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WO2017019959A1 - Formulations et procédés pour la récupération après une chirurgie de la colonne vertébrale - Google Patents

Formulations et procédés pour la récupération après une chirurgie de la colonne vertébrale Download PDF

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Publication number
WO2017019959A1
WO2017019959A1 PCT/US2016/044714 US2016044714W WO2017019959A1 WO 2017019959 A1 WO2017019959 A1 WO 2017019959A1 US 2016044714 W US2016044714 W US 2016044714W WO 2017019959 A1 WO2017019959 A1 WO 2017019959A1
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WO
WIPO (PCT)
Prior art keywords
dexamethasone
composition
patient
bone
spinal
Prior art date
Application number
PCT/US2016/044714
Other languages
English (en)
Inventor
James Rutkowski
Original Assignee
Clarion Research Group
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 Clarion Research Group filed Critical Clarion Research Group
Publication of WO2017019959A1 publication Critical patent/WO2017019959A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite 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
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs

Definitions

  • the present invention relates generally to the field of surgery generally and to spinal surgery specifically and methods to improve recovery after surgery by promoting faster bone healing and de novo bone growth.
  • the present invention is directed to methods and formulations for the
  • compositions relate to a bone filler or bone graft extending composition for promoting bone growth following spinal fusion surgery in a patient that is used in with spinal stabilization hardware.
  • the composition comprises:
  • a scaffolding material comprising a Type 1 collagen matrix and a crystalline non-ceramic form of hydroxylapatite
  • dexamethasone or a pharmaceutically acceptable salt thereof dissolved in saline.
  • the dexamethasone is used at a concentration between about 10 ⁇ 9 to 10 ⁇ 7 molar; and the dexamethasone is present from about 0.1 to about 1.0 ml per cc of scaffolding material; and the total dose of dexamethasone may preferably be 1.2 mg. .
  • the dexamethasone can be substituted with a glucocorticoid selected from the group consisting of: betamethasone, triamcinolone hexacetonide, prednisone, hydrocortisone, fludrocortisone acetate, aldosterone, cortisone acetate, and derivatives and structural analogs thereof.
  • a glucocorticoid selected from the group consisting of: betamethasone, triamcinolone hexacetonide, prednisone, hydrocortisone, fludrocortisone acetate, aldosterone, cortisone acetate, and derivatives and structural analogs thereof.
  • glucocorticoids can be used.
  • Additional reagents may be present in the composition including, melatonin, tri- calcium phosphate, platelet-rich plasma, platelet-rich fibrin, bone marrow aspirate concentrate, bone marrow aspirate, whole blood, allografts, alloplasts, xenografts, autogenous bone grafts, purmorphamine, 17- ⁇ estradiol, alendronate and Vitamin K2 or antibiotics.
  • spinal immobilization is also employed and may be for example, an anterior cage, or a rod and screw fixation device.
  • compositions are used in spinal fusion procedure performed on a patient suffering from degenerative disc disease, Grade 1
  • the invention also provides therapeutic methods for promoting de novo bone growth in a patient undergoing spinal fusion procedures, using compositions of the invention. Following placement of an appropriate anterior lumbar interbody fusion case in the targeted lumbar interbody space; a sterile sodium chloride 0.9% solution is added to the dexamethasone sodium phosphate and mixed mixing to dissolve the
  • dexamethasone sodium phosphate to make a dexamethasone-saline solution.
  • This solution is applied to the scaffolding material comprising Type 1 collagen matrix and a crystalline non-ceramic form of hydroxylapatite to make a prepared scaffolding material.
  • the prepared scaffolding material is placed into the hardware cage; and subsequent surgical steps for completion of the spinal fusion procedure are performed.
  • the dexamethasone may be used at a concentration between about 10 "9 to 10 "7 molar; and the dexamethasone may be present from about 0.1 to about 1.0 ml per cc of scaffolding material and wherein the total dose of dexamethasone is 1.2 mg.
  • the total dose of dexamethasone may range, depending on the exact application, from 0.5 to 5.0 mg.
  • the spinal immobilization hardware may be, for example, an interbody fusion device including interbody fusion cases, allograft cages, etc., an anterior cage, a rod and screw fixation device, and/or an anterior plate device.
  • the spinal fusion procedure is performed on a patient suffering from
  • degenerative disc disease Grade 1 spondylolistesis or grade 1 restrolisthesis and is performed in a skeletally mature patient.
  • composition may be implanted in any desireable surgerical means. As a nonlimiting example, it may be implanted via an anterior open or laparascopic approach.
  • Kits may also be provided comprising various components of the compositions, as well as syringes and instructions in use of the kit components.
  • the glucocorticoid may be included in a vial in a preset amount for ease in dilution for the user.
  • the kit may optionally include a predetermined volume of saline to allow for appropriate dilution of the glucocorticoid and simple administration by the user.
  • compositions and methods of the invention may also utilize a blood component such as PRP.
  • a blood component such as PRP.
  • Figure 1 provides a graph showing mean bone density testing results after lumbar spinal fusion, comparing using "CRGrafting" (a composition of the invention) as compared to results not using these compositions. It provides the percent increase in Hounsfield Units.
  • Figure 2 provides a graph showing mean Hounsfield units over time at the grafting site.
  • Figure 3 provides bone density as measured in Hounsfield units using
  • Figure 4 provides a graph showing an increase as measured in Hounsfield units over time at the grafting site.
  • Figure 5 provides a graph showing an increase as measured in Hounsfield units over time at the adjacent bone.
  • Figure 6 provides a graph showing an increase as measured in Hounsfield units over time at the disk.
  • the present invention encompasses formulations and methods for the treatment of patients following bone-impacting surgery or injury. While the present invention is described with regards to spinal surgery, the formulations and methods of the present invention are equally applicable to patients recovering from any bone-impacting surgery or injury. For example, the present invention may be used in cervical spinal fusion and it can also be used in the healing of long bone fractures. The present formulations and methods preferably improve the recovery of patients through generating a synergistic effect between the individual components of the formulation.
  • One benefit of the present invention is an increased rate of bone growth and de novo bone growth.
  • Formulations for promoting spinal bone growth following spinal surgery include a scaffolding material containing a collagen matrix and a non ceramic form of hydroxylapatite; and a glucocorticoid hormone.
  • the collagen matrix may be Type I collagen isolated from animal sources or may be a synthetic collagen.
  • a publically available collagen matrix is sold under the trade name of OSTEOTAPE®.
  • a matrix or scaffold is applied to the surgical site to promote bone growth and recovery.
  • the collagen-containing matrix may take numerous forms including a collagen-containing sheet, strip of tape, plug, or powder.
  • the collagen-containing matrix material maybe a collagen tape, such as OSTEOTAPE®.
  • the non ceramic form of hydroxyapatite may be used at about 250 mg for a piece of 20x60 x 2.5 mm collagen tape.
  • the hydroxylapatite may be used at ratio of about around 80 mg per cc of collagen matrix.
  • the non ceramic form of hydroxylapatite (Ca5(P0 4 )3(OH)) is a highly crystalline material, with higher purity and crystallinity than ceramic hydroxylapatite as specified by ASTM standards. It has no ⁇ / ⁇ tricalcium phosphates, amorphous phases, or bone inhibiting pyrophosphates, as found in ceramic HA products (which are devoid of the hydroxyl group, due to their sintering process).
  • a publically available form of non- ceramic form of hydroxylapatite is sold under the trade name of OSTEOGEN®.
  • the non ceramic form of hydroxylapatite may be combined with the collagen matrix material to mimic the natural collagen matrix and mineral porous structure of human bone and provide a scaffold for de- novo growth.
  • the non ceramic form of hydroxylapatite may be contained in the collagen matric material itself, or applied to the collagen matrix material.
  • the combination of collagen scaffolding and hydroxyapatite also works to prevent soft tissue in-growth with the early angiogenesis, and provides a mechanism for release of the pharmaceutical agents.
  • the glucocorticoid hormones may be dexamethasone, betamethasone, and pharmaceutically acceptable salts thereof.
  • Dexamethasone sodium phosphate (CAS Number 50-02-2) (C22H29FO5) is a preferred glucocorticoid.
  • Other glucocorticoids that may be used include, but are not limited to, triamcinolone hexacetonide, prednisone, hydrocortisone, fludrocortisone acetate, aldosterone, cortisone acetate, and derivatives and structural analogs thereof.
  • Other glucocorticoids are well known in the art and may also be employed within the context of the present invention. Triamcinolone
  • hexacetonide may be included as either ARISTOSPAN or KENALOG-10.
  • compositions of the invention also include mixtures of glucocorticoid hormones.
  • dexamethasone or a pharmaceutically acceptable salt thereof is dissolved in saline and is applied to the spinal bone surgery cite in a patient.
  • the dexamethasone is used at a concentration between 10 ⁇ 9 to 10 ⁇ 7 molar, final concentration.
  • the dexamethasone is used at about 0.1 to about 1.0 ml per cc of collagen scaffolding material used at the site.
  • dexamethasone When employed within the context of the present invention dexamethasone, betamethasone, triamcinolone hexacetonide, or pharmaceutically acceptable salts thereof may be used at about 10 "9 to 10 "7 molar with between about 0.1 and about 1.0 milliliters being administered to the patient at the surgical site per cc of grafting material.
  • matrices or scaffolds such as block, crystal, or powder forms of ⁇ -tricalcium phosphate either alone or mixed with a xenograft material with or without collagen; osteoblastic cell sheet with or without a scaffolding matrix; collagen-chitosan-hydroxyapatite nano-composite scaffolds; poly(3- hydroxybutyrate-co-3-hydroxyhexanoate)-(PHBHHx); poly(3-hydroxybutyrate)-(PHB); poly(3-hydroxybutyrate-co-3-hydroxyvalerate)-(PHBV).
  • Other commonly employed collagen containing matrix materials may also be used within the context of the present invention.
  • compositions described herein may use TCP (tri-calcium phosphate) instead of hydroxylapatite, or may use mixtures of TCP and hydroxyapatite.
  • TCP tri-calcium phosphate
  • allograft bone, PRP (platelet-rich plasma), PRF (platelet-rich fibrin), BMAC (bone marrow aspirate concentrate), bone marrow aspirate, whole blood, alloplast, or autogenous bone may be used in addition to the collagen-containing scaffolding material with the hydroxylapatite or the TCP or mixtures of hydroxyapatite and TCP.
  • pharmaceutical agents that possess the characteristic of inducing differentiation of mesenchymal stem cells into osteoblasts may be employed in combination with the blood component and glucocorticoid hormone.
  • Such compounds include, but are not limited to, melatonin, 17p-estradiol, purmorphamine,
  • bisphosphonates e.g., alendronate, risedronate, ibandronate
  • vitamin K2 e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolinate, kaolinate, kaolinate, ibandronate), vitamin K2 and platelet rich plasma (PRP).
  • alendronate e.g., alendronate, risedronate, ibandronate
  • PRP platelet rich plasma
  • compositions may also employ growth factors such as insulin-like growth factor, bone morphogenetic protein, or transforming growth factor-h, including derivatives or analogs of those recited compounds. Numerous other examples of compounds within those generic groups are well known in the art and could be employed within the context of the present invention as well known to those of skill in the art. Compositions may also comprise antibiotics.
  • growth factors such as insulin-like growth factor, bone morphogenetic protein, or transforming growth factor-h, including derivatives or analogs of those recited compounds.
  • growth factors such as insulin-like growth factor, bone morphogenetic protein, or transforming growth factor-h, including derivatives or analogs of those recited compounds. Numerous other examples of compounds within those generic groups are well known in the art and could be employed within the context of the present invention as well known to those of skill in the art. Compositions may also comprise antibiotics.
  • compositions may include a blood component that is obtained from the patient on whom the spinal surgery is being performed. When whole blood is used, it may be obtained either from the surgical site or through venipuncture through standard phlebotomy techniques. For platelet-rich plasma and platelet-rich fibrin, platelet enrichment may be achieved by standard practices that are currently employed throughout the medical community, such as centrifugation. Standard practices that are currently employed throughout the medical community may be used to obtain bone marrow aspirate concentrate. By using blood components from the same patient, the formulations of the present invention would avoid any medical complications that might arise from the use of blood products from another individual.
  • the specific volume of the blood component to be administered to the patient varies widely depending on the type and size of the surgical site. Volumes may range from about 100 microliters to about 1 milliliter per cc of bone grafting material.
  • Platelet-rich-plasma is a highly concentrated suspension of platelets with minimal plasma that has been used as a healing aid.
  • blood is withdrawn from a patient and centrifuged, resulting in distinct layers in the blood. Through the isolation of one of the layers (buffy coat), a volume of PRP may be obtained.
  • the PRP suspension may be applied to a site of a wound to promote healing.
  • PRP's use has been clinically shown to decrease healing time for patients undergoing surgical procedures (e.g., extractions, bone grafts, implant placement) as well as decrease the incidence of complications resulting from the surgery. While generation of PRP involves additional steps for its production, whole blood may be more easily obtained from patients— either from direct extraction at the surgical site or by employing standard phlebotomy techniques.
  • Platelet-rich plasma may be obtained in the following manner.
  • Whole blood is drawn from a patient using a 21 gauge 1.5 inch latex- free needle, and 4.5 mL or 9.0 mL vacutainer blood collection tubes containing approximately 0.45— 0.9 mL of the anticoagulant trisodium citrate (9:1).
  • the vacutainer tubes are centrifuged for various times at 1150-1350 x g using a clinical centrifuge to assess the optimal spin time (typically 6 to 10 minutes) for the recovery of platelets in PRP. After centrifugation, the tubes are removed and placed in a test tube rack on the bench. The red blood cell/plasma interface is allowed to settle for at least 3 minutes. Pre-made labels can be placed on the outside of the tube to reproducibly delineate the PRP layer to be harvested. The PRP layer of the centrifuged blood is then carefully extracted from the suspension.
  • concentration of additional pharmaceutical agent employed in the formulations of the present invention may vary widely depending on the compound itself and the type of surgery or injury from which the patient is recovering. Accordingly, the following concentrations are meant to be illustrative and not limiting.
  • Melatonin may be used at about 25 nanomoles/milliliter to about 500
  • micromoles/milliliter with between about 0.1 and about 5 milliliters being administered to the patient at the surgical site per cc of grafting material.
  • Purmorphamine may be used at about 0.01 to about 1000 micromoles/milliliter with between about 0.1 and about 5 milliliters being administered to the patient at the surgical site per cc of grafting material
  • 17- ⁇ estradiol may be used at about 1 nanomoles/milliliter to about 100 micromoles/milliliter with between about 0.1 and about 5 milliliters being administered to the patient at the surgical site per cc of grafting material.
  • Alendronate may be used at about 0.1 nanomoles/milliliter to about 1000 micromoles/milliliter with between about 0.1 and about 5 milliliters being administered to the patient at the surgical site per cc of grafting material.
  • Vitamin K2 may be used at about 1 to about 1000 micromoles/milliliter with between about 0.1 and about 5 milliliters being administered to the patient at the surgical site per cc of grafting material. Sustained release
  • the scaffolding material may also contain chemical components that support sustained release vary depending on the particular pharmaceutical agent that is employed in the formulation.
  • chemical components that support sustained release such as silane-based and lactone-based polymers, as well as polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxy butyrate, and copolymers thereof.
  • pharmaceutical agent or agents may be micro- or nano-encapsulated to provide for their sustained release.
  • the blood component and/or the glucocorticoid may be mixed with or coated onto the collagen matrix prior to placement at the surgical site.
  • the glucocorticoid hormones or other additional agent components of the formulations of the present invention may be initially in powder form. They may then be reconstituted in the cellular suspension at the time of administration for application to the surgical or injury site. Alternatively, the formulations could be formulated in sterile aliquots and stored for extended periods of time prior to administration. These sterile aliquots may be included in a kit for use during treatment of patients.
  • the formulations of the present invention that include a pharmaceutical agent and a blood component may also be combined with additional compounds and reagents to improve patient recovery.
  • additional reagents may include autogenous bone grafts (e.g., cancellous or cortical), allografts (e.g., irradiated cancellous bone, demineralized freeze-dried bone, mineralized freeze-dried bone), alloplasts, and xenografts.
  • the formulation may also include antibiotics (e.g., neomycin, clindamycin, or polymyxin B).
  • the formulation of the present invention may also be used in conjunction with immobilization hardware, such as anterior cages.
  • Anterior cages contemplated in this present invention include, Innovasis ABox® system, IntegraTM ZUMA-CTM, Integra RedondoTM, SynFix® LR system. Some anterior cages are attached with separate hardware, while others will have integrated screws and/or blades for fixation. Anterior cages without fixation would further require the use of an anterior plate, such as Synthes Antegra-T system or Synthes Anterior Tension Band system. Other methods of fixation include Innovasis Excella® Rod and pedicle screw devices, which are also acceptable in place of the anterior plate.

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

Abstract

La présente invention concerne des procédés et une composition pour l'amélioration de la récupération après une lésion médullaire ou la chirurgie de la colonne vertébrale ayant un impact sur l'os. La composition comprend un matériau d'échafaudage comprenant une matrice de collagène de type 1 et une forme cristalline non céramique d'hydroxyapatite, et de la dexaméthasone ou un sel pharmaceutiquement acceptable de celle-ci ou une hormone glucocorticoïde dissoute dans une solution saline. Un avantage de la présente invention est une vitesse accrue de la croissance osseuse et de la nouvelle croissance osseuse.
PCT/US2016/044714 2015-07-30 2016-07-29 Formulations et procédés pour la récupération après une chirurgie de la colonne vertébrale WO2017019959A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562198945P 2015-07-30 2015-07-30
US62/198,945 2015-07-30

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WO2017019959A1 true WO2017019959A1 (fr) 2017-02-02

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070077267A1 (en) * 2005-10-03 2007-04-05 Sdgi Holdings, Inc. Bioactive composite implants
WO2013043529A1 (fr) * 2011-09-19 2013-03-28 Emory University Activation de la voie de la protéine morphogénétique osseuse, compositions pour ossification et méthodes associées
US8431148B2 (en) * 2007-03-08 2013-04-30 Warsaw Orthopedic, Inc. Bone void filler
US20140134211A1 (en) * 2008-05-30 2014-05-15 James Louis Rutkowski Formulations and Methods for Recovery From Dental Surgery
US20140294985A1 (en) * 2011-10-21 2014-10-02 University Of Maryland,Baltimore Bone pastes comprising biofunctionalized calcium phosphate cements with enhanced cell functions for bone repair
US20140303744A1 (en) * 2002-06-13 2014-10-09 Kensey Nash Corporation Devices and methods for treating defects in the tissue of a living being
US20140308332A1 (en) * 2010-12-13 2014-10-16 Biomimetic Therapeutics, Llc Compositions and Methods for Spine Fusion Procedures

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303744A1 (en) * 2002-06-13 2014-10-09 Kensey Nash Corporation Devices and methods for treating defects in the tissue of a living being
US20070077267A1 (en) * 2005-10-03 2007-04-05 Sdgi Holdings, Inc. Bioactive composite implants
US8431148B2 (en) * 2007-03-08 2013-04-30 Warsaw Orthopedic, Inc. Bone void filler
US20140134211A1 (en) * 2008-05-30 2014-05-15 James Louis Rutkowski Formulations and Methods for Recovery From Dental Surgery
US20140308332A1 (en) * 2010-12-13 2014-10-16 Biomimetic Therapeutics, Llc Compositions and Methods for Spine Fusion Procedures
WO2013043529A1 (fr) * 2011-09-19 2013-03-28 Emory University Activation de la voie de la protéine morphogénétique osseuse, compositions pour ossification et méthodes associées
US20140294985A1 (en) * 2011-10-21 2014-10-02 University Of Maryland,Baltimore Bone pastes comprising biofunctionalized calcium phosphate cements with enhanced cell functions for bone repair

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