPa and a strain at failure of 239% demonstrating that the compounded material was ductile.
  • Example 5 Tack for Attachment of Plastic Surgery Mesh
  • Rods of compounded material from Example 3 were produced at the same time as the injection molding of the interference screws. These rods were subsequently machined using a lathe to produce tacks. The design and dimensions (in mm) of the tacks are shown in FIG. 2.
  • Holes were produced in surrogate bone and cow bone using drills and awls and it was shown that the tack could be used to hold a resorbable mesh in place. Tacks of this design were also produced from PHA material without ceramic filler. Tacks of this design are suitable for use in plastic surgery procedures such as brow lifts to attach mesh to the skull.
  • Example 6 Analysis of TCP Distribution in a P4HB/TCP Blend and P4HB/TCP Device
  • The distribution of TCP in a P4HB/TCP pellet and a P4HB/TCP pin was characterized by energy dispersive spectroscopy (EDS). Each test sample was embedded in paraffin and cross-sectioned using a microtome. Cross sections in the transverse and longitudinal directions were obtained from each article. The test articles were analyzed by EDS to verify the absence of foreign material, and to map the locations of TCP particles in the polymer medium. Backscatter electron micrographs at 75× and 500× magnification were collected from each test article to examine the general distribution pattern of the TCP particles. The TCP particles of both test samples were found to be evenly distributed through the polymer medium.
  • Example 7 Assessment of Local Tissue Reaction to P4HB/TCP Pins in a Rabbit Tibial Defect Model and Retention of Shear Strength and Molecular Weight Loss in a Subcutaneous Pocket
  • The purpose of this study was to test the local response in bone to an implanted P4HB/TCP pin, and additionally the strength retention and molecular weight loss of the P4HB/TCP pins implanted subcutaneously. The test articles were 2×70 mm P4HB/TCP pins. For the bone implantation, Orthosorb® (poly-p-dioxanone (PDS)) Resorbable Pins measuring 2×40 mm were used as controls.
  • Two bilaterial drill defects were created in the tibia and filled with the test article (n=10) on one side, and a control article (n=10) on the other. The test and control articles were cylindrical implants approximately 2 mm in diameter and 6 mm in length. In addition, each animal had two rods, approximately 2×35 mm, of the test material implanted into separate subcutaneous pockets on the dorsal back that were retrieved at necropsy.
  • At necropsy, after an in-life period of 4 weeks, the tibial defect sites were excised, placed in formalin, and processed for standard histopathological analysis. One section was prepared from each implant, each stained by hemotoxylin/eosin (H&E). Each site was analyzed by a pathologist for local tissue reaction and any signs of bone development and ingrowth. The subcutaneously implanted test article was evaluated macroscopically for capsule formation or other signs of irritation and then tested for molecular weight retention by GPC relative to polystyrene, and shear strength.
  • The P4HB/TCP pins in the rabbit tibial drill model to assess local tissue reaction to bone implants at 4 weeks were found to be non-irritants when compared to the control article. The subcutaneously implanted P4HB/TCP pins were found to have retained 92% of their shear strength and 87% of their original weight average molecular weight after 4 weeks in vivo.

Claims (19)

We claim:
1. A biocompatible composition comprising poly-4-hydroxybutyrate polymer or copolymer thereof, wherein the poly-4-hydroxybutyrate polymer or copolymer has a weight average molecular weight between 1,000 and 800,000 Da, and a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition.
2. The composition of claim 1 wherein the bioceramic is α-tricalcium phosphate (TCP), β-TCP, a combination of α- and β-TCP, biphasic calcium phosphate (BCP), hydroxylapatite, calcium sulfate, calcium carbonate, or a calcium phosphate salt-based bioceramic.
3. The composition of claim 1 wherein the composition comprises a blend of one or more polymers with poly-4-hydroxybutyrate polymer or copolymer thereof.
4. The composition of claim 3 wherein the polymers are resorbable.
5. The composition of claim 4 wherein the one or more polymers are derived from glycolic acid, glycolide, lactic acid, lactide, p-dioxanone, trimethylene carbonate, or ε-caprolactone monomers.
6. The composition of claim 5 wherein the polymer is poly-L-lactic acid or poly-DL-lactic acid.
7. A medical device comprising a biocompatible composition of claim 1, wherein the poly-4-hydroxybutyrate polymer or copolymer thereof has a weight average molecular weight between 1,000 and 800,000 Da, and a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition.
8. The device of claim 7 wherein the device is formed by injection molding of the composition, extrusion of the composition, or by machining a modeled form of the composition.
9. The device of claim 8 selected from the group consisting of a suture anchor, screw, pin, bone plate, interference screw, tack, fastener, rivets, staples, tissue engineering scaffold, rotator cuff repair device, meniscus repair device, guided tissue repair/regeneration device, articular cartilage repair device, tendon repair device, ligament repair device, fixation device for an implant, fixation device for a plastic surgery device including facial and breast cosmetic and reconstructive devices, fixation device for a surgical mesh, facial reconstructive device, spinal fusion device, device for treatment of osteoarthritis, imaging device, and bone graft substitute.
10. The device of claim 7 having a tensile modulus of >50,000 psi (>0.34 MPa).
11. The device of claim 9 wherein the fixation device is used to fix surgical mesh to bone.
12. The device of claim 9 wherein the fixation device is used for a brow-lift.
13. The device of claim 7 wherein the device further comprises a bioactive agent, contrast agent, radiopaque marker and/or a radioactive substance.
14. The bioactive agent of claim 13 wherein the bioactive agent is a small-molecule drug, peptide, protein, antibody, sugar, polysaccharide, nucleotide, oligonucleotide, hyaluronic acid or derivatives thereof, aptamer, siRNA, or nucleic acid.
15. A method of preparing a biocompatible composition comprising poly-4-hydroxybutyrate polymer or copolymer thereof, wherein the polymer or copolymer has a weight average molecular weight between 1,000 and 800,000 Da, and a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition, comprising providing powder or pellets of the poly-4-hydroxybutyrate polymer or copolymer thereof and the bioceramic, heating to a melt temperature in the range of 150 to 300° C., and extruding the melted composition.
16. A method of preparing a biocompatible composition comprising injection molding at a melt temperature in the range of 150 to 300° C., a poly-4-hydroxybutyrate polymer or copolymer thereof, wherein the polymer or copolymer has a weight average molecular weight between 1,000 and 800,000 Da, together with a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition.
17. A method of preparing a biocompatible composition comprising solvent blending a poly-4-hydroxybutyrate polymer or copolymer thereof, wherein the polymer or copolymer has a weight average molecular weight between 1,000 and 800,000 Da, together with a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition.
18. A method of preparing a device comprising a biocompatible composition comprising a poly-4-hydroxybutyrate polymer or copolymer thereof, wherein the polymer or copolymer has a weight average molecular weight between 1,000 and 800,000 Da, together with a resorbable bioceramic comprising up to 70% by weight or 50% by volume of the composition, comprising machining a molded rod of the composition to produce the required device design.
19. The device of claim 7 wherein the device is formed by extrusion of the composition or by machining an extruded form of the composition.
US13/793,858 2012-05-21 2013-03-11 Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers Abandoned US20130309275A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/793,858 US20130309275A1 (en) 2012-05-21 2013-03-11 Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261649506P 2012-05-21 2012-05-21
US201261713139P 2012-10-12 2012-10-12
US13/793,858 US20130309275A1 (en) 2012-05-21 2013-03-11 Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers

Publications (1)

Publication Number Publication Date
US20130309275A1 true US20130309275A1 (en) 2013-11-21

Family

ID=48045691

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/793,858 Abandoned US20130309275A1 (en) 2012-05-21 2013-03-11 Resorbable Bioceramic Compositions of Poly-4-Hydroxybutyrate and Copolymers
US13/800,853 Active 2033-08-22 US9149561B2 (en) 2012-05-21 2013-03-13 Injection molding of poly-4-hydroxybutyrate

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/800,853 Active 2033-08-22 US9149561B2 (en) 2012-05-21 2013-03-13 Injection molding of poly-4-hydroxybutyrate

Country Status (4)

Country Link
US (2) US20130309275A1 (en)
EP (2) EP3238751B1 (en)
ES (2) ES2734126T3 (en)
WO (1) WO2013176734A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019112925A1 (en) 2017-12-04 2019-06-13 Tepha, Inc. Vacuum membrane thermoformed poly-4-hydroxybutyrate medical implants
US10525172B2 (en) 2014-09-22 2020-01-07 Tepha, Inc. Oriented P4HB implants containing antimicrobial agents
US20200261624A1 (en) * 2017-10-24 2020-08-20 Davol Inc. Soft tissue repair implants comprising hydroxybutyrate

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9687585B2 (en) 2013-08-20 2017-06-27 Tepha, Inc. Thermoformed poly-4-hydroxybutyrate medical implants
US9302029B2 (en) * 2013-10-31 2016-04-05 Tepha, Inc. Pultrusion of poly-4-hydroxybutyrate and copolymers thereof
ES2834498T3 (en) 2013-12-26 2021-06-17 Tepha Inc Medical implants including poly-4-hydroxybutyrate laminates and copolymers thereof
CN104098882B (en) * 2014-07-31 2016-01-20 宁国市日格美橡塑制品有限公司 A kind of degradable plastics material
WO2016028292A1 (en) * 2014-08-20 2016-02-25 Tepha, Inc. Thermoformed poly-4-hydroxybutyrate medical implants
DE102014017015A1 (en) * 2014-11-19 2016-05-19 Bio-Tec Biologische Naturverpackungen Gmbh & Co. Kg Biodegradable multilayer film
EP4442767A2 (en) 2018-06-11 2024-10-09 Tepha, Inc. Methods for 3d printing of poly-4-hydroxybutyrate

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8912388D0 (en) 1989-05-30 1989-07-12 Ici Plc 3-hydroxybutyrate polymer composition
JP3064470B2 (en) * 1991-04-19 2000-07-12 杉郎 大谷 Artificial prosthetic materials
JP3044857B2 (en) * 1991-09-12 2000-05-22 凸版印刷株式会社 Plastic container
AU3795395A (en) * 1994-11-30 1996-06-06 Ethicon Inc. Hard tissue bone cements and substitutes
US5811272A (en) 1996-07-26 1998-09-22 Massachusetts Institute Of Technology Method for controlling molecular weight of polyhydroxyalkanoates
US6867248B1 (en) 1997-05-12 2005-03-15 Metabolix, Inc. Polyhydroxyalkanoate compositions having controlled degradation rates
US6610764B1 (en) 1997-05-12 2003-08-26 Metabolix, Inc. Polyhydroxyalkanoate compositions having controlled degradation rates
US6245537B1 (en) 1997-05-12 2001-06-12 Metabolix, Inc. Removing endotoxin with an oxdizing agent from polyhydroxyalkanoates produced by fermentation
US6828357B1 (en) 1997-07-31 2004-12-07 Metabolix, Inc. Polyhydroxyalkanoate compositions having controlled degradation rates
US6309659B1 (en) 1997-09-02 2001-10-30 Gensci Orthobiologics, Inc. Reverse phase connective tissue repair composition
EP1015565B1 (en) 1997-09-19 2006-04-12 Metabolix, Inc. Biological systems for manufacture of polyhydroxyalkanoate polymers containing 4-hydroxyacids
EP2258742A1 (en) 1997-12-22 2010-12-08 Metabolix, Inc. Polyhydroxyalkanoate compositons having controlled degradation rates
EP2267133B1 (en) 1998-05-22 2017-07-12 CJ Research Center LLC Method for making poly(3-hydroxyproprionate)
GB9820874D0 (en) * 1998-09-26 1998-11-18 Smith & Nephew Melt-mouldable composites
DK1163019T3 (en) 1999-03-25 2008-03-03 Metabolix Inc Medical devices and applications of polyhydroxyalkanoate polymers
US7025980B1 (en) 1999-09-14 2006-04-11 Tepha, Inc. Polyhydroxyalkanoate compositions for soft tissue repair, augmentation, and viscosupplementation
EP1224715B1 (en) 2000-05-10 2008-07-16 Thomas & Betts International, Inc. Coaxial connector having detachable locking sleeve
ES2741964T3 (en) 2002-05-10 2020-02-12 Tepha Inc Bioabsorbable polymer containing 2-hydroxy acid monomers
CA2531833C (en) 2003-07-08 2009-10-20 Tepha, Inc. Poly-4-hydroxybutyrate matrices for sustained drug delivery
WO2006015316A1 (en) * 2004-07-30 2006-02-09 University Of Nebraska Bioresorbable composites and method of formation thereof
DK1778305T3 (en) 2004-08-03 2010-10-18 Tepha Inc Non-curly polyhydroxyalkanoate sutures
WO2007092417A1 (en) 2006-02-07 2007-08-16 Tepha, Inc. Toughened polylactic acid polymers and copolymers
WO2007140325A2 (en) * 2006-05-26 2007-12-06 University Of Nebraska Office Of Technology Development Bioresorbable polymer reconstituted ceramic matrices and methods of formation thereof
US7943683B2 (en) 2006-12-01 2011-05-17 Tepha, Inc. Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers
WO2008095083A1 (en) * 2007-01-31 2008-08-07 Board Of Regents Of The University Of Nebraska Bioresorbable polymer/calcium sulfate composites and method of formation thereof
ES2415104T3 (en) 2007-12-19 2013-07-24 Tepha, Inc. Medical devices containing molten-blown non-woven poly-4-hydroxybutyrate and copolymers
EP2427147A1 (en) * 2009-05-08 2012-03-14 Tornier, Inc. Joint reconstruction system and method
JP2013534978A (en) 2010-06-15 2013-09-09 テファ, インコーポレイテッド Medical device comprising dry-spun nonwoven of poly-4-hydroxybutyrate and copolymer
EP2637734B1 (en) 2010-11-09 2017-09-13 Tepha, Inc. Drug eluting cochlear implants
US8545546B2 (en) * 2011-05-13 2013-10-01 Abbott Cardiovascular Systems Inc. Bioabsorbable scaffolds made from composites

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10525172B2 (en) 2014-09-22 2020-01-07 Tepha, Inc. Oriented P4HB implants containing antimicrobial agents
US10874771B2 (en) 2014-09-22 2020-12-29 Tepha, Inc. Oriented P4HB implants containing antimicrobial agents
US20200261624A1 (en) * 2017-10-24 2020-08-20 Davol Inc. Soft tissue repair implants comprising hydroxybutyrate
WO2019112925A1 (en) 2017-12-04 2019-06-13 Tepha, Inc. Vacuum membrane thermoformed poly-4-hydroxybutyrate medical implants

Also Published As

Publication number Publication date
EP2852417B1 (en) 2019-06-12
WO2013176734A1 (en) 2013-11-28
EP2852417A1 (en) 2015-04-01
ES2734126T3 (en) 2019-12-04
ES2822000T3 (en) 2021-04-28
EP3238751B1 (en) 2020-07-08
EP3238751A1 (en) 2017-11-01
US9149561B2 (en) 2015-10-06
US20130309166A1 (en) 2013-11-21

Similar Documents

Publication Publication Date Title
EP2852417B1 (en) Resorbable bioceramic compositions of poly-4-hydroxybutyrate and copolymers
US7012106B2 (en) Reinforced implantable medical devices
Heidemann et al. Degradation of poly (D, L) lactide implants with or without addition of calciumphosphates in vivo
Hasırcı et al. Versatility of biodegradable biopolymers: degradability and an in vivo application
JP6719447B2 (en) Anisotropic biocomposite material, medical implant containing anisotropic biocomposite material, and method for treating such medical implant
KR101742017B1 (en) Resorbable and biocompatible fibre glass compositions and their uses
Gunatillake et al. Recent developments in biodegradable synthetic polymers
Cameron et al. Synthetic bioresorbable polymers
AU2004303600B2 (en) Tunable segmented polyacetal
EP1804850B1 (en) Bioabsorbable polymers comprising calcium carbonate
Adeosun et al. Characteristics of biodegradable implants
Tams et al. High-impact poly (L/D-lactide) for fracture fixation: in vitro degradation and animal pilot study
Szczepanska et al. Influence of ceramic phosphate powders on the physicochemical and biological properties of Poly (L-lactide)
Demina et al. Biodegradable nanostructured composites for surgery and regenerative medicine
WO2000018443A1 (en) Melt-mouldable composites
Nonhoff et al. The Potential for Foreign Body Reaction of Implanted Poly-L-Lactic Acid: A Systematic Review
Schroeter et al. Biodegradable materials
Kaur et al. Polymers as bioactive materials II: synthetic/biodegradable polymers and composites
Rizzarelli et al. Analytical methods in resorbable polymer development and degradation tracking
US20240325598A1 (en) Compositions having chair-side handling properties for dental and soft tissue applications
Bargmann et al. PLA-Based Biodegradable and Cytocompatible Implant Materials: Material Development, Processing and Properties
Rich In vitro characterization of bioresorbable polymers and composites for drug delivery and bone replacement
US9777148B2 (en) Biocompatible material and device
CN118755249A (en) Absorbable interface screw
Lebens III The study of hydroxyapatite reinforced polylactic acid composites for orthopedic applications

Legal Events

Date Code Title Description
AS Assignment

Owner name: TEPHA, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CARTER, ANDREW J.;RIZK, SAID;MARTIN, DAVID P.;SIGNING DATES FROM 20130322 TO 20130409;REEL/FRAME:030216/0232

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION