EP4126089A1 - Procédés de production d'un matériau de phosphate de calcium ostéo-inducteur pour greffe osseuse - Google Patents

Procédés de production d'un matériau de phosphate de calcium ostéo-inducteur pour greffe osseuse

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Publication number
EP4126089A1
EP4126089A1 EP20927892.8A EP20927892A EP4126089A1 EP 4126089 A1 EP4126089 A1 EP 4126089A1 EP 20927892 A EP20927892 A EP 20927892A EP 4126089 A1 EP4126089 A1 EP 4126089A1
Authority
EP
European Patent Office
Prior art keywords
granule
granules
needle
soaking
calcium phosphate
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.)
Pending
Application number
EP20927892.8A
Other languages
German (de)
English (en)
Other versions
EP4126089A4 (fr
Inventor
Sahil Jalota
Russell Cook
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.)
Secada Medical dba Ventris Medical Llc LLC
Original Assignee
Secada Medical dba Ventris Medical Llc LLC
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 Secada Medical dba Ventris Medical Llc LLC filed Critical Secada Medical dba Ventris Medical Llc LLC
Publication of EP4126089A1 publication Critical patent/EP4126089A1/fr
Publication of EP4126089A4 publication Critical patent/EP4126089A4/fr
Pending legal-status Critical Current

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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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, 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
    • A61L27/02—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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present disclosure generally relates to methods of producing a bone grafting product and use of such products.
  • Osteoconductivity is the ability to serve as a scaffold for new bone growth while osteoinductivity refers to the ability of graft material to induce de novo bone growth with biomimetic substances, such as bone morphogenetic proteins.
  • Calcium phosphates may include hydroxyapatite (HA) or beta- tricalcium phosphate (PTCP) or biphasic calcium phosphate (a combination of HA and PTCP).
  • HA hydroxyapatite
  • PTCP beta- tricalcium phosphate
  • biphasic calcium phosphate a combination of HA and PTCP.
  • the osteoinductivity of calcium phosphates is a qualitative feature and depends on various material parameters. A way to improve the osteoinductivity of calcium phosphates is through manipulation of its surface morphology including the cultivation of HA needles or nanorods on the material surface instead of the inherent grain-like morphology of the post-sintering starting material.
  • the present invention provides methods for preparing biphasic calcium phosphate materials with an osteoinductivity-boosting needle-like or nanorod-like surface morphology using chemical processes including exposure to peroxides (e.g., hydrogen peroxide).
  • Methods of the invention are able to produce the desired needle-like or nanorod-like surface morphology on biphasic calcium phosphate materials of any ratio including bTOR/HA granules with bT €R content below 80% or even 40%.
  • the inclusion of chemical processing methods of the invention avoids the need for higher heat and pressure hydrothermal treatments while still providing the osteoinductivity-increasing surface characteristics.
  • the post-processing surface morphology of the biphasic material of the invention provides increased osteoinductivity and, therefore, a superior artificial bone material suitable for a variety of orthopedic and maxillofacial treatments.
  • chemical processing methods include exposing biphasic calcium phosphate materials to a peroxide (e.g., hydrogen peroxide) for a period sufficient to generate a needle-like or nanorod-like surface morphology on the material.
  • a peroxide e.g., hydrogen peroxide
  • the peroxide exposure may take place at room temperature or temperatures higher than room temperature in a sealed container. This treatment can be performed either before or after hydrothermal treatment.
  • peroxide exposure can reduce the required temperature, pressure, and/or time of hydrothermal treatments while delivering a bone graft product with high osteoinductivity.
  • Methods of the invention are able to produce the desired needle-like or nanorod-like surface morphology on biphasic calcium phosphate materials of any ratio including bTOR/HA granules with less than 80% bT €R content.
  • Methods of the invention are compatible with biphasic calcium phosphate starting granules in a variety of sizes (e.g., 0.1 - 10 mm). Treatment methods may vary depending on the composition of the starting material. For example, biphasic granules consisting of 20% HA and 80% bTOR (20/80 granules) can be subjected to a chemical treatment that requires soaking in hydrogen peroxide at less than 125°C to develop the desired needle-like or nanorod-like surface morphology while 60/40 granules may first undergo a hydrothermal treatment at temperatures above 125°C followed by a chemical treatment such as soaking in a hydrogen peroxide solution at temperatures less than 125°C to replicate the desired needle-like or nanorod-like surface morphology.
  • Biphasic calcium phosphate of the invention can have a particle size ranging from about 0.1mm to about 10mm and can be used as a medical implant material or tissue scaffold.
  • Granules of the invention may be used in injections with or without a carrier fluid.
  • the material may be formed into a composite of any size and shape depending on the desired application and can be sized on-site to repair a specific bone defect.
  • aspects of the invention include methods for producing a bone grafting product including steps of providing a granule comprising hydroxyapatite (HA) and b-tricalcium phosphate (b- TCP) and conducting a process on the granule to produce one or more HA needle-like or nanorod-like protrusions from the surface of the granule, wherein the process comprises soaking the granule in a solution comprising a peroxide.
  • the process may further include hydrothermally treating the granule prior to soaking.
  • the hydrothermal treatment can include autoclaving the granule at about 140 °C.
  • the granule may be autoclaved at about 140 °C for about 8 hours.
  • Steps of the method may further include drying the granule between autoclaving and the soaking step.
  • Granules may comprise about 60% HA and about 40% b-TCP.
  • the peroxide may be hydrogen peroxide (H2O2) and the solution may comprise about 50% H2O2.
  • the soaking step may be performed in a sealed container for about 6 hours according to certain embodiments.
  • the hydrothermal treatment may include autoclaving the granules prior to soaking at a temperature more than 125°C.
  • Granules may comprise about 20% HA and about 80% b-TCP.
  • the solution may comprise about 30% H2O2. Soaking can occur in a sealed container for about 4 hours.
  • methods of the invention may include producing a bone grafting product by providing a granule comprising b-tricalcium phosphate (b-TCP) and at least about 60% by weight hydroxyapatite (HA), performing a hydrothermal treatment on the granule, and soaking the granule in a solution comprising a peroxide to thereby produce one or more HA needle-like protrusions from the granule.
  • the treatment may occur in an open container.
  • the solution may comprise 50% hydrogen peroxide and the soaking can occur for about 6 hours in a closed container.
  • aspects of the invention may include a method for producing a bone grafting product by providing a granule comprising b-tricalcium phosphate (b-TCP) and about 20% by weight hydroxyapatite (HA), and soaking the granule in a solution comprising a peroxide to thereby produce one or more HA needle-like protrusions from the granule.
  • the solution can include 30% hydrogen peroxide. Soaking can occur for about 4 hours in a closed container.
  • Materials of the invention may have a porosity ranging from about 50% to about 60% with about 55% - 60% consisting of micropores (less than about 3 pm) and about 30% - about 35% being made up of macropores (greater than about 70 pm).
  • Total pore area of treated biphasic calcium phosphate of the invention may be about 3 to 4 m2/g, or higher.
  • the specific surface area (BET) of the materials of the invention may be more than about 2 to 3 m2/g, or higher and may comprise a needle density of about 1 needle/pm2 or more. Needle diameters for treated biphasic materials may range between about 100 and 400 nm with median diameters in a range of about 200 to 250 nm. As discussed in the examples below, osteoinductivity of materials of the invention was found to be increased over that of untreated biphasic materials.
  • FIG. 1 shows two scanning electron micrograph (SEM) images of post-sintering biphasic granules consisting of 60% HA and 40% bTOR (60/40 granules).
  • FIG. 2 shows two SEM images of 60/40 granules after processing according to certain methods of the invention.
  • FIG. 3 shows two SEM images of post-sintering biphasic granules consisting of 20% HA and 80% pTCP (20/80 granules).
  • FIG. 4 shows two SEM images of 20/80 granules after processing according to certain methods of the invention.
  • FIG. 5 shows representative histology images for different groups of the study. Treatment groups had more bone formation than the control group.
  • Methods of preparing bone grafting materials consisting of biphasic calcium phosphate are disclosed herein using chemical processing to induce an osteoinductive needle-like surface morphology through exposure to peroxides.
  • the invention relates to treating biphasic calcium phosphate granules to transform the standard post-sintering grain-like surface morphology into a needle-like surface morphology shown to exhibit superior osteoinductivity.
  • methods of the invention produce the needle-like or nanorod-like surface morphology desired for artificial bone grafts without reliance on the high-temperature and pressure hydrothermal treatments of existing techniques.
  • the chemical processing methods of the invention can generate the desired needle-like or nanorod-like surface morphology on granules of any ratio of calcium phosphate to apatite including b-tricalcium phosphate/hydroxyapatite (bTOR/HA) granules with less than 80% or even 40%bT €R content. Previous treatment methods have been unable to consistently produce such a material.
  • Methods of the invention use chemical treatments including soaking of biphasic calcium phosphate granules in a peroxide solution to generate the desired needle-like or nanorod-like surface morphology without the need for high-temperature or pressure hydrothermal treatments. Further, such chemical processing methods have proven effective on materials with a lower proportion of calcium phosphate to apatite than is possible with current techniques.
  • Needle-like or nanorod-like surface morphology refers to the presence of HA needles or nanorods as shown in FIGS. 2 and 4.
  • Grain-like surface morphology of the post- sintering biphasic calcium phosphate starting granules refers to a relatively smooth surface with a substantial lack of HA needles as shown in FIGS. 1 and 3. Unless otherwise specified, percentages discussed herein with respect to HA and bTOR granule composition refer to percent by weight.
  • Methods of the invention primarily involve the chemical processing of biphasic calcium phosphate materials using peroxides (along with other optional treatments) to produce a needle like surface morphology in the material.
  • the soak time and the concentration of peroxide in the solution can vary depending on the type of peroxide used, whether the granules have been hydrothermally treated, and the ratio of HA to bT €R in the granules being processed.
  • hydrothermal treated granules having less than 60% bTOR content may be soaked in a 50% hydrogen peroxide (H2O2) solution for about 6 hours while granules with higher bTOR content (e.g., 20/80 granules) may be soaked in a 30% H2O2 solution for about 4 hours to generate the desired needle-like surface morphology.
  • H2O2 hydrogen peroxide
  • peroxide treatment may occur in a sealed container.
  • Peroxides used in processing biphasic calcium phosphate materials are preferably hydrogen peroxide but may be any compound having a peroxide group including peroxy acids, metal peroxides, organic peroxides, and main group peroxides. In certain embodiments, various agents may be substituted for the peroxide in the processing steps described above.
  • Examples include oxidizers, NaHCCE, NaiHPCE, calcium sulfate, calcite, NaCl, ammonium hydroxide, sodium hydroxide, po 1 y ( D , L- 1 ac t i c- co-g 1 yco 1 i c acid), pectin and gelatin, vesicants, cetyltrimethyl ammonium bromide, polytrimethylene carbonate, sucrose, inorganic peroxides, perchloric acid, nitric acid, perborates, periodates, peroxyacids, chlorates, chromate.
  • peroxide solutions may comprise 3%, 5%, 10%, 20%, 30%,
  • 40%, 50%, 60%, 70%, 80%, 90%, or 100% peroxide and soaking times may be less than about 30 minutes, less than about 60 minutes, less than about 100 minutes, less than about 200 minutes, less than about 300 minutes, less than about 400 minutes, less than about 500 minutes, less than about 600 minutes, less than about 700 minutes, less than about 800 minutes, less than 900 minutes or less than about 1000 minutes.
  • Biphasic calcium phosphate granules are used as a starting material and can be prepared using known methods. Such granules are also commercially available in a variety of ratios including the 60/40 and 20/80 HA/bTOR compositions primarily discussed herein.
  • Methods of the invention contemplate using particles of any size (e.g., 0.1mm - 10mm) and preferably use sintered biphasic calcium phosphate granules commercially available between 0.5 mm and 2 mm in size. Particles used are preferably sintered biphasic calcium phosphate granules commercially available between 1mm and 2mm in size.
  • Methods for preparing biphasic calcium phosphate materials through sintering and the use of foaming and/or porogenic agents (including hydrogen peroxide) are known in the art and described, for example, in U.S. Pat. No. 10,064,892 and U.S. Pat. Pub. No. 20110020419, the contents of each of which are incorporated herein by reference.
  • starting biphasic calcium phosphate materials may be produced through foaming of an aqueous slurry including a calcium phosphate powder using a foaming agent followed by drying and sintering of the resulting foamed slurry. Particle size of the starting material may be altered by milling of the sintered material to achieve the desired size range.
  • the ratio of calcium phosphate to hydroxyapatite in the biphasic particles is not a limiting aspect of the invention, and the methods of the invention may be carried out using granules having all different ratios of calcium phosphate to apatite.
  • 60/40 HA/pTCP granules may be used as a starting material.
  • granules After pre-processing according to the invention (or provision of commercially available material), granules have a grain-like morphology with multidirectional interconnected porosity structure, that is about 20-30% microporous (e.g., having a pore size ⁇ 10 about pm) and 50-55% macroporous.
  • FIG. 1 An exemplary scanning electron micrograph (SEM) for such granules is shown in FIG. 1.
  • SEM scanning electron micrograph
  • the grain-like surface morphology along with the microporosity of the material can be seen in the figure.
  • granules having higher bTER content e.g., 20/80 HA/bTER granules
  • a pre-processing image of exemplary 20/80 granules with mostly grain-like morphologies and some needles is shown in FIG. 3.
  • apatite minerals include any calcium phosphate minerals with the repeating stoichiometric chemical formula Cas/PO ⁇ /OH) such as hydroxyapatite, fluoro-apatite, chloro- apatite, carbonated apatite or a calcium deficient apatite among others.
  • Cas/PO ⁇ /OH repeating stoichiometric chemical formula
  • Processing of bi-phasic calcium phosphate granules may include a hydrothermal treatment the details of which may depend on the ratio of HA to bTOR.
  • Hydrothermal treatment involves exposing the granules to a combination of heat, pressure, and water such as in an autoclave. Hydrothermal treatments may be performed before, after, and/or during chemical processing with peroxide as described above.
  • temperature ranges for hydrothermal treatment may depend on the composition of the starting material and can be less than about 125°C for granules with 60% or more bTER content and preferably less than about 90°C.
  • Pressure ranges for hydrothermal treatment are preferably between about 2 and 4 bar.
  • hydrothermal treatment may be performed at about 140°C.
  • Treatment may occur, for example, by placing dry granules in an open bottle and then placing in an autoclave.
  • Hydrothermal treatment may be performed at about 140°C for about 600 minutes in preferred embodiments but longer and shorter treatment times are possible as well and can produce similar results.
  • temperatures may be less than 125°C, less than 100°C, less than 90°C, less than 75°C, or less than 50°C.
  • Hydrothermal treatment times may be less than about 30 minutes, less than about 60 minutes, less than about 100 minutes, less than about 200 minutes, less than about 300 minutes, less than about 400 minutes, less than about 500 minutes, less than about 600 minutes, less than about 700 minutes, less than about 800 minutes, less than 900 minutes or less than about 1000 minutes.
  • a thermal treatment may be used in lieu or in addition to a hydrothermal treatment.
  • dry granules may be treated in an autoclave without any liquid or may simply be heated at atmospheric pressure, in an oven for example.
  • Hydrothermal treatment can be performed using granules in any liquid.
  • granules may be submerged in an aqueous or non-aqueous solution.
  • Aqueous solutions can include water, hydrogen peroxide, acids, bases, etc.
  • Non-aqueous solutions may include alcohols, etc.
  • Hydrothermal treatment of bi-phasic calcium with greater bTOR content can occur at temperatures lower than 140°C, lower than 125°C, and preferably around 90°C or lower.
  • Such hydrothermal treatments can optionally be performed in an autoclave as described above.
  • hydrothermal treatment may be performed for shorter time periods (e.g., about 4 hours) than for granules with lower bTOR content.
  • hydrothermal treatment is not required and biphasic calcium phosphate granules may begin processing with soaking in a peroxide solution. If a hydrothermal treatment is performed, granules may be recovered and dried before soaking.
  • FIGS. 2 and 4 show SEM images of post processing 60/40 and 20/80 granules respectively. Notably, granules in both images exhibit a clear development of needle-like or nanorod-like surface morphology subsequent to processing methods of the invention.
  • methods of the invention may be applied to surface coatings of biphasic calcium phosphate to similarly generate the desired osteoinductive needle-like or nanorod-like morphology for various implants or other devices.
  • Materials of the invention may have a porosity ranging from about 50% to about 60% with about 55% - 60% consisting of micropores (less than about 3 pm) and about 30% - about 35% being made up of macropores (greater than about 70 pm).
  • Total pore area of treated biphasic calcium phosphate of the invention may be about 3 to 4 m2/g, or higher.
  • the specific surface area (BET) of the materials of the invention may be more than about 2 to 3 m2/g, or higher and may comprise a needle density of about 1 needle/pm2 or more. Needle diameters for treated biphasic materials may range between about 100 and 400 nm with median diameters in a range of about 200 to 250 nm. Osteoinductivity of materials of the invention is increased over that of untreated biphasic materials.
  • Treated biphasic calcium phosphate can be used as an implant material for medical procedures such as orthopedic surgery and maxillofacial procedures.
  • Bone graft materials of the invention may be used as fillers or scaffolds to facilitate bone formation and promote wound healing and can be used in solid material (block) forms trimmed to fit a certain defect or may be used in a putty or paste (particulated) format.
  • Applications of the materials prepared according to methods of the invention include dental implants (e.g., to restore edentulous area of a missing tooth).
  • materials of the invention may be used to form large bone sections to restore skeletal integrity to long bones of limbs in which congenital bone defects exist or to replace segments of bone after trauma or malignant tumor invasion. Graft material may also be used to fuse joints to prevent movement, repair broken bones that have bone loss, and repair broken bone that has not yet healed.
  • Example 1 preparation of osteoinductive 60/40 HA/ TCP material with needle-like surface morphology.
  • 60/40 HA/pTCP granules were obtained from Biomatlante.
  • the granules have a grain like morphology with multidirectional interconnected porosity structure, that is 20-30% microporous (pore size ⁇ 10 pm) and 50-55% macroporous.
  • the scanning electron micrograph (SEM) for this granule is shown in FIG. 1. Microporosity is clearly visible in the granule along with grain-like surface structure.
  • the granule was further processed using the following techniques and was subsequently imaged to see the difference in the microstructure: First, the granules underwent a hydrothermal treatment. The treatment involved placing granules (dry) contained in an open bottle and then placing in an autoclave. The autoclave treatment was performed at 140°C for 600 minutes. The granules were recovered and dried at 90°C prior to the next step.
  • the hydrothermally treated granules were soaked in a 50% hydrogen peroxide (H2O2) solution in a closed bottle for 6 hours. The granules were subsequently washed with deionized water and dried at 90°C prior to imaging.
  • H2O2 hydrogen peroxide
  • the SEM image shown in FIG. 2 demonstrates the change in microstmcture from the pristine granules.
  • the image demonstrates needle-like morphology for the treated 60/40 HA/pTCP granules.
  • Example 2 preparation of osteoinductive 20/80 HA/BTCP material with needle-like surface morphology.
  • the 20/80 HA/bTOR granules are also obtained from Biomatlante.
  • the surface topography of the pristine granules show mostly grains with some needles being present.
  • the SEM image of the pristine granule is shown in FIG. 3.
  • the granule was further processed using the following technique and was subsequently imaged to see the difference in the microstmcture:
  • the granules were soaked in a 30% hydrogen peroxide (H2O2) solution in a closed bottle for 4 hours.
  • the granules were subsequently washed with deionized water and then dried at 90°C prior to imaging.
  • H2O2 hydrogen peroxide
  • the SEM image shown in FIG. 4 shows the change in microstmcture from the pristine granules.
  • the image demonstrates needle-like morphology for the treated 20/80 HA/bTOR granules.
  • the sheep used in the study were greater than 2 years of age and the granules were implanted for a period of 12 weeks in the sheep to evaluate the tissue reaction and osteoinductive property of the treated groups.
  • an intravenous catheter was placed in a cephalic, jugular, or lateral saphenous vein, and following anesthetic induction, the sheep was endotracheally intubated.
  • IV fluids Lacated Ringers Solution, or equivalent balanced electrolyte solution at a rate of 2.5 - 10 mL/kg/hr
  • the wool over the back was clipped, and the area was scrubbed with alternating chlorhexidine and isopropyl alcohol for at least three cycles or until the sheep was clean.
  • a sterile surgical scrub was performed using chlorhexidine.
  • Prophylactic antibiotics were administered perioperatively. Exposed areas outside of the surgical field were covered as much as possible.
  • a skin incision starting at approximately LI and continuing approximately 10 inches caudally, was made approximately 2 inches off midline on one side of the lumbar spine.
  • the paraspinous muscles was exposed and 6 intra-muscular incisions, approximately 1.5 cm in length and 1 inch apart, were made through the fascia and the underlying muscle fibers were separated to create a pocket.
  • the representative histological images for the control and two treatment groups are presented in FIG. 5. As shown in Table 2 and FIG. 5, significantly more bone formation was observed in the treatment groups than the control group. The new bone is represented by the darkest staining toward the center of the two treated groups and nearly absent from the control group.
  • Scanning electron microscopy in the secondary electron mode was used to evaluate the surface topography of the starting granules and the treated granules. After hydrothermal treatment, the diameter of 100 formed needles was measured, and median values were calculated. All measurements were performed with the tool ‘length measurement’ in ImageJ (vl.43u, NIH, USA) using the SEM scale bar as reference.
  • Example 5 BET Surface Area Procedure For BET surface area by gas physisorption, the analysis was conducted using the
  • Micromeritics TriStar II instrument Briefly, a representative aliquot of sample (approximately 2 g) was added to a sample cell with 0.5" neck. To remove moisture from the sample surfaces and pores, the sample was degassed under vacuum at 40°C for 16 hours prior to analysis. Analysis was conducted at 77.35K using nitrogen gas as the adsorbate. Saturation pressure of nitrogen was measured by the instrument throughout the experiment. Adsorption and desorption process was allowed to equilibrate at each relative pressure (P/PO) for 20 seconds. The surface area was calculated from 5 adsorption points in the P/PO range of 0.05-0.20 using the BET method.
  • Results BET surface area are mentioned in Table 4. The data suggests that the needle-like or nanorod-like formations on the granule surface lead to increase in their specific surface area.
  • pore size distribution and porosity by mercury intrusion porosimetry were conducted using the Micromeritics AutoPore V instrument. Briefly, a representative aliquot of sample (approximately 0.7 g) was added to a calibrated 5 cc powder penetrometer with a stem volume of 1.131 cc. To remove moisture from the sample surfaces and pores, the sample was evacuated on the instrument at room temperature to a target pressure of 30 pmHg. After further applying vacuum for 5 minutes, the penetrometer bulb was filled with mercury at about 0.5 psia. Pressures of up to around 50,000 psia were applied to force intrusion of mercury into the void space in the sample.
  • Needle density on the granule was determined by counting the number of needles visible on a lOOOOx SEM image (window size 1132.81 um 2 ). The density was calculated per um 2.

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Abstract

La présente invention concerne des procédés de production de matériaux de phosphate de calcium biphasique faisant appel à des processus de traitement chimique, dont une exposition à des peroxydes. Les matériaux obtenus présentent une morphologie de surface en aiguille ostéo-inductrice et sont utiles en tant que greffons osseux artificiels.
EP20927892.8A 2020-03-24 2020-03-24 Procédés de production d'un matériau de phosphate de calcium ostéo-inducteur pour greffe osseuse Pending EP4126089A4 (fr)

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PCT/US2020/024473 WO2021194477A1 (fr) 2020-03-24 2020-03-24 Procédés de production d'un matériau de phosphate de calcium ostéo-inducteur pour greffe osseuse

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EP4126089A1 true EP4126089A1 (fr) 2023-02-08
EP4126089A4 EP4126089A4 (fr) 2023-11-22

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