EP4100074A1 - Expandable bone and tissue regeneration system, and applications of same - Google Patents
Expandable bone and tissue regeneration system, and applications of sameInfo
- Publication number
- EP4100074A1 EP4100074A1 EP20917632.0A EP20917632A EP4100074A1 EP 4100074 A1 EP4100074 A1 EP 4100074A1 EP 20917632 A EP20917632 A EP 20917632A EP 4100074 A1 EP4100074 A1 EP 4100074A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- poly
- expandable scaffold
- scaffold
- bone
- living subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 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
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- 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
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- 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
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
- C08L75/04—Polyurethanes
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- 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
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Definitions
- [9] represents the ninth reference cited in the reference list, namely, Jackson, B. K., Bow, A. J., Kannarpady, G., Biris, A. S., Anderson, D. E., Dhar, M., & Bourdo, S. E. (2016). Polyurethane/nano-hydroxyapatite composite films as osteogenic platforms. Journal of Biomaterials Science, Polymer Edition, 29(12), 1426–1443.
- FIELD The present disclosure relates generally to an expandable bone and tissue regeneration system, and more particularly to a system of an expandable three-dimension (3D) biodegradable and biocompatible polymer/nanomaterial scaffold and applications of the same.
- One of the objectives of this disclosure is to provide an expandable scaffold formed by a composite material that may be applied in a liquid, such as water or bodily fluid of a living subject, and uptake the liquid and expand to an expansion volume.
- the expandable scaffold may be introduced into certain locations of the living subject, such as a bone defect or a tissue defect, or may be introduced within or around an implantable device that is then disposed into the living subject.
- the disclosure relates to an expandable scaffold.
- the expandable scaffold includes a three-dimensional (3D) porous structure comprising a composite material composed by a first material and a second material.
- the 3D porous structure has a tunable expansion capacity. When applied in a liquid, the 3D porous structure is configured to uptake the liquid and expand from an original volume to an expansion volume up to 1000 times of the original volume.
- the 3D porous structure is formed by a plurality of layers of the composite material, and the layers of the composite material are arranged in accordance with a shape and a size of the expansion volume.
- the liquid is water or bodily fluid of a living subject.
- the 3D porous structure is disposed in a bone defect or a tissue defect of the living subject, and is configured to uptake bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the expandable scaffold is disposed inside or around an implantable carrier, and the implantable carrier is disposed at a location within the living subject.
- the 3D porous structure is formed by injecting the composite material into a bone defect or a tissue defect of the living subject using an application device, such that the injected composite material uptakes bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the application device is a syringe.
- the expandable scaffold is loaded with a plurality of cells, drugs, antibiotics, growth factors or proteins.
- the first material includes one or more biocompatible and biodegradable polymers
- the second material is selected from a group consisting of hydroxyapatite, apatite, bone particles, calcium phosphate family or particles of multiple phases, calcium sulfate family or particles of multiple phases, graphitic materials, graphene, carbon nanotubes, carbon spheres, gold, silver nanomaterials, magnesium, zinc, or a combination thereof.
- the first material is polyurethane
- the second material is nanosized hydroxyapatite (nHA).
- the expandable scaffold is configured to be exposed to a gas plasma or corona discharge process to induce surface charges of positive, neutral or negative polarity.
- the expandable scaffold is configured to be exposed to a plasma polymerization coating process to introduce a surface coating on an external surface and an internal surface of the 3D porous structure, or to modify a surface charge of the expandable scaffold.
- a thickness of the surface coating ranges from 0.001 nm to 10 cm.
- the surface coating is formed by a biocompatible and biodegradable polymer material, comprising: (poly( ⁇ -esters), polyglycolide, polylactide, poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), poly(lactide-co-glycolide), polyhydroxyalkanoates, poly(3- hydroxybutyrate), PHBV, Polycaprolactone (PCL), Poly(propylene fumarate) (PPF), polyanhydrides, polyacetals, poly(ortho esters), polycarbonates, poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl ester carbonates) (PDTEs), polyurethanes, polyphosphazenes, (poly[bis(trifluoroethoxy)phosphazene], polyphosphoesters, poly(ester ether)s, polydioxanone (P
- the expandable scaffold is designed to have a non-uniform density and packing density.
- the 3D porous structure has a porosity ranging from 1% to 99%.
- the expandable scaffold is designed to have a liquid uptake property ranging from 0 to 50000 times weight of the expandable scaffold.
- a composition weight ratio of the first material to the second material ranges from 0.01% to 99.99%.
- construction of the expandable scaffold is done by 3D bio- printing and hybrid printing and deposition technology by layer-by-layer deposition. Another aspect of the disclosure relates to a bone regeneration system, which includes the expandable scaffold as discussed above.
- the expandable scaffold is configured to be disposed at a location within a living subject in which bone formation and regeneration is required, wherein the second material includes bone particles, and the 3D porous structure of the expandable scaffold is configured to uptake bodily fluid of the living subject and expand at the location within the living subject.
- the expandable scaffold is disposed in a bone defect of the living subject, and the 3D porous structure of the expandable scaffold is configured to uptake bodily fluid of the living subject and expand to self-fit in the bone defect.
- the expandable scaffold is disposed inside or around an implantable carrier, and the implantable carrier is disposed at the location within the living subject.
- the bone regeneration system further includes an application device configured to inject the expandable scaffold into the location within the living subject, such that the injected composite material uptakes bodily fluid of the living subject and expand to form the expandable scaffold.
- the application device is a syringe.
- a further aspect of the disclosure relates to a soft tissue regeneration system, which includes the expandable scaffold as discussed above.
- the expandable scaffold is configured to be disposed within a tissue defect of a living subject in which soft tissue formation and regeneration is required, wherein the 3D porous structure of the expandable scaffold is configured to uptake bodily fluid of the living subject and expand to self-fit in the tissue defect.
- the soft tissue of the living subject includes muscle, skin, nerve, blood arteries and vessels of the living subject.
- a further aspect of the disclosure relates to a bleed stopping device, which includes the expandable scaffold as discussed above.
- the expandable scaffold is configured to be disposed at a location of a living subject in which bleeding occurs, wherein the 3D porous structure of the expandable scaffold is configured to uptake blood of the living subject and expand to stop the bleeding.
- the disclosure relates to a method for fabricating an expandable scaffold.
- the method includes: providing a three-dimensional (3D) porous structure comprising a composite material composed by a first material and a second material, forming the expandable scaffold, wherein the 3D porous structure has a tunable expansion capacity, and when applied in a liquid, is configured to uptake the liquid and expand from an original volume to an expansion volume up to 10000 times of the original volume.
- the method also includes: forming the 3D porous structure by a plurality of layers of the composite material; and arranging the layers of the composite material in accordance with a shape and a size of the expansion volume.
- the method also includes: disposing the 3D porous structure in a bone defect or a tissue defect of a living subject, such that the 3D porous structure uptakes bodily fluid of the living subject and expand to fit in the bone defect or the tissue defect.
- the method also includes: disposing the expandable scaffold inside or around an implantable carrier; and disposing the implantable carrier at a location within a living subject.
- the method also includes: injecting the composite material into a bone defect or a tissue defect of the living subject using an application device to form the expandable scaffold, such that the injected composite material uptakes bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the expandable scaffold is loaded with a plurality of cells, drugs, antibiotics, growth factors or proteins.
- the first material includes one or more biocompatible and biodegradable polymers
- the second material is selected from a group consisting of hydroxyapatite, apatite, bone particles, calcium phosphate family or particles of multiple phases, calcium sulfate family or particles of multiple phases, graphitic materials, graphene, carbon nanotubes, carbon spheres, gold, silver nanomaterials, magnesium, zinc, or a combination thereof.
- the first material is polyurethane
- the second material is nanosized hydroxyapatite (nHA).
- the method further includes: exposing the expandable scaffold to a gas plasma or corona discharge process to induce surface charges of positive, neutral or negative polarity. In one embodiment, the method further includes: exposing the expandable scaffold to a plasma polymerization coating process to introduce a surface coating on an external surface and an internal surface of the 3D porous structure, or to modify a surface charge of the expandable scaffold. In one embodiment, a thickness of the surface coating ranges from 0.001 nm to 1 cm.
- the surface coating is formed by a biocompatible and biodegradable polymer material comprising: (poly( ⁇ -esters), polyglycolide, polylactide, poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), poly(lactide-co-glycolide), polyhydroxyalkanoates, poly(3- hydroxybutyrate), PHBV, Polycaprolactone (PCL), Poly(propylene fumarate) (PPF), polyanhydrides, polyacetals, poly(ortho esters), polycarbonates, poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl ester carbonates) (PDTEs), polyurethanes, polyphosphazenes, (poly[bis(trifluoroethoxy)phosphazene], polyphosphoesters, poly(ester ether)s, polydioxanone (PDO
- the expandable scaffold is designed to have a non-uniform density and packing density.
- the 3D porous structure has a porosity ranging from 1% to 99%.
- the expandable scaffold is designed to have a liquid uptake property ranging from 0 to 50000 times weight of the expandable scaffold.
- a composition weight ratio of the first material to the second material ranges from 0.01% to 99.99%.
- construction of the expandable scaffold is done by 3D bio- printing and hybrid printing technology by layer-by-layer deposition.
- FIGS.1A and 1B show images of an expandable scaffold in different spots of its 3D porous structure according to certain embodiments of the disclosure.
- FIG.2 shows images of a combination of an expandable scaffold with an implant in different viewing angles according to one embodiment of the disclosure.
- FIG.3 shows a schematic view of an expandable scaffold according to one embodiment of the disclosure.
- FIG.4 shows 3D laser microscopy of the expandable scaffold according to one embodiment of the disclosure, where (a) represents an image of a non-uniform bone defect, (b) shows the expandable scaffold being implanted or positioned inside the defect before hydration, and (c) shows the scaffold expanding and filling up the volume of the defect after the hydration.
- FIG.5 shows images of the expandable scaffold in a self-fitting test inside a PVC mold taken at different times after swelling started according to one embodiment of the disclosure.
- FIG.6 shows a chart of the swelling plot of the expandable scaffold according to one embodiment of the disclosure, where three samples were tested.
- FIG.7 shows 3D laser microscopy images of cross sections a dry scaffold and a wet scaffold according to one embodiment of the disclosure.
- FIG.8 shows a chart of the thermogravimetry curve for three scaffold samples according to one embodiment of the disclosure.
- FIG.9 shows micro-CT scan images for dry and wet scaffold samples according to certain embodiments of the disclosure.
- relative terms such as “lower” or “bottom” and “upper” or “top”, may be used herein to describe one element's relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation shown in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on the “upper” sides of the other elements. The exemplary term “lower” can, therefore, encompass both an orientation of lower and upper, depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements.
- the terms “comprise” or “comprising”, “include” or “including”, “carry” or “carrying”, “has/have” or “having”, “contain” or “containing”, “involve” or “involving” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.
- the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the disclosure.
- terms such as “about,” “approximately,” “generally,” “substantially,” and the like unless otherwise indicated mean within 20 percent, preferably within 10 percent, preferably within 5 percent, and even more preferably within 3 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “about,” “approximately,” “generally,” or “substantially” can be inferred if not expressly stated.
- “nanoscopic-scale,” “nanoscopic,” “nanometer-scale,” “nanoscale,” the “nano-” prefix, and the like refers to elements or articles having widths or diameters of less than about 1 ⁇ m, preferably less than about 100 nm in some cases.
- Specified widths can be smallest width (i.e. a width as specified where, at that location, the article can have a larger width in a different dimension), or largest width (i.e., where, at that location, the article’s width is no wider than as specified, but can have a length that is greater), unless pointed out otherwise.
- smallest width i.e. a width as specified where, at that location, the article can have a larger width in a different dimension
- largest width i.e., where, at that location, the article’s width is no wider than as specified, but can have a length that is greater
- this invention in certain aspects, relates to three-dimension (3D) biodegradable, biocompatible polymer/nanomaterial expandable scaffolds, fabricating methods thereof, and applications of the same.
- 3D three-dimension
- autografts as fillers to reconstruct the bone defects is limited.
- Tissue engineering providing an alternative solution by utilizing biocompatible materials to make a bone scaffold, mimicking the bone structure and component of organic (soft) and inorganic (hard) components.
- Biocompatible Polymers have been widely used for fabrication of synthetic bone scaffolds, and the biodegradable polyurethane promote the growth of cells and tissues in vitro and in vivo.
- HA Hydroxyapatite
- nHA nanosized HA
- nHA nanosized HA
- nHA nanosized HA
- a composite material of polyurethane and nHA is shown to be cytocompatible, and provide suitable environmental cell adhesion, proliferation, and osteogenic differentiation in vitro.
- a composition of 80% polyurethane and 20 % nHA shows a linear increase in proliferation of MC3T3-E1 cells in vitro.
- the ratio can be varied from 0.01 wt.% to the value that would result in the disintegration of the composite and its inability to maintain its structure (usually over 50 wt.%).
- Natural bone particles decellularized or demineralized bone matrix
- various sources bovine, human/cadaveric, porcine, etc.
- biodegradable/biocompatible polymers polyurethanes, etc
- nHA for making synthetic bone scaffolds.
- an injectable scaffold needs to meet a number of requirements.
- bone osseointegration needs the scaffold to firmly fill the defect, and the scaffold has to be osteoconductive and porous to promote the new bone growth inside its structure.
- the scaffold material should be biodegradable, as the scaffold material needs to degrade in the new bone growth process to allow new bone formation.
- the disclosure is to provide an expandable scaffold, which formed by a composite material in one or more layers forming a 3D porous structure.
- the 3D porous structure When the 3D porous structure is applied in a liquid, such as water or bodily fluid of a living subject, the 3D porous structure may uptake the liquid and expand to an expansion volume.
- the expandable scaffold may be introduced into certain locations of the living subject, such as a bone defect or a tissue defect, or may be introduced within or around an implantable device that is then disposed into the living subject.
- the implantable device may be an implant normally used in the medical practice such as a carrier, a spine cage or similar device, or a bone implant that is metallic or non-metallic.
- the expansion could take place due to the structural or morphological changes that take place within the bulk of the scaffold or other mechanisms that include the body fluids uptake and swelling.
- the scaffold can increase in the volume from 0 to a volume that is equal with the volume that is required to be filled by the final structure of the scaffold.
- the scaffold for example could expand up to 10000 times or more or less of its original volume, depending upon the actual application.
- the scaffold can be used for bone regeneration, but also for soft tissue regeneration (muscle, skin, nerve, blood arteries and vessels, etc).
- the 3D porous structure of the expandable scaffold includes a composite material composed by a first material (which is a soft material) and a second material (which is a hard material), or mixture of soft and hard materials.
- the 3D porous structure has a tunable expansion capacity. When applied in a liquid (such as water or bodily fluid of a living subject), the 3D porous structure is configured to uptake the liquid and expand from an original volume to an expansion volume up to 10000 times of the original volume.
- the 3D porous structure is formed by a plurality of layers and mixtures of the composite material, and architecture and shape of the layers of the composite material are arranged in accordance with a shape and a size of the expansion volume.
- the 3D porous structure is formed by controlled mixing, in a successive or simultaneous manner, of the components into a uniform composition.
- the mixture that is formed by the mixing of the components can be arranged into layers or various geometrical shapes.
- the 3D porous structure is formed by the controlled mixing of the various materials in a simultaneous or in a certain order based on the desired characteristics of the scaffold.
- construction of the expandable scaffold is done by selective solvent extraction and by controlled mixing of the components and followed by possible controlled removal of the solvent.
- the scaffolds can also be mixed and printed into anatomically correct shapes that mimic the part of the bone that needs to be regenerated.
- the expandable scaffold can take any complex shape during the application.
- FIGS.1A and 1B show images of an expandable scaffold in different spots of its 3D porous structure according to certain embodiments of the disclosure.
- the internal morphology of the expandable scaffold can be nano- or micro-fibers formed by the composite materials.
- the 3D porous structure of the expandable scaffold acts as the self-fitting bone or tissue filler, which can expand by swelling in the liquid or by transformation into its volume structure, in order to occupy the shape of defect or the volume to be filled and increase its shape dynamically as a function of time.
- the 3D porous structure is disposed alone in a bone defect or a tissue defect of the living subject.
- the scaffold would uptake bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the expandable scaffold can also be disposed inside or around an implantable carrier, and the implantable carrier is then disposed at a location within the living subject.
- the scaffold can be applied inside of various rigid or non-rigid industry standard or customized implantable carriers or cages (which may be metallic, carbon or polymeric), and then the implant can be implanted into any part of the body such as craniomaxillofacial, extremities, spine, pelvis, etc.
- the application of the expandable scaffold can be done with an application device either in a solid or expanded state.
- the 3D porous structure may be formed by injecting or placing the composite material into a bone defect or a tissue defect of the living subject using an application device, such that the injected composite material uptakes bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the application device may be a syringe, or may be a medical device that allows the precise delivery and accurate positioning of the scaffold into the desired bone defect and location.
- the scaffold can also be placed during surgery by exposing the bone void and by tightly placing the scaffold into the desired position.
- the scaffold can be rigid with no volume expansion, or can expand multiple times its original volume through liquid (water, blood, body fluids, etc) interactions and uptake.
- the scaffold can be applied as an injectable scaffold, where a sample of known volume can be injected or introduced through an applicator such as syringe, with openings of various diameters.
- the expandable scaffold which is formed by a composite material composed of the first material (which is a soft material) and the second material (which is a hard material), is designed to mimic the natural bone of soft and elastic component (collagen) and hard mineral component.
- the porosity of the scaffold can be varied between basically 0 to 99.999999 % and its water uptake properties can be varied from 0 to 50000 times the scaffolds’ weight.
- the 3D porous structure may be designed to have a porosity ranging from 1% to 99%, and a liquid uptake property ranging from 0 to 50000 times weight of the expandable scaffold.
- the composite material forming the expandable scaffold includes multiple major types of materials.
- the first material is a soft material, such as one or multiple polymers.
- the second material is a hard material, which can be organic or inorganic, such as one or more components of human/animal or synthesized origin.
- the second material may include, without being limited thereto, the following materials and their derivatives: hydroxyapatite, apatites, bone particles (processed, decellularized or demineralized, or unprocessed), calcium phosphate family or particles of various phases (b-Tricalcium phosphate, or the family of such materials, etc), calcium sulfate family or particles of various phases, graphitic nano-, micro- or macro-sized materials such as graphene, carbon nanotubes, carbon spheres, gold, silver nanomaterials, magnesium, zinc, or other metals/metal oxides in both nano, micro or bulk sizes, etc.
- the bone particles could be human, bovine, porcine or other animal origins. All these materials can be sized at the nano, micro size or bulk, and they can be mixed in various dimensional ranges.
- the ratio between the soft material (such as polymers) and the hard material (such as various organic and inorganic systems) may be varied from 0.001 to 99.99 wt. %.
- a composition weight ratio of the first material to the second material ranges from 0.01% to 99.99%.
- the polymers used as the first material are biocompatible and biodegradable, with a degradation rate from minutes to multiple years.
- Examples of the natural or synthetic biocompatible and/or biodegradable polymers may include, without being limited thereto, (Poly( ⁇ -esters), Polyglycolide, Polylactide, poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), Poly(lactide-co-glycolide), Polyhydroxyalkanoates, poly(3-hydroxybutyrate), PHBV, Polycaprolactone (PCL), Poly(propylene fumarate) (PPF), Polyanhydrides, Polyacetals, Poly(ortho esters), Polycarbonates, poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl ester carbonates) (PDTEs), Polyphosphazenes, (poly[bis(trifluoroethoxy)phosphazene], Polyphosphoesters, Poly(ester ether)s, polydioxanone (PDO), poly( ⁇
- the first material is a biocompatible/biodegradable polymer such as polyurethane or ether-based hydrophilic urethanes (or a mixture of such polymers with various degradable rates), and the second material is nanosized/macrosized hydroxyapatite (nHA).
- the polymer/hydroxyapatite composite is integrated with bone derived particles (such as decellularized, demineralized, etc) or calcium phosphate family of materials or calcium sulfate family of particulate materials, or combination of these materials.
- a sacrificial material (salt, sugar, or a fast degrading/dissolving polymer or material) can be integrate in this composite and upon removal into a water or solvent bath, would generate desired porosity with interconnected pores.
- the expandable scaffold is configured to be exposed to a gas (nitrogen, oxygen, helium, argon, or mixtures, etc) plasma or corona discharge process to induce surface charges of positive, neutral or negative polarity or mixtures.
- the process can be used to increase the roughness of the surface morphology and introduce atoms and functional groups onto the surface.
- the expandable scaffold is configured to be exposed to a plasma polymerization coating process to introduce a surface coating on an external surface and an internal surface of the 3D porous structure, or to modify a surface charge of the expandable scaffold.
- the internal and external surfaces of the 3D porous structure and/or a bulk of the 3D porous structure of the expandable scaffold may be coated with nanostructural materials by using plasma polymerizations coating.
- a thickness of the surface coating ranges from 0.001 nm to 1 cm.
- Different materials can be used modify the internal/external surface coating of the expandable scaffold, such as a natural or synthetic biocompatible and/or biodegradable (fast or slowly) polymer, with a degradation rate from minutes to multiple years.
- biocompatible and biodegradable polymer material for the surface coating may include, without being limited thereto, HydroMedTM family ( D1, D2, D3, D4, D6, D640, D7), Pellethane® thermoplastic polyurethanes, TecobaxTM thermoplastic polyurethane (TPU), TecoflexTM aliphatic polyether-based thermoplastic polyurethanes (TPUs), TecophilicTM thermoplastic polyurethanes (TPUs), TecoplastTM thermoplastic polyurethanes (TPUs), TecothaneTM aromatic polyether-based thermoplastic, (poly( ⁇ - esters), polyglycolide, polylactide, poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), poly(lactide-co-glycolide), polyhydroxyalkanoates, poly(3- hydroxybutyrate), PHBV, Polycaprolactone (PCL), Poly(propylene fumarate) (
- some of the polymers can be composed of groups such as PEG, PPO, PBO, that would help with water uptake.
- the polymer can be hydrogel.
- the expandable scaffold can be designed to have a uniform or non-uniform density and packing density. For example, the density at the edges of the expandable scaffold can be higher or lower compared to the interior thereof.
- the construction of the scaffold can be done by using solvent extraction, mixing of components, selective materials removal approaches, high air pressure spraying, 3D bio-printing and hybrid printing/deposition technology such as layer-by-layer deposition or additive manufacturing.
- the construction of the expandable scaffold can be done by placing the wet scaffold into a water bath, dried, and shaped to the required size or shape by cutting or molding into the desired shapes and sizes.
- the expandable scaffold is loaded with a plurality of cells, drugs, antibiotics, growth factors or proteins that are pertinent to tissue formation and controlling and removing infections and diseases.
- the expandable scaffold can be delivered in vivo with one or multiple bio-active systems, including, without being limited thereto: ⁇ Antibiotics to fight infections involving both gram positive and gram negative bacteria: that include but are not limited to Cefazolin, Cefuroxime, Flucloxacillin and gentamicin, Ceftriaxone, Clindamycin, Vancomycin, ciprofloxacin, tigecycline, tobramycin, Piperacillin, tazobactam, lovastatinetc.
- the loading ratios of the antibiotics could be varied from 0 to the maximum loading capacity.
- the antibiotic uptake can take place in the porosity of the scaffold or in the structure of the polymers used in the construction of the scaffold.
- Anti-cancer drugs include but are not limited to: Doxorubicin (Adriamycin) , Mitotane, Cisplatin , Carboplatin , Etoposide (VP-16), Ifosfamide (Ifex), Cyclophosphamide (Cytoxan), Vincristine (Oncovin), Abitrexate (Methotrexate), Cosmegen (Dactinomycin) , Doxorubicin Hydrochloride, Folex (Methotrexate), Folex PFS (Methotrexate) ,Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ (Methotrexate), Xgeva (Denosumab), Vincristine, ifosfamide, doxorubicin, etoposide (VIDE), Vincristine, actinomycin and
- the loading ratios of the drugs could be varied from 0 to the maximum loading capacity.
- the drug uptake can take place in the porosity of the scaffold or in the structure of the polymers used in the construction of the scaffold.
- Osteoporosis treatment drugs such as: Fosamax, Zometa, estradiol, hydrochlorothiazide, Boniva, calcium / vitamin d, calcium carbonate, Alendronate, Forteo, Reclast, Prolia,Caltrate, Caltrate 600+D, Evista, risedronate, Citracal + D, Atelvia, ibandronate, Premarin, raloxifene, Actonel, calcitonin, teriparatide, zoledronic acid, denosumab, ⁇
- growth factors one or multiple
- growth factors include, but are not limited to: platelet-rich plasma (PRP), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (F
- the expandable scaffold may be used for bone regeneration based on the final architecture.
- a bone regeneration system may include the expandable scaffold, which is used to be disposed at a location within a living subject in which bone formation and regeneration is required.
- the hard material of the expandable scaffold being used in the bone regeneration system may include bone particles, and the 3D porous structure of the expandable scaffold is configured to uptake bodily fluid, cells, and/or growth factors of the living subject and expand at the location within the living subject.
- the expandable scaffold may be disposed in a bone defect of the living subject.
- the 3D porous structure of the expandable scaffold may uptake bodily fluid of the living subject and expand to self-fit in the bone defect.
- the expandable scaffold may be disposed inside or around an implantable carrier, and the implantable carrier is disposed at the location within the living subject.
- an application device such as a syringe
- the expandable scaffold may be used for soft tissue regeneration (muscle, skin, nerve, blood arteries and vessels, etc).
- a soft tissue regeneration system may include the expandable scaffold, which is disposed within a tissue defect of a living subject in which soft tissue formation and regeneration is required.
- the 3D porous structure of the expandable scaffold may uptake bodily fluid of the living subject and expand to self-fit in the tissue defect.
- the expandable scaffold alone or along with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be placed into a bone defects of various shapes or sizes, or in bone defects that have 4, 3, 2, or 1 bone walls/surfaces.
- the expandable scaffold alone or along with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be placed next to a bone wall in order to increase the amount of bone formed along that particular bone surface.
- the expandable scaffold can be placed around a medically used implant, nails, screws, devices that could be metallic or non-metallic and used in joint replacement, bone fixation, bone fracture stabilization, and other medically relevant applications in which bone formation and regeneration is required.
- the expandable scaffold may be included into medically used devices such as cages that are placed into bone structures.
- the scaffold possibly carrying bio-active molecules, proteins, (growth factors, ex BMPs) and/or drugs (antibiotics, or various drugs as seen above) can be included into the cages and expand as the cages are introduced into the bone structures (dental, spine, pelvis, long bone, etc) and the scaffold can expand along with cage expansion.
- the expandable scaffold may be used for dental applications, where the scaffold is placed into an extraction socket, around the tooth root, around the implant surface and intertwined with the implant structure and morphology, large segmental bone defect, alone or in the presence of antibiotics, drugs, cells or growth factors.
- the expandable scaffold is placed around a dental implant either during the scaffold manufacturing or the implant is placed into the scaffold after the scaffold it is manufactured.
- FIG.2 shows images of a combination of an expandable scaffold with an implant in different viewing angles according to one embodiment of the disclosure. As shown in FIG.2, the expandable scaffold is disposed around the implant.
- the combination of the two systems can be implanted together in order to provide mechanical support and also provide a medium of bone regeneration and integration of the implant.
- the combination scaffold/implant along with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be implanted together.
- the thickness of the scaffold around the implant surface can vary from 0.001 mm to 10 cm or the actual value that is needed for a particular application.
- the scaffold can also have an anatomically correct shape that is required to build a complex bone defect, and such a defect can be obtained through 3D CT scanning.
- the scaffold with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be used for the partial or complete craniomaxillofacial bone regeneration, such as but not limited to regenerate bone gaps or the entire structure in the mandible, skull, nasal bone and septum, maxilla, zygomatico- maxillary structure, maxilla, etc.
- Such combination can be used for the partial or complete regeneration of long bones, such as but not limited to tibia, femur, humerus, ulma, radius, fibula, but also patella, phalanges, metatarsals, metacarpals, sacrum, pelvic structure, vertebrae, ribs, spinal column, spine, cervical vertebrae, etc.
- the scaffold with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be placed can be used for spine tissue regeneration alone or inside a cage (metal, carbon, polymer, etc) of another devices of various dimensions that are normally used for such applications.
- the scaffold with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins can be used to fill up the space and ensure bone regeneration between the surface of an implant and the bone surface. This volume can be of various shapes and dimensions in various parts of the body.
- the expandable scaffold may be used as a bleed stopping device, which may be disposed at a location of a living subject in which bleeding occurs.
- the 3D porous structure of the expandable scaffold may uptake blood of the living subject and expand to stop the bleeding. Based on the degree of expansion or fluid uptake, the expandable scaffold may expand up to 1000 times of its original size, and may uptake/store fluid within range of (0-10000) of its original weight.
- the expandable scaffold may be used to treat internal/or external bleeding. Further, the expandable scaffold may also prevent/fight/treat skin/or tissue inflammation.
- the expandable scaffold (or one or more 2D layers thereof) with one or multiple combinations of cells, drugs/antibiotics, growth factors/proteins may work as skin graft/scaffold.
- the scaffold may be formed from different layers, such as 1- 10000 layers.
- Each layer can be design to have it unique fluid uptake, and the thickness of each layer may range from 0.001 nm to 10cm.
- the device can be directly loaded/coated the injury site through high air pressure spraying.
- the expandable scaffold as described in the embodiments of the disclosure provides a promising solution for bone fracture therapy. In case of critical size bone defects or bones that are located in critical position, doing surgery becomes very hard and minimum surgical intervention is needed.
- the expandable scaffold has the self-fitting and/or injectable feature, which may occupy the irregular shape of a bone defect by injection through small hole or have small scaffold that can expand to take the shape of defect.
- the expandable scaffold is biocompatible, biodegradable and porous in order to improve the healing process of bone while promoting neovascularization and allowing the cells proliferate and expand in its bulk and surface.
- the expandable scaffold is also provided with tunable expansion capacity based on the particular applications and possibly injectable scaffold that can expand by swelling at exposure to bodily fluids or other liquids to take the non-uniform shape of bone defect, or be injected through small hole and fill the defect shape.
- the scaffold may match the expansion volume of a medical device that is introduced thereto.
- the scaffold may be introduced alone in the non-uniform bone defect, or inside a commonly used industry standard device or around a device (implant, etc.) that is desired to be anchored into the bone structure.
- the scaffold design is such that mimics the natural architecture of bone, with nano-macro hard/soft components that support osteogenesis.
- the disclosure relates to a method for fabricating an expandable scaffold.
- the method includes: providing the 3D porous structure comprising a composite material composed by a first material and a second material, forming the expandable scaffold, where the 3D porous structure has a tunable expansion capacity, and when applied in a liquid, is configured to uptake the liquid and expand from an original volume to an expansion volume up to 1000 times of the original volume.
- the method also includes: forming the 3D porous structure by a plurality of layers of the composite material; and arranging the layers of the composite material in accordance with a shape and a size of the expansion volume.
- the method includes: forming a 3D porous structure by controlled mixing of a variety of composition materials and arranging them into the shape that is desired for the regeneration application and then by solvent extraction obtain the desired porosity. The scaffold can then be introduced a liquid and then dried, before being shaped into the desired shape and size.
- the method also includes: disposing the 3D porous structure in a bone defect or a tissue defect of a living subject, such that the 3D porous structure uptakes bodily fluid of the living subject and expand to fit in the bone defect or the tissue defect.
- the method also includes: disposing the expandable scaffold inside or around an implantable carrier; and disposing the implantable carrier at a location within a living subject.
- the method also includes: injecting or placing the composite material into a bone defect or a tissue defect of the living subject using an application device to form the expandable scaffold, such that the injected composite material uptakes bodily fluid of the living subject and expand to self-fit in the bone defect or the tissue defect.
- the method further includes: exposing the expandable scaffold to a gas plasma or corona discharge process to induce surface charges of positive, neutral or negative polarity. In one embodiment, the method further includes: exposing the expandable scaffold to a plasma polymerization coating process to introduce a surface coating on an external surface and an internal surface of the 3D porous structure, or to modify a surface charge of the expandable scaffold.
- an expandable scaffold is formed with the first material (i.e., the soft material) being polyurethane (PU) and the second material being nanosized hydroxyapatite (nHA) and bone particles.
- the additional material can be a sacrificial one (salt, sugar, fast dissolving/degrading polymers) that can be removed by immersion in water of other liquids or solvents.
- the two polymers were dissolved in 60 ml of absolute ethanol (ACS regent grade, Fisher Scientific; Hampton, NH) and 5 ml of ultrapure deionized water (0.055 uS/18MOhm, dispensed from a Siemens Lobster unit, Washington, DC) in a 125-ml screw-top flask.
- the nHA (BABIHAP-N100, 100 nm particle size, Berkeley Advanced Biomaterials; Berkeley, CA) was dispersed in ethanol and sonicated for 30 minutes in an ice bath. A stir bar was added, and then flask was put on a stirring and heating plate at 300 rpm and 45°C for 2 days to be completely mixed.
- the mixture was then poured in silicon mold in a way that no air bubbles form inside the composites. Then, the mixture was dried by having the mold in the oven at 50 °C for 15 hours, and then left to cool at room temperature.
- the result is a film of two types of polyurethane [D640 and D3] with nHA, The ratio between these polymers can be varies from 0:100 to 100:0 wt.%.
- the PU-nHA film has a thickness of 0.28-0.31 mm. Then, the PU-nHA film was cut into uniform rectangular pieces, each with a length of 45 mm and a width of 6.8 mm. These pieces were used to build the 3D scaffold.
- FIG.3 shows a schematic view of the expandable scaffold.
- the expandable scaffold was designed to mimic the actual bone component of soft and hard component.
- the mass ratio of the hard material [nHA and bone particles (InterOss or BioOss, or similar)] and the soft material [PU] is 3/2, but it can be varied from 10000/0.01 to 0.01/10000.
- the bone was massed and distributed uniformly per iteration.
- the bone particles (or the tricalcium phosphate, Calcium suphate, etc particles or the sacrificial material – salt, sugar, fast dissolving polymer or materials, or the mixtures of them) can be introduced in the desired ratios, as described above.
- the resulted mixture is uniformized and could be introduced into a mold and into a water bath. Then it can be dried (at varies conditions such as: under vacuum, under heat treatment, at room condition etc. and cut to shapes and sizes.
- Scaffold Characterization Self-fitting: The self-fitting property of the sample of the expandable scaffold was tested by making nonuniform defect in a hard PCV piece of material.
- the sample scaffold was loaded in the center of defect, and drops of deionized water was added as the liquid using a syringe to allow the scaffold to swell the water and expand.
- a camera was used to make images showing how the scaffold expands by swelling in the water to occupy the shape of defect.
- Another test to the sample scaffold was done by making a nonuniform defect in a rubber, and then a dry sample scaffold was placed in the defect. Water was added, and the scaffold was left to swell in water to expand to occupy the shape of defect.
- a 3D laser microscopy was used to take images for dry scaffold, and 30 minutes after the scaffold immersed in DI water. Water Uptake: The scaffold absorption and swelling characterizations were evaluated in this example.
- the rate of water uptake by the sample scaffold in ultra-pure water were determined.
- a dry scaffold was first weighted, and then reading was taken at 0.5, 1, 2, 5, 10 and 30 minutes after the scaffold was placed in water.
- the mass of the initial dry sample scaffolds were 170-190 mg.
- the water uptake increase percent was calculated as: (1) where R t is the measurement at each chosen time point, and R inital is initial or dry mass thereof.
- the scaffold samples with an average weight of 24 mg were placed in crucible, and then the crucible was put in a Matter Toledo TGA-DSC 3+ instrument. The temperature was raised from 25 o C to 850 o C at a rate of 10 o C/min and an air flow rate of 50 ml/min. The mass percentage change vs temperature was recorded and analyzed.
- Surface Area Analysis Nitrogen absorption/desorption techniques were used to find the pore size and surface area of the sample scaffold. The sample scaffold was placed in a glass vessel, and then the scaffold was degassed at 35°C for at least 8 hours. By the meaning of Nitrogen adsorption-desorption isotherm and utilizing the Brunauer-Emmett-Teller (BET) method, the scaffold surface area was evaluated.
- BET Brunauer-Emmett-Teller
- the Barrett, Joyner, and Halenda (BJH) method was used to calculate the pore size/volume.
- the ASAP 2020 software suite was used in this analysis.
- Three-Dimensional Laser Microscopy A laser scanning confocal microscope (LSCM, VK-X260K, Keyence, USA) was used to study the scaffold morphology by utilizing the Keyence’s Multi-File Analyzer software for analysis of the 3D measurement data of sample cross section. The samples were tested in dry and wet condition with an 5X lens. For wet test samples, the scaffold samples were placed in DI water for 30 minutes, and then the samples were removed from the water, and the excess water was taken from the scaffold by tissue followed by imaging.
- Micro-CT The bone and void space content of the scaffold was studied using micro- computed tomography (micro-CT, Scanco Medical ⁇ CT 40).
- the scaffold was placed in 20 ml of DI water for at least 24 hours prior to scanning. Triplicate scans were performed at 55 kVp, 145 ⁇ A (medium resolution, 12 ⁇ m voxel, calibrated to 1200 mg HA/cm).
- Result and Discussion The expandable scaffold was made by using layer-by-layer method, which has the hard material of nHA and macro-sized bone particles that give the scaffold a nano/macro structure, making the scaffold suitable to use as a platform for osteogenesis.
- the scaffold characterizes in term of self-fitting properties, composition, porosity, topography.
- the scaffold was designed to occupy and take the shape the defect.
- the process start when the scaffold swells in the fluids available in the body (by taking fluids 450% times its weight).
- the swelling process was associated with expansion in the scaffold volume (3.62 times its original volume, stdv 0.2019 ).
- the hydrophilic polymer continent of the scaffold provides the scaffold with its high water uptake rate and volume expansion.
- the polyurethane polymer [D640, 80% from total polymer mass] that has high linear expansion [100.44%] was used for that purpose.
- This high linear expansion and high water uptake make the scaffold adopt like a jelly structure, which assists the scaffold in taking the defect shape during the expansion.
- this feature creates difficulties to keep the scaffold structure after swelling.
- D3 polyurethane polymer
- D3 polyurethane polymer
- Different ratios of D640/D3 were examined to obtain a maximum volume expansion and at the same time maintain the scaffold structure.
- the 9/1 ratio scaffold starts to lack in structure cohesion.
- the optimum ratio was found to be the 4/1 ratio.
- the hard, nonorganic materials of this scaffold are InerOss® bone particles and nHA.
- the ratio of the hard/soft materials was studied, and the optimum hard/soft ratio was found to be is 3/2.
- FIG.4 shows 3D laser microscopy of the expandable scaffold according to one embodiment of the disclosure, where (a) represents an image of a non-uniform bone defect, (b) shows the expandable scaffold being implanted or positioned inside the defect before hydration, and (c) shows the scaffold expanding and filling up the volume of the defect after the hydration. All images as shown in FIG.4 are top views of the defect with a 5X lens. As shown in FIG. 4, the 3D image analysis of wet and dry scaffold shows that the wet scaffold volume become 3.62 times the dry scaffold. Another self-fitting test was done to show time line of expansion, in which a camera was used to take the pictures proving the concept of self-fitting of the expandable scaffold.
- FIG.5 shows images of the expandable scaffold in a self-fitting test inside a PVC mold taken at different times after swelling started according to one embodiment of the disclosure. As shown in FIG.5, the images taken after 1, 2, 3, 5, 7 and 10 minutes from the swelling start demonstrate the expansion as function of time.
- FIG.6 shows a chart of the swelling plot of the expandable scaffold according to one embodiment of the disclosure, where three samples were tested. For each sample, the dry sample was weighted first, and was then immersed in DI water. The samples were removed from the DI water, and after removal of the excess of water from the samples using tissues, the samples were weighted, and the average of the three readings were recorded and plotted with time, with standard error being recorded at each measurement point.
- FIG.7 shows 3D laser microscopy images of cross sections a dry scaffold and a wet scaffold according to one embodiment of the disclosure.
- the images as shown in FIG.7 demonstrate the expansion due to water absorption, and present porosity of the scaffold in wet and dry conditions.
- the assessment exhibit weight increase of 450% of dry weight as shown in FIG.7.
- the high-water uptake can attribute to hydrophilic nature of the polymer resulted from the hydrogen bonding interaction between water molecules and the PEG and the porous structure of the scaffold.
- the change in the dimension of the expandable scaffold after it was immersed in water was evaluated over a period of 30 minutes.
- the change in volume was recorded to evaluate the scaffold size for the in vivo implantation.
- the images from 3D laser microscopy as shown in FIG.7 were used to compare between the dry sample and the wet sample 30 minutes after it was immersed in DI water.
- the 3D image analysis of the wet and dry scaffold shows that the volume of the wet scaffold becomes 3.62 times the volume of the dry scaffold.
- the top view of the scaffold slice image shows the expansion in that plane.
- the wet sample image shows nonuniform deformation during the expansion, which makes the scaffold able to take the shape of a defect that the scaffold is disposed therein.
- FIG.8 shows a chart of the thermogravimetry curve for three scaffold samples according to one embodiment of the disclosure. As shown in FIG. 8, three samples were subjected to the TGA test to detect the ratios of the scaffold mass components. In the thermographic process, the furnace temperature increases, which causes the material to thermally decompose by combustion, and the soft/hard materials of the scaffold will decompose at different temperatures.
- the soft material (polymer) of the scaffold decomposes first due to its low thermal satiability, where 40% of scaffold mass was expected to be removed, leaving the 60% of the mineral hard material of nHA and bone particles.
- the mass percent-temperature curve as shown in FIG.8 shows that the water mass losses is 2.56% of the total mass of the scaffold, followed by the PU mass losses, leaving the bone particles and nHA, where the bone particles thermally decompose at the temperature higher than 650 o C.
- the TGA analysis shows the that the average of the hard material of the scaffold is 61.69%, which agrees with the theoretical mass ratio assumed in fabrication [60 %]. Nitrogen adsorption isotherm was utilized to determine the pore volume and pore size for the scaffold.
- FIG.9 shows micro-CT scan images for dry and wet scaffold samples according to certain embodiments of the disclosure. As shown in FIG.9, a bar graph represents the bone to total volume fraction in the wet and dry scaffold, and a relatively uniform distribution of bone particles appeared in the scaffold. The images of bone particles distributing in the scaffold in the dry scaffold before and after expansion are shown in FIG.9.
- the bone-to-total volume ratio (BV/TV) of the dry scaffold (before expansion) is 51%, while the BV/TV for the wet scaffold (after expansion) is 0.14%.
- the bone to total volume ratio decreases after expansion, where the polymer contained in the scaffold is responsible for volume expansion.
- the calculation is provided as follows: (2) (3) where BV represents the bone volume, BTd represents the total dry volume of the scaffold (before expansion), and BTw represents the total wet volume of the scaffold (after expansion).
- BTd represents the total dry volume of the scaffold (before expansion)
- BTw represents the total wet volume of the scaffold (after expansion).
- PCLTF-GMPs An injectable poly ( caprolactone trifumarate-gelatin microparticles ) scaffold for irregular bone defects: Physical and mechanical characteristics. Materials Science & Engineering C, 72, 332–340. https://doi.org/10.1016/j.msec.2016.11.086 [2]. Albrektsson, T., & Johansson, C. (2001). and osseointegration, 96–101. [3]. Ceramics, M., & Dubok, V. A. (2001).
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| PCT/US2020/016932 WO2021158222A1 (en) | 2020-02-06 | 2020-02-06 | Expandable bone and tissue regeneration system, and applications of same |
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| AU (1) | AU2020427699A1 (en) |
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| US20070083268A1 (en) * | 2003-11-21 | 2007-04-12 | Osteopore International Pte Ltd | Bioabsorbable plug implants and method for bone tissue regeneration |
| CN1953935B (en) * | 2004-05-14 | 2010-05-05 | 索尼德国有限责任公司 | Composites including carbon nanotubes and metal carbonates |
| US20100168869A1 (en) * | 2008-12-31 | 2010-07-01 | Howmedica Osteonics Corp. | Tissue integration implant |
| GB0903810D0 (en) * | 2009-03-05 | 2009-04-22 | Regentec Ltd | Delivery system |
| CA2867167A1 (en) * | 2012-02-13 | 2013-08-22 | Board Of Regents, The University Of Texas System | Scaffold system for tissue repair |
| US20180161437A1 (en) * | 2012-06-08 | 2018-06-14 | Udayan G. Patel | Foamed Medical devices with Additives |
| GB201514788D0 (en) * | 2015-08-20 | 2015-10-07 | Ecole Polytech | Malleable scaffold material and uses thereof |
| US10022231B2 (en) * | 2016-07-22 | 2018-07-17 | Cytex Therapeutics, Inc. | Articular cartilage repair |
| US20190022279A1 (en) * | 2017-06-15 | 2019-01-24 | Board Of Trustees Of The University Of Arkansas | Tunable porous 3d biodegradable, biocompatible polymer/nanomaterial scaffolds, and fabricating methods and applications of same |
| CN107961398B (en) * | 2017-11-29 | 2020-05-26 | 南宁越洋科技有限公司 | Preparation method of bone tissue engineering scaffold material artificial tooth root capable of enhancing osseointegration |
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