EP3122652A1 - Kit for delivering bone grafting materials - Google Patents
Kit for delivering bone grafting materialsInfo
- Publication number
- EP3122652A1 EP3122652A1 EP14887214.6A EP14887214A EP3122652A1 EP 3122652 A1 EP3122652 A1 EP 3122652A1 EP 14887214 A EP14887214 A EP 14887214A EP 3122652 A1 EP3122652 A1 EP 3122652A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- bioactive glass
- kit
- composition
- collagen
- microns
- 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.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
- A61M5/1452—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons
-
- 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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
- A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
- A61B17/8802—Equipment for handling bone cement or other fluid fillers
- A61B17/8805—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it
- A61B17/8811—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it characterised by the introducer tip, i.e. the part inserted into or onto the bone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
- A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
- A61B17/8802—Equipment for handling bone cement or other fluid fillers
- A61B17/8805—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it
- A61B17/8816—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it characterised by the conduit, e.g. tube, along which fluid flows into the body or by conduit connections
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
- A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
- A61B17/8802—Equipment for handling bone cement or other fluid fillers
- A61B17/8805—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it
- A61B17/8819—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it characterised by the introducer proximal part, e.g. cannula handle, or by parts which are inserted inside each other, e.g. stylet and cannula
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
- A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
- A61B17/8802—Equipment for handling bone cement or other fluid fillers
- A61B17/8805—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it
- A61B17/8822—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it characterised by means facilitating expulsion of fluid from the introducer, e.g. a screw pump plunger, hydraulic force transmissions, application of vibrations or a vacuum
-
- 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
- A61L27/10—Ceramics or glasses
-
- 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
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
-
- 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
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- Bone is composite material that is comprised of collagen, cells, a form of calcium hydroxyapatite crystals and small quantities of other proteins and organic molecules.
- the chemistry and physical nature of this composite affords it unique properties of high strength, rigidity, and an ability to adapt to changing loads in the body.
- injuries to bone it is sometimes necessary to find a way to fill voids or gaps, and to encourage the repair and regeneration of the bone tissue.
- Autograft bone usually taken from the iliac crest remains the gold standard for filling bony defects. Autograft bone is said to be osteoinductive; that is it will grow bone wherever it is placed in the body due to the cellular content and the presence of growth factors. Despite the generally favorable results from autograft transplants, there remain serious concerns about donor site morbidity, graft collapse and length of hospital stay in comparison to using other materials. Allograft bone in various forms has also been used extensively as bone grafts with mixed results. Allograft, while yielding outcomes generally similar to autograft, is expensive to produce, is generally slower to incorporate, and is variable in performance due to different processing methods and carries the potential risk of infection and disease transmission, though that risk is quite small.
- Hydroxyapatite materials have been used mainly in dental procedures and in some long bone grafting procedures. In cervical fusion procedures there have been few reports of the use of synthetic hydroxyapatite. In a clinical study by Zdeblick, coralline-derived HA
- Tri calcium phosphates are another form a ceramic material that is used, usually in a porous form for non-load bearing bone grafts. While the success has been good in small defects, the particulate material is somewhat difficult to work with and cannot always be maintained in the surgical site.
- Calcium sulfate materials are a form of highly resorbable ceramic bone graft substitute. These have been used with some success as well, but are again limited in their use due to the particulate nature of the material and the difficulty of keeping it in the surgical site. In addition, there have been reports that the material resorbs too quickly, leaving bone voids and poor clinical outcomes. In addition to the synthetic bioceramic materials, there has been some attempt to use xenograft bone for repair and regeneration. However, there is always a risk of antigenicity from this bone, derived mainly from the atelo groups on the collagen fibers within the bone structure. There is also a fear of transmission of CJD (Crutzfeld Jacobs Disease) from the bovine source, although the risk is actually quite small. However, these elements have severely limited its use.
- CJD Crutzfeld Jacobs Disease
- Calcium, sodium phosphosilicate materials commonly referred to as bioactive glasses are another class of bioceramic material that has been successfully used in bone graft procedures. Calcium sodium phosphosilicates are unique in that they are not only
- osteoconductive but are also osteostimulative.
- the material When exposed to an aqueous environment, such as found in bony defects, the material releases specific ions (Ca, P, Si, Na) in certain
- bioactive glass NaovaBone, NovaBone Products, LLC
- blood loss was significantly less in the bioactive glass group (1280mL in the autograft group versus 853mL in the bioactive glass group).
- bioactive glass particles are limited by the same constraints as the other bioceramic materials.
- the US 6,187,047 describes a process where dilute solutions of collagen, type I, are mixed with fine particles of calcium phosphate, where the particles are 5 microns or less. This process forms a porous 3-dimensional matrix that maintains its structural integrity for at least 3 days and maintains porosity for up to 14 days. While this method allows for the immobilization of the particles initially, once the material starts to degrade, the release of small particles can be problematic is it is know that small particles can cause an osteolytic process that results in inflammation and bone resorption.
- US 6,417,166 discloses a thin flexible mineralized collagen membrane for such uses as guided barrier membranes and periodontal defect repair as well as bone grafts and wound repair.
- the process utilizes up to 70% collagen with 30% to 70%> calcium phosphate minerals.
- the process relies on the addition of calcium solutions and phosphate solutions to a collagen slurry and casting the slurry into a mold and drying said mixture. This is said to form a mineralized collagen composite.
- This process is severely limited, however, to thin small membranes as the process is ineffective and very expensive for making larger shapes and forms.
- a bone restorative composite material that consists of a resorbable polymer that can be collagen, a range of meso, micro and macro porosity to allow for the inclusion of fluid and to assist in bone ingrowth, as well as the inclusion of calcium phosphate particles.
- the patents further describe a specific oxidation-reduction reaction of very specific calcium and phosphorous containing salts to precipitate calcium phosphate within the collagen structure. These devices typically require very precise control of the chemistry in order to obtain the desired results of the precipitation of the calcium phosphate materials and appear to be limited to calcium based osteoconductive materials.
- Figure 1 depicts an exemplary delivery system kit for delivering a composition for regenerating bone.
- Figure 2A-B depicts schematic drawings of an adapter (2 A) and a delivery gun (2B) for the composition for regenerating bone.
- Figure 3 depicts a schematic drawing of a plunger of the delivery system.
- Figure 4A depicts exemplary tips for a delivery system.
- Figure 4B depicts exemplary tips for a delivery system.
- Figure 5 A is a photograph of the tubes filled with a composition for regenerating bone for use with a delivery system.
- Figure 5B depicts a schematic drawing of a tube for use with a delivery system.
- Figure 6A is a photograph of an exemplary delivery system for a composition for regenerating bone.
- Figure 6B is a photograph of an exemplary delivery system for a composition for regenerating bone.
- Figure 7 is a photograph of an exemplary delivery system for a composition for regenerating bone.
- Figure 8 is a photograph of an exemplary delivery system for a composition for regenerating bone.
- Figure 9 is a photograph of an exemplary delivery system for a composition for regenerating bone.
- Figure 10 depicts a graph of blood absorption of bioactive strip, composite and packable products.
- Figure 11 depicts a bar graph showing the average porosity of MacroFORM
- Figure 12A is a photograph of the exemplary bioactive strip in a hydrated state.
- Figure 12B is a photograph of the exemplary bioactive strip in a hydrated state.
- an extracellular matrix protein collagen in combination with bioactive glass ceramic, which contains silica or boron, is disclosed.
- the protein component of the compositions provides amino acids which upon resorption of the collagen provide the building blocks (amino acids) for cells to produce a new collagen matrix which is mineralized during the bone regeneration process.
- the bioactive glass ceramic component undergoes an ion exchange with the surrounding body fluid to form hydroxyapatite analogous to bone mineral.
- the ceramic of the present invention releases calcium and silicate or calcium and borate ions which facilitate the differentiation and proliferation of osteoblasts (defined as osteostimulation), which increases the rate of regeneration of hard tissue.
- these bioactive glass ceramics release, calcium and silicate or calcium and borate ions, which stimulate the genes responsible for the differentiation and proliferation of osteoblast cells within the bony defect upon implantation.
- This genetic response is activated through introducing and maintaining critical concentrations of calcium and silica or borate ions.
- This activation of the genetic cascade responsible for osteoblast proliferation and differentiation subsequently promotes the increased rate regeneration of hard tissue.
- These composites also provide a three dimensional scaffold for (bone forming cells) osteoblasts to reside to facilitate the regeneration of hard tissues.
- kits for a minimally invasive delivery of a composition for regenerating bone at or near the site of a bony defect includes at least one tube comprising the composition for regenerating bone comprising about 2-60% collagen and about 40-98% bioactive glass, wherein the at least one tube is capped when not in use, a dispensing gun, an adapter and a plunger.
- the kit optionally, includes one or more dispensing tips.
- the components of the kit are snap fit into a tray and a retainer is placed to maintain position of the components in the tray.
- the tray holds up to four tubes comprising the composition for regenerating bone.
- the kit may further include a syringe.
- the kit may also include a "Y" connector, tube connector, or an aspiration needle, or a combination thereof.
- the bioactive glass of the composition for regenerating bone has a porosity of up to 90%.
- the bioactive glass has pores ranging from about 1 to about 5100 microns.
- the bioactive glass has average pore size of ⁇ 50 microns; alternatively, the bioactive glass has average pore size of 100 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 200 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 300 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 400 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 500 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 600 microns plus or minus 50 microns; alternatively, the bioactive glass has average pore size of 700 microns plus or minus 50 microns.
- the composition for regenerating bone of the kit includes about 3-60% collagen and about 40-97% bioactive glass; alternatively, the composition for regenerating bone includes about 3-50%> collagen and about 50-90%) bioactive glass.
- the composition for regenerating bone may further include an extracellular matrix molecule selected from the group consisting of integrins, fibronectin, vitronectin, osteopontin, bone sialoprotein thrombospondin, and fibrinogen, or a homo or copolymer of glycerol, glycols, glycolides, acrylates, lactic acids or other organic acids, and caprolactone.
- the composition for regenerating bone may be un- crosslinked or crosslinked.
- the composition for regenerating bone may be freeze-dried.
- the composition for regenerating bone may be in a lyophilized form.
- the bioactive glass of the composition for regenerating bone of the kit may be pre -reacted with a buffer.
- the bioactive glass comprises 55-65% 1000-2000 um bioactive glass, 10-20%) 90-710 um bioactive glass, and 10-20%) 32-125 um bioactive glass; alternatively, the bioactive glass comprises 60%> 1000-2000 um bioactive glass, 12.5% 90-710 um bioactive glass, and 12.5% 32-125 um bioactive glass.
- the 1000-2000 um bioactive glass may be porous.
- the composition for regenerating bone may be in a form of a collagen bioactive glass composite, wherein the collagen bioactive glass composite is lyophilized, or wherein the collagen and bioactive glass composite is lyophilized and
- composition for regenerating bone where the composition is in a form of a mixture of collagen in a granular, particulate, sphere or bead form, or a combination thereof, and bioactive glass in a granular, particulate, sphere or bead form, or a combination thereof.
- the composition for regenerating bone wherein the composition is in a granular, particulate, sphere or bead form, or a combination thereof, and comprises collagen and bioactive glass.
- the composition for regenerating bone of the kit may further comprise at least one therapeutic agent, a signaling protein, or glycosaminoglycan.
- the bioactive glass of the composition for regenerating bone may be in a granular form, particulate form, matt form, fiber form, hemostatic sponge form, foam form, paste or putty form, or sphere or bead form, or a combination thereof.
- the composition for regenerating bone may be pre -treated with water, saline, blood, bone marrow, a combination thereof, or other biocompatible substance to form a paste.
- the bioactive glass may include silicate based glasses or borate based glasses.
- a further embodiment relates to a method for repairing or regenerating a bony defect comprising dispensing the composition for regenerating bone comprising about 2-60% collagen and about 40-98% bioactive glass at or near the site of the bony defect using the components of the kit described herein.
- the composition for regenerating bone is moldable upon mixing with saline, blood, bone marrow, or other biocompatible fluid.
- the composition for regenerating bone may be pre-treated with water, saline, blood, bone marrow, a combination thereof, or other biocompatible substance to form a paste.
- the compositions, systems, kits and methods relate to composite structures with enhanced bone regeneration capabilities, and which remain in the surgical site, adsorb body fluids, blood, bone marrow aspirate and hold other biomolecules.
- the composite structure is a composition for regenerating bone that includes bioactive materials, such bioactive glass and collagen.
- Bioactive materials suitable for the present invention are any surface active materials able to chemically bond to body tissue.
- bioactive materials suitable for the compositions, systems, kits and methods include bioactive glasses, glass ceramics and ceramics.
- Bioactive glasses are typically amorphous whereas bioactive glass ceramics typically contain crystalline particles embedded in an amorphous glass phase.
- Bioactive ceramics typically have a crystalline structure.
- the bioactive materials may be amorphous, crystalline or
- amorphous particles having some crystalline domains i.e., amorphous particles having some crystalline domains, crystalline particles having some amorphous domains or mixtures of crystalline and amorphous particles.
- the bioactive material may be prepared by any suitable technique known to those skilled in the art.
- the particles may be native calcium phosphate or sodium phosphosilicate particles (amorphous bioactive glass particles), or combinations thereof.
- the calcium phosphate materials may be naturally occurring or synthetic.
- the calcium phosphate may be amorphous or crystalline or combinations thereof.
- Illustrative calcium phosphates have the general chemical formula Ca 5 (P0 4 )3X, where X is OH (hydroxyapatite), F (fluorapatite), or CI (chlorapatite).
- hydroxyapatite or "HA” as used herein, generally refers to a form of apatite with the formula Cas(P0 4 )3(OH). More typically, HA is represented as Cai 0 (P0 4 )6(OH) 2 to denote that the crystal unit cell comprises two molecules. Hydroxylapatite is the hydroxylated member of the complex apatite group. The hardness of hydroxyapatite may be altered by replacing the OH ion with other anions (e.g., fluoride, chloride or carbonate). Additionally, HA has a relatively high affinity for peptides, making it an ideal carrier for the delivery and sustained release of polypeptides over long periods of time in situ.
- anions e.g., fluoride, chloride or carbonate
- sodium phosphosilicate particles and calcium phosphate particles may be present in the compositions in an amount of about 1% to about 99%, based on the weight of sodium phosphosilicate particles and calcium phosphate particles.
- calcium phosphate may be present in the composition in about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
- calcium phosphate may be present in the composition in about 5 to about 10%, about 10 to about 15%, about 15 to about 20%, about 20 to about 25%, about 25 to about 30%), about 30 to about 35%, about 35 to about 40%, about 40 to about 45%, about 45 to about 50%), about 50 to about 55%, about 55 to about 60%, about 60 to about 65%, about 65 to about 70%), about 70 to about 75%, about 75 to about 80%, about 80 to about 85%, about 85 to about 90%), about 90 to about 95%, or about 95 to about 99%.
- Some embodiments may contain substantially one of sodium phosphosilicate particles and calcium phosphate particles and only traces of the other.
- the term "about" as it relates to the amount of calcium phosphate present in the composition means ⁇ 0.5%. Thus, about 5% means 5 ⁇ 0.5%.
- the particles may have particular size and/or geometry.
- the particles may be spherical (e.g., microspheres) or may possess any other geometry such as flat surfaces (e.g., microdisks).
- the particle size may be about 50 microns to about 5 mm in diameter.
- the average particle size is about 500 to about 1500 microns, about 1000 to about 2000 microns or from about 1200 micron to about 2500 microns.
- the particles may have average diameter of about 50, about 100, about 200, about 500, about 750, about 1000, about 1200, about 1400, about 1600, about 1800, about 2000, about 2200, about 2500, about 2750, about 3000, about 3500, about 4000, about 4500, or about 5000 microns.
- the bioactive glass particle has a diameter of between about 1 micrometer and about 2,000 micrometers.
- the term "about” means ⁇ 100 microns or ⁇ 10% of the average particle size, whichever is smaller.
- about 50 microns means 50 ⁇ 5 microns
- about 3500 microns means 3500 ⁇ 100 microns.
- the bioactive material may be a bioactive glass or glass ceramic.
- the bioactive material may be calcium phosphate or calcium sodium phosphosilicate particles.
- Bioactive glass may be melt-derived or sol-gel derived. Depending on their composition, bioactive glasses may bind to soft tissues, hard tissues, or both soft and hard tissues. The composition of the bioactive glass may be adjusted to modulate the degree of bioactivity. Furthermore, borate may be added to bioactive glass to control the rate of degradation. Additional elements, such as barium, copper, fluorine, silver, zinc, and strontium may be added to bioactive glass to facilitate healthy bone growth or provide other desirable properties.
- the bioactive glass may be in the form of a particle, a glass sheet, a fiber, a mesh, or any combination of these forms.
- Bioactive glass is capable of bonding to bone, which begins with the exposure of bioactive glass to aqueous solutions.
- Sodium ions in the glass can exchange with hydronium ions in body fluids, which increases the pH.
- Calcium and phosphorous ions can migrate from the glass to form a calcium and phosphate -rich surface layer.
- Borate ions can also migrate from the glass to from a surface layer rich in boron.
- Strontium ions also can migrate from the glass to form a strontium-rich surface layer. Underlying this surface layer is another layer which becomes increasingly silica rich due to the loss of sodium, calcium, strontium, boron, and/or phosphate ions (see, e.g., U.S. Pat. No. 4,851,046).
- Hydrolysis may then disrupt the Si-O-Si bridges in the silica layer to form silanol groups, which can disrupt the glass network.
- the glass network is then thought to form a gel in which calcium phosphate from the surface layer accumulates. Mineralization may then occur as calcium phosphate becomes crystalline hydroxyapatite, which effectively mimics the mineral layer of bones.
- Bioactive glass particles, fibers, meshes or sheets may be prepared by a sol-gel method. Methods of preparing such bioactive active glasses are described in Pereira, M. et al, "Bioactive glass and hybrid scaffolds prepared by sol-gel method for bone tissue engineering” Advances in Applied Ceramics, 2005, 104(1): 35-42 and in Chen, Q. et al, "A new sol-gel process for producing Na 2 0-containing bioactive glass ceramics” Acta Biomaterialia, 2010, 6(10):4143-4153.
- the composition can be allowed to solidify.
- particles of bioactive glass are sintered to form a porous glass.
- a glass drawing apparatus may be coupled to the spinner and the source of molten bioactive glass, such as molten bioactive glass present in a crucible, for the formation of bioactive glass fibers.
- the individual fibers can then be joined to one another, such as by use of an adhesive, to form a mesh.
- the bioactive glass in molten form may be placed in a cast or mold to form a sheet or another desired shape.
- a bioactive glass material may have silica, sodium, calcium, strontium, phosphorous, and boron present, as well as combinations thereof.
- sodium, boron, strontium, and calcium may each be present in the compositions in an amount of about 1% to about 99%, based on the weight of the bioactive glass ceramic.
- sodium, boron, strontium and calcium may each be present in the composition in about 1%, about 2%, about 3%), about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
- silica, sodium, boron, and calcium may each be present in the composition in about 5 to about 10%, about 10 to about 15%, about 15 to about 20%, about 20 to about 25%, about 25 to about 30%, about 30 to about 35%, about 35 to about 40%, about 40 to about 45%, about 45 to about 50%, about 50 to about 55%, about 55 to about 60%, about 60 to about 65%, about 65 to about 70%, about 70 to about 75%, about 75 to about 80%, about 80 to about 85%, about 85 to about 90%, about 90 to about 95%, or about 95 to about 99%.
- Some embodiments may contain substantially one or two of sodium, calcium, strontium, and boron with only traces of the other(s).
- divalent cations or ions that may be present in any of the bioactive glasses of this and other aspects of the invention include one or more of iron-II, iron-Ill, alumina, chromate, cobalt, titania, zirconia, copper, magnesium, and zinc. Additionally, silver and gold may be added to the composition for additional therapeutic benefits.
- the bioactive glass materials may further comprise one or more of a silicate, borosilicate, borate, strontium, or calcium, including SrO, CaO, P 2 0 5 , Si0 2 , and B 2 0 3 .
- An exemplary bioactive glass is 45S5, which includes 46.1 mol% Si0 2 , 26.9 mol% CaO, 24.4 mol% Na 2 0 and 2.5 mol% P 2 0 5 .
- An exemplary borate bioactive glass is 45S5B1, in which the Si0 2 of 45S5 bioactive glass is replaced by B 2 0 3 .
- bioactive glasses include 58S, which includes 60 mol% Si0 2 , 36 mol% CaO and 4 mol% P 2 0 5 , and S70C30, which includes 70 mol% Si0 2 and 30 mol% CaO.
- SrO may be substituted for CaO.
- bioactive glass may include glasses having about 40 to about 60 wt-% Si0 2 , about 10 to about 34 wt-% Na 2 0, up to about 20 wt-% K 2 0, up to about 5 wt-% MgO, about 10 to about 35 wt-% CaO, up to about 20 wt-% B 2 0 3 , about 0.5 to about 12 wt-% P2O5.
- the bioactive glass may additionally contain up to 10-wt% CaF 2 .
- the bioactive glass has the following composition 53 wt-% Si0 2 , 6 wt-% Na 2 0, 12 wt-% K 2 0, 5 wt-% MgO, 20 wt-% CaO, and 4 wt-% P 2 0 5 .
- Other compositions are also suitable.
- the bioactive glass is 45S5 bioactive glass.
- the 45S5 bioactive glass may vary in size from 1 micrometer to 5 millimeters.
- the bioactive glass may be about 1-5 micrometers, about 5-15 micrometers, about 15-50 micrometers, about 50-200 micrometers, about 200-1,000 micrometers, about 1-2 millimeters, about 2-3 millimeters, about 3-4 millimeters, or about 4-5 millimeters.
- compositions having a weight % of each element in oxide form in the range indicated, will provide one of several bioactive glass compositions that may be used to form a bioactive glass:
- the particles are sintered to form porous particulate made from the bioactive glass particles.
- fine particles of the bioactive glass are mixed with a sacrificial polymer and a binder to create a pre-shaped construct (e.g., a block or disk).
- the construct is then heated under specific conditions that allow a welding of the particles together without completely melting them. This process uses a temperature high enough to allow for the polymer material to burn off leaving a porous structure.
- the compression strength as well as the porosity of the construct may be controlled by varying the type and the amount of the sacrificial polymer and the sintering time and temperature used. Porosities as high as 90% may be achieved under suitable conditions.
- the pores in the bioactive glass material range from about 10 microns to about 5100 microns with an average pore size of 100 ⁇ 50 microns, 200 ⁇ 50 microns, 300 ⁇ 50 microns, 400 ⁇ 50 microns, 500 ⁇ 50 microns, 600 ⁇ 50 microns or 700 ⁇ 50 microns.
- the bioactive glass ceramic can be in the form of a three-dimensional compressible body of loose glass-based fibers, in which the fibers comprise one or more glass-formers selected from the group consisting of P 2 0 5 , Si0 2 , and B 2 0 3 . Some of the fibers have a diameter between about 100 nm and about 10,000 nm, and a length:width aspect ratio of at least about 10. The pH of the bioactive glass can be adjusted as-needed.
- the body comprises fibers having a diameter between about 100 nm and about 10,000 nm.
- the especially small diameter of these fibers renders them highly flexible so they form into the compressible body without breaking.
- the body includes fibers meeting these dimensional requirements in addition to other glass morphologies, such as fibers of other dimensions, spheres, microspheres, particles, ribbons, flakes or the like.
- the fibers may have a variety of cross section shapes, such as flat, circular, oval, or non-circular.
- fine particles of the bioactive glass are mixed with a sacrificial polymer and a binder to create a pre-shaped construct (e.g., a cylinder, block or disk).
- a sacrificial polymer and a binder to create a pre-shaped construct (e.g., a cylinder, block or disk).
- the construct is then heated under specific conditions that allow welding of the particles together without completely melting them. This process uses a temperature high enough to allow for the polymer material to burn off leaving a porous structure.
- the compression strength as well as the porosity of the construct may be controlled by varying the type and the amount of the sacrificial polymer and the sintering time and temperature used.
- Porosities as high as 90% may be achieved under suitable conditions.
- the pores in the bioactive glass material range from about 10 microns to about 5100 microns with an average pore size of 100 ⁇ 50 microns, 200 ⁇ 50 microns, 300 ⁇ 50 microns, 400 ⁇ 50 microns, 500 ⁇ 50 microns, 600 ⁇ 50 microns or 700 ⁇ 50 microns.
- the bioactive glass has average pore size of ⁇ 50 microns.
- the bioactive glass material may be ground with mortar and pestle prior to converting it to a paste. Any other method suitable for grounding the bioactive glass material may be used.
- the bioactive glass material is be mixed with other constituents to produce templates or granules that may be formed into a paste that can be shaped and/or incorporated into kits before further treatments are made.
- a suitable bioresorbable polymer may be used to prepare a composite in a form of a paste of a bioactive material (for example, glass or ceramic material) and bioresorbable polymer.
- a paste of a non-crystalline, porous bioactive glass or ceramic material is prepared that permit in vitro formation of bone tissue when exposed to a tissue culture medium and inoculated with cells.
- a bioresorbable polymer may be any biological polymer that facilitates cell adhesion, including but not limited to integrins, collagens, fibronectin, vitronectin, osteopontin, bone sialoprotein thrombospondin, fibrinogen, or combinations thereof.
- the bioactive glass may be mixed with integrins or other extracellular matrix molecules, such as various forms of collagens, fibronectin,
- bioresorbable polymers may include homo and copolymers of glycolides, acrylates, lactic acids, and caprolactone. Additional bioresorbable polymers suitable for the present invention are those described in U.S. Patent Nos. 6,322,797, 6,238,687, 6,166,173, 6,153,212, and 5,912,225, each of which is hereby incorporated by reference.
- the composition for regenerating bone may further comprise a polysaccharide (such as dextran, dextran sulfate, diethylaminoethyl dextran, or dextran phosphate or mixtures thereof).
- a polysaccharide such as dextran, dextran sulfate, diethylaminoethyl dextran, or dextran phosphate or mixtures thereof.
- the composition for regenerating bone comprises about 2- 60% collagen and about 40-98% bioactive glass.
- a bone regenerative composition comprises about 3-60%> collagen and about 40-97%) bioactive glass; and preferably, about 3-50%> collagen and about 50-97%) bioactive glass.
- the composition for regenerating bone may be in a form of a collagen-bioactive glass composite.
- the collagen-bioactive glass composite may be lyophilized and/or crosslinked.
- the composition for regenerating bone may be in a form of a mixture of
- the composition for regenerating bone includes about 2-60% collagen and about 40- 98%o bioactive glass.
- a bone regenerative composition comprises about 3-60%> collagen and about 40-97%) bioactive glass; and preferably, about 3-50%> collagen and about 50- 97%o bioactive glass.
- the composition for regenerating bone may be in a granular form, particulate form, matt form, fiber form, hemostatic sponge form, foam form, paste or putty form, or sphere or bead form, or a combination thereof, and include collagen and bioactive glass.
- the composition for regenerating bone includes about 2-60% collagen and about 40-98% bioactive glass.
- a bone regenerative composition comprises about 3-60%> collagen and about 40-97%) bioactive glass; and preferably, about 3-50%> collagen and about 50-97%) bioactive glass.
- collagen may be Type I collagen that may be used as the bioresorbable polymer of the composition for regenerating bone.
- Type I collagen is the most plentiful in the body and has been widely used for medical applications. It can be derived from bovine, ovine or other sources.
- collagen is extracted from the native source, for example, bovine hides using a neutral or dilute acidic buffer. In this extraction process, a slurry of collagen in an aqueous buffer, either acidic around pH 3 or by a slightly different process a neutral pH around 7, is produced. In another form of production, the acid treated collagen is further broken down enzymatically to remove the telo peptides at the end of the collagen chains. This treatment renders the collagen more soluble and may lessen any possible antigenicity caused by the telo groups on the ends of the collagen fibrils.
- concentration of the collagen varies anywhere from 3mg/mL of solution to upwards of
- the samples were evaluated for wickability and retention of fluids after wetting. To achieve this, the samples (in triplicate) were cut into 1 inch x 1 inch sizes. Liquids such as water, saline or sheep blood were used in 1 :1 volumetric ratio dependent on the sample size. Liquids were added in increments (drops) to the strip and the wicking property was evaluated dependent on the absorption time of the liquids and the volume of fluids required to completely saturate the samples.
- Liquids such as water, saline or sheep blood were used in 1 :1 volumetric ratio dependent on the sample size. Liquids were added in increments (drops) to the strip and the wicking property was evaluated dependent on the absorption time of the liquids and the volume of fluids required to completely saturate the samples.
- Wicking evaluation parameters Sample absorption ratio— with a desired volume ratio of 1 : 1 or more;
- the samples were typically able support the weight of the standard without collapsing
- Desirable samples exhibit some level of shape/memory retention quality. Desirable samples retain a level of moisture, maintaining consistency without disintegrating.
- the composition for regenerating bone may comprise any one or more of adhesives, grafted bone tissue, in vitro-generated bone tissue, collagen, calcium phosphate, stabilizers, antibiotics, antibacterial agents, antimicrobials, drugs, pigments, X-ray contrast media, fil lers, and other materials that faci litate grafting of the composition for regenerating bone to bone.
- the silica and/or calcium ions released by the bioactive glass may improve the expression of osteostimulative genes.
- the silica and/or calcium ions may also increase the amount of and efficacy of proteins associated with such osteostimulative genes.
- the bone repair material is osteostimulative and can bring about critical ion concentrations for the repair and regeneration of hard tissue without the necessity of any therapeutic materials or agents.
- bioactive glass can be mixed with water, buffer, saline, blood, bone marrow or other biocompatible fluid to produce a paste.
- the paste of a composition for regenerating bone including pre-treated bioactive glass or ceramic particles and a bioresorbable polymer is freeze-dried, it retains the osteostimulative effect of the glass while retaining its physical integrity and remaining wettable.
- the composition for regenerating bone including bioactive glass or ceramic particles and collagen is treated with water, certain buffer solutions, saline, blood, bone marrow aspirate or other biocompatible fluid prior to the preparation of the paste.
- the composition for regenerating bone may also be pre-treated with bone-morphogenetic proteins, platelet-rich plasma, and osteogenic proteins.
- the pre -treatment prepares the surface of the bioactive particles for cell adhesion and controls pH prior to the exposure of the particles with cells.
- the bioactivity and bone formation using the glass particles of the present invention may be enhanced by treating the glass particles with water, certain buffer solutions, saline, blood, bone marrow aspirate or other biocompatible fluid prior to mixing the bioactive glass particles with a bioresorbable polymer (i.e., collagen).
- the pre -treatment solution has a starting pH of from about 6 to about 8 but may reach an end pH of about 9.5.
- the end pH does not exceed 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.8, 8.9, 8.7, 8.6, 8.5, 8.3, 8.2, 8.1, or 8.0.
- the composition for regenerating bone or the bioactive glass or ceramic particles may be pretreated for different periods such that the particles become suitable for preparing constructs suitable for bone regeneration. Pre-treating the bioactive glass or ceramic particles much longer than necessary to activate them may deactivate the particles. Similarly, if the bioactive glass or ceramic particles are not pre-treated long enough, they may remain too active and attempts to convert them into a paste may encounter premature gellation of the paste.
- the bioactive glass or ceramic particles may be pretreated with water, certain buffer solutions, saline, blood, bone marrow aspirate or other biocompatible fluid for as short as 30 minutes. Other embodiments of the bioactive glass may require pretreatment as long as 24 hours.
- the bioactive glass may be pretreated about 1 to about 2 hours, about 3 to about 4 hours, about 5 to about 6 hours, about 7 to about 8 hours, about 9 to about 10 hours, about 11 to about 12 hours, about 13 to about 14 hours, about 15 to about 16 hours, about 17 to about 18 hours, about 19 to about 20 hours, about 21 to about 22 hours, or about 23 to about 24 hours.
- Some bioactive glasses may require pretreatments longer than 24 hours.
- the term "about” means ⁇ 30 minutes. A person skilled in the art can easily design simple experimental procedures to determine the optimum pretreatment time for bioactive glass or ceramic particles using water, buffer solutions, saline, blood, bone marrow aspirate or other biocompatible fluid.
- a paste of the pre-treated bioactive glass or ceramic particles and a bioresorbable polymer may be prepared using methods known to those skilled in the art.
- the paste may then be shaped into a desirable form, left un-crosslinked or, optionally crosslinked, and freeze dried before contacting the freeze-dried paste with a culture medium or implanted into an animal.
- the paste may be used to fill the tubes of the kit or delivery system. Once inside the tubes, the paste may be dried. Drying process includes and may not be limited to air drying, vacuum drying, or freeze drying (lyophilized).
- one embodiment of the present invention relates to methods of forming a composition for regenerating bone comprising providing bioactive material (e.g., porous bioactive glass particles), immersing the bioactive material in a pre-treatment solution (e.g., water, certain buffer solutions, saline, blood, bone marrow aspirate or other biocompatible fluid), isolating the pre-treated particles, forming a paste of the pre-treated particles and a bioresorbable polymer (e.g., collagen), shaping the paste to a construct with the desired shape, and freeze- drying the construct.
- the freeze-dried construct so obtained may be immersed in a tissue culture medium to produce a construct having enhanced bone cell activity when cells are inoculated on its surface.
- the construct is inoculated with cells and bone tissue is permitted to form thereon.
- the properties of the construct i.e. porosity, pore size and compressive strength, can be adjusted to a desired level by adjusting the amount and type of the bioresorbable polymer used to prepare the paste, the choice of the particle size, the pre-treatment solution used to pre- treat the particles, and length of time the particles are exposed to the pre-treatment solution.
- the lyophilized construct may be subjected to crosslinking or a fixation treatment to preserve the structural integrity of the construct.
- Any reagent suitable for fixation/crosslinking of biological constructs may be suitable.
- fixation/crosslinking may include exposing the freeze-dried construct to gluteraldehyde and may occur without any mechanical, hydrostatic, or other external stress placed on the construct. Fixing the construct without application of external stress would allow for some shrinkage of the construct to occur without affecting the orientation of the bioresorbable polymer or the biomechanical properties of the construct.
- the construct is inoculated with cells and bone tissue is permitted to form thereon.
- the construct is inoculated with cells from the patient by implanting the construct in a patient.
- the construct is inoculated with osteoblasts or precursor cells to osteoblasts.
- the osteoblasts or the precursor to the osteoblasts may have been extracted from the patient that is to receive the construct as an implant.
- the osteoblasts or its precursor may be extracted from a donor.
- the porous bioactive glass constructs may be implanted in sites where there is an immediate need for bone.
- kits and delivery systems for minimally invasive delivery of a composition for regenerating bone at or near the site of a bony defect or hard tissue defect includes a composition for regenerating bone comprising about 2- 60% collagen and about 40-98% bioactive glass.
- the composition for regenerating bone as part of the kit and delivery system may be in a form of a collagen-bioactive glass composite.
- the collagen- bioactive glass composite may be lyophilized and/or crosslinked.
- composition for regenerating bone as part of the kit and delivery system may be in a form of a mixture of
- bioactive glass in a granular form, particulate form, matt form, fiber form, hemostatic sponge form, foam form, paste or putty form, or sphere or bead form, or a combination thereof.
- the composition for regenerating bone includes about 2-60% collagen and about 40- 98%o bioactive glass.
- a bone regenerative composition comprises about 3-60%> collagen and about 40-97%) bioactive glass; and preferably, about 3-50%> collagen and about 50- 97%o bioactive glass.
- the composition for regenerating bone as part of the kit and delivery system may be in a granular form, particulate form, matt form, fiber form, hemostatic sponge form, foam form, paste or putty form, or sphere or bead form, or a
- the composition for regenerating bone includes about 2-60%> collagen and about 40-98%> bioactive glass.
- a bone regenerative composition comprises about 3-60% collagen and about 40- 97%o bioactive glass; and preferably, about 3-50%> collagen and about 50-97%> bioactive glass.
- a further embodiment relates to a kit for minimally invasive delivery of a composition for regenerating bone at or near the site of a bony defect or hard tissue defect that includes at least one tube including a composition for regenerating bone comprising about 2-60% collagen and about 40-98% bioactive glass, wherein the at least one tube is capped or sealed (e.g., sealed with foil) when not in use.
- the kit also includes a dispensing gun, an adapter, a plunger, and optionally, one or more dispensing tips.
- Other optional components of the kit include a syringe, aspiration needle, or other suitable delivery device and accompanying accessories.
- the exemplary dispensing gun 100, adapter 110, plunger 120 (see also Figure 3), tube(s) 130 (see also Figures 5A and 5B), caps 140, and assorted dispensing tips (optional; Figure 4A and Figure 4B) that may be included with the kits are shown.
- the composition for regenerating bone may be deposited into the tube(s) 130 as part of the kit ( Figure 5 A).
- An exemplary kit for delivery of other materials, such as Bioactive Synthetic Bone Graft Putty is currently being sold by NOVABONE® (NOVABONE® Bioactive Synthetic Bone Graft Putty MIS Cartridge Delivery System, NovaBone Products, LLC, Alachua, FL).
- the dispensing gun 100 may include a cover 150, a latch 160, a lever 170 and a handle 180 ( Figure 2B).
- the adapter 110 (shown also in Figure 2A) may be inserted into the dispensing gun at an opening 111.
- a plunger (not shown) may be inserted through the front of the gun and pushed through the opening in the back 190 of the gun.
- Figure 3 depicts an exemplary plunger 120 including gradient markings 200 facing up.
- Figures 4A-B depict exemplary tips for use with the dispensing gun.
- the tips may be straight (Figure 4A) or at an angle (Figure 4B) and their inclusion in the kit and subsequent use are optional.
- Figure 5 A is a picture of tubes filled with the composition for regenerating bone
- Figure 5B is a graphical illustration of an exemplary tube for use with the kit and specifically with the delivery gun described above.
- the tubes have a substantially constant inner diameter along their entire length such that the outlets have substantially the same inner diameters as the rest of the tubes.
- a "Y" connector, luer syringe and a tube connector may be included to facilitate the simultaneous delivery of biologies or other grafting materials and to maintain position during shipping (as shown in Figure 9).
- the components of a kit may be packaged and sold as a kit.
- the components of a kit may snap fit into a (inner) tray of a packaging and a retainer may be placed over the components of the kit to maintain position of the components during shipping.
- the inner tray may hold up to four tubes that can be prefilled with the irrigation resistant bone repair composition and capped on each end.
- the inner tray may also contain cavities for the placement of assorted tips, a "Y" connector, tube connector, a syringe and aspiration needle.
- the inner tray may be sealed with a lid and placed into an outer tray also sealed with a lid.
- the sealed trays are radiation sterilized for use in medical applications.
- the sealed trays may then be placed in a box.
- the kit may be placed in an operating room and the outer tray is opened.
- the inner tray is removed by a sterile technician and placed into the sterile field.
- the inner tray is opened and the dispensing gun is assembled by inserting the finger grip of the plunger 120 (with the gradient markings 200 facing up and teeth facing down) through the opening in the front of the gun 100 and pushing the plunger through the back of the gun until the piston end of the plunger is seated completely within the gun (see Figures 6A, 7 and 8).
- the adapter 110 is then inserted into the front of the gun 100.
- a prefilled tube is removed from the inner tray. One cap is removed from the prefilled tube. The tube is threaded into the adapter and the other cap is removed from the tube ( Figure 6B).
- a tip can be placed on the end of the tube to direct the flow of the graft material.
- the tip of the instrument may be placed into the surgical site.
- the plunger is ratcheted forward to express the composition for regenerating bone into the surgical site.
- the dispensing gun consists of, a handle, in which a block is moved forward through pressing the trigger which engages the teeth of the plunger moving the piston forward displacing the material from the tube.
- the trigger is manually disengaged by pushing the lever at the back of the dispensing gun upward allowing the plunger to be pulled back to a starting position.
- the first tube can be removed from the adapter and additional tubes can be threaded in place as needed.
- Another embodiment involves altering the adapter for the attachment of two tubes and the plunger modified from a single piston to one have two pistons moving simultaneously with each compression of the trigger. Subsequently, the plungers dispense the composition for regenerating bone from the two tubes through a static mixer to facilitate the addition of a biological or drug material into the non-setting bone grafting material during injection into the surgical site.
- Any of the above-described aspects and embodiments of the invention may be in injectable form. Injection may occur by means of a syringe, for example.
- the compositions are particularly useful when injected in a gel or liquid form into a bone gap or bone defect. The injected gel or liquid would then solidify at body temperature when placed on or near the bone gap or the bone defect.
- ASG acid swollen gel
- DM3 digested, pepsin treated collagen (higher solubility)
- base treated gel pH 7, all at 10 mg/mL concentration.
- the acid swollen gel ASG was mixed with the pepsin treated collagen DM3 at 1 :2, 1 : 1 and 2: 1 ratios.
- the total collagen concentration used was lOmg/mL along with a 97% by weight concentration of particles.
- the particles were mixed with the collagen slurry and it was noticed that the slurry began to gel prior to pouring into the molds, just as in the previous experiment. After the lyophilization process was complete, the resulting materials were wetted and again it was noted that liquid was not absorbed into the material. It was also noted that particles of the bioactive glass were falling out of the composite material upon handling.
- the particle size of the bioactive glass was reduced to 800 microns to 1.7mm and a combination of ASG/DM3 collagen at a 2: 1 ratio was used.
- the loading of the particulates was lowered from 97% to 95%.
- the outcome was similar to that in Experiment 2 in that the mixture was noted to react in the mixer and the slurry began to gel, limiting the working time of the mixtures.
- this ratio of the ASG to DM3 collagen allowed for some adsorption of liquid when tested after the lyophilization process, the handling characteristic resulted in a material that did not hold together after wetting.
- one embodiment of the present invention is to pre-react the particles in such a manner that the surface ionic reactivity would be reduced enough so that the particles did not interfere with the proper setting of the collagen structure while maintaining enough reactivity so that the composite material exhibited the unique osteostimulative properties imparted by the bioactive glass particles.
- the process of pre-reacting the particulate depends on the particle size, volume of particles used and the reagent used. Because the reactivity is sensitive to the surface area of particles exposed to the solution and to the volume of the solution, it will be appreciated that the examples below are only for the specific volumes and mass of particles used.
- the process consists of reacting a specific weight of particulate, in this case 25 g of particles with a surface area of 1 m 2 /g in 200 ml of a tris hydroxyl-aminomethane (TRIS) buffer that is titrated to a pH of 7.2 using hydrochloric acid. Particles were reacted for 1, 2, 6, 12 and 18 hrs and the starting and ending pH measured. The rise in pH is related to the amount of ions released from the particles.
- TMS tris hydroxyl-aminomethane
- bioactive glass particles are used as a filler in a resorbable polymer matrix.
- the surface passivated bioactive glass is reacted for 3 days in order to form a complete hydroxyapatite layer. It was found that this surface reacted layer produced a composite that had enhanced mechanical properties.
- the invention describes the passivation of the bioactive glass as being made incapable of reacting with water. This technology would prevent the bioactive glass particles in the current invention from further enhancing the bone regeneration through the further release of ions to the surrounding tissue and would therefore not be applicable to the composite devices of the current invention.
- bioactive glass particles are subjected to repeated immersions in a number of different solutions in order to incorporate proteins within the hydroxyapatite layer that forms as a result of reactions.
- the presence of proteins within the bioactive particle surface would likely have adverse reactions with the side chains of the organic collagen molecule and the result would likely be constructs that do not absorb fluid and could possibly cause inflammatory responses.
- ASG/DM3 collagen, at 20mg/mL was mixed with 90% by weight of 0.85mm - 1.4mm bioactive glass particles. Two sets of particles were used; one pre-reacted for 6 hours and one reacted for 18 hours. In both cases, the slurry pH did not rise significantly after mixing in the particles; the material was mixed for 2 minutes and cast into molds. It was then placed in the lyophilizer and the samples were freeze-dried. Upon removal the materials were homogeneous, porous and of a uniform consistency. The samples all absorbed moisture rapidly, and when handled after the absorption of the liquid, they all maintained their structural integrity.
- a "Packable graft” as defined herein is a loose collagen and 45S5 bioactive glass mixture that becomes moldable when hydrated.
- control sample "1" was prepared by hydrating 100% collagen with DI WATER (reverse osmosis deionized water prepared using the Sartorius system) until the material became moldable and then by forming a 2.5cc sphere. The sphere was then soaked in DI WATER for 24 hours.
- DI WATER reverse osmosis deionized water prepared using the Sartorius system
- test samples "2", “3”, and “4" were prepared by combining 1-2 mm, 90-710 ⁇ 45 S5 bioglass, and 32-125 ⁇ 45 S5 bioglass with collagen. The dry materials were then hydrated with varying CaCl 2 solutions and then soaked in DI WATER for 24 hours.
- Test samples "5" and "7" were prepared similarly to Samples 2-4 except HC1 was used to adjust the pH of the different percent CaCl 2 solutions to 6.5.
- Test sample "6" was prepared by replacing 5wt% of the 32-125 ⁇ 45S5 bioactive glass with ionomer glass, in particular ionomer glass powder TF-325. The packable graft was then hydrated and soaked in DI WATER.
- test sample 1 The data in Table 1 indicates that after soaking, packable graft containing bioactive glass is stronger than a packable graft containing only collagen (control sample 1).
- control sample 1 The data for test samples 3-5 and 7 indicates that the increasing concentration of Ca 2+ ions in the hydration solution increases the compressive strength.
- Test sample 6 was prepared with the same hydrating and soaking solutions as the control (sample 1) and exhibited higher compressive strength because of the presence of the bioactive and ionomer glasses.
- a "CBG strip” as defined herein is collagen and 45S5 bioactive glass that is lyophilized into a rectangular shape.
- control Sample A was prepared by making a slurry with collagen and DI WATER in a 1 : 1 ratio by weight. The slurry was then lyophilized and subjected to DHT in molds to form 5 cc strips. The collagen strips were then soaked in DI WATER for 3 hours and lyophilized once more.
- Test Sample B was prepared similarly to Sample A, except the soaking solution following DHT was 1% Fe 2 (S0 4 ) 3 in place of DI WATER.
- Test Samples C and E were prepared with a slurry of glass, collagen, and DI WATER adjusted to a pH of 5. Sample C contained 90 wt% glass and Sample E contained 85 wt% glass. The slurries were then lyophilized and then subjected to DHT to form strips, soaked in DI WATER for 3 hours and lyophilized once more.
- Test Sample D was prepared similarly to sample E except the slurry solution was pH adjusted CaCl 2 in place of DI WATER and HC1 and the soaking solution was PBS in place of DI WATER.
- Test Sample F was prepared by combining the glass and collagen, hydrating with DI WATER, and placing the sample into the tray. The tray was then soaked in DI WATER for 3 hours and lyophilized. Sample E did not undergo DHT.
- a "plate" shape was used to evaluate the strips on the Shimadzu Mechanical Strength Tester. Tests were conducted under ambient conditions and all samples were tested in accordance with SOP PR-06.06 Mechanical Testing of CBG Product. Stress was applied in a circumferential direction. Specimens were elongated at a rate of 5 mm/min until failure, with the force and extension recorded over time.
- Sample A is the control.
- Samples prepared with bioglass exhibited greater tensile strength than the control that was only crosslinked with DHT.
- Sample F indicates that the collagen can be crosslinked and a high tensile strength can be achieved without DHT processing.
- a slurry was prepared by mixing 0.28g of collagen with 4.55mL reverse osmosis deionized water and 0.49mL 2N HCl. The slurry was mixed until all collagen was saturated. Next, all glass starting with l-2mm (1.68g), then 710-90um (0.42g), then 32-125um (0.42g) was poured into the beaker labeled "slurry" and the components mixed until homogenous.
- the slurry was then lyophilized in molds to form 5 cc strips.
- the autoclaved molds were selected based on the desired amount of slurry to be placed in the mold and as per recommendations in the Table below (e.g., 2.5cc mold for making 2.5cc composites). Size of Well Max Amount of
- the objective of the study was to determine the extent of fluid/blood absorption for the Bioactive Strip, MacroFORM Composite and Packable products.
- the study was conducted at ambient conditions: 68-74°F and 40-60% relative humidity.
- Dry weights were taken for each product.
- the devices were then hydrated with citrated sheep's blood and molded until the entirety of the product was saturated in blood. The hydrated weight was then taken of each sample and a measure of amount of blood absorbed per gram of product was calculated.
- the MacroFORM products absorbed similar amounts of blood, approximately 0.6 - 0.75 grams of blood per gram of dry product.
- Samples were evaluated using mercury porosimetry.
- the process measures porosity by applying pressure to a sample immersed in mercury.
- the pressure required to inject mercury into the sample is inversely proportional to the size of the pores (MPS).
- the applicable variables were dependent (percent porosity), independent (device) and lot number),
- Mercury parameters were as follows: Adv. Contact Angle: 130.000 degrees; Hg Surface Tension: 485.000 dynes/cm; Rec. Contact Angle: 130.000 degrees; and Hg Density: 13.5335 g/mL.
- Samples were evaluated using mercury porosimetry.
- the process measures porosity by applying pressure to a sample immersed in mercury.
- the pressure required to inject mercury into the sample is inversely proportional to the size of the pores (MPS).
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US14/227,886 US9199006B2 (en) | 2010-03-03 | 2014-03-27 | Combination products including bioactive glass and collagen and kits including the same |
PCT/US2014/070633 WO2015147923A1 (en) | 2010-03-03 | 2014-12-16 | Kit for delivering bone grafting materials |
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EP3122652A1 true EP3122652A1 (en) | 2017-02-01 |
EP3122652A4 EP3122652A4 (en) | 2017-12-13 |
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EP14887214.6A Withdrawn EP3122652A4 (en) | 2014-03-27 | 2014-12-16 | Kit for delivering bone grafting materials |
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EP (1) | EP3122652A4 (en) |
AU (1) | AU2014388246A1 (en) |
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MX2009011268A (en) * | 2007-04-23 | 2009-11-02 | Baxter Int | Fibrin compositions containing strontium compounds. |
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2014
- 2014-12-16 AU AU2014388246A patent/AU2014388246A1/en not_active Abandoned
- 2014-12-16 EP EP14887214.6A patent/EP3122652A4/en not_active Withdrawn
- 2014-12-16 CA CA2940879A patent/CA2940879A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO2015147923A1 * |
Also Published As
Publication number | Publication date |
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CA2940879A1 (en) | 2015-10-01 |
EP3122652A4 (en) | 2017-12-13 |
AU2014388246A1 (en) | 2016-09-01 |
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