Hydratable compositions comprising large particles and methods of making the same

Abstract

A homogeneous hydrated composition and a method for preparing the homogeneous hydrated composition are provided. The method includes providing a plurality of freeze-dried porous macroparticles in a chamber, each of the plurality of freeze-dried porous macroparticles having an average diameter of about 0.1 mm to about 10 mm and comprising a ceramic material and a polymer; mixing each of the plurality of freeze-dried porous macroparticles with a fluid in the chamber to homogeneously hydrate each of the plurality of freeze-dried porous macroparticles, thereby forming a homogeneous hydrated composition. A hydrateable composition is also provided.

Description

Background Technology

[0001] Various bone repair materials and bone void fillers are used in the medical field. Among known bone repair materials and bone void fillers, autologous cancellous bone is the most commonly used. This type of bone has the advantages of osteoinductive properties and non-immunogenicity. Unfortunately, this type of bone cannot be used in all cases. Furthermore, morbidity and trauma at the donor site increase the limitations of autologous cancellous bone.

[0002] Allogeneic bone is a viable alternative to autologous bone grafting. It is readily available from cadavers, avoiding the surgical complications and patient morbidity associated with autologous bone harvesting. Allogeneic bone is essentially a load-bearing matrix containing cross-linked collagen, hydroxyapatite, and bone-inducing morphogenetic proteins (BMPs). Human allogeneic bone is widely used in orthopedic surgery. However, allogeneic bone does not always possess the same strength properties or the cells and proteins that can influence new bone growth, as provided by autologous bone grafts. Furthermore, when using allogeneic bone, the risk of disease transmission is low and the effectiveness may be reduced due to the removal of bone growth cells and proteins during cleaning and sterilization processes.

[0003] Alternatives to autologous and allogeneic bone are synthetic bone materials, such as ceramic-based bone materials. Synthetic bone materials can be administered via syringes so that the bone material can be injected into the surgical site. However, when synthetic bone materials are hydrated with fluids for application, they often clump and / or agglomerate, making it difficult for the user to hydrate the synthetic bone material evenly. Clumping of the material can cause syringe blockage, further complicating the application of the synthetic bone material. Furthermore, if the fluid is not mixed evenly with the synthetic bone material, excess fluid may remain in the syringe, which could be mistakenly injected into the surgical site.

[0004] Therefore, there is a need for a composition that can achieve uniform hydration when mixed with a fluid and reduce undesirable separation of the fluid from the composition. There is also a need for a flowable and stably applied composition. Summary of the Invention

[0005] Methods and compositions are provided that include a composition that homogeneously hydrates upon mixing with a fluid and reduces undesirable separation of the fluid from the composition. The composition comprises large particles having a surface area that enhances hydration, such that the composition is homogeneously hydrated and does not clump during hydration. In some embodiments, a method for producing a homogeneously hydrated composition is provided. The method includes providing a plurality of freeze-dried porous large particles in a chamber, each of which has an average diameter of about 0.1 mm to about 10 mm and comprises a ceramic material and a polymer; mixing each of the plurality of freeze-dried porous large particles with a fluid in the chamber to homogeneously hydrate each of the plurality of freeze-dried porous large particles, thereby forming a homogeneously hydrated composition.

[0006] In some embodiments, a hydrateable composition is provided. The composition comprises a plurality of lyophilized porous macroparticles, which, based on the total weight of each lyophilized porous macroparticle, comprise from about 50% to about 98% by weight of a ceramic material and from about 2% to about 50% by weight of a polymer. The average diameter of each lyophilized porous macroparticle is from about 0.1 mm to about 10 mm. The plurality of lyophilized porous macroparticles are configured to hydrate with a fluid to form a homogeneous hydrated composition.

[0007] In some embodiments, a hydrateable composition is provided. The composition comprises a plurality of lyophilized porous macroparticles, each macroparticle comprising, based on its total weight, porous ceramic particles having an average diameter of about 50 μm to 800 μm in an amount of about 50 wt% to about 98 wt% and collagen in an amount of about 2 wt% to about 50 wt%. The average diameter of each lyophilized porous macroparticle is about 0.1 mm to about 10 mm. The plurality of lyophilized porous macroparticles are configured to hydrate with a fluid to form a homogeneous hydrated composition.

[0008] While several embodiments have been disclosed, other embodiments of this application will become apparent to those skilled in the art from the following detailed description, taken in conjunction with the accompanying drawings. It will be apparent to them that modifications are possible in various obvious respects, all without departing from the spirit and scope of this disclosure. Therefore, the detailed description is to be regarded as substantially illustrative rather than restrictive. Attached Figure Description

[0009] 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.

[0010] Figure 1 It is a perspective view of one embodiment of multiple freeze-dried porous large particles shaped into cylinders.

[0011] Figure 2 It is a perspective view of one embodiment of multiple freeze-dried porous large particles shaped into cubes.

[0012] Figure 3 It is a perspective view of one embodiment of multiple freeze-dried porous large particles shaped into rods or tubes.

[0013] Figure 4 This is a perspective view of one embodiment of freeze-dried porous large particles formed as individual hollow tubes.

[0014] Figure 5 It is a perspective view of one embodiment of freeze-dried porous large particles shaped as half or hemispheres of a single hollow tube.

[0015] Figure 6 This is a perspective view of one embodiment of freeze-dried porous large particles shaped as individual rectangles.

[0016] Figure 7 This is a perspective view of one embodiment of freeze-dried porous large particles shaped as individual discs.

[0017] Figure 8 This is a perspective view of multiple freeze-dried porous macroparticles shaped as cylinders to be inserted into the chamber of a syringe. Fluid is added to the syringe and moves uniformly around the multiple freeze-dried porous macroparticles.

[0018] Figure 9 This is a perspective view of freeze-dried, porous, large particles shaped into single hollow tubes for insertion into the chamber of a syringe. Fluid is added to the syringe, moves through the hollow tubes, and permeates inwards.

[0019] Figure 10 It is a perspective view of freeze-dried porous large particles shaped as half or hemispheres of a single hollow tube to be inserted into the chamber of a syringe. Fluid is added to the syringe and the fluid permeates inward.

[0020] Figure 11 It is a perspective view of multiple freeze-dried porous large particles, shaped as two halves or two hemispheres of a hollow tube to be inserted into the chamber of a syringe. Fluid is added to the syringe and flows concentrically from the inside and outside.

[0021] Figure 12 This is a side view of a hydration method in which multiple freeze-dried porous large particles, shaped into cylinders, are loaded into the chamber of a syringe. The syringe is then connected to a second syringe filled with fluid, such as the patient's own blood, bone marrow aspirate (BMA), or water, and the fluid is inserted into the syringe containing the large particles. The fluid can be pumped into the chamber containing the large particles, or it can be injected without pumping. If fluid is injected without pumping, the large particles soak with the fluid for a period of time.

[0022] Figure 13 It is similar to Figure 12 A side view of the hydration method shown. Figure 13 In this case, the syringe needle is optionally perforated to increase the rate of hydration of large particles.

[0023] Figure 14 This is a perspective view of multiple freeze-dried, porous, large particles of electrospun fibers shaped and loaded into the chamber of a syringe. Fluid is added to the syringe and dispersed throughout the electrospun fibers.

[0024] Figure 15 yes Figure 14The image shows a SEM image of a proposed electrospun fiber. The electrospun fiber is made of a polymer embedded with a ceramic material, which comprises porous ceramic particles.

[0025] Figure 15A yes Figure 15 A magnified perspective view of electrospun fibers.

[0026] Figure 15B yes Figure 15 A perspective view of electrospun fibers configured as spheres.

[0027] Figure 16 This is a perspective view of the experimental procedure involving loading multiple freeze-dried porous macroparticles shaped into cylinders into the chamber of a syringe. The macroparticles hydrate with blood to obtain a homogeneous hydrated graft composition.

[0028] Figure 17 This is a perspective view of multiple lyophilized porous large particles inside the chamber of a syringe.

[0029] Figure 18 This is a perspective view of multiple lyophilized porous macroparticles contained in the chamber of a syringe. Fluid is added to the syringe and moves uniformly around the multiple lyophilized porous macroparticles.

[0030] Figure 19 This describes the freeze-dried porous large particles that are dispensed from the syringe in a ribbon-like form after being combined with water.

[0031] Figure 20 This describes the freeze-dried porous large particles that are dispensed from the syringe in a ribbon-like form after being combined with water.

[0032] Figure 21 This describes the freeze-dried porous large particles that are dispensed from the syringe in a ribbon-like form after being combined with water.

[0033] Figure 22 This describes lyophilized porous large particles that are combined with blood or bone marrow aspirate (BMA) water and dispensed from a syringe in a strip form.

[0034] Figure 23 This describes freeze-dried porous large particles shaped into cubes.

[0035] Figure 24 This describes freeze-dried porous large particles shaped into cubes containing blood or BMA.

[0036] Figure 25 This describes freeze-dried porous large particles shaped into cubes containing blood or BMA.

[0037] Figure 26 This describes how water was combined with water and hand-molded into tubular, freeze-dried, porous large particles.

[0038] 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

[0039] definition

[0040] For the purposes of this specification and the appended claims, unless otherwise specified, all figures representing the amount of ingredients, percentages or proportions of materials, reaction conditions, and other numerical values ​​used in this specification and the claims should be understood to be modified by the term "about" in all cases. Similarly, when a value is expressed as an approximation, by using the antecedent "about," it should be understood that the specific value forms another embodiment as + / - 10% of the enumerated value. Therefore, unless indicated to the contrary, 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 this disclosure. 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 figures reported and by applying general rounding techniques. Furthermore, as used in the specification and included in the appended claims, the singular forms "a / an" and "the" include the plural forms, and the specific numerical value mentioned includes at least the stated specific value, unless the context clearly specifies otherwise. A range may be expressed herein as from “about” or “approximately” a particular value and / or to “about” or “approximately” another particular value. When expressing such a range, another embodiment includes from one particular value and / or to another particular value.

[0041] While the numerical ranges and parameters used to illustrate the broad scope of this application are approximations, the numerical values ​​described in specific examples are reported as precisely as possible. However, any numerical value inherently contains some error that is 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 therein. 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.

[0042] As used in this article, biocompatibility is defined as the ability of a material to be administered in vivo without inducing unwanted long-term effects.

[0043] The bone used in this article refers to cortical, cancellous, or cortical-cancellous bone of autologous, allogeneic, xenogeneic, or transgenic origin.

[0044] The term "autograft" refers to graft material collected from the same individual patient who is also a graft recipient, obtained surgically from a non-essential donor site.

[0045] As used herein, bone graft means any implant prepared according to the embodiments described herein, and may therefore include expressions such as bone void fillers.

[0046] As used herein, the term "osteoinducible" refers to the property 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.

[0047] The term "bone induction" refers to the ability to stimulate the proliferation and differentiation of pluripotent mesenchymal stem cells (MSCs). In intrachondral bone formation, stem cells differentiate into chondroblasts and chondrocytes, forming chondrocyte emulsions (ECMs), which subsequently calcify and remodel into sheet-like bone. In intramembranous bone formation, stem cells directly differentiate into osteoblasts, which form bone through a direct mechanism. Osteogenic growth factors can stimulate bone induction, although some ECM proteins can also drive progenitor cells to develop an osteogenic phenotype.

[0048] The term "osteogenicity" refers to the ability of graft material to independently generate bone. For a graft to possess direct osteogenic activity, it must contain cellular components that directly induce bone formation. For example, allogeneic grafts seeded with activated MSCs can have the potential to directly induce bone formation without recruiting and activating the host MSC population. Since many osteoconductive allogeneic grafts also possess the ability to bind and deliver bioactive molecules, their osteoinductive potential is significantly enhanced.

[0049] 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.

[0050] As used herein, the term "implantable" refers to a biocompatible device (e.g., a composition) that retains the potential for successful placement within a mammal. As used herein, expressions describing "implantable composition" and similar expressions refer to objects that can be implanted surgically, by injection, or by other suitable means, which perform their primary function through their physical presence or mechanical properties. An example of an implantable device is a composition.

[0051] The term "moldable" includes compositions that can be shaped by hand or machine or injected into a variety of configurations in a target tissue site (e.g., bone defects, fractures, or cavities) to fit within the bone defect.

[0052] As used herein, the term "internal viscosity" refers to the tendency of a composition to maintain a single quality of bond when fluids, autologous bone grafts, or during operation are added, including the ability to mold or shape without breaking when operated, decomposed, or become unstable.

[0053] The terms "large particles" or "macrobody" include bone material visible to the naked eye. Bone material can be natural bone, synthetic bone materials (e.g., demineralized bone, ceramics, etc.), or a combination thereof that is solid or semi-solid before hydration. Typically, large particles can range in length from 0.01 mm to approximately 50 mm. It should be understood that the terms "large particles" and "macrobody" are used interchangeably.

[0054] The term "flowable" includes compositions that can be applied in an injectable state via a syringe and / or cannula. The composition is flowable when it has a fluid consistency and its viscosity is lower than that of a composition in putty or paste form. Flowable compositions include liquids or fluids (e.g., solutions, suspensions, etc.) or semi-solid compositions (e.g., gels, cement) that are easy to manipulate and can be brushed, sprayed, dripped, injected, shaped, and / or molded at or near a target tissue site. "Flowable" ranges from compositions with low viscosity or a watery consistency to compositions with high viscosity, such as paste materials. In various embodiments, the flowability of the composition allows it to conform to irregularities, fissures, cracks, and / or voids in bone defect sites (e.g., bone cavities). For example, in various embodiments, the composition can be used to fill one or more voids in an osteolytic lesion.

[0055] The term "injectable" refers to the mode of administration of the composition. The composition can be administered in a variety of ways, such as via syringe and / or cannula. For example, the composition can be administered parenterally, such as via anterior lumbar intervertebral body administration for fusion, or via posterior lumbar intervertebral body administration for fusion, or via transforaminal lumbar vertebral body administration for fusion, other intraspinal injections, or other local administrations.

[0056] The terms “hydrate,” “hydration,” “hydratable,” “hydrating,” or “hydrated” refer to the addition of a certain amount of fluid to a composition to increase the amount of water content in the composition, thereby forming a flowable putty or paste.

[0057] The term "dehydrated" or "dehydrated" refers to a composition containing a small amount of residual moisture or containing no moisture and may be in the form of a dry composition. Based on the total weight of the composition, a dehydrated composition may have a moisture content of about 0 to about 10%. In some embodiments, a fluid may be added to the composition to hydrate it during dehydration. Dehydrated compositions include lyophilized or freeze-dried compositions.

[0058] The term "bone marrow aspirate" or "BMA" refers to the collection of bone marrow fluid from a patient using a syringe and needle. Bone marrow aspirate is a fluid containing a heterogeneous mixture of stem cells and progenitor cells, platelets, and leukocytes. Bone marrow aspirate can be collected from various sources within the body, including but not limited to the iliac crest.

[0059] The term "soluble collagen" refers to the solubility of a single procollagen molecule in an acidic aqueous environment. Procollagen can be considered the monomeric unit of collagen fibers, and its triple helix structure is well-established.

[0060] As used herein, “insoluble collagen” refers to collagen that is not chemically modified and cannot be dissolved in alkaline aqueous solutions or any inorganic salt solutions, and includes, for example, animal hides, slits, and other mammalian or reptile coverings. For example, “natural insoluble collagen” can be derived from the dermis, the middle layer of animal skin (e.g., cow, pig, fish, etc.) located between the fascia and the lining.

[0061] As used in this article, the term “electrospun” (or “electrospinning”) refers to a fiber production method that uses electricity to stretch an electrical wire through a polymer solution or polymer melt to fiber diameters ranging from micrometers to hundreds of nanometers.

[0062] Composition

[0063] like Figure 1-16 As shown, a hydratable composition 10 is provided. This composition can be a bone graft material and is configured to hydrate uniformly when mixed with fluid 12. The composition is configured to reduce undesirable separation between the fluid and the composition and to prevent clumping or agglomeration during hydration. The final form of the composition can be a flowable putty, cement, or gel.

[0064] The hydrateable composition comprises a plurality of freeze-dried porous macroparticles 14 configured to hydrate with a fluid to form a homogeneous hydrated composition. Based on the total weight of each of the freeze-dried porous macroparticles, the plurality of freeze-dried porous macroparticles comprises about 50% to about 98% by weight of a ceramic material and about 2% to about 50% by weight of a polymer. Based on the total weight of each freeze-dried porous macroparticle, the plurality of freeze-dried porous macroparticles may each comprise from about 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, 70% by weight, etc. 71% by weight, 72% by weight, 73% by weight, 74% by weight, 75% by weight, 76% by weight, 77% by weight, 78% by weight, 79% by weight, 80% by weight, 81% by weight, 82% by weight, 83% by weight, 84% by weight, 85% by weight, 86% by weight, 87% by weight, 88% by weight, 89% by weight, 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight Ceramic materials from about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, and 25% by weight, from approximately 97% to 98% by weight. % , 26 wt% , 27 wt% , 28 wt% , 29 wt% , 30 wt% , 31 wt% , 32 wt% , 33 wt% , 34 wt% , 35 wt% , 36 wt% , 37 wt% , 38 wt% , 39 wt% , 40 wt% , 41 wt% , 42 wt% , 43 wt% , 44 wt% , 45 wt% , 46 wt% , 47 wt% , 48 wt% , 49 wt% to about 50 wt% of polymer.

[0065] The polymer component of each of the multiple freeze-dried porous large particles may be porcine or bovine collagen, bovine type I collagen, tendon or dermal derived collagen, or a combination thereof.

[0066] The ceramic material may comprise hydroxyapatite and β-tricalcium phosphate in a calcium-to-phosphate ratio of 1.0 to about 2.0. In some embodiments, the calcium-to-phosphate ratio is between 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and about 2.0.

[0067] Based on the total weight of the ceramic material, the amount of hydroxyapatite is from about 8 wt% to about 22 wt%. Hydroxyapatite can range from about 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt% to about 22 wt%. In some embodiments, hydroxyapatite can be from about 1 wt% to about 99 wt%, such as 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%. 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt% 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt% 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt% to about 99 wt%.

[0068] Based on the total weight of the ceramic material, the amount of β-tricalcium phosphate is from about 78 wt% to about 92 wt%. The amount of β-tricalcium phosphate can be from about 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt% to about 92 wt%. In some embodiments, β-tricalcium phosphate can be in the range of from about 1 wt% to about 99 wt%, for example from about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%. 22% by weight, 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight, 30% by weight, 31% by weight, 32% by weight, 33% by weight, 34% by weight, 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, 81 wt%, 82 wt%, 83 wt%, 84 wt%, 85 wt%, 86 wt%, 87 wt%, 88 wt%, 89 wt%, 90 wt%, 91 wt%, 92 wt%, 93 wt%, 94 wt%, 95 wt%, 96 wt%, 97 wt%, 98 wt% to about 99 wt%.

[0069] The average diameter of each freeze-dried porous macroparticle is from approximately 0.1 mm to approximately 10 mm. For example, the average diameter of each freeze-dried porous macroparticle can be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4. 8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 to approximately 10mm.

[0070] The average height and / or length of each freeze-dried porous macroparticle can be from about 0.01 mm to about 10 mm or from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 to about 10 mm.

[0071] The ceramic material provided in each freeze-dried porous large particle can be in the form of porous ceramic particles 16, such as Figure 15AAs shown. The porous ceramic particles are similar to those found and described in U.S. Application Serial No. 16 / 523,259, filed July 26, 2019, assigned to Warsaw Plastic Surgery Co., Ltd., which is incorporated herein by reference. The average diameter of the porous ceramic particles is from about 50 μm to 800 μm. In some embodiments, the average diameter of the particles can be from about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225 μm. 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 42 0, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610 The sizes range from 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795 to approximately 800 μm. It should be understood that the size of ceramic materials is smaller than that of large particles.

[0072] When porous ceramic particles are used in the composition, the amount of particles is from about 50% to about 98% by weight, based on the total weight of each lyophilized porous macroparticle, and the amount of collagen is from about 2% to about 50% by weight. Each porous ceramic particle contains hydroxyapatite and β-tricalcium phosphate in a calcium-to-phosphate ratio of 1.0 to about 2.0, as described above regarding ceramic materials.

[0073] Each porous ceramic particle includes an outer surface comprising multiple concave shapes 18, such as Figure 15AAs shown. The concave shape can be disc-shaped in appearance and can be of a specific size. Each concave shape can have a diameter of about 400 to about 600 micrometers. In some embodiments, each diameter can range from about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 to about 600 micrometers.

[0074] The concave shape on the outer surface of each particle can promote increased new bone attachment because the surface makes it easier for new bone to attach (e.g., for the vascularization and permeation of associated cells) than on standard ceramic particles. In some embodiments, porous ceramic particles promote rapid and uniform bone integration, supporting bone healing by acting as a scaffold on which bone can grow.

[0075] Each porous ceramic particle has a diameter of approximately 0.2 to approximately 10 μm. 2 / g Brunauer–Emmett–Teller (BET) surface area. BET surface area can be approximately 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 to approximately 10 m². 2 / g. The increased surface area further promotes new bone growth by enabling the particles to dissolve and release calcium more quickly than conventional particles.

[0076] Each porous ceramic particle has micropores, each micropore having a diameter of about 0.01 to about 10 micrometers. In some embodiments, the diameter of each micropore may be about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 to about 10 micrometers.

[0077] Multiple freeze-dried porous large particles can be formed into various shapes after freeze-drying or by using a cryogel application. These shapes can be cut from textured or flat sheets of bone material containing ceramic materials and polymers, or they can be prepared as individual large particles produced in a mold. The large particles are porous, but in some embodiments, the large particles are highly porosimetric. For example, porous large particles may have a porosity of about 10 to about 80%, or from about 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 to about 80%. Large particles with high porosity can include large particles with a porosity of about 81 to about 99% or about 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 to about 99%.

[0078] The shape and size of large particles create a high level of surface area, which increases uniform hydration when fluid is applied to them. For example, due to the high surface area, fluid will move rapidly into the large particles via wicking. The shape of the large particles can include cylinders 20, such as... Figure 1 As shown; cube 22, as Figure 2 Figure 23-25 As shown; rod or tube 24, such as Figure 3 and Figure 26 As shown; one or more hollow tubes 26, such as Figure 4 As shown; one or more hemispherical hollow tubes or tubes 28, such as Figure 5 As shown; one or more rectangles 30, as Figure 6 As shown; one or more disks 32, as Figure 7 As shown; electrospun fiber 34, as Figure 15 As shown, or a combination thereof.

[0079] Multiple lyophilized porous macroparticles can be loaded into the barrel or chamber 38 of syringe 36. The multiple lyophilized porous macroparticles in the chamber can have a packing density that maximizes the hydration of the multiple lyophilized porous macroparticles when fluid is introduced into the chamber. In some embodiments, the packing density can be high. The packing density can be from about 1 to about 5 g / cm³. 3 Approximately 1 to approximately 4 g / cm³ 3 Approximately 1 to approximately 3 g / cm³ 3Or approximately 1 to approximately 2 g / cm³ 3 The filler density can be approximately 1, 2, 3, or 4 to approximately 5 g / cm³. 3 In some implementations, the combination of the large particle packing density and the large particle surface area produces a non-agglomerated and flowable homogeneous hydrated composition.

[0080] Figure 8-11 This demonstrates how large particles in the composition promote uniform hydration. Figure 8 Showing Figure 1 Large cylindrical particles are loaded into the chamber of the syringe. Fluid is added to the syringe, and the fluid will move around each large particle to produce uniform hydration. The fluid can fill the spaces or voids surrounding each large particle in the chamber, and can also be wicked into each large particle.

[0081] Figure 9 Showing Figure 4 Large particles, shaped like single hollow tubes, are loaded into the chamber of the syringe. When fluid is added to the syringe, it moves through the single hollow tube shape and also permeates into the internal channels of the tube.

[0082] Figure 10 Showing Figure 5 A single hollow tube, half or half-sphere, is inserted into the chamber of the syringe. Fluid is added to the syringe, and the fluid permeates inward into the tube.

[0083] Figure 11 Showing Figure 5 The syringe contains two halves or hemispheres of a hollow tube inserted into its chamber. Fluid is added to the syringe and flows concentrically from the inside and outside. The two halves of the hollow tube can be inserted into the chamber to increase the surface area available for hydration.

[0084] like Figure 14-15B As described above, large particles can be formed into electrospun fibers. These fibers can be made from polymers such as collagen and embedded with ceramic materials in the form of porous ceramic particles, such as... Figure 15A As shown. Electrospun fiber shapes can provide the largest surface area to achieve maximum hydration, ease of hydration, and the shortest hydration time.

[0085] The average length of the electrospun polymer fiber can be from about 1 mm to about 50 mm or from about 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 to about 50 mm. The average diameter of electrospun polymer fibers can be approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 to approximately 10 mm.

[0086] In some embodiments, the final form of the composition comprising electrospun fibers may be in the shape of a "cotton ball," such as... Figure 15B As shown. The cotton ball shape may also include electrospinning rods and / or ceramic materials shaped into rods 24.

[0087] Figure 14 The image shows electrospun fibers loaded into the chamber of a syringe. Fluid is added to the syringe and dispersed throughout the electrospun fibers. The electrospun fibers are uniformly hydrated to form a flowable composition.

[0088] The fluid used to hydrate the large particles may include bone marrow aspirate, saline, sterile water, injectable blood, phosphate-buffered saline, glucose, Ringer's lactate solution, or combinations thereof. The ratio of the fluid to the plurality of lyophilized porous large particles may be from about 0.5:1 to about 3:1. In some embodiments, the ratio of the fluid to the plurality of lyophilized porous large particles may be from about 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1 to about 3:1.

[0089] In some implementation schemes, such as Figure 12 and 13 As shown and as described above, the composition can be hydrated in a syringe. Figure 12In this process, multiple freeze-dried porous large particles shaped into cylinders are loaded into the chamber of a syringe. The syringe is then connected to a second syringe 40, which is filled with fluid and includes a plunger 42 for dispensing fluid from the second syringe. The fluid can be the patient's own blood, bone marrow aspirate (BMA), or water. The fluid is then inserted into the first syringe containing the large particles. In some embodiments, the fluid can be pumped into the chamber of the first syringe via a plunger, or the fluid can be injected without pumping. If fluid is injected without pumping, the large particles are immersed in the fluid for a period of time. Figure 13 In this syringe, a perforated needle 44 is included to increase the hydration rate of large particles. The perforated needle also minimizes the amount of dry / unhydrated large particles, thus improving injectability.

[0090] Autologous bone grafts can be added to the hydrateable composition before or after hydration. The autologous bone grafts can be cut into various shapes, including fibers, fragments, granules, powder, shavings, or combinations thereof. The autologous bone grafts can be cut to specific sizes. For example, the autologous bone grafts can be from about 1 to about 10 mm. In some embodiments, the size of the autologous bone grafts added to the composition can be from about 1, 2, 3, 4, 5, 6, 7, 8, 9 to about 10 mm. In some embodiments, the autologous bone grafts are cut into bone fragments of about 1 to about 4 mm in size and added to the hydrateable composition after hydration.

[0091] A certain amount of autologous bone graft can be added to the hydrated composition, for example, from about 0 to about 50% by volume, based on the total weight of the hydrated composition, or from about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 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 to about 50% by volume. In some embodiments, the composition may contain more than 50% by volume of autologous bone graft without losing its adhesive properties.

[0092] In some embodiments, the hydratable composition has a flowable viscosity from about 50 Pascal-seconds (Pa-s), 100 Pa-s, 150 Pa-s, 200 Pa-s, 250 Pa-s to about 300 Pa-s, and reaches higher viscosities from about 500 Pa-s, 750 Pa-s, 1000 Pa-s, 1500, 2000 Pa-s, 2500 Pa-s to about 3000 Pa-s. In some embodiments, the hydratable composition has a flowable viscosity starting from about 50 Pa-s to about 3000 Pa-s and reaches higher viscosities from about 3000 Pa-s to about 300,000 Pa-s.

[0093] The hydrated composition may have a certain density when hydrated. For example, when the composition is hydrated, the density may be about 1.2 to about 2.0 g / cc or about 1.4 to about 1.6 g / cc. In some embodiments, the hydrated composition may have a density of about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 to about 2.0 g / cc.

[0094] The hydrateable composition may have an elastic modulus of about 2 MPa to about 12 MPa, for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 to about 12 MPa.

[0095] In some embodiments, if autologous bone grafts are added to the composition after hydration, the elastic modulus can increase with the addition of autologous bone grafts.

[0096] In some embodiments, the fluid used for the hydration composition may include sterile water, saline, phosphate-buffered saline (PBS), hyaluronic acid, cellulose ethers (e.g., carboxymethyl cellulose), water, collagen, gelatin, autoclaved bone meal, osteoconductive carriers, whole blood, blood fractions, concentrated bone marrow aspirate, and mixtures thereof. Non-limiting examples of blood components include serum, plasma, platelet-rich plasma, concentrated platelet-rich plasma, anemic platelet plasma, and concentrated anemic platelet plasma.

[0097] Viscosity enhancers may be added to the composition, including but not limited to mannitol, trehalose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose and its salts, Carbopol, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinations thereof.

[0098] In some embodiments, additional materials may be incorporated into the composition, such as one or more of the following: poly(alpha-hydroxy acid), polyglycolic acid (PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acid), polyorthoester (POE), polyaspirins, polyphosphagenes, gelatin, hydrolyzed gelatin, a portion of hydrolyzed gelatin, elastin, starch, pregelatinized starch, hyaluronic acid, chitosan, alginate, albumin, fibroin, vitamin E analogs such as alpha-tocopherol acetate, d-alpha-tocopherol succinate, D,L-lactide or L-lactide, caprolactone, dextran, vinylpyridine Pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylate, PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, POE, SAIB (sucrose acetate isobutyrate), polydioxanone, methyl methacrylate (MMA), MMA and N-vinylpyrrolidone, polyamide, oxidized cellulose, copolymer of glycolic acid and trimethylene carbonate, polyesteramide, polyetheretherketone, polymethyl methacrylate, polysiloxane, hyaluronic acid or combinations thereof.

[0099] In some embodiments, the large particles may optionally or additionally comprise at least one biodegradable polymer comprising one or more of the following: poly(lactide-co-glycolic acid) (PLGA), polylactide (PLA), polyglycolic acid (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone, L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolic acid-co-ε-caprolactone, poly(D,L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone), poly(D-lactide-co-caprolactone), poly(D,L-lactide), poly(D-lactide), poly(L-lactide), poly(esteramide), carboxymethyl cellulose (CMC), alpha-oxygen copolymer (AOC), or combinations thereof.

[0100] In some embodiments, the large particles optionally or additionally comprise at least one ceramic material, including but not limited to synthetic ceramics selected from one or more materials, wherein the one or more materials comprise calcium phosphate ceramics or silicon ceramics. Bioglasses (e.g., calcium silicate-based bioglasses), calcium silicate phosphate, tricalcium phosphate (TCP), biphasic calcium phosphate, calcium sulfate, hydroxyapatite, coral hydroxyapatite, silicon carbide, silicon nitride (Si3N4), and biocompatible ceramics can be used. In some embodiments, the ceramic material is tricalcium phosphate or biphasic calcium phosphate and silicon ceramics. In some embodiments, the ceramic material is tricalcium phosphate.

[0101] In some embodiments, the ceramic material is a combination of calcium phosphate ceramic and silicon ceramic. In some embodiments, the calcium phosphate ceramic is absorbable biphasic calcium phosphate (BCP) or absorbable tricalcium phosphate (TCP).

[0102] The ceramic material disclosed herein may also be an oxide ceramic, such as alumina (Al2O3) or zirconium oxide (ZrO2), or a composite of oxides with non-oxides such as silicon nitride.

[0103] freeze-dried

[0104] As described herein, compositions and their components, such as large particles, can be lyophilized. The lyophilization process typically involves sublimating water from the frozen formulation under controlled conditions. Lyophilization can be performed using standard equipment for lyophilization or vacuum drying. Cycling can vary depending on the equipment and facilities used for filling and finishing.

[0105] Initially, in some embodiments, the composite material producing large particles (e.g., ceramic materials combined with polymers) is placed in a freeze-drying chamber within a temperature range and then subjected to temperatures well below the material's freezing point, typically for several hours. After freezing, the freeze-drying chamber and condenser are evacuated by a vacuum pump; the condenser surface has previously been cooled by circulating refrigerant. The condenser will then be cooled below the material's freezing point. Furthermore, evacuation of the chamber should continue until a pressure of approximately 50 to approximately 600 mTorr, preferably approximately 50 to approximately 150 mTorr, is achieved.

[0106] The lyophilized material is then heated under vacuum in the chamber and condenser. This is typically done by heating the racks within the freeze dryer where the lyophilized composition is located during the lyophilization process at a pressure of approximately 50 to approximately 600 mTorr. The heating process will proceed very slowly over several hours. Complete drying can be achieved by stabilizing the vacuum, condenser temperature, and the temperature of the lyophilized composition racks. After the initial drying, the temperature of the lyophilized material can be increased and maintained for several 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).

[0107] In some embodiments, after freeze-drying, the material forming large particles is about 95% to about 99.5% free of moisture. The material can be from 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 material has a moisture content of about 0.5% to about 5% after freeze-drying. In various embodiments, the 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 material is stable and can be stored over a wide temperature range.

[0108] Production method

[0109] A method for preparing a homogeneous hydrated composition is provided. The method includes providing a plurality of freeze-dried porous macroparticles in a chamber, each of the plurality of freeze-dried porous macroparticles having an average diameter of about 0.1 mm to about 10 mm and comprising a ceramic material and a polymer; mixing each of the plurality of freeze-dried porous macroparticles with a fluid in the chamber to homogeneously hydrate each of the plurality of freeze-dried porous macroparticles, thereby forming a homogeneous hydrated composition. It should be understood that the composition is the hydrateable composition 10 described above.

[0110] The ratio of fluid to multiple freeze-dried porous macroparticles can be from about 1:1 to about 3:1. In some embodiments, based on the total weight of each freeze-dried porous macroparticle, the amount of ceramic is from about 50% to about 98% by weight, and the amount of polymer is from about 2% to about 50% by weight. The multiple freeze-dried porous macroparticles in the chamber can have a packing density that maximizes the hydration of the multiple freeze-dried porous macroparticles. In some embodiments, the shape of the multiple freeze-dried porous macroparticles includes cylinders, cubes, rods, tubes, hollow tubes, rectangles, disks, hemispherical hollow tubes, electrospun fibers, or combinations thereof.

[0111] In various embodiments, gamma radiation is used to sterilize the composition, which involves utilizing the ionizing energy from gamma rays that penetrate deeply into the composition. Gamma rays efficiently kill microorganisms without leaving residue and do not have sufficient energy to make the composition radioactive. Gamma rays can be used when packaging the composition, and gamma sterilization does not require high pressure or vacuum conditions, so packaging seals and other components are not subjected to stress. In addition, gamma radiation eliminates the need for permeable packaging materials.

[0112] In various embodiments, the composition can be sterilized using electron beam (e-beam) radiation. E-beam radiation comprises the form of ionizing energy characterized by low penetration and high dose rate. E-beam irradiation 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.

[0113] Other methods may also be used to sterilize the composition, including, but not limited to, gas sterilization, such as sterilization with ethylene oxide or steam.

[0114] In some embodiments, the composition can be used as a bone graft in any suitable application. For example, the composition can be administered in a bone graft that can be used in a variety of orthopedic, periodontal, neurosurgical, oral and maxillofacial surgeries, such as repairing simple and / or complex fractures and / or non-fusion; external and / or internal fixation; joint reconstruction, such as arthroplasty; general arthroplasty; hip cupping arthroplasty; femoral and humeral head replacement; femoral head resurfacing replacement and / or total joint replacement; spinal repair, including spinal fusion and internal fixation; tumor surgery, such as lack of filling; intervertebral discectomy; laminectomy; resection of spinal cord tumors; anterior cervical and thoracic spine surgery; repair of spinal injuries; treatment of scoliosis, kyphosis and lordosis; intermaxillary fixation of fractures; genioplasty; temporomandibular joint replacement; alveolar ridge enhancement and reconstruction; inlay implant matrix; implant placement and correction; sinus floor elevation; cosmetic surgery; and so on. The specific bones that can be repaired in this article include the ethmoid bone, frontal lobe, nose, occipital bone, parietal bone, temporal bone, mandible, maxilla, zygomatic bone, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, sacrum, ribs, sternum, clavicle, scapula, humerus, radius, ulna, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis, femur, tibia, fibula, patella, calcaneus, tarsal bones, and / or metatarsals.

[0115] In some embodiments, a method is provided for producing large particles in the shape of electrospun fibers. The method includes adding a polymer carrier to a solution such as a volatile solvent, and then dissolving or heating the polymer. A ceramic material in particulate form is then added to the solution. The solution is then fed into an electrospinning machine. The end result is electrospun polymer fibers embedded with ceramic particles. It should be understood that the electrospun fibers can be manufactured using a single-injection or multi-injection system. In some embodiments, the method employs coaxial electrospinning, emulsion electrospinning, or melt electrospinning techniques.

[0116] In some implementations, electrospinning parameters include, but are not limited to, the molecular weight of the parameters, the molecular weight distribution and structure of the polymer (e.g., branched or linear), solution properties (e.g., viscosity, conductivity, and surface tension), potential, flow rate and concentration, distance between the capillary and the collecting screen, environmental parameters (e.g., room temperature, humidity, and airflow rate), movement and size of the target screen (collector), and needle specifications.

[0117] In some embodiments, the term "solution" is used to describe a liquid in a container during an electrospinning process. The term is broadly defined as including any liquid containing the material to be electrospinned. It should be understood that any solution capable of forming material during electrospinning is included within the scope of this application. In this application, the term "solution" also refers to a suspension or emulsion containing the material or any substance to be electrodeposited. A "solution" can be in an organic or biocompatible form. Given the wide variety of solvents or other liquid and carrier molecules (e.g., polyethylene oxide (PEO)) that can be used in electrospinning, this broad definition is appropriate. In this application, the term "solution" also refers to melts, hydrated gels, and suspensions containing the material, substance, or anything to be electrodeposited.

[0118] In some embodiments, the solution may be water, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol (also known as hexafluoroisopropanol or HFIP), urea, monochloroacetic acid, HFIP, isopropanol, HFIP, lower alcohols such as haloalcohols, acetamide, N-methylformamide, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide, N-methylpyrrolidone (NMP), acetic acid, trifluoroacetic acid, ethyl acetate, acetonitrile, trifluoroacetic anhydride, 1,1,1-trifluoroacetone, maleic acid, and / or hexafluoroacetone.

[0119] One or more electrical discharge techniques may be used as an alternative to electrospinning, such as electrospraying, electrosol, electrosputtering, or any combination thereof.

[0120] Reagent test kit

[0121] In various embodiments, a kit is provided comprising a hydratable composition and / or components of the hydratable composition, such as large particles, and a fluid separate from the composition. The kit may include additional components and the composition combined together for application of the composition (e.g., swabs, needles, syringes, mixing syringes, or other mixing devices). The kit may include large particles or large particles already added to the composition in a first compartment. A second compartment may include any other instruments required for delivery. A third compartment may include a fluid for hydrating the composition. A fourth 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 apply the composition. A fifth compartment may contain additional needles and / or sutures. Each tool may be individually packaged in a sterilized plastic pouch. A sixth compartment may contain agents for radiographic imaging. The kit cap may contain instructions for the implantation procedure, and a transparent plastic cap may be placed on the compartments to maintain sterility.

[0122] In some implementations, the composition, either alone or in a kit, may have a shelf life of 3 to 5 years.

[0123] These and other aspects of this application will be further understood upon consideration of the following embodiments, which are intended to illustrate certain specific implementations of this application but are not intended to limit the scope of this application as defined by the claims.

[0124] Example

[0125] Example 1

[0126] Porous ceramic particles

[0127] Consider porous ceramic particles prepared using the methods discovered and described in U.S. Application Serial No. 16 / 523,259, filed July 26, 2019, which is assigned to Warsaw Orthopedic Surgery, Inc., and is incorporated herein by reference. The porous ceramic particles have an average diameter of about 50 μm to about 800 μm, comprising biphasic calcium phosphate in amounts of about 8 to about 22 wt% hydroxyapatite and about 78 to about 92 wt% β-tricalcium phosphate, having a microporosity of about 0.1 to about 10 μm, including an outer surface comprising a plurality of concave shapes, each concave shape having a diameter of about 400 to about 600 μm, and each porous ceramic particle having a micropore diameter of about 0.2 to about 10 μm. 2 / g BET surface area.

[0128] Example 2

[0129] Implantable Composition

[0130] Consider implantable compositions, which can be in the form of a formable putty or a non-curing, flowable viscous cement or gel. The implantable composition can be dehydrated and then hydrated to form a formable putty. The formable putty can then be further hydrated to form a non-curing, flowable viscous cement or gel.

[0131] The implantable composition comprises porous ceramic particles, which, based on the total weight of the ceramic particles, contain about 8 to about 22% by weight of hydroxyapatite and about 78 to about 92% by weight of β-tricalcium phosphate; and a collagen carrier. The average diameter of the porous ceramic particles is about 50 μm to 800 μm. Based on the total weight of the composition, the composition comprises about 50 to about 98% by weight of the porous ceramic particles and about 2 to about 50% by weight of the collagen carrier. The collagen carrier is porcine or bovine collagen and the implantable composition has an elastic modulus of about 2 MPa to about 12 MPa. The implantable composition can be hydrated with bone marrow aspirate.

[0132] Example 3

[0133] Implantable Composition

[0134] Consider implantable compositions, which may be in the form of a formable putty or a non-curing, flowable viscous cement or gel. Implantable compositions can be dehydrated and then hydrated to form formable putties and / or non-curing, flowable viscous cement or gels.

[0135] The implantable composition comprises porous ceramic particles, which, based on the total weight of the ceramic particles, contain about 15% by weight of hydroxyapatite and about 85% by weight of β-tricalcium phosphate, and a collagen carrier. The calcium to phosphate ratio is 1.525. The average diameter of the porous ceramic particles is about 200 μm to 500 μm. Based on the total weight of the composition, the composition comprises about 77 to about 93% by weight of porous ceramic particles and about 7 to about 23% by weight of collagen carrier. The collagen carrier is bovine type I collagen, and the multiple concave shapes on the outer surface of the particles each have a diameter of about 400 to about 600 micrometers. The porous ceramic particles contain micropores with a volume of about 0.01 to about 10 micrometers. Each porous ceramic particle has a diameter of about 0.2 to about 0.6 μm. 2 / g BET surface area. The implantable composition can hydrate with bone marrow aspirate.

[0136] Example 4

[0137] Flowable and moldable composition

[0138] Background: The processing properties of the composition (e.g., texture, compressive strength, modulus of elasticity, and flowability) are important for implantation and use. Qualitative processing evaluation of the composition was performed to confirm the internal tack and adhesive properties, which are crucial for putty moldability, modularity, compatibility with autologous grafts, and versatility under known use conditions. Quantitative tests characterizing the processing properties were also performed, and the results are briefly summarized below.

[0139] Texture values:

[0140] The texture value per unit is the area under the curve of the unconstrained load versus displacement under compression. A 1.5cc material was tested, consisting of a 10.25mm diameter cylinder with a height of 18mm formed by combining it with water at various hydration ratios (0.5-1.5 volume / volume). The test specimen was compressed for 12s using a 5mm diameter piston at a crosshead speed of 1.0mm / s.

[0141] For test articles measured under the above conditions, the measured texture value was ≥200. Results showed that the texture value increased with decreasing hydration level. The texture value increased with increasing ceramic content and ceramic particle size. The optimal texture value for the composition in moldable putty form (hydrated at a 1:1 volume / volume ratio) was determined to be ≥1000. Lower texture values ​​(e.g., 200-1000) were determined to be optimal for flowable / injectable forms (hydrated at >1:1 volume / volume ratio). These texture values ​​were determined after 25-40 kGy of gamma radiation.

[0142] Young's modulus of elasticity:

[0143] When the composition is hydrated with water at various hydration ratios (0.5-1.5 volume / volume) to form a cylinder with a height of 18 mm and a diameter of 10.25 mm, and compressed at a crosshead speed of 1.0 mm / s for 12 s, the elastic modulus of the composition is calculated from the unconstrained stress curve and strain curve.

[0144] For test articles measured under the above conditions, the modulus of elasticity is calculated to be ≥2 MPa. The modulus of elasticity increases with decreasing hydration level. The modulus of elasticity increases with increasing ceramic content and ceramic particle size. The optimal modulus of elasticity for the composition in moldable putty and flowable cement forms was determined after 25–40 kGy γ-radiation as ≥2 MPa, ≥6 MPa, and ≥10 MPa, respectively.

[0145] Pressure resistance - peak load:

[0146] When the composition is hydrated with water at various hydration ratios (0.5–1.5 volume / volume) to form a cylinder with a height of 18 mm and a diameter of 10.25 mm, and compressed at a crosshead speed of 1.0 mm / s for 12 s, the peak load of the composition is measured by an unconstrained load versus displacement curve.

[0147] For test articles measured under the above conditions, the peak load was measured as 30 ≥ gf ≥ 500. The peak load increased with decreasing hydration level. The peak load increased with increasing ceramic content and ceramic particle size. The optimal peak loads for the moldable putty and flowable cement forms of the composition were determined after 25–40 kGy γ-radiation as: 30 ≥ gf ≥ 500, 50 ≥ gf ≥ 400, and 100 ≥ gf ≥ 400.

[0148] Example 5

[0149] Homogeneous hydrated composition

[0150] like Figure 16The diagram discloses the homogeneous hydration of a composition comprising large particles, the large particles comprising a ceramic material and a polymer disposed within the chamber of a closed container, such as a syringe. Prior to shaping the large particles, a sheet of ceramic material bonded to the polymer is freeze-dried and then cut into multiple porous large particles using a biopsy puncturist. The large particles are shaped into cylinders with an average diameter of approximately 8 mm and loaded into the chamber of a syringe. The syringe used includes a perforated needle. The large particles hydrate with blood within the syringe, thereby producing a homogeneously hydrated graft composition. The resulting composition is then combined with simulated autologous bone grafts. The autologous bone grafts are in the form of bone fragments ranging from 1 to 4 mm in size.

[0151] exist Figure 23-25 The image shows large particles shaped into cubes 22, which can be hydrated with fluids (e.g., water, blood, BMA, etc.). The desired large particle shape can be obtained by filling the large particles into a mold, then freeze-drying them and removing them from the mold in the desired shape (e.g., pellets, cylinders, cubes, etc.). The large particles can be placed in a container such as... Figure 17 and 18 The mixture shown is uniformly hydrated with the fluid in the mixing device. Large particles are packed in... Figure 17 In room 38, and displayed as Figure 18 The water in syringe 36 is hydrated with fluid 12 until the desired consistency is achieved and the composition is uniformly hydrated. Large hydrated particles can be hydrated in conjunction with water (e.g., ...). Figure 19 , 20 (as shown in Figure 21) or they are hydrated with blood or BMA (such as...) Figure 22 (As shown) is then distributed in strips. For example... Figure 26 As shown, the dispensed strip-shaped large particles can be molded into tubular shapes by hand. For example... Figure 18 The syringe shown does not have a perforated needle. It is understood that when hydrating large particles (e.g., pellets) with fluid, either a receiving tube with a perforated needle or a standard receiving tube without a needle can be used.

[0152] Example 6

[0153] Hydration of compositions with different macroscopic volume parameters

[0154] Purpose:

[0155] The purpose of this experiment was to further evaluate the hydration of the composition within the Nordson syringe barrel, including changes in the macroscopic shape, size, density, filling, and hydration parameters of the pre-filled syringe product.

[0156] method:

[0157] Prior to macrobody formation, ceramic material sheets bonded to the polymer were sterilized and freeze-dried using 25-40 kGy gamma radiation. The sheets were then cut into cylindrical macrobodies using 4 mm and 6 mm biopsy puncturists. The macrobodies were hydrated with heated (37°C) bovine blood. Specifically, 4 mm and 6 mm macrobodies were loaded into Nordson syringe barrels. The syringe plunger was then compressed to determine the macrobody filling density. Blood was then added to the syringe through a perforated needle attachment. The syringe was left to stand on a workbench for 10 minutes to allow sufficient soaking time. The composition in putty form was then injected down the cannula into a weighing boat. The injected putty was combined at a 1:1 v / v hydration ratio to simulate the combination with autologous grafts (1-4 mm bovine bone fragments).

[0158] result:

[0159] The lyophilized ceramic material sheets bonded to the polymer were readily fabricated into macroforms, and minimal loss of compression or putty thickness was observed. As expected, the smaller 4mm and 6mm macroforms exhibited smoother hydration and occupied less space within the syringe compared to the previously evaluated 8mm macroforms. A 10-minute benchtop soaking time was sufficient for hydration at the trial volume.

[0160] Putty injection was performed easily using a syringe and cannula without clogging. As shown in Table 1, the macroscopic cylinder dimensions, density, surface area (SA), volume, surface area to volume ratio (SAVR), and filler density for each macroscopic size were determined / calculated.

[0161] As shown in Table 1 below, the following macrobody parameters can be used. A macrobody diameter range of 4 to 6 mm yields a smooth and cohesive injection, but a range of approximately 0.2 to approximately 10 mm is also acceptable. A macrobody density of 0.1 to 0.6 g / cc yields a smooth and cohesive injection, but a range of approximately 0.1 to approximately 0.75 g / cc is also acceptable. The SAVR of the macrobody is 10 to 30. The fill density within the syringe should allow for equal volumes of macrobody and open space so that fluid can fill the open space volume (1:1 ratio). The fill density within the syringe can be in the range of 0.2 to 1.0 g / cc compression. When the hydration fluid is added at ratios of 1:1 g / g and 2:1 g / g, all ultimately hydrated graft volumes are similar (1.75 to 2 cc), regardless of macrobody size.

[0162]

[0163] Table 1. Macroscopic Parameters

[0164] Although the invention has been described with reference to preferred 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 the invention.

Claims

1. A method for preparing a homogeneous hydrated composition, the method comprising providing in a chamber a plurality of freeze-dried porous macroparticles, each of the plurality of freeze-dried porous macroparticles having an average diameter of 0.1 mm to 10 mm and comprising 50 wt% to 98 wt% ceramic material and 2 wt% to 50 wt% polymer; mixing each of the plurality of freeze-dried porous macroparticles with a fluid in the chamber to homogeneously hydrate each of the plurality of freeze-dried porous macroparticles to form a homogeneous hydrated composition, wherein the ceramic material has an average diameter of 50 μm to 800 μm and comprises 8 to 22 wt% hydroxyapatite and 78 to 92 wt% biphasic calcium phosphate of β-tricalcium phosphate in a calcium-to-phosphate ratio of 1.0 to 2.0, the polymer is a collagen carrier, and wherein the ceramic material bound to the polymer forms a macrobody having a diameter of 4 to 6 mm and a density of 0.1 to 0.6 g / cc.

2. The method according to claim 1, wherein the ratio of the fluid to the plurality of freeze-dried porous large particles is 1:1 to 3:

1.

3. The method of claim 1, wherein the plurality of freeze-dried porous macroparticles in the chamber have a packing density that maximizes the hydration of the plurality of freeze-dried porous macroparticles.

4. The method of claim 1, wherein the shape of the plurality of freeze-dried porous large particles includes cylinders, cubes, rods, tubes, rectangles, disks, or combinations thereof.

5. The method according to claim 4, wherein the tube is a hollow tube.

6. The method according to claim 4, wherein the tube is a hemispherical hollow tube.

7. A hydratable composition comprising a plurality of lyophilized porous macroparticles, wherein, based on the total weight of each of the lyophilized porous macroparticles, the macroparticles comprise, in an amount of 50% to 98% by weight, porous ceramic particles with an average diameter of 50 μm to 800 μm and in an amount of 2% to 50% by weight, collagen, wherein each of the lyophilized porous macroparticles has an average diameter of 0.1 mm to 10 mm, the plurality of lyophilized porous macroparticles being configured to hydrate with a fluid to form a homogeneous hydrated composition, wherein each of the porous ceramic particles comprises, in an amount of 8 to 22% by weight, hydroxyapatite and 78 to 92% by weight, biphasic calcium phosphate of β-tricalcium phosphate in a calcium to phosphate ratio of 1.0 to 2.0, and wherein the ceramic material bound to the polymer forms a macrobody with a diameter of 4 to 6 mm and a density of 0.1 to 0.6 g / cc.

8. The composition of claim 7, wherein each of the porous ceramic particles comprises an outer surface comprising a plurality of concave shapes each having a diameter of 400 micrometers to 600 micrometers.

9. The composition according to claim 7, wherein, Each of the porous ceramic particles has a micropore, and the diameter of each of the micropores is 0.01 to 10 micrometers.

10. The composition of claim 7, wherein each of the porous ceramic particles has a Brunauer–Emmett–Teller (BET) surface area of ​​0.2 to 10 m². 2 / g.

11. The composition according to claim 7, wherein the collagen is (i) porcine or bovine collagen; (ii) bovine type I collagen; or (iii) tendon or dermal-derived collagen.

12. The composition of claim 7, wherein the shape of the plurality of freeze-dried porous large particles comprises cylinders, cubes, rods, tubes, rectangles, disks, or combinations thereof.

13. The composition according to claim 12, wherein the tube is a hollow tube.

14. The composition according to claim 12, wherein the tube is a hemispherical hollow tube.

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