text:
WO2002064181A1 - Implant derived from bone - Google Patents
Implant derived from bone Download PDF
WO2002064181A1 PCT/US2002/004131 US0204131W WO02064181A1 WO 2002064181 A1 WO2002064181 A1 WO 2002064181A1 US 0204131 W US0204131 W US 0204131W WO 02064181 A1 WO02064181 A1 WO 02064181A1
demineralized
Lawrence A. Shimp
Daryl R. Sybert
Osteotech, Inc.
2002-02-12 Application filed by Osteotech, Inc. filed Critical Osteotech, Inc.
A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
A61L27/3843—Connective tissue
A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
A61F2/02—Prostheses implantable into the body
A61F2/28—Bones
A61F2/30—Joints
A61F2/46—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
A61F2/4644—Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material
A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
A61L27/3654—Cartilage, e.g. meniscus
A61L27/3658—Intervertebral discs
A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
A61L27/3695—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this
A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
A61L27/54—Biologically active materials, e.g. therapeutic substances
A61F2/38—Joints for elbows or knees
A61F2/3872—Meniscus for implantation between the natural bone surfaces
A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
A61F2/442—Intervertebral or spinal discs, e.g. resilient
A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity
A61F2002/2839—Bone plugs or bone graft dowels
A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
A61F2002/30004—The prosthesis made from materials having different values of a given property at different locations within the same prosthesis
A61F2002/30018—The prosthesis made from materials having different values of a given property at different locations within the same prosthesis differing in bending or flexure capacity
A61F2002/30059—The prosthesis made from materials having different values of a given property at different locations within the same prosthesis differing in bone mineralization, e.g. made from both mineralized and demineralized adjacent parts
A61F2002/30108—Shapes
A61F2002/30199—Three-dimensional shapes
A61F2002/302—Three-dimensional shapes toroidal, e.g. rings
A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
A61F2002/30678—Gene therapy
A61F2002/4649—Bone graft or bone dowel harvest sites
A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
A61F2230/0063—Three-dimensional shapes
A61F2230/0065—Three-dimensional shapes toroidal, e.g. ring-shaped, doughnut-shaped
A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
A61F2250/0014—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
A61F2250/0029—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in bending or flexure capacity
A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
A61F2310/00005—The prosthesis being constructed from a particular material
A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
A61L2300/406—Antibiotics
A61L2300/412—Tissue-regenerating or healing or proliferative agents
A61L2300/414—Growth factors
A61L2430/00—Materials or treatment for tissue regeneration
A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
An implant which is particularly suitable for the repair and/or replacement of a skeletal joint, e.g., a vertebral joint, includes a unit of monolithic bone possessing at least one demineralized region exhibiting properties of flexibility and resilience, the demineralized region having diminished or insignificant capacity for promoting new bone growth.
IMPLANT DERIVED FROM BONE
This invention relates to an implant fabricated from bone. More particularly, the present invention relates to a stable, yet flexible, prosthetic implant having little if any capacity for promoting new bone growth that could result in the unwanted fusion of bone structures at the implantation site. 2. Description of the Related Art
The vertebral column (spine) is a biomechanical structure composed of a series of joints known as motion segment units. Each motion segment unit includes two adjacent vertebrae and their facet capsules, the intervertebral disc, and connecting ligament tissue. The spine is divided into four major regions which include the cervical, thoracic, lumbar, and sacral regions and functions to protect the spinal cord and nerve roots and provide support to the body.
The intervertebral disc is a fϊbro-cartilaginous structure located between the two end plates of adjacent vertebrae and is composed of the nucleus pulposus (a gel-like ball located at the center of the disc) and the annulus fibrous (collagen fibers surrounding the nucleus pulposus). The intervertebral disc separates, cushions, and stabilizes the spine providing the spine with resiliency and the ability to withstand compression, rotation, and bending strain. Various types of spinal disorders are known and include kyphosis (backward curvature of the spine), spondylolysis, spondylolisthesis (forward displacement of lumbar vertebrae), scoliosis (abnormal curvature of the spine), and disorders involving ruptured, slipped, damaged and diseased discs, damaged vertebrae, and the like. Patients suffering from the aforementioned disorders typically experience severe pain, numbness, decreased mobility, muscle weakness, and nerve damage and may be treated by surgical removal of the discs. Removal of the discs may then require fusion of the bony elements of the spine. Spinal fusion can be accomplished within the disc space, anteriorly between adjacent vertebral bodies and/or posteriorly between consecutive processes, e.g., transverse processes, laminae or other posterior elements of the vertebrae. One frequently used spinal fusion technique involves removal of the intervertebral disc and insertion of an anterior supporting structure, e.g., bone grafts, bone substitutes, plugs, bone dowels, cages, and the like, into the intervertebral disc space to prevent collapse of the disc space and promote fusion of the adjacent vertebrae. Unfortunately, this procedure virtually precludes any degree of spinal flexibility.
Other diseases of the spinal joints also require new methods of treatment. For example, the present treatment of lumbar disc herniation provides a compromised functional recovery at best. The disc that has come out of its place has no physiological function and at this time no method is known that will bring back the functional lumbar disc. Fusion is unable to preserve the natural structure and function of the spine. Therefore, a disc prosthesis is needed which can be applied to the disc space and provide the cushioning effect for the disc that is expected of the normal disc. Several unacceptable attempts have been made to solve this problem such as applying spring loaded disc prosthesis or saline injectable discs with suction cups on the surfaces. The spring loaded disc is so bulky it cannot be inserted into the disc space through the limited opening that is available for this kind of surgery. The saline injectable disc is unstable and the suction cups do not hold it onto the vertebral bodies which have irregular spiky surfaces. While various artificial polymers have been proposed for use as a disc segment, these tend not to have the right biological properties to provide biological attachment to adjacent vertebras or to encourage growth of a supplementary fibrous tissue matrix.
U.S. Patent No. 4,309,777 describes an artificial disc having a plurality of springs positioned between lower and upper disc portions. In addition, a plurality of spikes extends from the upper and lower portions of the disc to engage the vertebrae. U.S. Patent No. 4,759,769 describes an artificial spinal disc comprising upper and lower portions connected by both hinge and spring devices. The discs of U.S. Patent Nos. 4,309,777 and 4J59J69, while stable, lack a physiological structure which probably accounts for their apparent lack of acceptance by the medical community.
U.S. Patent No. 4,834,757 describes vertebral implant plugs or blocks that are useful in fusing together adjoining vertebral bodies. Once fusion has occurred, articulation of the vertebral joint is no longer possible.
U.S. Patent No. 4,863,476 describes a spinal implant intended for insertion in an intervertebral space. However, the implant lacks the ability to maintain full contact with the vertebral surfaces.
U.S. Patent No. 4,863,477 describes a synthetic intervertebral disc prosthesis composed of a rubber-type material having a hollow interior. The interior may be filled with fluid imparting a certain degree of resiliency to the prosthesis. One disadvantage of the prosthesis, however, is that in the anatomical context of the intervertebral space, its design provides very little stability.
A need continues to exist for a truly stable yet fully flexible prosthetic implant that better preserves the natural structure and function of skeletal joints such as the vertebral joints. It is an object of the invention to provide an implant fabricated from bone, one which is both flexible and resilient and capable of bearing mechanical loads while possessing little if any capacity for promoting new bone growth that could result in the unwanted fusion of bone structures with which the implant comes into contact following its implantation. It is a particular object of the invention to provide an implant useful in the repair or replacement of skeletal joints.
It is a further object of the invention to provide a replacement intervertebral disc which does not cause the fusion of adjacent vertebrae following its implantation. SUMMARY OF THE INVENTION In keeping with these and related objects of the invention, there is provided an implant which comprises a unit of monolithic bone possessing at least one demineralized region exhibiting properties of flexibility and resilience, the demineralized region having diminished or insignificant capacity for promoting new bone growth.
The implant of this invention is particularly suitable for the repair and/or replacement of skeletal joints, e.g., vertebral joints, where its mechanical properties of flexibility and resilience are advantageously utilized and its diminished or insignificant capacity for promoting new bone growth precludes the formation of new bone tissue which would otherwise result in unwanted fusion of adjacent bone structures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The implant of the invention is preferably a substantially monolithic unit or section of bone sized appropriately for the repair or replacement of a skeletal joint, e.g., an intervertebral disc. At least one region up to and including the entire implant has been demineralized in order to impart flexibility and resilience to the implant and the implant has been further treated in order to diminish or suppress the new bone growth-promoting capacity of the untreated demineralized bone. The multistep process for producing the prosthetic implant of this invention is described below.
The expressions "implant" and "prosthetic implant" as used herein contemplate devices for the replacement of entire skeletal components such as intervertebral discs as well as portions of skeletal components and also includes devices for augmenting existing bone structures.
The expression "monolithic bone" as utilized herein refers to relatively large pieces of human or animal bone, i.e., pieces of bone, autograft, allograft or xenograft, that are of such dimensions as to be capable of withstanding the sort of mechanical loads to which functioning bone structures are typically subjected. The monolithic bone of this invention is to be distinguished from particles, filaments, threads, etc. as disclosed in U.S. Patent Nos.
5,073,373, 5,314,476 and 5,507,813, which, due to their relatively small dimensions, are incapable of sustaining significant mechanical loads, either individually or in the aggregate.
The monolithic bone can be provided as a single integral piece, or unit, of bone or as a piece of bone permanently assembled from a number of smaller bone elements, e.g., as disclosed and claimed in U.S. Patent No. 5,899,939 the contents of which are incorporated by reference herein.
The term "demineralized" as used herein refers to bone that has been treated such that some of its original mineral content has been removed. Such bone can be treated so that it has a relatively uniform mineral content or it can be treated such that only a region, or portion, of the bone has had its original mineral content removed, e.g., as would be the case with surface demineralization, segmental demineralization, etc. Therefore, the term
"demineralized" applies to any bone element or region thereof having less than its full original mineral content. The term "flexibility" as applied to the demineralized region(s) of the bone-based implant of this invention refers to the characteristic ability, tendency or capacity of the demineralized region(s) of the implant to accommodate, absorb or withstand bending, twisting or torsional forces applied to said region(s), said ability, tendency or capacity being commensurate with the extent and degree of demineralization of the demineralized region(s).
The term "resilience" as applied to the demineralized region(s) of the bone-based implant of this invention refers to the characteristic ability, tendency or capacity of the surface(s) of the demineralized region(s) of the implant to accept, or be conformed to, the shape of impressed surface(s), said ability, tendency or capacity being commensurate with the extent and degree of demineralization of the demineralized region(s).
The implant of this invention comprises a unit of demineralized monolithic bone which has been further treated to reduce, suppress or eliminate its capacity for promoting new bone growth. The bone is preferably chosen to be a section of strong cortical bone such as that obtained from the femur, tibia, fibula, radius, ulna, and the like. The source of the bone can be allograft or xenograft with the appropriate cautionary steps known in the art being taken in each case to prevent contamination by pathogenic and/or antigenic agents. The monolithic bone unit is preferably obtained from a section of a long bone shaft (such as the aforementioned femur, tibia, radius, ulna, etc.) and is configured, e.g., by machining (before or after demineralization and/or the deactivation treatment described below) into the size and shape of the desired prosthetic implant.
Demineralization can be carried out by any of the known and conventional demineralization procedures to reduce the mineral content of at least one region of the monolithic bone unit up to and including the entire bone. The demineralized bone is rubbery in feel, which is to say, it possesses properties of flexibility and resilience. In addition, the demineralized monolithic bone unit possesses sufficient strength to support the sort of mechanical loads that are typical of bone.
The monolithic bone can be provided as a single piece or section of whole bone or, as stated above, it can be built up from two or more smaller bone elements ("built-up monolithic bone"), e.g., as disclosed in U.S. Patent Nos. 5,899,939 and 6,123,731, the contents of which are incorporated by reference herein. In one embodiment of the latter, smaller bone elements, e.g., particles, fibers, etc., can be assembled by any one of several techniques into a monolithic unit, the monolithic unit can be machined into a prosthetic implant of desired configuration and the implant is thereafter treated as described below in order to render at least its exposed surface, or portion thereof, incapable of promoting significant new bone growth. In another embodiment of a built-up monolithic bone unit, partially or fully demineralized bone sections, e.g., in the form of thin-to-thick sheets or slabs, can be treated to reduce or suppress their capacity for promoting new bone growth and a sheet or slab can then be bonded to each of the two major surfaces of a relatively thick, rigid fully mineralized bone section to form a laminate structure with the flexible resilient demineralized sheets or slabs as its outermost components. This laminate structure can be used as such or further shaped as required into the desired implant configuration.
The aforedescribed laminate embodiment can be particularly advantageous where it is desirable to combine the properties of flexibility and resilience possessed by its outer treated demineralized sheet or slab components with the high mechanical strength properties possessed by its inner fully-mineralized bone core component. Thus, e.g., such a laminate configured as an intervertebral disc will possess outer surfaces that remain flexible and resilient and which do not encourage new bone growth that might lead to fusion of the adjacent vertebrae but will also possess the high mechanical strength properties that are characteristic of fully-mineralized bone.
One skilled in the art will readily recognize that numerous other built-up monolithic bone arrangements besides those described above can be fabricated in accordance with the invention. When the implant of the present invention is formed from a single piece, or section, of bone, the bone can be substantially completely demineralized, i.e., it can be made to contain less than about 5 weight percent of its original mineral content. It will, of course, be appreciated that a substantially completely demineralized bone monolith will possess the maximum degree of flexibility and resilience but, conversely, the lowest degree of mechanical strength. A partially demineralized bone section, e.g., bone containing a uniformly distributed residual mineral content of from about 20 to about 80 weight percent of the original mineral content, will exhibit less flexibility and resilience than a comparable fully-demineralized bone section but will exhibit greater mechanical strength than the latter, a strength which is proportionate to its residual mineral content. In one embodiment of the single piece monolithic bone implant that is similar to the built-up bone laminate described above, the single bone section can be surface-demineralized or superficially demineralized, either before or after the bone has been shaped into the desired implant configuration, while the interior or core of the bone section retains its original mineral content. Following treatment of the demineralized surface to reduce or suppress its capacity for promoting new bone growth, the ultimate prosthetic implant will possess functional advantages similar to the built-up laminate embodiment, i.e., flexible, resilient outer surfaces and a high mechanical strength core. The mineralized core is especially advantageous in reducing the possibility of collagen fiber separation, which is a common cause of failure of the implant when placed under axial, compressive loading. Yet another embodiment of the implant herein can be obtained by segmental, or selective, demineralization of one or more regions of a monolithic bone unit, e.g., as described in U.S. Patent No. 6,090,998, the contents of which are incorporated by reference herein. The demineralized segments of the bone are then treated, as described below, to suppress their bone growth promoting capacity, either before or after the bone has been shaped into the desired implant configuration.
The order of the steps involved in manufacturing the implant of this invention can vary but begins with the selection of allogenic and/or xenogenic bone stock from which the desired implant will be derived. Suitable sources of xenogenic bone include bone that is of bovine, equine, porcine, ovine or caprine origin. A preferred source of xenogenic bone is porcine bone. The selected bone may be large enough that an implant of the desired dimensions can be machined from it in one piece. If the selected bone is of relatively small dimensions, a quantity of such bone can be assembled into a single large piece as in the built- up monolithic bone referred to above. Alternatively, two or more smaller individual prosthetic implants in accordance with the invention can be provided which, after installation at a bone repair or reconstruction site, function as though they were a single implant.
The bone stock is preferably obtained fresh/frozen and the desired section of bone is obtained by any suitable procedure, e.g., cutting with a saw accompanied by frequent rinsing of the bone in a fluid such as distilled water or saline to keep the bone moist and cool (at or below physiological temperatures to prevent denaturation of bone material). Preferably, the bone section is taken from the diaphysis of a long bone. Associated connective tissue (tendons, ligaments and fascia) is removed. Optionally, the bone section can be frozen at this point if further processing is to be deferred to a later time.
Any conventional means of machining hard materials, including the use of drills, saws, grinders, carving tools, and the like, can be used to obtain the desired final prosthetic implant from the bone section. For example, a rough outline of the outer circumference of the implant can be drawn on the bone and this section can be cut from the bone using a saw. Guide markings can be made on the bone section to indicate any depressions, ridges, openings, or other details that may be desired in the final implant. Preferably, the monolithic bone useful in the invention herein is formed by substantially planar parallel crosscuts across the diaphysis of a femur or similar long bone to produce transversal slices approximately 5 to 30 mm in thickness. Such slices are preferably prepared using, for example, a precision electric saw. The bone is cut with suitable irrigation of water or saline to prevent any increase in the temperature of the bone which is above physiologic temperatures. The bone sections can be further processed to remove residual blood and lipid residues.
Demineralization of a section of bone before or after any final shaping into the implant of the invention can be conducted using conventional procedures that are well known in the art, e.g., subjecting the bone section to strong acids such as hydrochloric acid such as described in Reddi et al., Proc. Nat. Acad. Sci. 69:1601-5 (1972), the contents of which are incorporated by reference herein. The extent of demineralization is a function of the strength of the acid solution, the size and shape of the bone and the duration of the demineralization treatment. Reference in this regard may be made to Lewandrowski et al., J. Biomed. Materials Res. 31 :365-372 (1996), the contents of which are incorporated by reference herein.
In a preferred demineralization procedure, the bone section or sections are subjected to a defatting/disinfecting step which is followed by an acid demineralization step. A preferred defatting/disinfectant solution is an aqueous solution of ethanol, the ethanol being a good solvent for lipids and the water being a good hydrophilic carrier to enable the solution to penetrate more deeply into the bone. The aqueous ethanol solution also disinfects the bone by killing vegetative microorganisms and viruses. Ordinarily at least about 10 to 40 weight percent by weight of water (i.e., about 60 to about 90 weight percent of defatting agent such as alcohol) should be present in the defatting/disinfecting solution to produce optimal lipid removal and disinfection within the shortest period of time. The preferred concentration range of the defatting solution is from about 60 to 85 weight percent alcohol and most preferably about 70 weight percent alcohol. Following defatting, the bone is immersed in acid over time to effect its demineralization. Acids which can be employed in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid. Generally, the concentration of inorganic acid utilized to achieve demineralization is from about 0.1N to about 2N and more preferably from about 0.2 N to about 1.0 N. The time of exposure to the acid is increased for lower acid concentrations and decreased for the higher acid concentrations. After acid treatment, the bone section(s) is rinsed with sterile water for injection, optionally buffered with a buffering agent to a final predetermined pH and then finally rinsed with water for injection to remove residual amounts of acid and buffering agent or washed with water to remove residual acid and thereby raise the pH.
Once the bone is demineralized, it is treated in order to reduce or suppress its bone growth-promoting capacity. While the bone may still induce or promote the formation of fibrous tissues on its treated surfaces, such surfaces will no longer possess their full capacity for promoting the growth of new bone. Thus, the treatment of the demineralized bone, which can be thought of as a type of deactivation procedure, results in an implant which resists the tendency to cause fusion of existing bone structures with which the applied implant comes into contact. The deactivation procedure can be carried out by a variety of methods, e.g., treatment with a chemical agent, irradiation with a high energy radiation source, thermal treatment, extraction of the bone growth-promoting proteins, and the like.
A preferred deactivation procedure involves contacting the surface of the demineralized region(s) of the bone with a chemical agent that simultaneously cross links collagen fibers which constitute the bulk of demineralized bone, thus stiffening the affected demineralized region(s), and denatures native proteins which play a role in the bone growth promoting process.
Suitable chemical cross-linking agents include those that contain bifunctional or multifunctional reactive groups and which react with functional groups on amino acids such as an epsilon-amine functional group of lysine or hydroxy-lysine, or the carboxyl functional groups of aspartic and glutamic acids. Chemical cross linking agents of this type include: mono- and dialdehydes, including glutaraldehyde and formaldehyde; polyepoxy compounds such as glycerol polyglycidal ethers, polyethylene glycol diglycidal ethers and other polyepoxy and diepoxy glycidal ethers; tanning agents that include polyvalent metallic oxides such as titanium dioxide, chromium dioxide, aluminum dioxide, zirconium salt, as well as organic tannins and other phenolic oxides derived from plants; chemicals for esterification of carboxyl groups followed by reaction with hydrazide to form activated acyl azide functionalities in the collagen; dicyclohexyl carbodiimide and its derivatives as well as other heterobifunctional cross linking agents; hexamethylene diisocyanate; sugars, including glucose will also cross-link proteins such as, e.g., collagen. Another treatment suitable for reducing the undesirable osteoinductive properties of demineralized bone is to subject the bone to high energy irradiation, e.g., gamma irradiation of sufficient strength and duration, e.g., about 15,000 to >36,000 gray, to denature the osteoinductive proteins present in the demineralized bone. Control of the environment during irradiation, such as having oxygen present, can influence the degree of cross-linking and favor cross-linking over undesirable chain scission that might weaken the ultimate implant. Yet another treatment method suitable for suppressing the undesirable bone growth- promoting properties of the demineralized bone involves guanadine hydrochloride extraction of the osteoinductive proteins contained in the demineralized region(s) of the bone. Thermal treatment of the surface of the demineralized region(s) of the bone, e.g., by brief exposure to temperatures high enough to denature the bone growth-promoting proteins, is also an advantageous expedient for accomplishing deactivation of these proteins. In general, temperatures, e.g., on the order of from about 50° to about 90°C maintained for from about 5 minutes to about 10 hours are suitable for achieving deactivation. The thus deactivated implant can be further treated by tanning or other means known in the art to reduce the antigenicity of the implant. For example, glutaraldehyde treatment (see U.S. Patent No. 5,053,049, the contents of which are incorporated by reference herein) can be used for this purpose if it had not been previously used to achieve deactivation of the bone-growth promoting proteins. As previously indicated, a preferred implant in accordance with the present invention is an intervertebral disc. The disc can be fabricated from one or more substantially fully- demineralized bone units, optionally possessing a gel-like center which approximates the mechanical properties of the nucleus pulposus.
Such gel-like center can be fabricated, e.g., from a hydrogel-forming polymeric gelling agent. Hydrogel-forming polymeric materials of this type are those that, upon contact with liquids such as water or body fluids, imbibe such liquids forming hydrogels. The polymeric gelling agent can be a substantially water-insoluble, slightly crosslinked, partially neutralized, hydrogel-forming polymer material. Such polymer gelling agent can be prepared from polymerizable, unsaturated, acid-containing monomers. Such monomers include the olefinically unsaturated acids and anhydrides which contain at least one carbon-to-carbon olefinic double bond. More specifically, these monomers can be selected from olefinically unsaturated carboxylic acids and acid anhydrides, olefinically unsaturated sulfonic acids and mixtures thereof. Olefinically unsaturated carboxylic acid and carboxylic acid anhydride monomers include the acrylic acids typified by acrylic acid itself, mefhacrylic acid, ethacrylic acid, alpha-chloroacrylic acid, alpha-cyano acrylic acid, beta-methyl-acrylic acid (crotonic acid), alpha-phenyl acrylic acid, beta-acryloxy propionic acid, sorbic acid, alpha-chloro sorbic acid, angelic acid, cinnamic acid, p-chloro cinnamic acid, beta-styryl acrylic acid (l-carboxy-4- phenyl butadiene- 1 ,3), itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, tricarboxy ethylene and maleic acid anhydride.
Olefinically unsaturated sulfonic acid monomers include aliphatic or aromatic vinyl sulfonic acids such as vinylsulfonic acid, ally] sulfonic acid, vinyltoluenesulfonic acid and styrene sulfonic acid; acrylic and methacrylic sulfonic acid such as sulfoethyl acrylate, sulfoethyl methacrylate, sulfopropyl acrylate, sulfopropyl methacrylate, 2-hydroxy-3- acryloxy propyl sulfonic acid, 2-hydroxy-3-methacryloxy propyl sulfonic acid and 2- acrylamido-2-methyl propane sulfonic acid.
In the hydrogel-forming polymeric gelling agents used herein, the polymeric component formed from unsaturated, acid-containing monomers may be grafted on to other types of polymer moieties such as starch or cellulose.
The polymeric gelling agent can be introduced into a central cavity formed in the prosthetic implant where it will swell in situ as a result of contact with aqueous body fluid or it can be contained within a fluid permeable structure such as a bag which is placed within the central cavity of the implant. The aforementioned central cavity can already be present in the implant if the bone from which the implant has been obtained possesses a cavity, e.g., as would be the case of a diaphysis section of a long bone which includes a portion of the medullary canal. Once the swollen gel has formed, it will contribute to the overall strength of the implant. The type, shape, and amount of polymeric gel-forming material will be selected so that the swollen material does not exert an undesirable pressure on the implant or adjacent tissues.
Materials can be added to the implant of the invention which will enhance fibrous tissue growth. Such materials can be introduced into the implant before its implantation and/or later applied to its surfaces. Examples of such materials are acellular dermal tissue (Alloderm) and small intestine mucosa.
Medically/surgically useful substances which promote healing can also be incorporated in, or associated with, the prosthetic implant of this invention. Useful substances of this kind which can be incorporated into the implant include, e.g., collagen, insoluble collagen derivatives, etc., and soluble solids and/or liquids dissolved therein, e.g., antiviral agents, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymyxin B, tetracyclines, viomycin, chloromycetin and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin, and gentamicin, etc.; biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids; peptides; vitamins; inorganic elements; co-factors for protein synthesis; endocrine tissue or tissue fragments, synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; antigenic agents; cartilage fragments, living cells such as chondrocytes, mesenchymal stem cells; natural extracts; genetically engineered living cells or otherwise modified living cells; tissue transplants; DNA delivered by plasmid or viral vectors; autogenous tissues such as blood, serum, soft tissue, bone marrow, etc.; bioadhesives; fibronectin; transforming growth factor-beta; endothelial cell growth factors; cementum attachment extracts; ketaserin; insulin-like growth factors (IGF-l)(IGF-2); platelet derived growth factors (PDGF); epidermal growth factor (EGF); interleukin; human alphathrombin; fibroblast growth factors; hormones, in particular, human growth hormone, animal growth hormone and growth hormones such as somatotropin; bone digesters; antitumor agents; immuno-suppressants; permeation enhancers, e.g., fatty acid ester such as laureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto aldehydes, etc.; and, nucleic acids. Suitable methods of incorporating one of the foregoing medically/surgically useful substances include coating, immersion saturation, packing, co-lyophilization wherein the substance is placed on the graft and lyophilized, spraying, injecting into the implant, etc. The amounts of medically/surgically useful substances utilized can vary widely with optimum levels being readily determined in a specific case by routine experimentation. Those skilled in the art will recognize that the implant of this invention can be configured by any one of several known and conventional shaping techniques into a limitless variety of shapes and sizes for application in a wide variety of skeletal repair/reconstruction procedures. For example, an implant of this invention can be applied to the repair of flexible joint tissues in the hand, elbow, knee, foot, ankle, spine or other anatomical location as desired. Furthermore, the implant of this invention can be applied as a replacement for any of a variety of joints. Methods and implant shapes known in the art for joint replacement (see, for example U.S. Patent Numbers 4,871,367; Des. 284,099; Des. 277,784; Des. 277,509; 3,886,600; 3,875,594; 3,772,709; 5,484,443; 5,092,896; 5,133,761; 5,405,400; and 4J59J68; the contents of all of which are incorporated by reference herein) can be readily adapted to the use of the prosthetic implant of this invention.
A preferred method of using the implant of the invention as applied to an intervertebral disc used as a replacement for a damaged intervertebral disc requires insertion of the replacement disc in such a manner that it extends between the bony surfaces of adjacent vertebrae. It is also desirable that the inserted implant be capable of forming a biological connection to the adjacent vertebrae in order to stabilize the construct while minimizing or eliminating the need for additional support devices and at the same time create conditions that will encourage the regrowth of a natural, fibrous, load-bearing material that will augment or replace (either partially or fully) the initially inserted implant. If needed, the auxiliary support devices are preferably load sharing to allow natural movement and loading of the disc prosthesis.
For best results, the disc implant should be placed such that the axis of the medullary canal runs parallel to the axis of loading. This ensures that the bone collagen fibers are loaded axially, which provides the strongest load-bearing capacity. The implant, of annular configuration due to the presence of the medullary canal, is preferably kept intact. If a portion is cut away to the point where the medullary canal is breached, the implant may lose some of its strength and stability.
A preferred prosthetic implant fabricated in accordance with the invention will possess a bulk density of at least about 0J g/cm" and a wet compressive strength of at least about 3 MPa. Wet compressive strength is a well known measurement of mechanical strength and refers to the compressive strength of the implant after it has been immersed in physiological saline (water containing 0.9 g NaCl/100 ml water) for a minimum of 12 hours and a maximum of 24 hours. The invention will be better understood by way of the following example which is intended to illustrate the invention herein but not to limit it in any way whatsoever.
EXAMPLE This example illustrates the fabrication of intervertebral disc implants according to the invention.
A femoral shaft and a fibula shaft were cleaned of soft tissue and cut into 15 mm long axial cross sections, ten from each bone. The cross sections were placed in a 5 liter plastic beaker and 4 liters of 0.6 N HC1 was added to the beaker to initiate the demineralization process. The beaker was covered and allowed to sit. After 24 hours, the acid was replaced with fresh acid and the cross sections allowed to sit for another 24 hours to complete the demineralization process. The acid was then drained off and the cross sections were rinsed with purified water until the pH of the water surrounding the implants was greater than 3.
The demineralized fibular rings were placed inside the medullary canals of the demineralized femoral rings. Half of the fibula and femoral demineralized cross sections assemblies were placed in a 1 liter beaker and covered with a 50 weight percent aqueous solution of glutaraldehyde while the other half of the cross sections were placed in another 1 liter beaker and covered with a 37 weight percent aqueous solution of formaldehyde. The glutaraldehyde and formaldehyde solutions were added in order to concurrently crosslink collagen fibers in the demineralized regions of the cross section assemblies and at the same time denature proteins in these regions which promote new bone growth. The implants were allowed to sit in the beakers for 24 hours whereupon they were removed and rinsed thoroughly with purified water and allowed to air dry. The compressive strengths of the treated implants were measured by placing them individually between two platens of a mechanical testing machine. The minimum compressive load sustained by any implant, at 4mm compressive strain, was greater than
1000 pounds.
In view of the foregoing disclosure and examples, in which various embodiments of the implant of this invention are disclosed and described, including the best mode, those skilled in the art will recognize that various modifications on the specifics of the invention disclosed herein come within the scope of the invention.
1 1. An implant which comprises a unit of monolithic bone possessing at least one
2 demineralized region exhibiting properties of flexibility and resilience, the demineralized
3 region having diminished or insignificant capacity for promoting new bone growth.
1 2. The implant of Claim 1 wherein the monolithic bone is derived from
2 allogeneic or xenogeneic bone.
1 3. The implant of Claim 1 wherein the monolithic bone is derived from a single
2 piece or section of bone.
1 4. The implant of Claim 1 wherein the monolithic bone is assembled from two or more bone pieces or sections.
l 5. The implant of Claim 1 which is substantially completely dimineralized.
1 6. The implant of Claim 1 which is partially and uniformly demineralized.
1 7. The implant of Claim 1 which is surface demineralized for at least a portion of
2 its surface.
l 8. The implant of Claim 1 which is segmentally demineralized in at least one of its regions.
9. The implant of Claim 3 which is substantially completely dimineralized.
10. The implant of Claim 3 which is partially and uniformly demineralized.
11. The implant of Claim 3 which is surface demineralized for at least a portion of its surface.
12. The implant of Claim 3 which is segmentally demineralized in at least one of its regions.
13. The implant of Claim 4 which is substantially completely dimineralized.
17. The implant of Claim 1 wherein at least the surface of the demineralized region(s) lacks any significant quantity of biologically active bone growth-promoting substances.
18. The implant of Claim 1 wherein the monolithic bone is derived from the diaphysis of a long bone.
19. The implant of Claim 18 configured as an intervertebral disc.
20. The implant of Claim 19 wherein the upper and lower surfaces of the disc are surface demineralized.
21. The implant of Claim 19 wherein the cavity of the intervertebral disc is filled at least in part with a gel-forming polymer or gel derived therefrom.
22. The implant of Claim 1 containing at least one substance which enhances fibrous tissue growth.
23. The implant of Claim 22 wherein the substance which enhances fibrous tissue growth is acellular dermal tissue and/or small intestine mucosa.
24. The implant of Claim 1 containing at least one medically/surgically useful substance.
25. The implant of Claim 24 wherein the medically/surgically useful substance is at least one member of the group consisting of collagen, insoluble collagen derivative, antiviral agent, antimicrobial agent, antibiotic, biocidal/biostatic sugar, amino acid, peptide, vitamin, inorganic element, co-factor for protein synthesis, hormone, endocrine tissue or tissue fragment, synthesizer, enzyme, peptidase, oxidase, polymer cell scaffold with parenchymal cells, angiogenic drug, polymeric drug carrier, collagen lattice, antigenic agent, cartilage fragment, living cells, natural extract, modified living cell, tissue transplant, DNA, autogenous tissue, bioadhesive, fibronectin, transforming growth factor-beta, endothelial cell growth factor, cemenrum attachment extract, ketaserin, insulin-like growth factor, platelet derived growth factor, epidermal growth factor, interleukin, human alphathrombin, fibroblast growth factor, bone digester, antitumor gent, immuno-suppressant, permeation enhancer, and nucleic acid.
26. The implant of Claim 1 possessing a bulk density of at least about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa.
27. The implant of Claim 4 wherein each of the upper and lower surfaces of a fully mineralized bone core is bonded to a layer of demineralized bone.
29. The implant of Claim 28 possessing a cavity filled at least in part with a gel- forming polymer or gel derived therefrom.
30. A method of making an implant which comprises: a) providing a unit of monolithic bone; b) demineralizing at least one region of the bone up to and including the entire bone; c) treating the demineralized region(s) of the bone to suppress, diminish or eliminate the capacity of said region(s) for promoting new growth; and, d) partially or full configuring the monolithic bone to a predetermined implant shape following step (a), (b) or (c)
31. The method of Claim 30 wherein the monolithic bone is derived from allogeneic or xenogeneic bone.
32. The method of Claim 30 wherein the monolithic bone is derived from a single piece or section of bone.
33. The method of Claim 30 wherein the monolithic bone is assembled from two or more bone pieces or sections.
34. The method of Claim 30 wherein demineralizing step (b) provides a substantially completely demineralized monolithic bone unit.
35. The method of Claim 30 wherein demineralizing step (b) provides a partially and uniformly demineralized monolithic bone unit.
36. The method of Claim 30 wherein demineralizing step (b) provides a monolithic bone unit having at least a portion of its surface demineralized.
37. The method of Claim 30 wherein demineralizing step (b) provides a monolithic bone unit which is segmentally demineralized in at least one of its regions.
46. The method of Claim 30 wherein the monolithic bone is derived from the diaphysis of a long bone.
47. The method of Claim 46 wherein configuring step (d) provides an intervertebral disc.
48. The method of Claim 47 wherein the upper and lower surfaces of the disc are surface demineralized.
49. The method of Claim 30 wherein treating step (c) utilizes a chemical agent which denatures proteins in the demineralized bone region(s) which promote bone growth.
50. The method of Claim 49 wherein treating step (c) utilizes a chemical agent which additionally crosslinks collagen fibers present in the demineralized bone region(s).
51. The method of Claim 50 wherein the chemical agent is gutaraldehyde.
52. The method of Claim 30 wherein treating step (c) utilizes radiation which denatures proteins in the demineralized bone region(s) which promote bone growth.
53. The method of Claim 30 wherein treating step (c) utilizes heat of sufficient intensity and duration to denature proteins in the demineralized bone region(s) which promote bone growth.
54. The method of Claim 30 wherein treating step (c) utilizes an extractant to remove proteins from the demineralized bone region(s) which promote bone growth.
PCT/US2002/004131 2001-02-14 2002-02-12 Implant derived from bone WO2002064181A1 (en)
CA 2438033 CA2438033A1 (en) 2001-02-14 2002-02-12 Implant derived from bone
EP02714875A EP1383549A1 (en) 2001-02-14 2002-02-12 Implant derived from bone
US10/468,198 US7931692B2 (en) 2001-02-14 2002-02-12 Implant derived from bone
US13/050,606 Continuation US8608803B2 (en) 2001-02-14 2011-03-17 Implant derived from bone
PCT/US2002/004131 WO2002064181A1 (en) 2001-02-14 2002-02-12 Implant derived from bone
WO2001049220A1 (en) 1999-12-30 2001-07-12 Osteotech, Inc. Intervertebral implants
US20030120274A1 (en) 2000-10-20 2003-06-26 Morris John W. Implant retaining device
WO2002064181A1 (en) * 2001-02-14 2002-08-22 Osteotech, Inc. Implant derived from bone
US7833245B2 (en) * 2001-07-12 2010-11-16 Osteotech, Inc. Intervertebral implant with movement resistant structure
US6855167B2 (en) 2001-12-05 2005-02-15 Osteotech, Inc. Spinal intervertebral implant, interconnections for such implant and processes for making
US7833255B2 (en) 2001-12-27 2010-11-16 Osteotech, Inc. Bone fasteners and method for stabilizing vertebral bone facets using the bone fasteners
CA2575740A1 (en) 2004-03-24 2005-10-13 Doctor's Research Group, Inc. Methods of performing medical procedures that promote bone growth, methods of making compositions that promote bone growth, and apparatus for use in such methods
AU2003253906A1 (en) * 2002-07-19 2004-02-09 Osteotech, Inc. Chisels and procedure for insertion of spinal implant in a spinal disc space
US20040098129A1 (en) * 2002-11-13 2004-05-20 Jo-Wen Lin Spinal implant insertion adjustment instrument and implants for use therewith
USRE43258E1 (en) 2003-04-29 2012-03-20 Musculoskeletal Transplant Foundation Glue for cartilage repair
US7067123B2 (en) * 2003-04-29 2006-06-27 Musculoskeletal Transplant Foundation Glue for cartilage repair
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
AU2004251664A1 (en) 2003-06-03 2005-01-06 Osteotech, Inc. Bioimplant with nonuniformly configured protrusions on the load bearing surfaces thereof
US20050038511A1 (en) * 2003-08-15 2005-02-17 Martz Erik O. Transforaminal lumbar interbody fusion (TLIF) implant, surgical procedure and instruments for insertion of spinal implant in a spinal disc space
WO2005037150A1 (en) * 2003-10-16 2005-04-28 Osteotech, Inc. System and method for flexible correction of bony motion segment
EP1701672A4 (en) 2003-12-19 2011-04-27 Osteotech Inc Tissue-derived mesh for orthopedic regeneration
WO2005072656A1 (en) * 2004-01-27 2005-08-11 Osteotech, Inc. Stabilized bone graft
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
WO2006044920A2 (en) 2004-10-19 2006-04-27 Osteotech, Inc. Adjustable instrumentation for spinal implant insertion
EP1819375A2 (en) * 2004-12-08 2007-08-22 Interpore Spine Ltd. Continuous phase composite for musculoskeletal repair
US8535357B2 (en) 2004-12-09 2013-09-17 Biomet Sports Medicine, Llc Continuous phase compositions for ACL repair
US20060229723A1 (en) * 2005-04-08 2006-10-12 Sdgi Holdings, Inc. Intervertebral fusion device and method
AU2006236548A1 (en) * 2005-04-15 2006-10-26 Musculoskeletal Transplant Foundation Vertebral disc repair
US7857853B2 (en) * 2005-04-29 2010-12-28 Sdgi Holdings, Inc Synthetic loadbearing collagen-mineral composites useful for spinal implants, and methods of manufacture
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
CA2623106C (en) 2005-09-19 2013-12-24 Histogenics Corp. Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
WO2008013763A2 (en) 2006-07-25 2008-01-31 Musculoskeletal Transplant Foundation Packed demineralized cancellous tissue forms for disc nucleus augmentation, restoration, or replacement and methods of implantation
US20070038303A1 (en) * 2006-08-15 2007-02-15 Ebi, L.P. Foot/ankle implant and associated method
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
AU2008216371B2 (en) 2007-02-12 2014-04-10 Warsaw Orthopedic, Inc. Joint revision implant
WO2008106478A1 (en) * 2007-02-27 2008-09-04 Lanx, Llc Compositions and methods for modification of target cells and to their uses thereof
WO2009111069A1 (en) 2008-03-05 2009-09-11 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
WO2008151119A2 (en) * 2007-06-01 2008-12-11 Lanx, Llc Compositions and methods for use of scar tissue in repair of weight bearing surfaces
CN104013479A (en) * 2007-09-14 2014-09-03 普渡研究基金会 Demineralized cancellous bone scaffolds
CA2708147A1 (en) * 2007-12-05 2009-06-18 Musculoskeletal Transplant Foundation Cancellous bone implant for cartilage repair
US20090222099A1 (en) * 2008-02-28 2009-09-03 Warsaw Orthopedics, Inc. Self Centering Nucleus Implant
US8293813B2 (en) * 2008-03-05 2012-10-23 Biomet Manufacturing Corporation Cohesive and compression resistant demineralized bone carrier matrix
US9149319B2 (en) * 2008-09-23 2015-10-06 Lanx, Llc Methods and compositions for stabilization of a vertebra
US9192695B2 (en) 2008-11-20 2015-11-24 Allosource Allografts combined with tissue derived stem cells for bone healing
US20110184468A1 (en) * 2010-01-28 2011-07-28 Warsaw Orthopedic, Inc., An Indiana Corporation Spinous process fusion plate with osteointegration insert
US9398960B2 (en) 2011-09-16 2016-07-26 Globus Medical, Inc. Multi-piece intervertebral implants
US9681959B2 (en) 2011-09-16 2017-06-20 Globus Medical, Inc. Low profile plate
US10245155B2 (en) 2011-09-16 2019-04-02 Globus Medical, Inc. Low profile plate
US9155607B2 (en) * 2011-11-16 2015-10-13 Purdue Research Foundation Compositions and methods for repair or regeneration of soft tissue
US8920511B2 (en) 2011-11-17 2014-12-30 Allosource Multi-piece machine graft systems and methods
TWI459978B (en) * 2011-12-20 2014-11-11 Metal Ind Res & Dev Ct Electro-spinning device, gtr implant and method for manufacturing the same
US10207027B2 (en) 2012-06-11 2019-02-19 Globus Medical, Inc. Bioactive bone graft substitutes
US9585764B2 (en) * 2012-07-26 2017-03-07 Warsaw Orthopedic, Inc. Bone implant device
US10172651B2 (en) 2012-10-25 2019-01-08 Warsaw Orthopedic, Inc. Cortical bone implant
US9265609B2 (en) 2013-01-08 2016-02-23 Warsaw Orthopedic, Inc. Osteograft implant
KR20150120986A (en) 2013-02-22 2015-10-28 알로소스 Cartilage mosaic compositions and methods
WO2014138612A1 (en) 2013-03-07 2014-09-12 Allosource Consistent calcium content bone allograft systems and methods
KR20150132152A (en) 2013-03-15 2015-11-25 알로소스 Perforated osteochondral allograft compositions
US9539286B2 (en) 2013-10-18 2017-01-10 Globus Medical, Inc. Bone grafts including osteogenic stem cells, and methods relating to the same
US9579421B2 (en) 2014-02-07 2017-02-28 Globus Medical Inc. Bone grafts and methods of making and using bone grafts
US9463264B2 (en) 2014-02-11 2016-10-11 Globus Medical, Inc. Bone grafts and methods of making and using bone grafts
US9801910B2 (en) 2014-03-17 2017-10-31 Ethicon, Inc. Decellularized pleural matrix
WO2015175983A1 (en) 2014-05-16 2015-11-19 Allosource Composite bone constructs and methods
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
US10016529B2 (en) 2015-06-10 2018-07-10 Globus Medical, Inc. Biomaterial compositions, implants, and methods of making the same
US20160361467A1 (en) * 2015-06-10 2016-12-15 Globus Medical, Inc. Biomaterial compositions, implants, and methods of making the same
US9839524B2 (en) * 2015-06-22 2017-12-12 Theodore Malinin Modified, pliable, and compressible cortical bone for spinal fusions and other skeletal transplants
USD849946S1 (en) 2015-12-30 2019-05-28 Nuvasive, Inc. Interspinous process spacer
US20180289496A1 (en) 2017-04-05 2018-10-11 Globus Medical, Inc. Decoupled spacer and plate and method of installing the same
US4627853A (en) * 1985-05-29 1986-12-09 American Hospital Supply Corporation Method of producing prostheses for replacement of articular cartilage and prostheses so produced
US4678470A (en) * 1985-05-29 1987-07-07 American Hospital Supply Corporation Bone-grafting material
US5053049A (en) * 1985-05-29 1991-10-01 Baxter International Flexible prostheses of predetermined shapes and process for making same
US5641518A (en) * 1992-11-13 1997-06-24 Purdue Research Foundation Method of repairing bone tissue
WO1999038453A1 (en) * 1998-02-02 1999-08-05 Regeneration Technologies, Inc. Luminal graft, stent or conduit
US5976186A (en) * 1994-09-08 1999-11-02 Stryker Technologies Corporation Hydrogel intervertebral disc nucleus
WO2000040179A1 (en) * 1999-01-08 2000-07-13 Sdgi Holdings, Inc. Flexible implant using partially demineralized bone
US6090998A (en) * 1997-10-27 2000-07-18 University Of Florida Segmentally demineralized bone implant
WO2000050102A1 (en) * 1999-02-23 2000-08-31 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US6123731A (en) * 1998-02-06 2000-09-26 Osteotech, Inc. Osteoimplant and method for its manufacture
US5290558A (en) * 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
US6432436B1 (en) * 2000-10-03 2002-08-13 Musculoskeletal Transplant Foundation Partially demineralized cortical bone constructs
WO2000035511A1 (en) * 1998-12-17 2000-06-22 Cambridge Scientific, Inc. Sequenced incorporation of cortical bone allografts
US6569168B2 (en) * 2000-05-05 2003-05-27 Osteotech, Inc. Intervertebral distractor and implant insertion instrument
ES2247113T3 (en) * 2000-05-12 2006-03-01 Osteotech, Inc. Demineralized bone implant surface and method of making.
US6666866B2 (en) 2000-11-07 2003-12-23 Osteotech, Inc. Spinal intervertebral implant insertion tool
WO2002058600A2 (en) 2001-01-26 2002-08-01 Osteotech, Inc. Implant insertion tool
US7833255B2 (en) * 2001-12-27 2010-11-16 Osteotech, Inc. Bone fasteners and method for stabilizing vertebral bone facets using the bone fasteners
US6911045B2 (en) 2002-04-04 2005-06-28 Osteotech, Inc. Bio-implant insertion instrument
US20040162562A1 (en) * 2003-02-13 2004-08-19 Osteotech, Inc. Instrumentation system for treating end plates of adjacent vertebrae
AU2004251664A1 (en) * 2003-06-03 2005-01-06 Osteotech, Inc. Bioimplant with nonuniformly configured protrusions on the load bearing surfaces thereof
AU2005221083A1 (en) * 2004-03-09 2005-09-22 Osteobiologics, Inc. Implant scaffold combined with autologous or allogenic tissue
WO2006044920A2 (en) * 2004-10-19 2006-04-27 Osteotech, Inc. Adjustable instrumentation for spinal implant insertion
Erbe et al. 2001 Potential of an ultraporous β-tricalcium phosphate synthetic cancellous bone void filler and bone marrow aspirate composite graft
den Boer et al. 2003 Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein‐I or autologous bone marrow
Gamradt et al. 2003 Bone graft for revision hip arthroplasty: biology and future applications.
EP0527936B1 (en) 1997-07-23 Prosthetic intervertebral disc
EP1779868B1 (en) 2013-10-16 Implant cleaning, perfusion and passivation process
US6206931B1 (en) 2001-03-27 Graft prosthesis materials
US7488348B2 (en) 2009-02-10 Cartilage allograft plug
ES2241154T3 (en) 2005-10-16 Reinforced bone graft substitute.
US7141066B2 (en) 2006-11-28 Bone tendon bone assembly with cylindrical allograft bone block
US7662184B2 (en) 2010-02-16 Osteoimplant and method for making same
US9717822B2 (en) 2017-08-01 Bone matrix compositions and methods
US6863694B1 (en) 2005-03-08 Osteogenic implants derived from bone
US5725579A (en) 1998-03-10 Process for treating bone tissue and corresponding implantable biomaterials
US5922027A (en) 1999-07-13 Articular cartilage heterografts
ES2195731B1 (en) 2005-04-01 Product mineral particulate bone for repairing cartilage defects and bone defects combined.
JP5758063B2 (en) 2015-08-05 Implantable cartilage tissue repair device
US20020128630A1 (en) 2002-09-12 Method and apparatus for providing nutrition to intervertebral disc tissue
US6911212B2 (en) 2005-06-28 Malleable putty and flowable paste with allograft bone having residual calcium for filling bone defects
US7959683B2 (en) 2011-06-14 Packed demineralized cancellous tissue forms for disc nucleus augmentation, restoration, or replacement and methods of implantation
EP1942960B1 (en) 2012-08-29 Methods for producing bone matrix composition
CA2563082C (en) 2012-07-10 Cartilage repair mixture containing allograft chondrocytes
US5314476A (en) 1994-05-24 Demineralized bone particles and flowable osteogenic composition containing same
EP2048226A9 (en) 2009-09-30 Soft and calcified tissue implants
US20010038848A1 (en) 2001-11-08 Implantable tissues infused with growth factors and other additives
Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZM ZW
Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
2003-01-09 DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
Ref legal event code: 8642
2006-03-31 WWW Wipo information: withdrawn in national office
Ref country code: JP


text:
Could not retrieve the oEmbed resource.
Melanie Shaw Given Two Years Following Secret Court Hearing - UPDATED
Brian Gerrish
Friday, 13th January 2017
On Wednesday 11 January 2016, Melanie Shaw, the whistleblower on the horrific abuse of children which occurred at the then county council-run Beechwood Children's Home in Nottinghamshire in the late 1980s, was given a two-year custodial sentence in a secret court hearing.
The nature of the charge against her is unclear and that information is refused when requested of court staff. The case took place late yesterday morning but it did not appear on any court lists until the hearing was past.
Melanie Shaw did not appear in person in court for this hearing, which was conducted by video link from her prison, as has also been the case with previous of her court 'appearances'. She states that without fail, whenever in the past she has given testimony by such video link, she has been cut off on the pretext that "you were shouting", which she denies.
The effect of this is to prevent her testimony from going on the court record, as well as to prevent her as defendant from hearing certain deliberations and assertions being made in the courtroom.
In addition, UK Column News is very confident that at this particular secret hearing, no member of the public was present, and particularly not any of the supporters who have been following Melanie Shaw's case very closely. The public is therefore entirely dependent on any transcripts—accurate and complete or otherwise—which may be produced in order to find out what was said at the hearing.
Time already served by Melanie Shaw in prison on remand, namely 11 months, mostly in solitary confinement, does not appear to have been set against the two-year custodial sentence imposed yesterday.
Melanie Shaw is one of the few child abuse whistleblowers who is prepared to name politicians as having been among the abusers of her fellow inmates, some of whom she asserts were murdered on site at Beechwood. Her reminiscences date from 1987, in which year the Cabinet was constituted of these politicians until the general election that May and of these politicians thereafter. (This does not constitute an allegation by UK Column News that any particular Cabinet minister at the above links was an abuser.)
Melanie Shaw's correspondence address in prison is:
Melanie Shaw
A4126DE
HMP Foston Hall
Uttoxeter Road
DE65 5DN
It is advisable if writing to Melanie Shaw to use a card or light letter containing no stamps, blank paper, return envelopes, money or any other objects. These are highly likely to be confiscated, potentially together with the letter or card itself.
Update 13th January 2017
Definition of terms: By "secret court hearing", UK Column News means:
(a) a court hearing not listed until after it took place;
(b) a court hearing whose outcome (i.e. of what alleged crime Melanie Shaw has been convicted) is withheld from the public on request, to the puzzlement of some court staff themselves.
By these two definitions, UK Column News is quite confident in describing Melanie Shaw as a political prisoner.
Founder and joint editor of UK Column.
Share on TwitterShare on FacebookPrint

redpajama_set_name: RedPajamaCommonCrawl


In the 1950s, Marcel Breuer began his master plan for Saint John's Abbey and University. Breuer designed ten buildings for the monastic community over twenty years that were constructed largely of cast-in-place concrete. The majority of the projects were completed, but an important part of Breuer's master plan, the Abbey Guesthouse, was never designed. While respecting Breuer's work, the Abbey also requested that the new guesthouse also provide visitors with a direct experience of monastic life. Guest retreatants follow the same daily rhythms of study, work and meditation. The facility includes conference and meeting areas, a library, a meditation room, dining facilities, and administrative offices with thirty guest rooms.


text:
Deputy Swerves To Avoid Crash, Wrecks His Cruiser
No Serious Injuries Reported
A Palm Beach County sheriff's deputy is recovering after crashing his cruiser into a store sign in Palm Beach Gardens.Investigators told WPBF 25 News that the deputy was heading west on Northlake Boulevard on Saturday night when he swerved to miss another accident.He was taken to the hospital but is expected to be OK.The drivers involved in the other accident were not hurt.
PALM BEACH GARDENS, Fla. —
A Palm Beach County sheriff's deputy is recovering after crashing his cruiser into a store sign in Palm Beach Gardens.
Investigators told WPBF 25 News that the deputy was heading west on Northlake Boulevard on Saturday night when he swerved to miss another accident.
He was taken to the hospital but is expected to be OK.
The drivers involved in the other accident were not hurt.


text:
Grim Fandango Remastered torrent download for PC
Grim Fandango Remastered
Something's rotten in the land of the dead, and you're being played for a sucker. Meet Manny Calavera, travel agent at the Department of Death. He sells luxury packages to souls on their four-year journey to eternal rest. But there's trouble in paradise. Help Manny untangle himself from a conspiracy that threatens his very salvation.
One of the most acclaimed adventure games of all time is now back, better than ever. Grim Fandango's epic story of four years in the life (or death) of Manny Calavera, travel agent to the dead, has been remastered to look, sound, and control even better than when it won GameSpot's Game of the Year award upon its original launch. Grim Fandango still stands as a classic of the genre, with unforgettable characters and unique combination of film noir and Mexican folklore.
Remastered version includes
- Repainted, hi-res character textures
- New, dynamic lighting
- Classic score re-recorded with a full live orchestra
- Over 2 hours of exclusive developer commentary
- Concept art browser
Developer: Double Fine Productions
Publisher: Double Fine Productions
Genre: Adventure, Point-and-click, Detective-mystery
CPU: Intel Core 2 Duo 2.4 GHz, AMD Athlon X2 2.8 GHz, or higher
OS: Windows Vista / 7 or Later
Video Card: ATI Radeon HD 4650 / NVIDIA GeForce GT 220 / Intel HD 4000 Graphics, or equivalent
Free Disk Space: 6000 MB
Category:Adventure, PC Games August 29th, 2018
The Brookhaven Experiment [VR]
Diastone: Confusion


The PRE V630 was developped with the target to enable ultimate transmission quality. Because of its double outputs and the optional remote control, V630 is best suited to be the ideal link between your analog sources and your power amp respectively your active speakers.
Optional remote control for input selection, volume control and mute.
Related links to "Violectric LINE PRE-AMPLIFIER PRE V630"
Customer evaluation for "Violectric LINE PRE-AMPLIFIER PRE V630"


text:
HomeChronicles
Chronicles of a Teen Supernatural Hunter
Life was never dull as a teenage supernatural hunter.
Teen supernatural hunters Jaz and Blake are orphans, who don't know where they've come from or how they have descended from the magical bloodline of hunters. Oz is a powerful Warlock and mentor who has taken in Jaz and Blake to teach them the ways of their destiny. Here are their magical adventures in two entertaining short stories and one novella. . .
In "Darkness Becomes Him" Jaz and Blake are hired to track a dark angel hungry for souls.
In "Mermania" Jaz is bitten and things are getting fishy around Chapel Hill.
In Jaz and Blake's novella, Supernatural Hunters, one of Oz's previous students returns to Chapel Hill. Marco is a world-traveling hunter, asking for help to battle something they have never battled before: a Necromancer. Could this be the reason ghouls have been causing havoc around town? As Jaz and Blake attempt to follow the clues of the dead, they are faced with Blake considering leaving Jaz and Oz for greater hunting adventures. While Jaz discovers she could be the one the Necromancer really wants. Is this the end of Jaz and Blake?
* Subgenres: Paranormal, Romance, Fantasy
For "Darkness Becomes Him":
"Kelly just has a very unique writing style that just completely captures a teenage girls feelings and sucks in the reader. I love that it is about a teenage monster hunting duo. The chemistry between them is awesome and I just want to keep reading about them."
~ Book Bite Reviews (Reviewer)
For "Mermania":
"Never predictable and kept a good pacing. Kelly Parra gave to her characters (hunters) a nice episode of hunting action with a splash of romance. It is a nice love story without been cliched. Great spin to the mermaid concept."
~ Jessy's bookends (Reviewer)
For Supernatural Hunters novella:
"Kelly Parra's Supernatural Hunters has just the right combination of butt-kicking and romance to keep you on the edge of your seat!"
~ Allison van Diepen, author of The Vampire Stalker and Takedown
• Amazon: Kindle
• Published November 2016
• ASIN: B01N07HL2R
• For ages 12+ Up
"I've heard things about you guys . . . strange things."
I didn't have to look at Blake to know a smile curved his mouth. I studied the girl standing in front of us, from her tiny designer boots to her preppy clothes to the sleek blonde hair. Her cheeks were pale, her eyes a little too wide. She said her name was Alexandria.
"Yeah, what kind of things," I said, and bit into my apple.
She glanced over her shoulder at the other high school preps mulling around Montgomery High during lunch break, reached into her back pocket and pulled something out.
Blake bumped me aside as he snatched it away from the girl's hand. I cursed as my half-eaten apple hit dirt.
"It can't be . . . " he murmured.
The girl stepped back. "W-what? What is it?"
Blake moved closer, likely giving her the iced blue intensity of his gaze. I knew that look. We'd caught another case. "Where did you get this?"
She swallowed. "My boyfriend. There's something wrong with him. He's not the same since last week. I've been finding these all over. We're supposed to go to prom in a few days. I need help. Your kind of help. Tiffany Wiser. She told me about you. How you helped her a few months back."
Yeah, the Tiffany girl, filed under Z for Zombie. As in, the infection of her brother. We'd caught it early enough before there was no going back for the kid.
"Okay, we'll help you," Blake said.
"For a price," I cut in from behind Blake. We had to eat.
"I heard. But I don't have much money. I work at Donna's Diner. I close Tuesday and Thursdays. I can hook you up with some hot meals."
Score.
"Give us your contact info. We'll be in touch," Blake told her.
With a look of relief, Alexandria handed Blake a paper with her number and email.
"Listen, just don't tell anybody what you're helping me with, okay?" Alexandria turned and jogged away.
"So," I said, and peered over his shoulder. "What's so interesting?" A feather. Glistening black with silver dust.
Blake ran his fingers over the fine surface. "It's an angel feather."
"What? That's impossible."
"No. It's angel all right."
"You mean—"
"A dark angel."
We took the feather straight to Ozwald—Oz for short. He was our mentor, our teacher, a warlock who took us in off the streets when we'd been labeled as outcasts for being different. Feeling different. I'd been with Oz for six months, Blake almost a year. There'd been others before us who grew into their own and I'm sure there'd be more after us. But right now it was just Oz, Blake, me and Desiree who took care of the housekeeping in the old three-story Victorian house on Chapel Hill.
Oz studied the feather under a thick eyeglass, making his gray eye seem ten times bigger. "Yes, you're right, Blake. It's definitely Angel. Dark." His fingers rubbed together sprinkling silver dust to the floor.
"But how? How do angels become dark?"
Oz sat back in his chair, shoving his reddish braid over his shoulder. "The ancients say they fall, for whatever reason. Unhappiness. Depression. Anger. They lose their grace completely. Their feathers begin to gray, soon turning completely black. Their gold dust fades to silver. Then they start sucking up human souls, trying to turn back to the way they once were, but there's no turning back."
"Is that what's happening to the boyfriend? His soul's been sucked?"
"Actually, if he's leaving behind feathers, it's likely he's possessed by a Dark One and sucking up other people's souls. You see, angels are a spiritual being of the other side. They cannot manifest here unless they possess someone of our world. Once they do, they can pretty much do anything."
"How do we get rid of it?"
"I've never heard of anyone doing so."
"We can't just let it possess some sorry dude and suck people dry."
Oz smacked his lips together. "Suppose you can't. I'll have to do more research. Never dealt with a Dark One myself, but others have. For now, you'll both have to get ready."
I shrugged. "Our fighting skills are up to par."
"No, not that kind of ready. Ready for prom."
"What?" we said as one.
"That prom will be a smorgasbord for that Dark One. You'll have to keep it from sucking souls before it takes out half the high school."
Blake sighed and looked at me. "Ever been to prom before?"
"Yeah, back in my fairy tale life."
"That's what I thought." He winked at me. "Well, you got yourself your first date."
Blake and I hadn't actually gotten along when I first arrived at Castle de Oz. I'd had a bad attitude. Shocker, right? I'd been on the streets for months. When you live on the streets you trust no one. You fight, steal, hide. You fear. Things changed with our first case together. A teenage girl had started dabbling in black magic. Kids were losing their hair, having freak accidents, one nearly died. I'd gone undercover to try to get close to the girl, but she'd discovered what I was. A hunter. Before she could shove me into the path of an oncoming train, Blake had saved me and captured the girl.
It was then that I realized for the first time in a long while that someone had my back. We'd been friends ever since. Best friends.
I widened my eyes. Sarcasm was my thing. "Oh thank you, thank you! My life will now be complete."
He laughed. "Smart ass."
"Both of you must do your best to stop the Dark One before he takes in too many souls," Oz told us. "If he manifests completely . . . "
"Yeah, we know, we're all doomed."


text:
Home > WORKS > 4694
Production and harvesting of microalgae and an efficient operational approach to biofuel production for a sustainable environment
Author First name, Last name, Institution
Shamshad Khan, Neijiang Normal University
M. Naushad, King Saud University; Yonsei University; Shoolini University
Jibran Iqbal, Zayed University
Chinna Bathula, Dongguk University
Gaurav Sharma, Shoolini University; Shenzhen University; Glocal University
Source of Publication
Biofuel derived from microalgae has developed as an environmentally benign alternative to conventional fossil fuels. Mass production of this biofuel remains difficult due to several of technological and economic issues ranging from commercial production and harvesting of microalgae to biofuel production. The major impediments to establishing an integrated system are large-scale microalgal production and harvesting in a manner that allows for downstream processing to produce biofuels and other useful bioproducts. We integrated and evaluated suspended cultures in open ponds and closed reactors for algal production systems, emphasizing the advantages of attached cultures for algal production. The challenge of harvesting microalgae in liquid growing media has been addressed by technical improvements that have incorporated chemical, mechanical, biological and thermal approaches for dewatering microalgal suspensions and extracting additional bioproducts. Nonbiological approaches such as centrifugation, electrocoagulation, chemical, electrical, and magnetic nanoparticle flocculation, filtering, and biological coculture-based methods were evaluated for their feasibility and considerations in establishing microalgae harvesting systems. The latest breakthroughs in bacteria and fungi-based coculture algae-flocculation technology are discussed. Additionally, this review considers the opportunities for genetic engineering innovation and resources for increasing microalgae production and harvesting, as well as for developing new bioproducts in a sustainable and cost-effective manner.
DOI Link
10.1016/j.fuel.2021.122543
Algae production, Biofuel, Wastewater treatment, Microalgae, Algae-flocculation
Khan, Shamshad; Naushad, M.; Iqbal, Jibran; Bathula, Chinna; and Sharma, Gaurav, "Production and harvesting of microalgae and an efficient operational approach to biofuel production for a sustainable environment" (2021). All Works. 4694.
https://zuscholars.zu.ac.ae/works/4694
Indexed in Scopus


text:
Apple Takes iPad Secrecy All the Way to 11
In order to have access to iPad testing units, developers and testers had to agree to keep the device tethered to a fixed object in an isolated room with blacked-out windows, according to a report by BusinessWeek.
That's pretty hardcore. It's unclear from BusinessWeek's report if that was a condition enforced before the iPad was unveiled to the public or if it's something that will be kept up until the April 3 launch date.
Apple is a notoriously secretive company, especially when it comes to new products. Outside of partnerships with content publishers like The New York Times, Wired and The Wall Street Journal who have either confirmed interest or already shown demonstrations of their applications, the few developers that do have access to the iPad are keeping their mouths shut.
It also appears that in order to be on the list for the iPad, developers or companies had to be pretty high on the totem poll. Not even Trip Hawkins, who founded Electronic Arts and once worked at Apple, could get a testing unit for his new company, Digital Chocolate.
Now, not having physical access to the device doesn't preclude developers from creating apps for the iPad — Apple actually started accepting apps for review today — but it does make refining the app much more difficult.
As was the case with the iPhone, we expect the best iPad apps to be those that can take advantage of multi-touch in ways that just feel better. Gestures and interactions on a bigger screen are probably features that will need to be refined over time — just as they were with the original iPhone.
The degree of Apple's iPad-related secrecy might sound well, paranoid, but the fact is, at least for now, the company can get away with it. The mobile ecosystem is so hot — especially for the iPhone — that getting on the iPad and getting on early is worth the hoop-jumping for many developers. Some would even to settle for using an emulator until the product is officially launched.
What do you think of Apple's corporate culture of secrecy? Let us know!
Topics: app store (iOS) , Apple, developers, iPad, secrecy, Tech


Cool teenage girls rooms decoist is one images from 41 best cool teenage girl room of SFConfelca Homes photos gallery. This image has dimension 600x463 Pixel and File Size 80 KB, you can click the image above to see the large or full size photo. Previous photo in the gallery is fun cool teen bedroom ideas freshome. For next photo in the gallery is girls bedroom ideas room design teenage. You are viewing image #20 of 41, you can see the complete gallery at the bottom below.


Ron Smith is a BC writer of poetry, children's books, fiction, non fiction and drama.
Today I received a note from Lynn Thompson of Salt Spring Island who wrote the following after reading Kid Dynamite: The Gerry James Story.
Just finished Kid Dynamite and thoroughly enjoyed it – brought back so many memories. I watched Gerry play against the Roughriders many years ago (hitchhiked to Regina from small town Sask.) and also when the Marlies won the Memorial Cup.
Then years later when I taught in Yorkton we crossed paths again. He was coaching when I was Vice-Principal of the Yorkton Regional High School and met with him when placing his players in our school. He was easily the best coach the Terriers ever had from our perspective. He had a priority for education and told the boys he didn't want any contact from the school re – attendance, etc. If they were a problem at school, they were off his team! I curled against Gerry in the men's league and can attest to his competitive nature. He was though always a good sport and good for a quip.
Thanks again for such a wonderful book – extremely well researched and written.
Your new website is looking really good.


You visited the company's web page Gene's Towing And Recovering. The company is located in the state Alabama, the city of Fort Deposit. The legal address of our company is 15 East Jones Street Fort Deposit, AL 36032. For more information, please call (334) 227-3677.


text:
Diocesan College (), also known as the College of St. Francis de Sales, is a private Catholic primary and secondary school located in Teresina, Piauí, Brazil. The school was founded in 1906 by the Jesuits.

Its Saraiva Square campus opened in 1925 and in 2003 a campus for two to six year olds was opened on Benjamin Constant Street.

History
In 1906, the first bishop of Piauí, Antonio Joaquim D'Almeida, founded the school along with the diocesan seminary. In 1914 the second bishop of Piauí closed the school for lack of funds, and took up residence in the building which has since had his court of arms on its facade. The third bishop of Piauí, Dom Severino Vieira de Melo, reopened the school in 1925 under the name of St. Francis de Sales, running a boarding school.

In 1945, the scientific and classic courses along with the technical trade school were initiated, including a course in accounting. At this time, a group of students also founded New People magazine. In the late 1950s, the boarding house was closed.

From October 1959 until early 1960, the school had its first lay director, Bernardo Lopes de Sousa, who administered the school during the transition period until the arrival of the Jesuit fathers in 1960. Since then it has networked with Jesuit schools.

The school's children's division was opened in 2003. Today it serves more than 600 students between two and six years old.

In 2015, the school placed twelfth in Piauí state in the national secondary school examination (Exame Nacional do Ensino Médio).

See also

 Catholic Church in Brazil
 Education in Brazil
 List of Jesuit educational institutions
 List of schools in Brazil

References

External links

1906 establishments in Brazil
Buildings and structures in Piauí
Education in Piauí
Educational institutions established in 1906
Jesuit schools in Brazil
Mixed-sex education
Catholic boarding schools
Catholic primary schools in Brazil
Catholic secondary schools in Brazil
Teresina

redpajama_set_name: RedPajamaWikipedia


text:
Home / Publications / Canada clarifies copyright
Canada-clarifies-copyright
05 September 2012 | Brief Counsel
The Supreme Court of Canada has been prolific on copyright issues in recent times – with mixed results for rights-holders and for content users.
Of particular interest is the Court's approach to the fair dealing defences and to technological issues surrounding the use of musical works.
Fair dealing
Commercial music selling websites will often permit users to preview a snippet of a musical work in order to decide whether to purchase it. The question before the Court was whether this was covered by the "fair dealing" defence allowing people to use a copyright work for research or private study.
The Court set a low threshold and concluded that the use of previews by a consumer for the non-creative purpose of investigating and identifying works for purchase could constitute research.
It also concluded that the dealing was "fair" because the limited length and degraded quality of the previews would ensure that they were only used for research purposes and that they would aid the legitimate dissemination of the genuine work and so would not negatively affect the copyright holders' interests.
In a companion case on a similar issue the Court looked at the fairness of research copying for education and concluded that the appropriate perspective to apply is that of the consumer and not the copier of the work.
Accordingly, a teacher who photocopied extracts from textbooks for a class, even without any request to do so, would come within the fair dealing exception. The Court considered that the purpose of the teacher in making the copies could not be severed from the students' study. It would be so severed, however, where the copying had a commercial purpose.
The Court's view on this issue is different from influential New Zealand High Court authority on the subject and may see the issue revisited here.
Musical works on the internet
When you download music off the internet are you reproducing it? Or communicating it? Why would you care? Because it may be relevant to the royalties that you are required to pay under a licence agreement.
The Court concluded that a download of a musical work over the internet is a reproduction of the work, rather than a communication, and that, for these purposes, the internet is a "technological taxi" – a mode of delivering a durable copy of the work to the ultimate user.
A communication, by contrast, is linked to the performance right which is impermanent in nature.
Interestingly, the Court noted that repeated point to point transmissions of the same work to multiple different recipients will constitute a communication to the public. That may be an observation of interest and relevance to providers of file sharing services.
Chapman Tripp comment
There is something for everyone in the Supreme Court of Canada's findings, however right-holders are probably not overly enthusiastic about the lower threshold for the research exception.
Given there is talk of New Zealand's fair dealing defences being reviewed and re-tooled at some point, it is likely that these Canadian developments will wield some influence. In the meantime, those previewing musical purchases on iTunes can honestly tell their parents that they are conducting research.
Our thanks to Justin Graham for writing this Brief Counsel. For further information, please contact the lawyers featured.
Download PDF Print this article Download free Acrobat Reader here
Related topics: Intellectual property; Copyright
Justin Graham; Matt Sumpter; Paul Sumpter


"We were worried about your personal salvation… was it heaven or hell that you saw when your eyes closed?
Our spiritual interventions ended up doing more harm than good. We could not even consider the possibility that we were wrong. We put you in the state of fallenness, casting ourselves as defenders of the truth. It was the marker from which we would no longer discuss your inner life.
Well intentioned, but in the end, we did more harm than good.
And so. Old friends no longer discuss God or spirituality. Former lovers no longer talk. Parents and children are in different spaces and places now.


text:
RICH REVIEWS: The Artist Behind Superman The Joe Shuster Story (GN)
by Richard Vasseur on May 10, 2018 RICH REVIEWS: The Artist Behind Superman The Joe Shuster Story (GN)2018-05-10T23:40:38-07:00 - Reviews, Rich Reviews
Title: The Artist Behind Superman The Joe Shuster Story (GN)
Publisher: Super Genius
Writer: Julian Voloj
Artist: Thomas Campi
Preface by: Chelle Mayer
Price: $ 19.99 US, $ 25.99 Can
Website: supergeniuscomics.com/
Comments: This is the story of Joe Shuster and of how he co-created Superman.
The art style is a lightly colored pastel style that is soft and subdued. It does fit the mood of the comic. The faces at times are illustrated to pasty.
Joe Shuster's childhood is shown. His family was poor but they got by. Joe had a happy childhood. His greatest joy was comics.
Joe and his family moved around a lot. When they move to Glenville Joe meets Jerry Siegel. These two immediately hit it off. We see them start to be creative and work together. They do get a small amount of success together but little pay.
Jerry and Joe finally get Superman published it took them a long time but they never gave up. Unfortunately, when they did so they signed away the ownership to Superman. The success of Superman was unheard of. Superman moved into radio and the big screen. The comics were still doing great too.
Then Joe started having health issues but worked around it. Jerry meanwhile was getting more and more upset over not getting a big enough cut.
Joe Shuster did have a hard life yes he co-created Superman but his life was anything but super. He deserved so much more.
Finally, the comic book world stood up Neal Adams and Jerry Robinson and others campaigned for Jerry and Joe.
This book delivers the true story of Joe Shuster and how he was mistreated over his co-creation of Superman. We see how long it took to finally give him and Jerry Siegel the credit and financial awards they so richly deserved.
Any fan of Superman and comics should read this and find out how the creators of Superman were treated and what it took for them to be treated right. It was a long hard struggle and they earned everything they got and deserved even more.
https://www.firstcomicsnews.com/rich-reviews-the-artist-behind-superman-the-joe-shuster-story-gn/https://www.firstcomicsnews.com/wp-content/uploads/2016/09/Superman-Logo-600x257.pnghttps://www.firstcomicsnews.com/wp-content/uploads/2016/09/Superman-Logo-150x64.png 2018-05-10T23:40:38-07:00 Richard VasseurReviewsRich Reviews
Title: The Artist Behind Superman The Joe Shuster Story (GN) Publisher: Super Genius Writer: Julian Voloj Artist: Thomas Campi Preface by: Chelle Mayer Price: $ 19.99 US, $ 25.99 Can Rating: 5 out of 5 stars Website: supergeniuscomics.com/ Comments: This is the story of Joe Shuster and of how he co-created Superman. The art style is a lightly colored...


The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending that Keytruda® (pembrolizumab), in combination with Alimta® (pemetrexed) and platinum chemotherapy, should be available through the Cancer Drugs Fund as a treatment option for certain patients with untreated non-small-cell lung cancer (NSCLC).
NICE estimates that more than 3000 patients in England may be eligible for this combination treatment.
The approval stems from data obtained from the KEYNOTE-189 trial, which demonstrated a significant improvement in overall survival and progression-free survival for patients (specifically untreated, metastatic, non-squamous NSCLC adult patients whose tumours have no EGFR– or ALK-positive mutations) randomized to pembrolizumab in combination with pemetrexed and platinum chemotherapy compared with pemetrexed and platinum chemotherapy alone.
NICE stated that the combination has the potential to be cost effective and was likely to extend life, making it eligible for use on the Cancer Drugs Fund. However, NICE stated that it will not yet be considered for routine NHS use as further evidence is needed on the benefits of the treatment.
Pembrolizumab is administered every 3 weeks by intravenous infusion. NICE noted that the regular price of a 200mg infusion is £5,260 ($6792), but the company offered the NHS a confidential discount.