WO2021206669A1 - Méthode et appareil pour assurer le maintien et l'intégrité de la survie des implants chirurgicaux chez les patients humains et animaux - Google Patents

Méthode et appareil pour assurer le maintien et l'intégrité de la survie des implants chirurgicaux chez les patients humains et animaux Download PDF

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WO2021206669A1
WO2021206669A1 PCT/US2020/021981 US2020021981W WO2021206669A1 WO 2021206669 A1 WO2021206669 A1 WO 2021206669A1 US 2020021981 W US2020021981 W US 2020021981W WO 2021206669 A1 WO2021206669 A1 WO 2021206669A1
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implant
accordance
patient
stem cells
bone
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PCT/US2020/021981
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Reosteon, Llc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • 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
    • A61L27/08—Carbon ; Graphite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3616—Blood, e.g. platelet-rich plasma
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/155—Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells

Definitions

  • the present invention is directed to the implantation of fabricated implants for insertion into living bone and tissue; more particularly, to methods and apparatus for utilizing such implants; and most particularly, to a protocol for maintaining the integrity and survival of medical, dental, and veterinary implants, especially in patients who are medically compromised
  • Implant failure is exponentially more common in patients receiving systemic chemotherapy or localized radiotherapy. Moreover, diabetic patients (both Type I and II) are also particularly sensitive to implant procedures and are prone to experience a statistically increased implant failure rate, which is equally true for smokers. Still further, there are an additional series of systemic issues that have yet to be identified that will either substantially affect or preclude successful implant placement, integration, and maintenance (e.g., all autoimmune diseases and specific allergic reactions to various metallic compounds currently used in the manufacture and fixation of existing implantable devices).
  • US Patent No. 8,337,873 B2 discloses constructs and methods for immobilizing stem and other precursor cells, as well as other bioactive materials of therapeutic value, on the surfaces of medical devices such as implants for bone, cartilage, spine, and teeth.
  • the invention disclosed is applicable to the incorporation of bioactive and therapeutic materials in or on a medical implant or other interventional devices. Most notably for the present invention's purposes, it has particular value with enabling the real-time utilization by medical personnel of bioactive materials extracted from a patient and subsequently reintroduced and immobilized on an implant device, such as by a surgical team in an operating room environment.
  • Such materials may include, but are not limited to, bioactive molecules and stem, progenitor, and other biological cells.
  • a dental implant composed of an enamel cap over a sintered titanium core and root is used.
  • US Patent Application Publication No. US 2013/002929A1 discloses a method and compositions for tooth regeneration.
  • Implants of both mesenchymal adipose-derived stems cells (“ADSC”) and mesenchymal dental pulp stem cells (“DPSC”) are able to grow self-assembled new teeth in extraction sockets when adding BMP-2.
  • the regenerated tooth is not only structurally similar to a normal tooth but is also well-developed in vascular and nervous systems with functions of growth, communication, and sensation.
  • the stem cells are necessary, as without them the implants are unable to grow any teeth.
  • the subject MSC subpopulation exists at the most apical end of the incisor of which 30% can differentiate following damage by cutting the tooth tip into odontoblasts which ultimately give rise to dentine forming dentinoblasts. Likewise, this long-lived MSC subpopulation can contribute to the formation of dental pulp cells following proliferation and downward migration through the tooth axis.
  • the present invention in contrast to the above two studies utilizes a unique combination of bone-inducing growth factors consisting of BMP-2, OPG, and PRP (which contains PDGF and FGF) in combination with dental pulp obtained from dental pulp stem cells (DPSCs) that contain a subpopulation of mesenchymal stem cells (MSCs) obtained from the molars of the same patients (autologous) and impregnated onto a novel graphene carbon ceramic implant that is surface fenestrated to induce osteointegration when placed in the patient's surgically created tooth socket and/or a surgically created osteotomy.
  • BMP-2 bone-inducing growth factors
  • OPG which contains PDGF and FGF
  • DPSCs dental pulp stem cells
  • MSCs mesenchymal stem cells
  • This unigue combination of growth factors in the present invention induces bone formation due to the ability of BMP-2, PDGF, and FGF to synergistically induce osteoblast formation from the pulp derived MSCs, while OPG prevents osteoclast formation from these MSCs which are cells that can destroy bone.
  • bone marrow derived MSCs [1] or DPSCs or periodontal ligament derived stem cells [2] in an in vitro setting to assess osteoblast formation in the presence of only BMP-2 when these cells are grown on a film of graphene oxide, graphene oxide titanium, or other graphene metal mixtures.
  • bone marrow derived MSCs obtained from the femurs of adult goats were induced to form bone, cartilage, and adipose tissue when grown on a film of graphene oxide on coated tissue culture dishes.
  • What is needed in the art is an improved medical, dental, and veterinary process for rendering an artificial implant structure less vulnerable to rejection or failure and more amenable to rapid osteointegration with bone at any implant site, and with a significantly improved long-term survival rate regardless of any existing medical diseases or conditions and modalities for treatment of the same.
  • the present invention comprises a method of using autologous mesenchymal stem cells (MSCs) and stem cell precursors and bone specific growth factor proteins such as BMP- 2 and OPG in combination with Platelet Rich Plasma (PRP) in order to harvest, cultivate and predispose any of the patient's MSCs from any location within the patient to form healthy bone, which in turn are used within the teachings of this invention to create an environment in which medically-placed implants can be made to survive in all medically compromised patients, and most notably in the most challenging - - chemotherapy and radiotherapy treated cancer patients.
  • the present invention all but eliminates any possibility for rejection of the implantable device through its employment and direction of the patients' own (autologous) mesenchymal stem cells and their precursors.
  • While one embodiment of the present invention employs a novel artificial implant structure formed of graphene carbon ceramic ("GCC") that further encourages osteointegration to take place more naturally, rapidly, and completely with a significant reduction of the likelihood for implant rejection by comparison with existing prior art implant configurations, the present invention will markedly improve osteointegration of any existing non-graphene carbon ceramic implants regardless of the implant's composition and configuration and the recipient's health.
  • GCC graphene carbon ceramic
  • chemotherapy may comprise chemotherapeutic agents selected from the group consisting of single use chemotherapy such as but not limited to Cisplatin, 5-Fluorouracil,
  • the present invention has universal utility in all patients, and by way of example when used in connection with at least the following orthopedic procedures: dental (mandible), knee (femur, patella, and/or tibia), hip (trochanter and/or pelvis), shoulder, and spine replacement, and in maxillofacial reconstruction.
  • dental mandible
  • knee femur, patella, and/or tibia
  • hip trochanter and/or pelvis
  • shoulder shoulder
  • spine replacement and in maxillofacial reconstruction.
  • the teachings of the present invention are additionally unique on both a biological and a structural level, particularly when considering the novel cocktail of growth factors that is used to induce and maintain osteoblast formation in all recipients when this novel cocktail is impregnated onto fenestrated implants, and most preferably graphene carbon ceramic composite implants in all recipients, and most remarkably in immunocompromised patients.
  • the in vitro data presented in the prior art not only provide proof of principal, they specifically reinforce and highlight the novelty and utility of the methodology taught by the present
  • FIG. 1 is a flow chart showing the steps in preparation for implanting an implant device into a patient in accordance with the present invention
  • FIG. 2 is a table showing comparative success of implants formed and implanted in accordance with the present invention versus control implants, when implanted into patients having four different kinds of cancers;
  • FIG. 3 is a dental x-ray image of two treated dental implants in Patient No. 1 on the day of placement;
  • FIG. 4 is a dental x-ray image of the implants shown in FIG. 3, taken at two weeks post-operative;
  • FIG. 5 is a dental x-ray image of the implants shown in FIGS. 3 and 4 taken at 11 weeks post-operative;
  • FIG. 6 is a dental x-ray image of the implants shown in FIGS. 3 and 4 taken at five and one half months post-operative;
  • FIG. 7 is a dental x-ray image of Patient No. 2 before implant surgery
  • FIG. 8 is a dental x-ray panoramic image of a plurality of dental implants in Patient No. 2 on the day of placement;
  • FIG. 9 is a dental x-ray panoramic image of the implants shown in FIGS. 7 and 8, taken at three weeks post-operative;
  • FIG. 10 is a dental x-ray panoramic image of Patient No. 2, taken at five weeks post-operative;
  • FIG. 11 is a dental x-ray panoramic image of Patient No. 2 at 24 weeks post-operative;
  • FIGS. 12(a-d) are a series of dental x-ray images of Patient No. 3 before implant surgery;
  • FIGS. 13(a-c) are a series of dental x-ray images of Patient No. 3 on the day of placement;
  • FIG. 14 is a dental x-ray panoramic image of the dental implants shown in FIGS. 13(a-c) taken at one week post operative;
  • FIGS. 15 (a,b) are dental x-ray images of Patient No. 3 taken at 4 months post-operative;
  • FIGS. 16(a,b) are dental x-ray images of Patient No. 4 taken on day of placement.
  • FIGS. 17(a,b) are dental x-ray images of Patient No. 4 taken at two months post-operative.
  • ⁇ mesenchymal stem cells and their subpopulation of precursors e.g., CD90/Thyl+, obtained from a source such as dental pulp, bone marrow, or blood, are used to colonize an implant surface.
  • These stem cells are biologically programmed using a unique and novel combination of FDA approved growth factors to facilitate and support differentiation into osteoblastic cells. These osteoblasts are then integrated into the surgeon's fixation of a structurally desirable and surface fenestrated implantable device.
  • mesenchymal stem cells are further encouraged through the present invention's fostering of natural cellular communication and differentiation to ensure that osteointegration and a profoundly stronger union of the patient's existing bone, ligaments, and tendons with the implant are achieved.
  • a population of quiescent mesenchymal stem cells obtained from dental pulp is induced to become mitotic by bone-specific growth factor proteins (BMP-2), transitions into mesenchymal stem cells, and then further transitions into osteoblasts capable of osteointegration at all implant bone interphases in patients, including severely medically-compromised patients.
  • BMP-2 bone-specific growth factor proteins
  • osteoblasts capable of osteointegration at all implant bone interphases in patients, including severely medically-compromised patients.
  • OPG osteoprotegerin
  • FIG. 1 an exemplary procedure is shown for carrying out the implantation of a known dental implantable device in accordance with the present invention, comprising the following steps:
  • the treating practitioner reviews the patient's medical history and conducts a full medical workup 10 regarding the patient's underlying present state of health, patient's current medications, and the patient's need for surgical insertion of an implantable device. It is very important that the practitioner determine whether the patient is medically compromised and to what level any such complicating factors and treatments thereof could potentially cause an adverse reaction between the patient's current medications and the modalities of the present invention.
  • whole blood 12 (40-80 ml and with reference to the present embodiment 60 ml) is drawn from the patient 14 by arm venipuncture.
  • the whole blood 12 includes 4-11 ml and most preferably for the present embodiment 7 ml of a large molecular weight heparin molecule (not shown) at 1 molar concentration to avoid premature clotting.
  • a fibrin clot 20 is next prepared by concentrating the remaining Platelet Poor Plasma 18 (PPP) by a separate second centrifugation 22 at 25,000 to 50,000 rpm for an additional 20 to 40 minutes and for the present embodiment most preferably at 30,000 rpm for an additional 10 minutes.
  • PPP Platelet Poor Plasma 18
  • PRP 16 is combined with an aliquot 24 of 1 nanomolar to 10 micromolar each of BMP-2 and OPG and most preferably for the present embodiment 1 micromolar BMP-2 and 1 micromolar OPG to form a pre-solution 26.
  • stem cells 28 and/or their precursors are obtained from, among other known sources, dental pulp 30, bone marrow 32, peripheral blood 34, or adipose tissue 36.
  • the practitioner may harvest stem cells 28, by way of example only, through extraction of a molar 30 and then splitting the tooth using a high-speed drill with cold water irrigation to prevent heat damage to the cells, or osteopuncture and aspiration of 1 to 5 ml of bone marrow 32 aspirate from the mandible, sternum, or pelvis (not shown).
  • the stem cells 28 and pre-solution 26 are placed into the fibrin clot 20 to form an implant solution 38 that will be utilized on the surface of an artificial implantable device 40 and is additionally used to irrigate the surgically prepared osteotomy 46.
  • An artificial implant structure 40 preferably a fenestrated graphene carbon ceramic (GCC) implant structure is provided.
  • the implant solution 38 is applied to the implant structure 40 by immersing the implant structure in the implant solution in, for example, a sterile, sealed polycarbonate tube, which then is incubated depending upon the circumstances at 35°C to 40°C for 45 to 90 minutes and for purposes of the present embodiment preferably at 37°C for 60 minutes 42, resulting in an implant structure 44 that is coated with and permeated by the implant solution 38.
  • GCC graphene carbon ceramic
  • the implant structure 40 may be formed from a mold of the patient's prior tooth or sized to fit the patient's needs selected from generically available implants that are unrelated to the patient.
  • the implant site 46 is irrigated with liquid residue of the immersion implant solution 38 for a period of time to ensure acceptance of the implant, which in accordance with the preferences for the present embodiment will continue for approximately 10 minutes.
  • the coated implant structure 40 is removed from the immersion 42 and installed 48 into the surgically prepared implant site 46, and the wound is closed and sutured.
  • the patient is started on an antibiotic, e.g., clindamycin, which has a high bone bonding capacity, and appropriate pain medications.
  • the nature of the implant should be preferably graphene carbon ceramic (GCC) but may be constructed from known substrates such as tungsten carbide, silicon carbide, barium titanium oxide, graphene, carbon, ceramic, or carbon fiber nanotubes.
  • GCC graphene carbon ceramic
  • the pre-surgical insertion biological regimens remain the same. That is, BMP-2, OPG, various obtained mesenchymal cells, PRP, and the fibrin clot are all prepared as previously described herein. Since all of these surgeries are operating-room based, all necessary hospital-based equipment must be readily available.
  • the patient is medically evaluated for joint replacement surgery prior to being admitted to the hospital.
  • FIG. 2 shows a comparison of actual implantations using the most medically accepted prior art method for implantation versus implantations performed in accordance with the present invention.
  • Each of the implants used in the underlying study was an existing 'off the shelf' mass produced implant manufactured by Sweden & Martina, Spa. that is constructed of clinical grade 4 titanium.
  • Column 1 lists four patients having different forms of cancer.
  • Column 2 shows the number of implants placed that had been treated previously in accordance with the present invention.
  • Column 3 shows the number of control implants placed in the four patients.
  • Columns 4 and 5 show the number of treated and control implants that were successful over the long term.
  • Figure 2 confirms that 100% of the implants prepared, fixed and maintained in accordance with the teachings of the present invention were successful, whereas only 20% of the control implants (implants prepared, fixed, and maintained using the most medically accepted prevailing regimens and procedures) survived.
  • Patient No. 1 is a 54- year old female patient with Adult Hodgkin's Lymphoma who was given ABVD therapy.
  • Several prior placed implants in this patient resulted in failure as a direct result of the patient's existing medical conditions and past and contemporaneous treatments of the same.
  • the need for a control in this patient was obviated in view of the abundance of relevant and well documented failures of the same in the medical history.
  • Patient No. l's relevant medical history implicated the surgical placement of only implants treated in accordance with the teachings of present invention. More precisely, as shown in FIGS. 3-5 the surgical placement solely of treated implants in Patient 1 made more sense since, under the circumstances it would provide the dual benefits of greater comfort and successful resolution of the patient's implantation issues in toto in addition to more abundant and meaning full data for the underlying study.
  • FIG. 5 which confirms that implementation of the present invention in connection with this patient's implants successfully yielded a significant increase in the patient's bone density at the treated locations within eleven weeks of implantation.
  • FIG. 6 which demonstrates among other things sufficient bone population and density at the five and a half months mark)to permit the implants to be uncovered and the emplacement of 3 mm healing abutments.
  • Patient No. 2 is a 57year old female with a prior medical history of recurrent breast adenocarcinoma who was given cisplatin and adriamycin therapy plus breast surgery.
  • the right-side implants (3) were treated and inserted in accordance with the present invention, whereas the left-side implants (2) were control (FIG. 8).
  • the terms "right” and "left” refer to the actual locations in the patient although the radiograph, as in a photograph, depicts the locations in reverse.
  • Patient No. 3 is a 63 year old female who is a lifetime smoker that was undergoing treatment for small cell carcinoma that was on active chemotherapy including 5-fluorouracil and Adriamycin during the relevant time period.
  • the patient additionally remained an active smoker throughout the relevant time period, which as indicated above presented an environment and circumstances further exacerbating the likelihood for failure.
  • FIGS. 12(a,b,c,d) are dental x-ray images of Patient No. 3 prior to implant surgery.
  • FIGS. 13 (a,b,c) are dental x-rays of Patient No. 3 taken at the time of surgical implant.
  • FIGS. 13(a,b) are x-rays of the treated implants and
  • FIG. 13(c) is an x-ray of the control implant, all of which were surgically placed in Patient No. 3.
  • FIG. 14 is an x-ray panoramic image depicting all of the implants placed in Patient No. 3 at one week post-operative.
  • FIGS. 15(a,b) provide x-ray images of the implants four month's post-surgical.
  • FIG. 15(a) which depicts the treated implants placed in Patient No. 3
  • the x-ray clearly demonstrates early signs of successful implantation and a significant increase of the bone's density and health.
  • the dental x-ray of FIG. 15(b) which is the control implant placed in Patient No. 3
  • Patient No. 3's failure as confirmed by the x-rays, predictably resulted from the inability of this systemically challenged patient's surrounding bone's inability to regenerate (i.e., there was absence of osteointegration).
  • it became necessary for both control implants to be surgically removed during Patient No. 3's four month visit in order to relieve her from further discomfort that was caused by the complete failure of osteointegration.
  • Patient No. 4 is a 47 year old male with NSCLC Stage II lung cancer. Patient No. 4 was previously treated with multiple rounds of chemotherapy following a complete surgical resection, and was then currently on 5-fluorouracil and dexamethasone at the time of implantation.
  • FIG. 16(a) is an x-ray of the rightside control implant and FIG. 16(b) is the leftside treatment implant as placed in Patient No. 4 at the time of surgery.
  • the right-side control implant FIG. 17(a) completely failed to integrate by the two month post-surgical mark.
  • the treated implant FIG. 17(b) not only showed significant bone regeneration and osteointegration with the implant, but like the other implants and surrounding bone treated in accordance with the teachings of the present inventions, presented results superior to those thatwould be expected from a healthy patient treated using prevailing regiments.

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Abstract

L'invention concerne un procédé d'implantation d'une structure artificielle dans une cavité réceptrice dans un os d'un patient, comprenant les étapes suivantes : l'obtention de cellules souches mésenchymateuses autologues et de précurseurs de cellules souches comprenant des cellules quiescentes du patient; l'obtention d'une protéine morphogénique osseuse, de l'ostéoprotégérine et d'un plasma riche en plaquettes; la combinaison des cellules souches mésenchymateuses et des précurseurs de cellules souches, de la protéine morphogénique osseuse, de l'ostéoprotégérine et du plasma riche en plaquettes pour former une solution d'implant; la fourniture d'une cavité réceptrice dans l'os; la fourniture d'une structure d'implant artificielle; l'imbibition de la structure d'implant artificielle dans la solution d'implant; et l'insertion de la structure d'implant artificielle dans la cavité réceptrice du patient. De préférence, la structure de l'implant artificiel est formée de céramique graphène-carbone.
PCT/US2020/021981 2020-04-06 2020-04-06 Méthode et appareil pour assurer le maintien et l'intégrité de la survie des implants chirurgicaux chez les patients humains et animaux WO2021206669A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100183561A1 (en) * 2008-07-07 2010-07-22 Arteriocyte Medical Systems Biological therapeutic compositions and methods thereof
US20110307073A1 (en) * 2008-10-17 2011-12-15 Swee Hin Teoh Resorbable Scaffolds For Bone Repair And Long Bone Tissue Engineering
US20130297038A1 (en) * 2012-05-07 2013-11-07 Warsaw Orthopedic, Inc. An Indiana Corporation Bone implants and methods comprising demineralized bone material
US20150134065A1 (en) * 2009-06-15 2015-05-14 Cartiheal (2009) Ltd Mulit-Phasic Solid Implants for Tissue Repair
US20160038639A1 (en) * 2013-03-15 2016-02-11 Theracell, Inc. Compositions of and methods for cancellous bone matrix
US20160312186A1 (en) * 2002-06-07 2016-10-27 P Tech, Llc Non-biologic surgical implant
US20170035809A1 (en) * 2013-02-12 2017-02-09 Lacerta Technologies Inc. Serum fraction of platelet-rich fibrin

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160312186A1 (en) * 2002-06-07 2016-10-27 P Tech, Llc Non-biologic surgical implant
US20100183561A1 (en) * 2008-07-07 2010-07-22 Arteriocyte Medical Systems Biological therapeutic compositions and methods thereof
US20110307073A1 (en) * 2008-10-17 2011-12-15 Swee Hin Teoh Resorbable Scaffolds For Bone Repair And Long Bone Tissue Engineering
US20150134065A1 (en) * 2009-06-15 2015-05-14 Cartiheal (2009) Ltd Mulit-Phasic Solid Implants for Tissue Repair
US20130297038A1 (en) * 2012-05-07 2013-11-07 Warsaw Orthopedic, Inc. An Indiana Corporation Bone implants and methods comprising demineralized bone material
US20170035809A1 (en) * 2013-02-12 2017-02-09 Lacerta Technologies Inc. Serum fraction of platelet-rich fibrin
US20160038639A1 (en) * 2013-03-15 2016-02-11 Theracell, Inc. Compositions of and methods for cancellous bone matrix

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