Container for storing, mixing and delivering bone material

Abstract

A container for mixing bone material is provided. The container includes an inner surface for receiving bone material and an outer surface having a distal end and a proximal end. The distal end of the outer surface includes a locking member configured to encapsulate the bone material onto the inner surface of the container. The proximal end of the outer surface of the container contains a port configured to receive a fluid to mix the bone material. A method of mixing and / or delivering bone material using the container is also provided.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 154,194, filed February 26, 2021, the entire disclosure of which is incorporated herein by reference. Background Technology

[0002] In orthopedic surgery, bone materials, including natural bone and bone substitutes, are frequently used to fill bone repair sites. While bone trauma can regenerate without forming scar tissue, fractures and other orthopedic injuries take a long time to heal, during which time the bone cannot support physiological loads without implantable medical devices. Metal pins, screws, rods, plates, and meshes are often needed to replace the mechanical function of injured bone. However, metal is significantly harder than bone. Using metal implants can reduce bone density around the implantation site due to stress shielding. Physiological stress and corrosion can cause metal implants to fracture. Unlike bone, which can heal small cracks through remodeling to prevent larger injuries and fractures, metal implants can simply be replaced or removed. The body's natural cellular healing and remodeling mechanisms coordinate the removal of bone and bone grafts by osteoclasts and the formation of bone by osteoblasts.

[0003] Rapid and effective repair of bone defects caused by injury, disease, wound, or surgery is a goal of orthopedic surgery. To this end, numerous materials have been used or proposed for bone defect repair. The biological, physical, and mechanical properties of these materials are the main factors influencing their suitability and performance in various orthopedic applications.

[0004] Autologous cancellous bone (ACB) has long been considered the gold standard for bone grafting. ACB consists of osteoblasts, which have the potential to aid bone healing, are non-immunogenic, and possess structural and functional characteristics suitable for healthy recipients. Some people do not have a sufficient amount of ACB to donate. These individuals include, for example, the elderly and those who have previously undergone surgery. However, most people do have a sufficient amount of ACB to donate. People may be reluctant to donate ACB due to pain at the donation site and potential donor site morbidity.

[0005] Bone regeneration is typically achieved by filling bone defects with bone material, such as bone grafts. Over time, the bone graft integrates with the host, and new bone remodels the graft. Bone material can include bone from the patient's own body or artificial, synthetic, or natural alternative bone materials. However, processing bone material, including mixing and dispensing it with different components, can be difficult to minimize waste, and contaminants can be introduced into the bone material.

[0006] To deliver bone material to bone defects, it is typically mixed with liquids or therapeutic agents, powders, fibers, or microparticles. Currently available mixing devices are cumbersome to use and do not achieve uniform and easy mixing of materials. Hydration of dry bone grafts with fluids is particularly difficult due to the need for mechanical force and / or additional instruments to effectively compress, mix, agitate, or knead the material to achieve uniform hydration or distribution of the fluid. Furthermore, bone material is often transferred to the delivery device via coarse packaging, and accidental spillage can increase the risk of contamination. Mixing and transferring graft material is often necessary for creating implantable structures and treating patients requiring bone grafts. This process can be performed aseptically in a surgical setting. Typically, the material can be transferred between blood vessels to fully mix it, resulting in an implantable structure. When this process is performed by a single person, when only one surgical staff member's two hands are available, the design of the container and delivery system should take into account the challenges of vascular and instrument manipulation. Currently available containers and delivery devices generally lack the features to facilitate simple aseptic transfer between blood vessels and lack accuracy in measuring bone material used to deliver to the target bone defect.

[0007] Therefore, it would be beneficial to provide a container for the effective and efficient placement, measurement, mixing, and dispensing of bone materials. Furthermore, a container for dispensing bone materials would also be beneficial, allowing for easy loading and mixing of bone and fluids within the container, and reducing the risk of contamination and spillage of bone materials from the container. Summary of the Invention

[0008] In some embodiments, a container is provided for mixing bone material, which allows for easy placement, measurement, mixing, and dispensing of the bone material. The bone material container facilitates container loading, reducing the risk of bone material contamination and spillage. In some embodiments, the bone material container enables uniform mixing and measurement of the bone material, reducing clogging and frictional resistance within the container.

[0009] In some embodiments, there is a container including an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate the bone material on the inner surface of the container, and the proximal end of the outer surface having a port configured to receive fluid to mix with the bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface from the container.

[0010] In some embodiments, there is a method for mixing bone material, the method comprising: providing a container for mixing bone material, the container including an inner surface for receiving bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate bone material on the inner surface of the container, the proximal end having a port configured to receive fluid to mix with bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container; opening the locking member and adding bone material to the inner surface of the container; closing the locking member to encapsulate bone material on the inner surface of the container; and adding fluid to the container by allowing fluid through the port of the container.

[0011] In some embodiments, there is a container for mixing bone material, the container including an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end of the outer surface including a head portion having an opening configured to allow loading of bone material onto the inner surface of the container; the head portion being disposed adjacent to a locking member which is also disposed on the outer surface of the container; the head portion having more holes than the proximal end of the outer surface; the proximal end of the outer surface having a port configured to receive fluid to mix with bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container.

[0012] In some embodiments, there is a method of encapsulating bone material in a container, the method comprising providing a container for adding bone material, the container including an inner surface for receiving bone material thereon and an outer surface having a distal end and a proximal end, the distal end of the outer surface of the container including a head portion having an opening configured to allow bone material to be added to the inner surface of the container, the head portion being disposed adjacent to and the locking member also being disposed on the outer surface of the container, the head portion having more holes than the proximal end of the outer surface, the proximal end of the outer surface of the container having a port configured to receive fluid for mixing with bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container; adding the bone material to the inner surface of the container through the opening of the head portion; and sealing the container to encapsulate the bone material in the container.

[0013] Although several embodiments have been disclosed, other embodiments of this disclosure will be apparent to those skilled in the art from the following detailed description. It will be apparent that modifications can be made to this disclosure in various obvious ways without departing from the spirit and scope of this disclosure. Therefore, the detailed description should be regarded as illustrative in nature and not restrictive. Attached Figure Description

[0014] To some extent, other aspects, features, benefits, and advantages of the embodiments will become apparent in part from the following description, the appended claims, and the accompanying drawings:

[0015] Figure 1 A perspective view of a container for holding, measuring, mixing and / or dispensing bone material, according to one aspect of this application, is depicted.

[0016] Figure 2 Depicting Figure 1 The container shown is in a partial view of an open structure, with the bone material portion filling the container.

[0017] Figure 3 Depicting the placement of fluid Figure 1 A perspective view of the syringe at the port in the container shown, used for mixing with bone material.

[0018] Figure 4A Depicting Figure 1 A perspective view of the container, showing the use of a resting surface with measuring features when the locking member is closed.

[0019] Figure 4B Depicting Figure 1 A perspective view of the container, showing the use of a resting surface with measuring features when the locking member is opened.

[0020] Figure 5 Depicting Figure 1 A perspective view of the container, showing the upper layer peeled off from the lower layer of the container cover.

[0021] Figure 6A Depicting Figure 1 A perspective view of the container, showing the removal of the port along a tear line located near the container port.

[0022] Figure 6B Depicting Figure 1 A perspective view of the container, showing the removal of the resting surface with measurement characteristics along a tear line located near the locking member.

[0023] Figure 7 Depicting Figure 1 A perspective view of the container shows bone material mixed with fluid being dispensed from the container by rolling it from the distal end to the proximal end.

[0024] Figure 8 Depicting Figure 1A perspective view of another embodiment of the container shows a head portion that is porous relative to a non-porous region proximal to the outer surface of the container. The head portion is porous to allow for the drying (e.g., freeze-drying, lyophilization, etc.) and / or sterilization of bone material loaded through an opening in the head portion and entering the inner surface of the container. According to one aspect of this application, the container also has a central locking member for holding, measuring, mixing, and / or dispensing bone material.

[0025] Figure 9 One aspect of this application is described Figure 8 The diagram shows a perspective view of another embodiment of the container, which has bone material loaded inside. The container has a first barrier seal at the head portion, and the bone material now loaded inside is ready to be dried and / or sterilized using the same container.

[0026] Figure 10 Depicting Figure 9 The diagram shows a perspective view of another embodiment of the container, which includes a head portion having a first barrier seal and a second barrier seal, wherein the second barrier seal is now applied near a central locking member after the bone material loaded in the container has been dried (e.g., freeze-dried, lyophilized, etc.) and / or sterilized. According to one aspect of this application, the second barrier seal is applied to a non-porous area of ​​the outer surface of the container and includes a tear element that allows the head portion to be torn apart from the remainder of the container and removed.

[0027] Figure 11 Depicting Figure 10 The diagram shows a perspective view of a container with a head portion removed along a tear element, such that a non-porous area of ​​the container retains a second barrier seal comprising a central locking member and an outer surface. In this way, a dry and / or sterilized, stable bone material is provided that can be mixed in and removed from the container.

[0028] It should be understood that the accompanying drawings are not drawn to scale. Furthermore, the relationships between objects in the drawings may not be to scale, and in fact, they may have inverse relationships regarding size. These drawings are intended to aid in understanding and clarifying the structure of each object shown, and therefore, some features may be enlarged to illustrate the specific characteristics of a structure. Detailed Implementation

[0029] definition

[0030] It should be noted that, unless explicitly and definitively limited to a single indicator, the singular forms “a,” “an,” and “described” as used in this specification and the appended claims encompass a plural of indicators. Thus, for example, reference to “container” includes one, two, three, or more containers.

[0031] The term "allogeneic graft" refers to a tissue graft obtained from a donor of the same species as the recipient but with a different genetic makeup, serving as a tissue transfer between two individuals.

[0032] The term "autologous" refers to a body that is derived from or transferred from the same individual, such as an autologous bone marrow graft.

[0033] The term "heterograft" refers to a tissue or organ from an individual of one species that is transferred to or transplanted to an organism of another species, genus, or family.

[0034] The term "mammal" refers to organisms belonging to the class "mammals" in the taxonomic system, including but not limited to humans; other primates (such as chimpanzees, apes, orangutans, and monkeys); rats, mice, cats, dogs, cattle, horses, etc.

[0035] The term "patient" refers to a biological system to which treatment can be administered. A biological system may include, for example, an individual cell, a group of cells (e.g., a cell culture), an organ, or a tissue. Additionally, the term "patient" may refer to an animal, including but not limited to humans.

[0036] The term "bone material" includes natural and / or inorganic materials, such as inorganic ceramics and / or bone substitutes. Bone material may also include natural bone material, such as autologous, allogeneic, xenogeneic, or genetically modified cortical, cancellous, or cortical-cancellous bone. In some embodiments, bone material may include demineralized bone material, such as substantially demineralized bone material, partially demineralized bone material, or completely demineralized bone material.

[0037] As used herein, “demineralized” refers to any material produced by removing mineral material from tissue (e.g., bone tissue). In some embodiments, the demineralized compositions described herein comprise formulations containing less than 5% by weight of calcium, and preferably less than 1% by weight of calcium. Partially demineralized bone (e.g., formulations having more than 5% by weight of calcium but containing less than 100% of the original starting amount of calcium) is also considered to be within the scope of this application. In some embodiments, demineralized bone has less than 95% of its original mineral content.

[0038] In some embodiments, the demineralized bone has less than 95% of its original mineral content. In some embodiments, the demineralized bone is less than 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53% of its original mineral content. %, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, and / or 5%. In some embodiments, “demineralized” is intended to encompass terms such as “substantially demineralized,” “shallowly demineralized,” “partially demineralized,” “surface demineralized,” and “completely demineralized.”

[0039] "Partially demineralized material" is intended to encompass "surface demineralized material". "Partially demineralized bone" is intended to refer to a formulation having more than 5% by weight of calcium but containing less than 100% of the original starting amount of calcium. In some embodiments, partially demineralized material comprises 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52% calcium. 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and / or 99% of the original starting amount of calcium.

[0040] In some embodiments, the demineralized bone may be approximately 1-99% surface demineralized. In some embodiments, the demineralized bone is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and / or 99% surface demineralization. In various embodiments, the demineralized bone may be about 15-25% surface demineralized. In some embodiments, the demineralized bone is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% and / or 25% surface demineralized.

[0041] As used herein, “shallowly demineralized” means bone-derived elements having at least about 90% by weight of their original inorganic mineral content, “partially demineralized” means bone-derived elements having about 8% to about 90% by weight of their original inorganic mineral content, and “fully demineralized” means bone containing less than 8% of its original mineral content.

[0042] As used herein, demineralized bone matrix refers to any material produced by removing minerals from bone tissue. In a preferred embodiment, the DBM composition used herein comprises a formulation containing less than 5% calcium, and preferably less than 1% by weight of calcium.

[0043] As used in this article, “biocompatibility” refers to materials that do not cause undesirable long-term effects when applied in vivo.

[0044] As used in this article, the term "osteoconduction" refers to the ability of a non-osteogenic substance to act as a suitable template or material along which bone can grow.

[0045] As used in this article, "osteogenesis" refers to the ability of a drug, material, or implant to enhance or accelerate the growth of new bone tissue through one or more mechanisms such as osteogenesis, osteoconduction, and / or osteoinduction.

[0046] As used herein, “osteoinducible” refers to the quality of being able to recruit cells from the host that have the potential to stimulate new bone formation. Any material that can induce ectopic bone formation in the soft tissues of an animal is considered osteoinducible. For example, most osteoinducible materials induce bone formation in athymic rats when measured according to the following method: Edwards et al., “Osteoinduction of Human Demineralized Bone: Characterization in a Rat Model,” Clinical Orthopaedics & Res., 357:219-228, December 1998, which is incorporated herein by reference.

[0047] In this document, the terms “upper,” “lower,” “top,” “bottom,” “side,” “near,” “far,” etc., are used for convenience only to describe the invention and its portions oriented as shown in the figures. However, it should be understood that these terms are by no means limited to this disclosure, as the conveying system described herein can obviously be arranged in different orientations when in use.

[0048] For the purposes of this specification and the appended claims, unless otherwise indicated, all figures expressing the amount of an ingredient, percentage or proportion of material, reaction conditions, and other numerical values ​​used in this specification and the claims shall be understood to be modified by the term "about" in all cases. Therefore, unless indicated otherwise, the numerical parameters set forth in the following specification and the appended claims are approximations that may vary depending on the desired characteristics sought to be obtained through the invention. To a minimum, and without attempting to limit the application of the equivalence principle to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant digits reported and by applying general rounding techniques.

[0049] Although the numerical ranges and parameters described herein are approximate, the numerical values ​​illustrated in specific examples are reported as precisely as possible. However, any numerical value inherently contains some error necessarily caused by the standard deviation found in its corresponding test measurement. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained herein. For example, the range “1 to 10” encompasses (and includes) any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, i.e., any and all subranges having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10, such as 5.5 to 10.

[0050] Reference will now be made to certain embodiments of this disclosure, examples of which are illustrated in the accompanying drawings. While this disclosure will be described in conjunction with the illustrated embodiments, it should be understood that they are not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined by the appended claims.

[0051] The following headings are not intended to limit this disclosure in any way; embodiments under any heading may be used in conjunction with embodiments under any other heading.

[0052] Bone materials

[0053] In some embodiments, a container is provided for holding, measuring, mixing, and / or dispensing bone material, enabling the measurement and easy mixing of the bone material. This container facilitates loading of the bone material, reducing the risk of contamination and spillage. In some embodiments, the container for mixing and / or dispensing the bone material allows for uniform mixing and measurement of the bone material, reducing clogging and frictional resistance within the bone material container. The bone material may be granular, paste-like, putty-like, or powdered.

[0054] In some embodiments, the bone material may be made of natural bone and / or synthetic bone. The bone material may include ceramics, collagen, allogeneic bone, autologous bone, demineralized bone matrix fibers, demineralized bone powder, demineralized bone fragments, or combinations thereof.

[0055] In various embodiments, the bone material may be in particulate form, such as bone fragments, powder, or fiber. In some embodiments, the bone material is in powder or wet form and has a particle size of 250 micrometers or less. In some embodiments, the bone material has 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 1 Particle sizes of 38, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248 and / or 250 micrometers. In some embodiments, the bone material is demineralized bone (DBM).

[0056] If the bone is demineralized, it can be granulated before, during, or after demineralization. In some embodiments, the bone can be monolithic and may not be granular.

[0057] Before or after demineralization, bone can be ground and pulverized or otherwise processed into particles of suitable size. The particles can be granular (e.g., powder) or fibrous. The terms grinding or milling are not intended to limit the production of a particular type of particle and can refer to the production of granular or fibrous particles. In some embodiments, the particle size can be greater than 25 micrometers, for example, from about 25 to about 250 micrometers, or from about 25 to about 200 micrometers, or from about 25 to about 150 micrometers.

[0058] After grinding, the bone particles can be sieved to select those of the desired size. In some embodiments, the particles can be sieved through 25-micron, 50-micron, 75-micron, 100-micron, 125-micron, 150-micron, 175-micron, and / or 200-micron sieves.

[0059] In some embodiments, the bone material comprises DBM and / or mineralized bone. In some embodiments, the size of the bone material is less than 25, 50, 75, 100, 125, 150, 175, 200, or 250 micrometers.

[0060] Following scraping, grinding, or other techniques used to obtain them, bone materials are demineralized to reduce their inorganic content to very low levels, in some embodiments, to no more than about 5% by weight of residual calcium and no more than about 1% by weight of residual calcium. Demineralization of bone materials typically results in some degree of shrinkage.

[0061] The bone used in the methods described herein can be an autologous graft, an allogeneic graft, or a xenograft. In various embodiments, the bone can be cortical bone, cancellous bone, or corticocancellous bone. Although demineralized bone matrix is ​​specifically discussed herein, the bone matrix processed according to the teachings herein can be undemineralized, demineralized, partially demineralized, or superficially demineralized. This discussion applies to demineralized, partially demineralized, and superficially demineralized bone matrices. In one embodiment, the demineralized bone is derived from bovine or human bone. In another embodiment, the demineralized bone is derived from human bone. In one embodiment, the demineralized bone is derived from the patient's bone (autologous bone). In another embodiment, the demineralized bone is derived from a different animal of the same species (including cadavers) (allogeneic bone graft).

[0062] Bone can be demineralized using any suitable method. Demineralization of bone material can be performed according to known conventional procedures. For example, in a preferred demineralization procedure, bone material suitable for use in the implantable compositions of this application undergoes an acid demineralization step followed by a degreasing / sterilization step. The bone material is immersed in acid, achieving demineralization over time. Acids that can be used in this step include inorganic acids, such as hydrochloric acid; and organic acids, such as peracetic acid, acetic acid, citric acid, or propionic acid. The depth of demineralization into the bone surface can be controlled by adjusting the treatment time, the temperature of the demineralization solution, the concentration of the demineralization solution, the intensity of agitation during treatment, and other applied forces, such as vacuum, centrifuge, pressure, and other factors as known to those skilled in the art. Therefore, in various embodiments, the bone material can be completely demineralized, partially demineralized, or surface-demineralized.

[0063] Following acid treatment, the bone is rinsed with sterile water for injection, buffered to the final predetermined pH value, and then finally rinsed with water for injection to remove residual acid and buffer, or washed with water to remove residual acid and thus raise the pH. After demineralization, the bone material is immersed in a solution to degrease it. The degreasing / disinfectant solution is an aqueous solution of ethanol, which is a good solvent for lipids, and water is a good hydrophilic carrier, allowing the solution to penetrate deeper into the bone. The aqueous ethanol solution also disinfects the bone by killing nutrient microorganisms and viruses. Typically, at least about 10 to 40% by weight of water (i.e., about 60 to 90% by weight of the degreasing agent, such as ethanol) should be present in the degreasing / disinfectant solution to achieve optimal lipid removal and disinfection in the shortest possible time. The concentration range of the degreasing solution is about 60 to 85% by weight of ethanol or about 70% by weight of ethanol.

[0064] Furthermore, according to this application, the DBM material can be used immediately for the preparation of bone implants, or it can be stored under sterile conditions, advantageously stored in a critical point dry state prior to such preparation. In one embodiment, the bone material can retain some of its original mineral content, allowing the composition to be imaged using radiographic techniques.

[0065] In various embodiments, this application also provides bone matrix compositions comprising critical point drying (CPD) fibers. DBM comprises a collagen matrix of bone and acid-insoluble proteins, including bone morphogenetic proteins (BMPs) and other growth factors. It can be formulated for use as granules, gels, sponge materials, or putties, and can be freeze-dried for storage. Sterilization procedures used to prevent the spread of disease may reduce the activity of beneficial growth factors in DBM. DBM provides an initial osteoconductive matrix and exhibits a degree of osteoinductive potential, inducing the infiltration and differentiation of osteoprogenitor cells from surrounding tissues.

[0066] DBM formulations have been used in orthopedic medicine for many years to promote bone formation. For example, DBMs have been found to repair fractures, fuse vertebrae, perform joint replacement surgery, and treat bone destruction caused by underlying diseases such as rheumatoid arthritis. DBMs are thought to promote bone formation in vivo through osteoconduction and osteoinduction processes. The osteoinductive effect of implanted DBM compositions is believed to be caused by the presence of active growth factors present on a separated collagen-based matrix. These factors include members of the TGF-β, IGF, and BMP protein families. Specific examples of osteoinductive factors include TGF-β, IGF-1, IGF-2, BMP-2, BMP-7, parathyroid hormone (PTH), and angiogenic factors. Other osteoinductive factors, such as osteocalcin and osteopontin, may also be present in DBM formulations. Other unnamed or undiscovered osteoinductive factors may also be present in DBMs.

[0067] In various embodiments, the DBM provided in this application is prepared from elongated bone fibers that have undergone critical point drying (CPD). The elongated CPD bone fibers used in this application are typically characterized by a relatively high average length-to-width ratio, also known as aspect ratio. In various embodiments, the aspect ratio of the elongated bone fibers is at least about 50:1 to at least about 1000:1. Such elongated bone fibers can be readily obtained by any of several methods, such as by grinding or cutting the entire surface of the bone or a relatively large portion of the bone.

[0068] In other embodiments, the fiber length may be at least about 3.5 cm, and the average width may be from about 20 mm to about 1 cm. In various embodiments, the elongated fiber may have an average length of about 3.5 cm to about 6.0 cm and an average width of about 20 mm to about 1 cm. In other embodiments, the elongated fiber may have an average length of about 4.0 cm to about 6.0 cm and an average width of about 20 mm to about 1 cm.

[0069] In other embodiments, the diameter or average width of the elongated fibers is, for example, no greater than about 1.00 cm, no greater than 0.5 cm, or no greater than about 0.01 cm. In other embodiments, the diameter or average width of the fibers can be from about 0.01 cm to about 0.4 cm or from about 0.02 cm to about 0.3 cm.

[0070] In another embodiment, the aspect ratio of the fibers may be from about 50:1 to about 950:1, from about 50:1 to about 750:1, from about 50:1 to about 500:1, from about 50:1 to about 250:1; or from about 50:1 to about 100:1. The aspect ratio of the fibers according to this disclosure may be from about 50:1 to about 1000:1, from about 50:1 to about 950:1, from about 50:1 to about 750:1, from about 50:1 to about 600:1, from about 50:1 to about 350:1, from about 50:1 to about 200:1, from about 50:1 to about 100:1, or from about 50:1 to about 75:1.

[0071] In some embodiments, the fragment to fiber ratio is about 90:10, 80:20, 75:25, 70:30, 60:40, 50:50, 40:60, 30:70, 25:75, 20:80, and / or 10:90. In various embodiments, the fragment to fiber ratio of the surface-demineralized material is about 90:10, 80:20, 75:25, 70:30, 60:40, 50:50, 40:60, 30:70, 25:75, 20:80, and / or 10:90. In some embodiments, the fragment to fiber ratio of the surface-demineralized material is about 90:10, 80:20, 75:25, 70:30, 60:40, 50:50, 40:60, 30:70, 25:75, 20:80, and / or 10:90.

[0072] In some embodiments, the DBM fibers have a thickness of about 0.5-4 mm. In various embodiments, the thickness of the DBM fibers is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, and / or 4 mm. In various embodiments, the ratio of DBM fibers to DBM powder is about 40:60 to about 90:10 W / W, W / V, or V / V. In some embodiments, the ratio of mineralized bone fibers to DBM powder is about 25:75 to about 75:25 W / W, W / V, or V / V. In various embodiments, the bone implant comprises DBM fibers and mineralized fibers in a ratio of 40:60 to about 90:10 W / W, W / V, or V / V. In some embodiments, the DBM fiber to DBM powder ratio, the mineralized bone fiber to DBM powder ratio, and / or the DBM fiber to mineralized fiber ratio is about 5:95 to about 95:5 W / W, W / V, or V / V. In some embodiments, the ratio of DBM fiber to DBM powder, the ratio of mineralized bone fiber to DBM powder, and / or the ratio of DBM fiber to mineralized fiber is 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, and / or 95:5 (W / W, W / V, or V / V).

[0073] In some embodiments, the bone material includes demineralized bone material, comprising demineralized bone, fibers, powder, fragments, triangular prisms, spheres, cubes, cylinders, debris, or other shapes having irregular or random geometry. These may include, for example, “substantially demineralized,” “partially demineralized,” or “completely demineralized” cortical and / or cancellous bone. These also include surface demineralized material, wherein the surface of the bone construct is substantially demineralized, partially demineralized, or completely demineralized, while the bulk of the bone construct is fully mineralized.

[0074] In various embodiments, the bone material comprises fully demineralized DBM fibers and surface-demineralized bone fragments. In some embodiments, the ratio of fully demineralized DBM fibers to surface-demineralized bone fragments is from 5:95 to approximately 95:5 fiber-to-fragment ratio. In some embodiments, the ratio of fully demineralized DBM fibers to surface-demineralized bone fragments is 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, and / or 95:5 fiber-to-fragment ratio. In various embodiments, the fully demineralized DBM fibers have a thickness of approximately 0.5-4 mm. In various embodiments, the full DBM fibers have a thickness of approximately 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5 and / or 4 mm.

[0075] In various embodiments, the fibers and / or powder are surface DBM. In some embodiments, the fibers and / or powder are surface DBM cortical allografts. In various embodiments, the surface demineralization involves surface demineralization at least to a certain depth. For example, the surface demineralization of an allograft can be from about 0.25 mm, 0.5 mm, 1 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4 mm, 4.5 mm to about 5 mm. The edges of the bone fibers and / or powder can be further machined into any shape or include features such as grooves, protrusions, depressions, etc., to help improve fit and limit any movement or micromotion, thereby facilitating fusion and / or osteoinduction.

[0076] To prepare osteogenic bone matrix (DBM), a certain amount of fiber is combined with a biocompatible carrier to obtain demineralized bone matrix.

[0077] DBM is typically dried, for example by freeze-drying or solvent drying, to store and maintain it under viable conditions for implantation. Furthermore, each of these procedures is believed to reduce the overall surface area structure of bone. Understandably, structural damage to the outer surface reduces the overall surface area. These physical alterations to the surface and the reduction in surface area may affect cell connectivity, migration, proliferation, and differentiation. The surface's affinity for growth factors and the kinetics of growth factor release from the surface may also be altered.

[0078] Therefore, in some embodiments, methods are provided for drying bone to store and maintain it under viable conditions for implantation, wherein the implantation maintains or increases the surface area of ​​the bone. In one embodiment, critical point drying (CPD) technology is used to treat the bone matrix, thereby reducing damage to the bone surface. Although critical point drying has been specifically described, it should be understood that supercritical point treatment may be used in alternative embodiments. In various embodiments utilizing CPD, the percentage of collagen fibrils on the bone surface remains unchanged to about 15% or less of residual moisture content after drying. In some embodiments, the bone matrix has about 8% or less of residual moisture content after drying. In some embodiments, the bone matrix has about 6% or less of residual moisture content after drying. In some embodiments, the bone matrix has about 3% or less of residual moisture content after drying.

[0079] Evaporative drying and freeze-drying of samples can cause surface structure deformation and collapse, resulting in a decrease in surface area. It is not desirable to be bound by any particular theory, but it is thought that this deformation and structural collapse occurs because when a substance crosses the boundary from liquid to gas, the evaporation of that substance reduces the volume of the liquid. When this happens, the surface tension at the solid-liquid interface pulls on any structure to which the liquid is attached. This surface tension often causes the breakage of fine surface structures. This damage may be caused by the effect of surface tension on the liquid / gas interface. Critical point drying is a technique that avoids the effect of surface tension on the liquid / gas interface by essentially preventing the formation of a liquid / gas interface. Critical point or supercritical drying does not cross any phase boundary but passes through the supercritical region, where the distinction between gas and liquid no longer applies. Therefore, materials dehydrated using critical point drying are not subjected to destructive surface tension. When the critical point of a liquid is reached, it can transition from liquid to gas without a sudden change of state. Critical point drying can be used with bone matrix for phase transitions from liquid to dry gas without being affected by surface tension. Therefore, bone dehydrated using critical point drying can retain or increase at least some surface structure and thus increase surface area.

[0080] In some embodiments, carbon dioxide is used for critical point drying. However, other media, such as Freon, containing Freon 13 (chlorotrifluoromethane), can be used. Typically, fluids suitable for supercritical drying include carbon dioxide (critical point at 304.25 K at 7.39 MPa or 31.1 °C or 31.2 °C and 73.8 bar at 1072 psi) and Freon (about 300 K at 3.5–4 MPa or 25–30 °C at 500–600 psi). Nitrous oxide has similar physical behavior to carbon dioxide, but is a potent oxidant in its supercritical state. Supercritical water is also a powerful oxidant, partly because its critical point occurs at such high temperatures (374 °C) and pressures (3212 psi / 647 K and 22.064 MPa).

[0081] In some embodiments, bone may be pretreated to remove water before critical-point drying. Thus, according to one embodiment, the bone matrix is ​​dried using carbon dioxide at (or above) its critical-point state. After demineralization, the bone matrix sample (in water) can be dehydrated to remove residual water content. This dehydration can be achieved, for example, by using a series of gradient ethanol solutions (e.g., deionized water containing 20%, 50%, 70%, 80%, 90%, 95%, and 100% ethanol). In some embodiments, tissue permeation with a gradient series of ethanol solutions or alcohols can be automated. For example, pressure and vacuum can be used to accelerate permeation into the tissue.

[0082] In some embodiments, the bone material comprises demineralized bone matrix fibers and demineralized bone matrix fragments in a ratio of 30:60. In some embodiments, the bone material comprises demineralized bone matrix fibers and demineralized bone matrix fragments, wherein the fiber-to-fragment ratio is from 25:75 to about 75:25.

[0083] In some embodiments, the bone material may be an inorganic material, such as inorganic ceramics and / or bone substitutes. Exemplary inorganic materials or bone substitutes include, but are not limited to, aragonite, feldspar, calcite, perlite, amorphous calcium carbonate, aragonite, wedge stone, charophyllite, struvite, urate, ferrihydrite, cristobalite, gibbsite, magnetite, goethite, dentin, calcium carbonate, calcium sulfate, calcium phosphosilicate, sodium phosphate, calcium aluminate, calcium phosphate, hydroxyapatite, tricalcium α-phosphate, dicalcium phosphate, tricalcium β-phosphate, tetracalcium phosphate, amorphous calcium phosphate, octacalcium phosphate, and bioglas. TM Fluoroapatite, chloroapatite, magnesium-substituted tricalcium phosphate, carbonate hydroxyapatite, substituted forms of hydroxyapatite (e.g., bone-derived hydroxyapatite can be substituted with other ions, such as fluoride, chloride, magnesium, sodium, potassium, etc.), or combinations or derivatives thereof.

[0084] In some embodiments, the bone material may include mineral particles comprising tricalcium phosphate and hydroxyapatite in a ratio of about 80:20 to about 90:10. In some embodiments, the mineral particles may comprise tricalcium phosphate and hydroxyapatite in a ratio of about 70:30 to about 95:5. In some embodiments, the mineral particles may comprise tricalcium phosphate and hydroxyapatite in a ratio of about 85:15.

[0085] In some embodiments, when mixing bone material, it may be inoculated together with harvested osteocytes and / or bone tissue (e.g., cortical bone, autologous bone, allogeneic bone, and / or xenogeneic bone).

[0086] Suitable bone materials for use with the container of this application include, for example, Magnifort. TM Bone grafts, Grafton that can be used with DMB fibers TM DBM, powder, granules, gel, matrix, strip, putty or paste, these materials are available from Medtronic Sofamor Danek, Inc., located in Memphis, Tennessee, USA.

[0087] In some embodiments, the bone material may be mixed with one or more therapeutic agents (e.g., anti-inflammatory agents, analgesics, bone-inducing growth factors, antimicrobial agents, or combinations thereof). Bone inducers include one or more members of the bone morphogenetic protein (“BMP”) family. BMPs are a class of proteins believed to have bone-inducing or growth-promoting activity in endogenous bone tissue, or to function as procollagen precursors.

[0088] BMPs used as bone inducers comprise one or more of the following: BMP-1; BMP-2; BMP-3; BMP-4; BMP-5; BMP-6; BMP-7; BMP-8; BMP-9; BMP-10; BMP-11; BMP-12; BMP-13; BMP-15; BMP-16; BMP-17; or BMP-18; and any combination of one or more of these BMPs, comprising full-length BMPs or fragments thereof, or combinations thereof, or as polypeptides or polynucleotides encoding polypeptide fragments of all said BMPs. Isolated BMP bone inducers can be administered as polynucleotides, polypeptides, full-length proteins, or combinations thereof.

[0089] In fact, bone-inducing factors are recombinant human bone morphogenetic proteins (rhBMPs) because they are available in unlimited quantities and do not transmit infectious diseases. In some embodiments, the bone morphogenetic protein is rhBMP-2, rhBMP-4, rhBMP-7, or a heterodimer thereof. Recombinant BMP-2 can be used at concentrations from about 0.4 mg / mL to about 10.0 mg / mL, preferably about 1.5 mg / mL.

[0090] Bone material may contain one or more members of the TGF-β superfamily or a mixture thereof. For example, the matrix may contain AMH, ARTN, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDNF, INHA, INHBA, INHBB, INHBC, INHBE, LEFTY1, LEFTY2, MSTN, NODAL, NRTN, PSPN, TGFB1, TGFB2, TGFB3, FGF, basic FGF, VEGF, insulin-like growth factor, EGF, PDGF, nerve growth factor, or combinations thereof.

[0091] Bone materials may contain or be mixed with therapeutic agents, including but not limited to IL-1 inhibitors, such as... Anakinra, a recombinant non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra), or AMG108, is a monoclonal antibody that blocks the action of IL-1. Bone materials may contain or be mixed with therapeutic agents, said therapeutic agents containing excitatory amino acids such as glutamate and aspartate, antagonists or inhibitors of glutamate binding to NMDA receptors, AMPA receptors, and / or alginate receptors. Bone materials may contain or be mixed with therapeutic agents for reducing inflammation, said therapeutic agents including, but not limited to, interleukin-1 receptor antagonists, thalidomide (a TNF-α release inhibitor), thalidomide analogs (which reduce TNF-α production by macrophages), quinapril (an inhibitor of angiotensin II, which upregulates TNF-α), interferons such as IL-11 (which regulates TNF-α receptor expression), or rutin (which inhibits TNF-α).

[0092] Bone materials may contain or be mixed with therapeutic agents, including but not limited to analgesics. Examples of analgesics include, but are not limited to, acetaminophen, tramadol, lidocaine, bupercaine, ropivacaine, narcotic analgesics such as buprenorphine, butorphanol, dextromethorphan, dezocine, dextropropoxyphene, diacetylmorphine, fentanyl, alfentanyl, sufentanil, hydrocodone, hydromorphone, ketomidone, levomethalone, pethidine, methadone, morphine, nalbuphine, opium, oxycodone, total opium alkaloids, tebuconazole, pethidine, phenperidine, piperazine, dextropropoxyphene, remifentanil, sufentanil, teridine, tramadol, codeine, dihydrocodeine, mepitafen, dezocine, etazocine, flupirtine, or combinations thereof.

[0093] Bone materials may contain or be mixed with therapeutic agents, which may include, but are not limited to, anti-inflammatory agents. Examples of anti-inflammatory agents include, but are not limited to, clonidine, sulfasalazine, naloxone, diclofenac, indomethacin, ibuprofen, flurbiprofen, ketoprofen, alclofenac, aproxen, aspirin, diflunisal, fenprofen, mefenamic acid, naproxen, phenobarbital, piroxicam, meloxicam, salicylamide, salicylic acid, desobutyric acid, tenoxicam, ketoralac, clonidine, flufenamic acid, salicylylsalicylic acid, triethanolamine salicylate, aminopyrine, antipyrine, phenobarbital, apatone, septanazine, flufenamic acid, clonisherin, clonidine, meclofenamic acid, flunixin, colchicine, colchicine Allopurinol, hydroxypurinol, benzyladenine hydrochloride, dimethylfaden, dimethoxybenzylindole, indole-tetrazole, methylyohenane hydrochloride, hydroquinone hydrochloride, tetrahydromethylindamine, benzoindole-purine hydrochloride, fluprofen, isobutyric acid, naproxo, fenbufen, cinchophen, diflumidone sodium, phenamyl, flutetrazine, metazamide, ethylamine oxazinone hydrochloride, nesilidine hydrochloride, oltadamide, miconazole, neocinchophen, nimazole, propazoline citrate, texicam, tesimide, tometetin, trifluoroaminobutyrate, mefenamic acid esters (methanil, meclofenamic acid), nabumetone, celecoxib, etodoxic acid, nimesulide, azapromide, gold, teposarrin; dithiocarbamates or combinations thereof.

[0094] Anti-inflammatory agents also include steroids such as 21-acetoxypregnenolone, aclomethasone, dihydroxyprogesterone, ancinonide, beclomethasone, betamethasone, budesonide, chlorprednisolone, clobetasol, clobetasol, chlorpromazine, corticosteroids, cortisone, cortisol, divazoline, difflux, hydroxyprednisolone, dexamethasone, dexamethasone 21-acetate, dexamethasone 21-phosphate disodium salt, difluralasone, diflucolone, difluprednisolone, glycyrrhetinic acid, fluzacrocin, fludiclofenac, flumethylphenidate, flunisolone, fluocinolone acetate, fluocinolone acetate, flucodone, fluocinolone acetonide, fluocinolone acetonide, and fluocinolone acetonide. Miron, methylflurane acetate, fluprednisolone acetate, fluprednisolone, fluticasone propionate, formococcal, halcinonide, halometasone propionate, halometasone, bromoflurane acetate, hydrocortisone, hydrocortisone, chlorteprednisolone, horseprednisolone, methylprednisolone, methylprednisolone, mometasone furoate, peramisone, prednicarbamate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednisolone valerate, prednisolone, dimethylpropionyl ether, tecortisone, triamcinolone, triamcinolone, benztriamcinolone, hexamcinolone, or combinations thereof.

[0095] Bone materials may comprise or be mixed with therapeutic agents, including but not limited to statins. Examples of useful statins include, but are not limited to, atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin (see U.S. Patent No. 3,883,140, ​​the entire disclosure of which is incorporated herein by reference), velotasone (also known as synvinolin; see U.S. Patent Nos. 4,448,784 and 4,450,171, the entire disclosure of which is incorporated herein by reference), fluvastatin, lovastatin, rosuvastatin, and flulinstatin (Sandoz XU-62-320), davastatin (EP Application Publication No. 738510A2, the entire disclosure of which is incorporated herein by reference), eptastatin, pitavastatin, or pharmaceutically acceptable salts thereof, or combinations thereof. In various embodiments, a statin may comprise a mixture of (+)R and (-)-S enantiomers of the statin. In various embodiments, statins may comprise a 1:1 racemic mixture of statins.

[0096] In some embodiments, the bone material may contain an antimicrobial agent. In some embodiments, the antimicrobial agent may contain one or more of the following: triclosan, also known as 2,4,4'-trichloro-2'-hydroxydiphenyl ether; chlorhexidine and its salts, including chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, and chlorhexidine sulfate; silver and its salts, including silver acetate, silver benzoate, silver carbonate, silver citrate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, and silver sulfadiazine; polymyxins; tetracyclines; aminoglycosides, such as tobramycin and gentamicin; rifampin; bacitracin; neomycin; chloramphenicol; miconazole; quinolones, such as oxacrylic acid, norfloxacin, nalidixic acid, pefloxacin, enoxacin, and ciprofloxacin; penicillins, such as oxacillin and piperacillin; nonylphenyl alcohol ether; fusidic acid; cephalosporins; or combinations thereof.

[0097] Examples of antibacterial agents include (by way of illustration and not limitation) exepapalacil; sulfadiazine sodium; alemycin; alexicin; ammicillin; pivomefloxacin; amicillin; amlodipine; amlodipine mesylate; amikacin; amikacin sulfate; aminosalicylic acid; aminosalicylic acid sodium; amoxicillin; amphotericin; ampicillin; ampicillin sodium; apracillin sodium; apopramine; asparagine; astamicin sulfate; bacitracin; avopatin; azithromycin; azocillin; azocillin sodium; bacitracin hydrochloride; bacitracin; bacitracin salicylate; bacitracin zinc; calcium benzalkonium chloride; erythromycin B; betamethasone sulfate; bleomycin sulfate; biapenem; binimycin; benzylaminophen hydrochloride; dipyridoxine; butikacin; buprofen sulfate Carbadox; Carbenicillin sodium; Carbenicillin indimide sodium; Carbenicillin sodium; Carbenicillin potassium; Carrumonan sodium; Claminophen; Cefadroxil; Cefadroxil; Cefamandole sodium; Cefamandole ester sodium; Cefparo; Ceftracin; Ceffluzole sodium; Cefazolin; Cefazolin sodium; Cefadroxil; Cefdinir; Cefepime; Cefadroxil hydrochloride Fepepime; Cefotiam; Cefixime; Cefotaxime Hydrochloride; Cefmetazole; Cefmetazole Sodium; Cefnicillin Sodium; Cefazolin; Cefradazole; Cefradazole Sodium; Cefotiam; Cefotiam Sodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin Sodium; Cefimazole; Cefimazole Sodium; Cefpirome; Cefpirome Sodium; Cefpirome Hydrochloride; Cefpodoxime Propionate; Cefoxitin; Cefazolin; Cefsulfonamide sodium; Ceftazidime; Cefbuprofen; Cefazolin sodium; Ceftriaxone sodium; Cefuroxime; Cefuroxime axetil; Cefuroxime axetil pivote; Cefuroxime axetil sodium; Cyanobacterium sodium; Cephalexin; Cephalexin hydrochloride; Cefalexin; Ceftriaxone; Thiophene cephalosporin sodium; Cefepime sodium; Cephalexin; Cefradine; Citocycline hydrochloride; Acetylchloramphenicol; Chloramphenicol; Chloramphenicol palmitate; Chloramphenicol pantothenate; Chloramphenicol sodium succinate; Chlorhexidine phosphatidylcholine; Chloroxylenol; Chlortetracycline hydrogen sulfate; Chlortetracycline hydrochloride; Sinoxacin; Ciprofloxacin hydrochloride; Ciprofloxacin; Siroxam; Clarithromycin hydrochloride; Clindamycin hydrochloride; Clindamycin palmitate hydrochloride; Clindamycin phosphate; Clofazimine ; Benzyl benzoate, o-cloxacillin; o-cloxacillin sodium; Chlorhexidine, chloroquine; Polymyxin E, sodium methanesulfonate; Antimycin sulfate; Cumarmycin; Cumarmycin sodium, cyclopenicillin; Cycloserine; Dapoxetine; Dapterin; Datocin; Demeclocycline hydrochloride, norcycline; Denomycin; Diaminophen, veratridine; Dicloxacillin; Dicloxacillin sodium; Dihydrostreptomycin sulfate; Dithiopyridine; Dierythromycin; Doxycycline; Doxycycline calcium; Doxycycline phosphate complex; Doxycycline hydrochloride; Oxyfurantoin sodium; Enoxacin; Epilicicillin; Tetracycline hydrochloride; Erythromycin; Esterol; Erythromycin etoricoside; Erythromycin ethylsuccinate; Erythromycin lactobionate; Erythromycin propionate; Erythromycin stearate; Ethambutol hydrochloride; Ethionamide;Fleroxacin; Fluclochlorpenicillin; Flude-deuterium alanine; Flumethoprim; Fosfomycin; Fosfomycin tromethamine; Fumoxicillin; Furazolidone; Furazolidone tartrate; Fusidic acid sodium; Closporic acid; Ganciclovir and Ganciclovir sodium; Gentamicin sulfate; Gromonam; Bacitracin; Haloprothiolane; Hetacillin; Ketoamycin potassium; Hexocidine; Ibafloxacin; Imipenem; Isopamicin; Isoniazid; Josamycin; Kanamycin sulfate; Kitarimycin; Levofurantoin; Levophenoxypropylpenicillin potassium; Erythromycin; Lincomycin hydrochloride; Lomefloxacin hydrochloride; Lomefloxacin mesylate; Chloramphenicol; Sulfamilone; Meclocycline; Meclocycline sulfosalicylate; Megamycin dihydrogen phosphate; Mequidone; Meropenem Penem; Methoxytetracycline; Methoxytetracycline Hydrochloride; Urotropine; Urotropine Hippurate; Urotropine Mandelate; Methicillin; Meteprine; Metronidazole Hydrochloride; Metronidazole Phosphate; Meropenem; Meropenem Sodium; Dimethylaminetetracycline; Dimethylaminetetracycline Hydrochloride; Milincomycin Hydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium; Nafidic Acid; Nafidicin; Acetobacterium; Neomycin Palmitate; Neomycin Sulfate; Neomycin Undecenoate; Netilmicin Sulfate; Neutralmycin; Nifuiradene; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifiupirinol; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Nifuratel; Norfloxacin; Neomycin Sodium; Ofloxacin ;onnetoprim; benzyloxazole penicillin and benzyloxazole penicillin sodium; oximonam; oximonam sodium; oxaquinic acid; oxtetracycline; oxtetracycline calcium; oxytetracycline hydrochloride; pardemycin; p-chlorophenol; pyromycin; pefloxacin; pefloxacin mesylate; penicillin; penicillin, such as benzathine penicillin G, penicillin G potassium, procaine penicillin G, penicillin G sodium, penicillin V, benzathine penicillin V, penicillin V hydralazine and penicillin V potassium; pentazocolone sodium; phenyl aminosalicylate; piperacillin sodium; pyridamole penicillin sodium; pyridamole sodium; pirizine hydrochloride; pirizine hydrochloride; pirizine dihydroxynaphthyl pirizine; pirizine propionate; polymyxin B sulfate; methylmitomycin; pirizine; pyrazinamide; pyrithione Zinc sulfate; Quinidicarmine acetate; Quinupordine; Racemic thiamphenicol; Ramolane; Ranibizumab; Repromycin; Rifabutin; Rifametane; Rifaxix; Rifapentine; Rifaximin; Hydropyrrocycline; Roserocycline nitrate; Roserocycline; Roserocycline butyrate; Roserocycline propionate; Roserocycline sodium phosphate; Roserocycline stearate; Rosoxofacin; Arslane nitrohydroxybenzoate; Roxithromycin; Cyclocycline; Samoxicillin; Sapicillin; Hygromycin; Sisomicin; Sisomicin sodium; Sparfloxacin; Spectinomycin hydrochloride; Spiramycin; Tencelin hydrochloride; Statimycin; Streptomycin sulfate; Streptomycin isoniazid; Sulfaben; Sulfabenzoyl; Sulfaacetyl; Sulfaacetyl sodium; Sulfaxine; Sulfamethoxine;Sulfamethazine sodium; sulfadoxine; sulfadiazine; sulfamethoxazole; sulfamethoxazole; sulfamethoxypyrimidine; sulfaxazole; zinc ammoniasulfonate; sulfanilide; sulfasalazine; sulfasalazine; sulfisothiazide; sulfathiazole; sulfapyrazole; sulfapyrazole; sulfisoxazole; sulfaacetylisoxazole; sulfisoxazole diethanolamine; sulfosmectin; thiopenem; sultamicillin; sulfabenzylpenicillin sodium; phthalimicillin hydrochloride; teicoplanin; temasofacin hydrochloride Temoxicillin; Tetracycline; Tetracycline hydrochloride; Tetracycline phosphate; Tetraoxone; Thiamphenicol; Tifencillin potassium; Carboxythiazolinone toluene sodium; Ticarcillin sodium; Ticarcillin monosodium; Ticladone; Cialis chloride; Tobramycin; Tobramycin sulfate; Tobramycin taufloxacin; Trimethoprim; Trimethoprim-sulfamethoxazole; Triple sulfadiazine; Acetaminophen; Spectinomycin; Leuconazole; Vancomycin; Vancomycin hydrochloride; Vitamycin; Lamemycin; or combinations thereof.

[0098] Antimicrobial agents in bone materials can be antiviral agents that can be mixed with bone materials. Antiviral agents may include, but are not limited to, vidarabine, acyclovir, famciclovir, valacyclovir, gancyclovir, valganciclovir, nucleoside analog reverse transcriptase inhibitors (e.g., AZT (zidovudine), ddI (didanosine), ddC (zalcitabine), d4T (stavudine), and 3TC (lamivudine)), nevirapine (ne... virapine, delavirdine, protease inhibitors (such as saquinavir, ritonavir, indinavir, and nelfinavir), ribavirin, amantadine, rimantadine, neuraminidase inhibitors (such as zanamivir and oseltamivir), pleconaril, cidofovir, foscarnet, and / or interferon.

[0099] Container for mixing and / or dispensing bone materials

[0100] In some embodiments, a container for mixing bone material is provided, the container comprising, substantially comprising, or consisting of an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate the bone material on the inner surface of the container, and the proximal end of the outer surface having a port configured to receive fluid for mixing with the bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface from the container. In some embodiments, the manufacturer may provide a container pre-loaded with dry bone material, or dry bone material may be loaded therein during surgical procedures.

[0101] refer to Figures 1 to 11 A container 10 is provided for mixing and dispensing bone material 22 (e.g., bone graft). The container 10 has an inner surface 12 and an outer surface 14, the inner surface being configured to receive the bone material 22 thereon, and the outer surface having a distal end 16 and a proximal end 18. A locking member 20 is provided at the distal end 16 of the outer surface, and a port 26 is provided at the proximal end 18 of the outer surface 14.

[0102] In many respects, port 26 is configured to receive fluid 24 onto or from the inner surface 12 of container 10 for mixing bone material 22 and / or for dispensing bone material mixed with fluid 23. Port 26 includes a channel 28 having a proximal end 28a and a distal end 28b. In some embodiments, port 26 and / or channel 28 includes, at its proximal end, an inner diaphragm 30, an outer diaphragm 31, or a fitting 29, such as a Luer fitting configured to engage a syringe 50 having a plunger 52 and / or another fluid delivery device, such as... Figure 3 As shown. In other embodiments, port 26 may be removed from container 10, such as... Figure 4A As shown. At its distal end, channel 28 connects to neck 42 located at proximal end 18 of outer surface 14. In some aspects, proximal end 18a of container 10 includes neck 42.

[0103] like Figure 2 and Figure 4B As shown, when in the closed position, the locking member 20 encapsulates the bone material 22 onto the inner surface 12 of the container 10, and when in the open position, the locking member allows the bone material 22 to remain on the inner surface 12. The locking member 20 comprises, substantially by, a first locking member 20a disposed on the outer surface 14, a second corresponding locking member 20b disposed on the inner surface 12, and, in some respects, a sliding member 20c that allows a seal to be formed between the outer and inner surfaces of the container 10 when the corresponding locking members engage and / or when mixed with fluid present or subsequently added to the container, to prevent loss of dry bone material. The locking member 20 is resealable. Figure 2In the illustrated embodiment, the locking member 20 includes a hole 21 centrally disposed on the first locking member 20a and / or the second corresponding locking member 20b. For example, the hole 21 can be used to suspend the container 10 on the hook 54.

[0104] In some embodiments, the outer surface 14 includes a resting surface 32 disposed near the locking member 20, the resting surface being used to receive, rest, and / or measure bone material entering the inner surface 12 when the locking member 20 is in the open position. In other embodiments, the resting surface includes measuring marks 33 and a tear line 34 configured to tear the resting surface off the container 10.

[0105] In many respects, container 10 includes an upper layer 36 comprising an outer surface 14 and a lower layer 38 comprising an inner surface 12. The upper layer 36 can be progressively peeled away from the lower layer 38 in a direction toward the distal end 16 of container 10 to allow contact with bone material 22 and / or fluid 24 on the inner surface 12 of container 10. In some respects, the upper layer 36 and lower layer 38 have sidewalls 44 and 46 that form a peripheral seal 47 around container 10. In other respects, such as Figure 5 As shown, the upper layer 36 and the lower layer 38 have tear lines 40a and 40b, both adjacent to the port 26 and together forming tear line 40. In some embodiments, the port can be permanently removed by tearing along tear lines 40a and / or 40b to form an opening 48 in the container 10 for dispensing bone material and / or fluid from the opening.

[0106] Containers include non-porous, non-biodegradable, transparent, and / or impermeable materials. In some aspects, containers can be made of polymers such as linear high-density polyethylene (HDPE), branched low-density polyethylene (LDPE), ultra-high molecular weight polyethylene (UHMWPE), polyethylene terephthalate (PET), polyvinyl chloride (V or vinyl or PVC), polypropylene (PP), and polystyrene (PS). Laminated plastics can also be used as materials for the inner and / or outer surfaces of the containers described in this application. Laminated plastics are a special form of polymer-based composite material consisting of reinforcing material layers impregnated with thermosetting resins, bonded together, and cured under heat and pressure. Nonwoven materials made of high-density polyethylene fibers (e.g., Electrospun materials, formed by needle-punching, felting, dot bonding, spunbonding, or combinations thereof, can be used to prepare the inner and / or outer surfaces of containers. In various embodiments, the container comprises, is substantially composed of, or is composed of nonwoven materials or fabrics, which in some aspects may be sheet-like. In various aspects, the nonwoven material is a sheet, web, or wadding made of oriented or randomly oriented fibers bonded by friction and / or adhesion, excluding paper and woven, knitted, tufted, stitch-bonded, stitch-bonded yarns or filaments, or products made by wet-grinding felting, whether or not additionally needle-punched. The fibers may be natural or synthetic. In various embodiments, the materials used to manufacture the inner and outer surfaces of the container may be made of the same or different materials. In some embodiments, one surface may be made of a polymer, while the other surface may be made of metal foil. In other embodiments, the container material may have enough voids to allow the material encapsulated therein to be freeze-dried and / or sterilized.

[0107] The container is flexible. In some embodiments, the container is flexible enough to be kneaded by hand. In some embodiments, the outer and inner surfaces of the container are kneadable. In some embodiments, the container may be made of a material with a diameter of approximately 1 × 10⁻⁶ mm. 2 Approximately 6×10 5 dynes / cm 2 , or 2×10 4 Approximately 5×10 5 dynes / cm 2 , or 5×10 4 Approximately 5×10 5 dynes / cm 2 The container is made of a material with an elastic modulus of approximately 3.15 × 10⁻⁶. In some embodiments, the container may be made of polyethylene terephthalate (PET) and has an elastic modulus of approximately 3.15 × 10⁻⁶. 8 dynes / cm 2 The elastic modulus. In some embodiments, the container is flexible when kneaded by hand. In some embodiments, the container is resistant to stretching.

[0108] In some embodiments, the components of the container may be manufactured from biologically acceptable materials suitable for medical applications, including metals, synthetic polymers, ceramics, and / or composites thereof. For example, the components of the container may be manufactured individually or collectively from materials such as: stainless steel alloys, commercially pure titanium, titanium alloys, grade 5 titanium, superelastic titanium alloys, cobalt-chromium alloys, stainless steel alloys, superelastic metal alloys (e.g., nickel-titanium), and superelastic-plastic metals, such as GUM manufactured by Toyota Material Incorporated of Japan. ), ceramics and their composites such as calcium phosphate (e.g., SKELITE manufactured by Biologix Inc., USA). TM Thermoplastics such as polyaryletherketone (PAEK), including polyetheretherketone (PEEK), polyetherketoneketone (PEKK) and polyetherketone (PEK), carbon-PEEK composites, PEEK-BaSO4 polymer rubber, polyethylene terephthalate (PET), fabrics, silicone, polyurethane, silicone-polyurethane copolymers, polymer rubber, polyolefin rubber, hydrogels, semi-rigid and rigid materials, elastomers, rubber, thermoplastic elastomers, thermosetting elastomers, elastomer composites, and rigid polymers including polyphenylene, polyamide, polyimide, polyetherimide, polyethylene, epoxy resins or any combination thereof.

[0109] In some embodiments, container 10 may be made of shape-memory polymers and / or alloys to allow container 10 to move from an unfolded configuration to a folded configuration without the need for a locking mechanism. In some embodiments, shape-memory materials (such as shape-memory polymers or alloys) may be used on the inner and outer surfaces of container 10. Shape-memory polymers include, but are not limited to, polyethers, polyacrylates, polyamides, polysiloxanes, polyurethanes, polyetheramides, polyurethane / urea, polyether esters, polynorbornene, crosslinked polymers (e.g., crosslinked polyethylene and crosslinked poly(cyclooctene)), inorganic-organic hybrid polymers, and copolymers such as urethane / butadiene copolymers and styrene-butadiene copolymers. Shape-memory alloys include, but are not limited to, TiNi, CuZnAl, and FeNiAl alloys. In some embodiments, container 10 may be manufactured by injection molding of plastic materials (including rigid, surgical-grade plastics) and / or metal materials.

[0110] The container can also be manufactured using additive manufacturing methods (e.g., 3D printing). In some embodiments, components of the container (such as the inner and outer surfaces of the container) can be made of impermeable yarns of monofilament or multifilament, and the yarns can be knitted, braided, non-woven shape memory, felted, dot-bonded, additively manufactured (e.g., 3D printed), or a combination thereof.

[0111] In some embodiments, fluid 24 may be glycerol, blood, bone marrow aspirate, mesenchymal stem cells, sterile water, dextran, other sugars including but not limited to sucrose, fructose, dextran, lactated Ringer's solution, polyols including but not limited to mannitol, xylitol, sorbitol, maltitol, lactitol, polysaccharides including but not limited to natural or pregelatinized starch, maltodextrin, cyclodextrin, inorganic compounds including but not limited to dihydrate or anhydrous dicalcium phosphate or tricalcium phosphate, cellulose derivatives including but not limited to microcrystalline cellulose, lactose monohydrate or anhydrous lactose, and mixtures thereof, such as dicalcium phosphate dihydrate, mannitol, pregelatinized corn starch, microcrystalline cellulose and mixtures thereof, water and / or NaCl (saline). In some embodiments, the saline is 0.90% saline, 0.45% saline, or phosphate-buffered saline. In some embodiments, other fluids may be used, such as D5W (5% dextrose aqueous solution), D5NS (5% dextrose aqueous solution and physiological saline), and D5W / 1 / 2NS (D5W and 1 / 2 physiological saline), lactated Ringer's solution, etc. In other embodiments, the fluids include bone marrow aspirate, saline, sterile water, blood for injection, phosphate-buffered saline, dextrose, Ringer's lactate solution, or combinations thereof.

[0112] Figures 4A to 7 This is a representative illustration of container 10 in use. For example, Figure 4A Bone material 22 is shown placed on a resting surface 32 near the locking member 20. The locking member 20 can be opened by the sliding member 20c to access the inner surface 12, so that the bone material 22 can be placed on the inner surface 12 for mixing with the fluid 24 that can be added through the port 26. Figure 4B The bone material 22 has been advanced onto the inner surface 12. Once inside the container 10, the locking member 20 can be closed and the bone material 22 can be manually mixed with the fluid 24. In various embodiments, the container 10 includes flexible sidewalls 44 and 46, configured to allow manual mixing of the fluid 24 and bone material 22 on the inner surface 12 by pressure applied by hand. The fluid 24 can be added through port 26, which in some respects is configured to receive a syringe 50 with a plunger 52 to deliver fluid to the container 10, or for precisely dispensing bone material from the container 10, for example, at a surgical site.

[0113] In some embodiments, such as Figure 5 As shown, container 10 includes an upper layer 36 having an outer surface 14 and a lower layer 38 having an inner surface 12. Bone material and / or fluid can be obtained by gradually or completely peeling off the upper layer 36 including the outer surface 14 in a direction toward the distal end of container 10.

[0114] In other embodiments, such as Figure 6A and Figure 6BAs shown, the port can be removed and an opening 48 formed by the neck 42 can be created by peeling away the upper and / or lower layers from the container 10 at tear lines 40a and / or 40b provided near the port 26. Similarly, as... Figure 6B As shown, the placement surface 32 can also be removed by tearing along the tear line 34. In various embodiments, such as Figure 7 As shown, after the bone material 22 is mixed with the fluid 24, the mixed bone material and fluid 23 can be extruded from the container 10 through the opening 48 by rolling the distal end 16a of the container 10 toward the proximal end 18a of the container 10. The distal end of the container is configured to roll toward the proximal end of the container to dispense bone material and / or fluid from the container. In many embodiments, the container 10 may be covered by additional coverings, a second or even a third covering (not shown) that can be peeled off from the container. Such additional coverings can be used to maintain the sterility of the container 10 and / or prevent oxidation of materials that may be present on the inner surface of the container 10. However, in some embodiments, the provided container may be empty, without any material (including bone material), which may be provided separately at the surgical site.

[0115] In some embodiments, the container is multifunctional and allows for long-term safe storage and containment of bone material, easy and safe addition and / or removal of fluids to the bone material, easy observation and manual mixing of the bone material, easy addition of bone material via a resealable container and integrated resting surface (e.g., a tongue-shaped landing pad / funnel / resting feature), precise dispensing via a built-in port, and / or batch entry via a peelable locking surface. The container may include measuring features.

[0116] In some embodiments, the container allows for the storage, removal, or addition of fluids and the manipulation of bone material within a closed system, which can reduce bioburden contamination and / or the possibility of the bone material drying out before use.

[0117] In various embodiments, a kit including a bone material container is provided. The kit may include additional components as well as the bone material container, which contains bone material and other components for administering the bone material (e.g., scrapers, wiping cloths, needles, syringes, delivery cannulas, other mixing devices, etc.). The delivery cannulas may be designed to connect or dock with other delivery systems and / or to connect directly to the container, allowing precise dispensing of the bone graft via built-in ports or fittings. The kit may include bone material in a first compartment. A second compartment may include vials containing a fluid carrier and any other instruments required for delivery. A third compartment may include gloves, drapes, wound dressings, and other surgical supplies for maintaining sterility during the implantation process, as well as instructions that may include diagrams showing how to administer the bone material after mixing. A fourth compartment may include additional needles and / or sutures. Each tool may be individually packaged in a sterilized plastic pouch. A fifth compartment may include medication for radiographic imaging. The kit's lid may include diagrams of the relevant surgical procedure, and transparent plastic caps may be placed over the compartments to maintain sterility.

[0118] In various embodiments, one or more components of the bone material container are sterilized by radiation in a final sterilization step during final packaging. This provides a higher level of sterility assurance for the final product sterilization compared to processes that require individual product components to be sterilized separately and then assembled into the final package in a sterile environment, such as aseptic processes.

[0119] In various embodiments, gamma radiation is used in the final sterilization step, which involves utilizing the ionizing energy from gamma rays that penetrate deeply into the bone material container. Gamma rays efficiently kill microorganisms, leaving no residue, and do not have sufficient energy to make the container radioactive. Gamma rays can be used when the container is in packaging, and gamma sterilization does not require high pressure or vacuum conditions, so the packaging seals and other components are not subjected to stress. In addition, gamma radiation eliminates the need for permeable packaging materials.

[0120] In various embodiments, electron beam (e-beam) radiation can be used to sterilize one or more components of a container used for mixing bone materials. E-beam radiation comprises the form of ionizing energy characterized by low penetration and high dose rate. E-beam radiation is similar to gamma treatment because it alters various chemical and molecular bonds upon contact, including those of the reproductive cells of microorganisms. The resulting beam for e-beam sterilization is a concentrated, large stream of charged electrons generated by electrical acceleration and conversion.

[0121] In various embodiments, gamma radiation, e-beam radiation, steam, or gas is used to pre-sterilize the container in a clean and controlled environment before aseptically filling it with bone material, thereby producing a sterile finished device that does not require final sterilization of the bone material in the final packaging.

[0122] Other methods may also be used to sterilize containers used for mixing bone materials, including, but not limited to, gas sterilization such as ethylene oxide or steam sterilization.

[0123] How to use

[0124] A method is provided for mixing bone material 22 into a container 10. The method includes: providing a container for mixing the bone material, the container including an inner surface for receiving the bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate the bone material on the inner surface of the container, the proximal end having a port configured to receive fluid to mix with the bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container; opening the locking member and adding bone material to the inner surface of the container; closing the locking member to encapsulate the bone material on the inner surface of the container; and adding fluid to the container by allowing fluid through the port of the container. In various aspects, the container has a resting surface to facilitate adding bone material to the container and / or measuring the bone material added to the container. In many embodiments, the bone material includes ceramics, collagen, allogeneic bone, autologous bone, demineralized bone matrix fibers, demineralized bone powder, demineralized bone fragments, or combinations thereof.

[0125] Bone materials may contain excipients such as mannitol, alginate, sodium or potassium phosphate, citric acid, tartaric acid, gelatin, glycine, lactose, sucrose, maltose, glycerol, dextrose, dextran, trehalose, hydroxyethyl starch, ascorbic acid, acetylcysteine, cysteine, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, or α-tocopherol acetate and / or chelating agents.

[0126] In some embodiments, the bone material is relatively dry and also includes a drying excipient that can be hydrated or mixed with a liquid during surgery. Some examples of drying excipients include, for example, starch, alginate, collagen, gelatin, chitosan, xanthan gum, cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, talc, magnesium stearate, glyceryl behenate, stearic acid, and / or titanium dioxide.

[0127] Bone material can be pre-loaded into the container in a relatively dry state, and then mixed with liquid material and optional therapeutic agents using a spatula when the locking mechanism is open, or manually kneaded in the container until the desired consistency of the bone material (e.g., putty, paste, etc.) is achieved when the locking mechanism is closed. The pre-loaded bone material can be relatively moist before being mixed with liquid. The bone material can be mixed with a suitable diluent outside the container and then loaded into the container via the locking mechanism. In some embodiments, the diluent comprises dextrose, other sugars including but not limited to sucrose, fructose, glucose, lactated Ringer's solution, polyols including but not limited to mannitol, xylitol, glycerol, sorbitol, maltitol, lactitol, polysaccharides including but not limited to natural or pregelatinized starch, maltodextrin, cyclodextrin, inorganic compounds including but not limited to dihydrate or anhydrous dicalcium phosphate or tricalcium phosphate, cellulose derivatives including but not limited to microcrystalline cellulose, lactose monohydrate or anhydrous lactose, and mixtures thereof, such as dicalcium phosphate dihydrate, mannitol, pregelatinized corn starch, microcrystalline cellulose and mixtures thereof, water and / or NaCl (saline). In some embodiments, the saline is 0.90% saline or 0.45% saline. In some embodiments, other delivery media may be used, such as D5W (5% dextrose aqueous solution), D5NS (5% dextrose aqueous solution and physiological saline), and D5W / 1 / 2NS (D5W and 1 / 2 physiological saline), blood, mesenchymal stem cells, etc.

[0128] In some embodiments, the method further includes removing the resting surface from the container and / or removing the port from the container by removing an upper layer including an outer surface and / or a lower layer including an inner surface. In other embodiments, the method of mixing bone material includes partially or completely peeling the upper layer from the lower layer in a direction toward the distal end of the container to allow contact with any bone and / or fluid on the inner surface of the container. In other embodiments, the method of mixing bone material includes rolling the distal end of the container toward the proximal end of the container to dispense bone material and / or fluid from the container. In still other embodiments, the method of mixing bone material includes removing the port by peeling the upper and / or lower layers along a tear line adjacent to the port.

[0129] Containers for mixing bone material can be used to treat a wide range of conditions, including osteoporosis, fracture repair or healing, dental procedures with clinical benefits in increasing bone formation in the jaw, repair of craniofacial bone defects induced by trauma or congenital defects (such as cleft palate / lip), and many other musculoskeletal conditions with insufficient natural bone growth, as will be readily apparent to those skilled in the art. Bone material can be administered to treat open fractures and fractures at high risk of nonunion, and to individuals with spinal conditions, including those requiring spinal fusion (e.g., anterior lumbar intervertebral body fusion, posterior lumbar vertebral fusion, and cervical fusion) or those with degenerative disc disease or arthritis affecting the lumbar and cervical spine.

[0130] Container with a head section

[0131] refer to Figure 8-11 In some embodiments, the distal end of the container has a head portion comprising a porous material that may be present on the outer surface, inner surface, or both of the outer and inner surfaces of the container adjacent to the central locking member 62. The head portion 68 has more pores than the non-porous top surface 87 and non-porous bottom surface 88 of the proximal outer surface of the container. The head portion allows for permeability (e.g., permeability) within the container and allows for drying (e.g., freeze-drying, lyophilization, critical point drying, etc.) and / or sterilization of the bone material 22 placed on the inner surface of the container without requiring transfer of the bone material to a separate drying and / or sterilization container. The head portion also avoids the need to transfer the bone material to a separate cleanroom. Containers with porous head portions provide an efficient means of drying and / or sterilizing bone material placed within the container.

[0132] The porous head section incorporates breathable material, which allows for the drying and / or gas sterilization of the loaded bone material within the same container. This head section also reduces transport stress on the container in the event of environmental stress and / or temperature fluctuations.

[0133] In this document, the term "breathable material" refers to a permeable material through which air, vapor, and / or moisture can be simultaneously filtered out contaminating particles (e.g., bacteria, viruses, fungi, spores, etc.) and prevented from passing through and contaminating the bone material. The breathable material can possess sufficient filtration performance to ensure that the purity of the bone material loaded in the container is not compromised. Therefore, in some embodiments, the porous head can act as a microbial barrier and prevent unnecessary expansion of the container.

[0134] Suitable porous materials for the head portion include, but are not limited to, polyethylene (PE), polyethylene terephthalate (PET), high-density polyethylene (HDPE), polyvinyl chloride (PVC), low-density polyethylene (LDPE), polypropylene (PP), polystyrene, polytetrafluoroethylene (PTFE), polycarbonate, polylactide, acrylic acid, acrylonitrile butadiene, styrene, glass fiber, nylon, polyolefins, or combinations thereof. The porous head portion may be a sheet, layer, or film disposed at the top of the container to form a porous top surface 84, at the bottom of the container to form a porous bottom surface 86, or simultaneously at the top and bottom of the container. In some embodiments, the sheet, layer, or film of the porous top surface 84 may be longitudinally joined to the porous bottom surface 86 of the head portion to form a first seal 70 and a second seal 72, such that the bone material does not fall out from the sides of the container during loading, drying, and / or sterilization of the bone material within the container.

[0135] In some embodiments, the porous head portion may be made of fibers ranging in size from about 0.5 μm to about 10 μm and may have pore sizes ranging from about 25 μm to about 150 μm or from about 0.5 μm to about 100 μm, having more pores than the pores on the non-porous sheet, layer or membrane of the non-porous top surface 87 or the non-porous bottom surface 88 of the container.

[0136] The porous head portion can have any shape, size, or location on the container. The head portion can be attached to the non-porous surface of the container, the upper layer 36, and / or the lower layer 38 of the outer surface of the container. Figure 8-11 In the illustrated embodiment, the head portion includes an opening 74 through which bone material 22 can be inserted into the inner surface of a container (e.g., a bag). The head portion can be attached to the outer surface 14 of the container's outer surface at a non-porous top surface 87 and / or a non-porous bottom surface 88 by means of, for example, heat sealing, adhesive, etc. However, it should be understood that the head portion can be attached to other surfaces of the container. In some embodiments, the head portion is attached to the container adjacent to the central locking member 62.

[0137] In some embodiments, the porous head portion may comprise approximately 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%, 55%, 60%, 65%, 70% to approximately 75% of the total surface area of ​​the container. This may depend on the amount of bone material added to the container and the size of the required mixing space for the bone material.

[0138] In some embodiments, the head portion 68, including the porous top surface 84 and / or the porous bottom surface 86, may be made of a porous material, such as that produced by DuPont. LyondellBasell produces Petroleum olefins; ExxonMobil TM Paxon TM Pax-Plus TM Chevron Phillips Chemical Company produces Nova Chemical Company produces Gore's products, etc.

[0139] For example, It is a 100% synthetic material made of high-density spunbond polyethylene fibers. It is lightweight, durable and breathable, but also waterproof, abrasion-resistant, antibacterial, and anti-aging. It is breathable, but prevents bacteria and dust from getting in. An advantageous material because it provides a sufficient barrier to prevent contamination of the bone material loaded in the container, while also because... It is a breathable material, thus preventing container expansion. Its porous fibrous structure allows gases and vapors used in sterilization / freeze-drying to pass through, while still providing a good microbial barrier. In some embodiments, the head portion... It can be heat-sealed, glued or overmolded to the non-porous top surface 87 and / or non-porous bottom surface 88 of the container.

[0140] In some embodiments, the container may be sterilized by irradiation (e.g., gamma irradiation) before use. Bone material may be aseptically placed into the sterile container at opening 74. Bone material that may be added to the container at opening 74 in the head portion 68 located at the distal end of the container allows for sealing, closing, or partially closing of the opening within the inner surface of the container.

[0141] In some embodiments, those skilled in the art will understand that the central opening 60 will be closed by the central locking member 62, such that bone material can only be loaded into the opening 74 of the head portion.

[0142] Bone material 22 may be moistened due to prior acid demineralization, buffering, degreasing, sterilization, and / or water treatment processes, or it may be dry. Moist or dry bone material can be placed in a container through the opening 74 of the porous head portion. The opening 74 of the head portion can then be aseptically sealed, for example by heat, light, or adhesive, to form a first barrier seal 76, thereby encapsulating the moist, wet, or dry bone material 22 in a container such as Figure 9 The inner surface of the container shown. In subsequent processing steps, the sealed bone material is protected from microbial contamination. It should be understood that when the seal is applied to form the first barrier seal 76, the bone material 22 loaded in the container (e.g., bag) may be retained within the porous head portion, non-porous portion, or both of the container.

[0143] like Figure 9 As shown, bone material 22 is located in the porous head portion and the non-porous portion of the container. Since the porous head portion of the container is now sealed, the bone material can now be further processed, including freeze-drying or lyophilization and / or sterilization. The container loaded with bone material does not need to be transferred to a separate drying and / or sterilization container. The head portion also avoids the need to transfer the bone material to a separate cleanroom. However, the container containing bone material can be easily transferred to a separate space, which reduces the risk of contaminants entering the container.

[0144] After the first barrier seal 76 is applied to the container, the bone material (e.g., wet, damp, or dry) loaded in the container with the head portion can be freeze-dried or lyophilized and / or sterilized. Typically, freeze-drying or lyophilizing of bone material involves drying the frozen bone material under very low pressure (e.g., in a high vacuum) so that the ice or another freezing solvent rapidly sublimates without melting.

[0145] like Figure 9 The container shown, having a head portion containing sealed bone material, can be placed in a freeze-drying chamber within a certain temperature range, and then subjected to temperatures well below the freezing point of the bone material, typically for several hours. In some embodiments, the temperature may be maintained at or below about -40°C for at least 2 hours. In some embodiments, after freezing, the freeze-drying chamber and condenser, whose surfaces have previously been cooled by circulating refrigerant, are evacuated by a vacuum pump. The condenser will be cooled to about -40°C below the freezing point of the bone material, in some cases to about -50°C or lower, and in others to about -60°C or lower. Furthermore, evacuation of the chamber should continue until a pressure of about 50 to about 600 mTorr is achieved, and in some cases, a pressure of about 50 to about 150 mTorr is achieved.

[0146] In some embodiments, the freeze-dried bone material can be heated under vacuum in a chamber and condenser. This is typically done by heating the racks within the freeze dryer at a pressure of approximately 50 to approximately 600 mTorr. Ideally, the heating process will proceed very slowly over several hours. For example, the temperature can initially be raised from approximately -30°C to approximately -10°C and maintained for approximately 10–70 hours. Furthermore, the freeze-dried bone material can be raised from its freezing temperature to approximately 25°C to -40°C over 30–192 hours. Complete drying can be achieved by stabilizing the vacuum, condenser temperature, and freeze-dried bone material rack temperature. After initial drying, the temperature of the freeze-dried bone material can be raised to approximately 25°C to -40°C and maintained for approximately 5–40 hours. Once the drying cycle is complete, the pressure in the chamber can be slowly released to atmospheric pressure (or slightly below atmospheric pressure) using sterile, dry nitrogen (or an equivalent gas).

[0147] In some embodiments, after freeze-drying, the bone material is about 95% to about 99.5% free of moisture. In various embodiments, the bone material is about 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99% to about 99.5% free of moisture. In some embodiments, the bone material has a moisture content of about 0.5% to about 5% after freeze-drying. In various embodiments, the bone material has a moisture content of about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% to about 5% after freeze-drying. The freeze-dried bone material is stable and can be stored over a wide temperature range. The freeze-dried bone material can be stored at or below 30°C, for example, refrigerated at 4°C, or stored at room temperature (e.g., about 25°C).

[0148] After freeze-drying, lyophilization, or sterilization, and the application of a seal (e.g., heat sealing, adhesive, Ziploc sealed plastic bag, etc.) to form a first barrier seal 76 on the container and encapsulating the bone material inside the container, the container can be aseptically sealed (e.g., heat sealing, adhesive, Ziploc sealed plastic bag, etc.) to form a barrier seal 76. Figure 10 The second barrier seal 78 shown, in some embodiments, may be part of a non-porous portion to enclose the dried and / or sterilized bone material 22 within the inner surface of the container. The second barrier seal 78 extends horizontally along the container from the first barrier edge 80 to the second barrier edge 82 and serves as a moisture barrier to prevent moisture and / or other contaminants from entering the container interior, which could degrade the stability and purity of the packaged bone material. Like the first barrier seal, the second barrier seal 78 is applied above the location of the loaded bone material. In some embodiments, the bone material may be placed in the container by hand or machine.

[0149] When the second barrier seal 78 is applied to the container, a tear element 89 is formed, or can be formed separately, such that the head can be torn along the tear element 89. It should be understood that the second barrier seal 78 can be applied at the intersection of the porous head portion and the non-porous portion of the container, and the tear element 89 allows the head portion to be torn off by hand, scissors, or machine, leaving the rest of the container non-porous.

[0150] like Figure 11 As shown, the head portion is being torn off from the rest of the container; the head portion can be discarded or recycled. Figure 11In this container, freeze-dried, lyophilized, and / or sterilized bone material is encapsulated and provides a stable bone material. The outer surface 14 of the container, having a non-porous top surface 87, may include a central locking member 62 that extends horizontally from a first side 64 to a second side 66 along a portion of the container and has a central opening 60 that can be opened and closed by the central locking member to allow more bone material and / or other additives to be added to the container, and the central locking member is closed by sealing it (e.g., like a Ziploc sealed plastic bag). Typically, the central locking member 62 is locked or closed before the bone material is dried, lyophilized, and / or sterilized. After the bone material has been dried, lyophilized, and / or sterilized, the head portion is removed, such as... Figure 11 As shown. The central locking member or locking element can be a Ziploc seal, a friction-fit seal, a two-part strip, and / or an interlocking groove and ridge that forms a tight seal when pressed together. This will close the central opening 60.

[0151] Additives that can be added to bone materials include, but are not limited to, physiologically acceptable water, saline, sodium chloride, dextrose, Ringer's lactate solution, phosphate-buffered saline (PBS), blood, bone marrow aspirate, bone marrow components, or combinations thereof.

[0152] Once the bone material is encapsulated in a container, it can be mixed with the different additives described above and removed from the container, in some embodiments, from port 26. It should be understood that the container may be transparent, thereby allowing the user to observe the loading, freeze-drying, sterilization, mixing, and / or removal of the bone material.

[0153] It should be understood that the non-porous surfaces or layers on the outer surface of the container (e.g., upper layer 36, lower layer 38, non-porous top surface 87 and / or non-porous bottom surface 88) have fewer pores than the porous head portion. Therefore, the pore diameter of the non-porous surfaces or layers on the outer surface of the container is smaller than the pore diameter of the head portion of the outer surface of the container.

[0154] In some respects, nonporous surfaces and layers can be made of polymers such as linear high-density polyethylene (HDPE), branched low-density polyethylene (LDPE), ultra-high molecular weight polyethylene (UHMWPE), polyethylene terephthalate (PET), polyvinyl chloride (V or vinyl or PVC), polypropylene (PP), polystyrene (PS), laminated plastics, or combinations thereof.

[0155] In some embodiments, there is a container for mixing bone material, the container including an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a head portion having an opening configured to allow loading of bone material onto the inner surface of the container; the head portion being disposed adjacent to a locking member which is also disposed on the outer surface of the container; the head portion having more holes than the proximal end; the proximal end of the outer surface having a port configured to receive fluid to mix with bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface from the container.

[0156] In some embodiments, the container includes wet or dry bone material in its inner surface, and the head portion has more holes than the rest of the container and includes a first seal that encapsulates the bone material within the container.

[0157] In some embodiments, the container includes a wet or dry bone material on its inner surface, the second seal is spaced apart from the first seal, and the head portion is porous relative to the rest of the container. In some embodiments, the head portion is configured to be removed from the rest of the container after the second seal has been applied to the container.

[0158] In some embodiments, there is a method of encapsulating bone material in a container, the method comprising providing a container for adding bone material, the container including an inner surface for receiving bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a head portion having an opening configured to allow bone material to be added to the inner surface of the container, the head portion being disposed adjacent to and the locking member also being disposed on the outer surface of the container, the head portion having more holes than the proximal end, the proximal end of the outer surface having a port configured to receive fluid for mixing with bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container; adding the bone material to the inner surface of the container through the opening of the head portion; and sealing the container to encapsulate the bone material in the container.

[0159] In some embodiments, the sealed container containing bone material is dried and / or sterilized. In some embodiments, a second seal is applied to the container to seal the dried and / or sterilized bone material within the inner surface of the container. In some embodiments, the head portion is configured to be removed from the remainder of the container after the second seal is applied.

[0160] Although the invention has been described with reference to embodiments, those skilled in the art will recognize that changes in form and detail may be made without departing from the spirit and scope of this disclosure.

Claims

1. A container for mixing bone material, the container comprising an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate the bone material on the inner surface of the container, the proximal end of the outer surface having a port configured to receive fluid for mixing with the bone material on the inner surface of the container or to remove the bone material mixed with fluid on the inner surface of the container from the container. in, The outer surface also includes a resting surface adjacent to the locking member to receive and measure the bone material when the locking member is in the open position, so that the bone material enters the inner surface.

2. The container of claim 1, wherein the port includes a channel to allow fluid to enter or exit the inner surface of the container.

3. The container of claim 2, wherein (i) the port and / or channel has a diaphragm to allow fluid to enter or exit the inner surface of the container; (ii) the port has an accessory configured to engage a syringe; or (iii) the port and / or channel is removable from the container.

4. The container of claim 1, wherein the locking member (i) encapsulates the bone material onto the inner surface of the container when in the closed position and allows the bone material to enter the inner surface of the container when in the open position; (ii) includes a first locking member disposed on the outer surface and a corresponding locking member disposed on the inner surface, to allow a seal to be formed between the outer surface and the inner surface when the respective locking members are engaged, so as to prevent loss of the bone material or fluid mixed with the bone material from the container; (iii) Can be resealed.

5. The container of claim 1, wherein the resting surface includes a tear line configured for removing the resting surface from the container.

6. The container of claim 1, comprising an upper layer having the outer surface and a lower layer having the inner surface.

7. The container of claim 6, wherein (i) the upper layer is peelable from the lower layer and peelable in a direction toward the distal end of the container to allow contact with any bone material and / or fluid on the inner surface of the container; (ii) the upper and lower layers have sidewalls forming a peripheral seal around the container; or (iii) the upper and lower layers have a tear line adjacent to the port, the tear line being configured to allow permanent removal of the port to form an opening in the container for dispensing bone material and / or fluid from the opening.

8. The container according to claim 1, wherein (i) the bone material comprises a non-porous material, a transparent and / or impermeable material; or (ii) ceramic, collagen, allogeneic bone, autologous bone, demineralized bone matrix fibers, demineralized bone powder, demineralized bone fragments, or a combination thereof.

9. The container of claim 2, wherein the fluid comprises bone marrow aspirate, saline, sterile water, blood for injection, phosphate-buffered saline, dextran, Ringer's lactate solution, or combinations thereof.

10. The container of claim 1, wherein (i) the proximal end of the container includes a neck; or (ii) the distal end of the container is configured to roll and / or squeeze toward the proximal end of the container to dispense bone material and / or fluid from the container.

11. The container of claim 8, wherein the container includes flexible sidewalls configured to allow manual mixing of the fluid and the bone material on the inner surface by pressure applied by hand.

12. The container of claim 1, wherein the port is configured to receive a syringe for adding fluid to or precisely dispensing bone material from the container.

13. A method for mixing bone materials, the method comprising: A container for mixing bone material is provided, the container including an inner surface for receiving bone material thereon and an outer surface having a distal end and a proximal end, the distal end including a locking member configured to encapsulate the bone material on the inner surface of the container, the proximal end having a port configured to receive fluid to mix with the bone material on the inner surface of the container or to remove bone material mixed with fluid on the inner surface of the container from the container. Open the locking member and add the bone material to the inner surface of the container; Close the locking member to encapsulate the bone material on the inner surface of the container; And fluid is added to the container by allowing fluid to pass through the port of the container, wherein the container also includes a resting surface adjacent to the locking member to receive and measure bone material added to the container when the locking member is in the open position, so that the bone material enters the inner surface.

14. The method of claim 13, wherein (i) the container has a resting surface for receiving and / or measuring bone material added to the container; (ii) the bone material comprises ceramic, collagen, allogeneic bone, autologous bone, demineralized bone matrix fibers, demineralized bone powder, demineralized bone fragments, or combinations thereof; or (iii) the fluid comprises bone marrow aspirate, saline, sterile water, blood for injection, phosphate-buffered saline, dextran, Ringer's lactate solution, or combinations thereof.

15. The method of claim 13, wherein (i) the container comprises a non-porous material, a transparent and / or impermeable material; or (ii) the container is sterile.

16. A container for mixing bone material, the container comprising an inner surface configured to receive bone material thereon and an outer surface having a distal end and a proximal end, the distal end of the outer surface including a head portion having an opening configured to allow loading of the bone material onto the inner surface of the container; The head portion is disposed adjacent to the locking member, and the locking member is also disposed on the outer surface of the container; The head portion has more holes than the proximal end of the outer surface; the proximal end of the outer surface has a port configured to receive fluid to mix with the bone material on the inner surface of the container or to remove the bone material mixed with fluid on the inner surface of the container from the container, wherein the outer surface also includes a resting surface adjacent to the locking member to receive and measure the bone material when the locking member is in the open position so that the bone material enters the inner surface.

17. The container of claim 16, wherein the bone material is wet and loaded into the inner surface of the container, and the head portion has a first seal applied thereon after the wet bone material is loaded into the inner surface of the container.

18. The container of claim 17, wherein the moistened bone material is dried to form dried bone material located on the inner surface of the container, and the container further includes a second seal spaced apart from the first seal, the head portion being porous relative to the remainder of the container.

19. The container of claim 18, wherein the head portion is configured to be removed from the remainder of the container after the second seal is applied to the container.

20. A method of enclosing bone material in a container, the method comprising providing a container for adding the bone material, the container including an inner surface for receiving the bone material thereon and an outer surface having a distal end and a proximal end, the distal end of the outer surface of the container including a head portion having an opening configured to allow the bone material to be added to the inner surface of the container, the head portion being disposed adjacent to and the locking member also being disposed on the outer surface of the container, the head portion having more holes than the proximal end of the outer surface, the proximal end of the outer surface of the container having a port configured to receive fluid for mixing with the bone material on the inner surface of the container or to remove the bone material mixed with fluid on the inner surface of the container from the container; adding the bone material to the inner surface of the container through the opening of the head portion; and sealing the container to encapsulate the bone material in the container, wherein... The container also includes a resting surface adjacent to the locking member to receive and measure bone material added to the container when the locking member is in the open position, so that the bone material enters the inner surface.

21. The method of claim 20, wherein the bone material added to the inner surface of the container is wet, and the method further comprises drying and / or sterilizing the wet bone material sealed in the inner surface of the container without transferring it to another container.

22. The method of claim 21, further comprising applying a second seal to the container to seal the dried and / or sterilized bone material in the inner surface of the container.

23. The method of claim 22, further comprising applying the second seal to the container and removing the head portion from the remainder of the container.

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