JP2003525696A - Shaped particles and compositions for bone defects and methods of making the particles - Google Patents

Abstract

(57) SUMMARY Shaped particles for use in an array of combined particles for repairing, replacing, ameliorating, or enhancing a bone defect are provided. In a preferred embodiment, the particles have six ends, with the interstitial space between the ends of one particle receiving the ends of adjacent particles in the array. The particles are suspended in the material, which facilitates the application of the particles to the bone, and the material can include biological agents that promote bone growth or prevent infection. Further provided is a method of forming shaped particles by producing a hardened calcium sulfate material.

Description

Detailed Description of the Invention

The present invention relates generally to shaped particles as a bone substitute for implants and the use of such substitutes to repair, replace, augment or ameliorate bone defects. The present invention also provides
It relates to a composition having particles in suspension material which enhances the utility of the particles as a bone substitute. Further provided is a method of making an improved and hardened calcium sulfate material between shaped particles.

[0002] Bone grafts are used to fill the spaces in bone tissue that are the result of trauma, disease degeneration or other loss of tissue. Clinicians, for a variety of reasons, often perform bone graft procedures to fill the bone gap created by bone loss or cancellous bone compression. Often, the clinician must also provide the implant bone material with some mechanical support, as is the case with compression implants around subchondral bone replacement or total joint replacement devices. In these cases, the clinician fills the material into the defect to create a stable platform to support the surrounding tissue and metal products. There are several bone graft options available to orthopedic clinicians. Most commonly, the source of transplant material is either the patient (autologous transplant) or the donor (allograft). In autografts and, to a lesser extent, allografts, there are biological factors such as proteins or cells that may be present and helpful in the process of fracture healing. Xenografts and bone substitutes are other options.

Autografts are the most commonly used implant materials that are removed from the patient's own body. Implants may be in the form of small pieces or masses, taken from ectopic bone sites within the body, such as the iliac crest, and used at the site of deficiency. In addition to limited bone supply, autografts have the potential drawback of increased pain and pathological conditions reminiscent of secondary surgical methods.

[0004] Allografts are another form of transplant that is derived from human bone tissue donated to a tissue bank, such as from cadaver. Allografts are available in many forms: in the form of granules or pieces, chunks or struts, and in processed forms such as gels or putties. In addition to the limited supply, a major drawback of allografts is the risk of disease transmission.

Xenografts are an option derived from non-human bone tissue donors, often processed and mixed with other ingredients such as hydroxyapatite or other calcium salts. Also, xenotransplantation is not convenient for human use due to disease transmission and immunogenicity concerns. Due to the disadvantages of autografts and allografts, many have focused their efforts on creating new artificial bone substitute materials that can meet existing needs.

Grafted bone substitutes are non-human material or non-human bone tissue. The advantages of artificially derived substitute materials over human derived bone and naturally derived substitutes are: 1) more control over product consistency; 2) lower risk of infection and disease; There is no morbidity or pain caused by bone harvesting; and 4) surrogates are available in many different volumes (ie, not limited to the patient harvest site).

The biological and physical requirements placed on the bone graft material depend on the processing instructions. For example, the clinician chooses different physical forms of the material (granules, lumps, dense, porous, putty / paste, cement) depending on the difficulty of filling the bone gap sufficient for implantation. Craniomaxillofacial defects typically impose relatively low load bearing requirements on the implant material. The size of the defect affects whether transfer grafts are sufficient or guided grafts are required. In some cases, the ability of the implant to withstand high loads for long periods of time (such as in the case of compression implants around modified joint prostheses) and maintain structural support (in the case of implants to achieve spinal fusion) like)
It is more important than the implant's ability to promote bone healing or fill the gap.
For this reason, it is important to have materials that are more compliant with the bone grafts than currently available products in the art that are insufficient to be easily adapted to a large number of applications. The use of such products has the inherent advantage of being less expensive and more effective for orthopedic personnel.

Two properties associated with currently available artificial granules have their own disadvantages. First, it is difficult to put the granules from the package into the defect. Granules are usually small, smaller than 10 mm in any size and difficult to grab individually. There is no way for granules to form aggregates and the clinician cannot treat them as a whole. Second
Moreover, if the granules spill into the open surgical wound, the granules will stick to the soft tissue making it difficult to remove them from the wound. Clinicians fear that if the granules are left in the wound, they can cause further complications, such as migration to an organized surface that can cause further damage.

Artificial implant bone granules are generally supplied in simple glass vials and are rarely made to improve handling characteristics or facilitate surgical procedures. There are a few exceptions. Syringe-like devices are available on the market to help deliver the granules to the implantation site, but this does not address the problem of preferential adherence of the granules to the soft tissue in the wound. Alternatively, demineralized allograft products are commercially available and premixed in gels or putties to improve handling.

Other implant bone substitutes are known in the art. US Patent No. 5,676,
No. 700 interlocking components for bone augmentation or replacement such that at least four pillars of the element protruding from the hub are not in more than one common plane in either direction of the pillars. Is oriented to. The element has pillars with an oval cross-section, and in the preferred embodiment the angle between each pillar is 109.47.
It is degree. US Patent No. No. 5,178,201 is directed to an implant method with particles having 4-8 pins radiating from the center and at least 3 pins attached in a basic pattern to the graft method. . The body diameter of the particles is up to 3 mm and the specification does not teach tapering the pins. US Patent No. No. 5,458,970 teaches shaped particles consisting of deformed fibers having a maximum length of 0.1 mm and the fibers having a large number of needle-like portions extending from its core are zinc oxide whiskers. ing.

US Patent No. No. 5,258,028 is directed to an injectable microimplant system that utilizes woven, extremely small particles, up to 3 mm in diameter, having a large number of apparently protruding columnar members. WO94 / 08912 teaches an assembly having six arms, which are usually regular square pyramidal pyramids, each having four sides. It is known to make products from the form of calcium sulfate hydrate. The conversion of gypsum powder to calcined gypsum powder (calcination) is well established and rehydration of calcined gypsum powder for conversion to gypsum is also well known.

US Patent No. No. 5,320,677 describes the formation of stronger component composites such as gypsum and wood fibers. The technique dehydrates and rehydrates the mixture. This is a method in which wood fibers are mixed in calcium sulfate and hardened.
The object to which such a method is applied is the preparation of wall coverings. German Patent Publication DE 3732281 C2 relates to a method of compaction of gypsum, followed by dehydration / rehydration at elevated temperature and pressure for the purpose of forming a hardened solid to bring the waste material into a more compact form for easier disposal. .

[0013] In the technology of forming shaped particles of calcium sulfate, there is a lack of methods to form small, precision parts with high density, strength and resistance to water dissolution. This method mainly requires that calcium sulfate be kept below a temperature of about 150 ° C to 300 ° C, especially below 500 ° C, in order to avoid thermal decomposition to the insoluble anhydrous form which is difficult to rehydrate. It is complicated. The low decomposition temperature eliminates the possibility of conventional high temperature sintering methods that sinter the calcium sulphate particles together, thereby strengthening and hardening the material. Sintering is defined here as the binding of powder particles by solid state diffusion.

Typical shaping methods for calcium sulphate are compression of dry powder (as in pharmaceutical tableting) or casting of calcined gypsum slurry. The wall industry uses a variety of wet forming methods that compress a slurry of calcined gypsum into large sheets. British Patent No. 2205089A is directed to a method of making calcium sulfate alpha hemihydrate. Calcium sulphate dihydrate was cast and introduced into an autoclave, and in the presence of an appropriate amount of water in the pores, the crystal growth and crystal form of calcium sulphate alpha hemihydrate, the temperature of 110 ℃ ~ 180 ℃. It is adjusted by adjusting the atmospheric pressure in the autoclave by keeping the temperature at ℃.

An object of the present invention is to provide shaped particles for use in the treatment of bone defects,
The particles are shaped for use in an array of interdigitated particles, comprising a central portion and at least four tapered ends projecting from the central portion, the protrusions defining a void space between adjacent ends. And each end has a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles defines at least one end of adjacent particles. It accepts and facilitates the assembly of adjacent particles in the array.

In a particular embodiment of the invention, the particles have at least 3 ends in one plane and the particles have 6 ends. In other particular embodiments, the particles are ceramic, bioactive glass, polymers, polymer / ceramic composites and polymers /
It consists of a material selected from the group consisting of glass composites. In a preferred embodiment, the particles consist of ceramic, more preferably calcium salts, such as calcium sulphate, calcium carbonate, calcium phosphate and calcium tartrate,
Most preferably it consists of calcium sulfate or gypsum.

In another embodiment of the invention, the particles consist of polymers such as polypropylene, polylactic acid, polyglycolic acid and polycaprolactone. In a preferred embodiment, the particles have a diameter of about 3-10 millimeters, more preferably 4-8 millimeters, most preferably 6 millimeters. It is another object of the invention to provide an array comprising multiparticulates, wherein the multiparticulates are a mixture of particles composed of different materials. In certain embodiments, the different materials are ceramics such as calcium salts, bioactive glasses, polymers, polymers /
It is selected from the group consisting of ceramic composites and polymer / glass composites.

In a further object of the invention there are shaped particles for the treatment of bone defects. The treatment is selected from the group consisting of bone augmentation, bone repair, bone replacement, bone improvement, bone strengthening and bone healing. In a particular embodiment, the bone defect is selected from the group consisting of fracture, fracture, bone loss, soft bone, fragile bone, hole in bone, interstitial space in bone, bone disease and degeneration of bone. In a further embodiment, the disease is osteoporosis, Paget's disease, fibrous dysplasia, dysplasia, periodontal disease, osteopenia, osteopetrosis, primary hyperparathyroidism, hypoalkaline phosphatase, fibrotic It is selected from the group consisting of bone dysplasia, osteogenesis imperfecta, myeloma bone disease and bone malignancy. In a particular embodiment, the arrays of the invention have a combination of adjacent particles, thereby providing adequate porosity to allow implantation from the host bone. In a particular embodiment, the porosity is 40-80%. In a more preferred embodiment, the porosity is 60-80%.

Another object of the invention is an array of shaped particles. The array comprises a number of shaped particles, the shaped particles having a first shaped particle comprising a central portion and at least four tapered ends projecting from the central portion [the gap between the adjacent ends due to the protrusions]. A space is defined, each end having a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape, wherein the interstitial space of one particle is at least one of the adjacent particles. Two ends to facilitate the assembly of adjacent particles in the array of shaped particles]; a central portion, at least two non-curved ends, and at least three curved ends protruding from the central portion. Second shaped particles consisting of [the protrusions defining interstitial spaces between adjacent ends, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receives at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array. ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. [1] or more shaped particles selected from the group consisting of

A further object of the invention is a shaped particle used to treat a bone defect,
The particles are shaped for use in an array of interdigitated particles, the particles comprising a polycyclic structure having at least four curved protrusions, the protrusions defining interstitial spaces between adjacent protrusions, The protrusions facilitate the assembly of adjacent particles in the array. In particular embodiments, the angles between the curved protrusions are equal. In another embodiment, the shaped particles consist of polymers such as polypropylene, polylactic acid, polyglycolic acid and polycaprolactone, or polymer / ceramic composites or polymer / glass composites.

Another embodiment of the present invention is a first shaped particle comprising a central portion and at least four tapered ends projecting from the central portion [wherein the protrusion defines a void space between adjacent ends. And each end has a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape such that the interstitial space of one of the particles defines at least one end of adjacent particles. Receiving and facilitating the assembly of adjacent particles in the array of shaped particles]; a first portion comprising a central portion, at least two non-curved ends, and at least three curved ends protruding from the central portion. 2 shaped particles [the protrusions define interstitial spaces between adjacent ends, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receives at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array. ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. And a shaped particle selected from the group consisting of: and a suspension material, the composition being used for treating a bone defect.

In a particular embodiment, the suspension material is selected from the group consisting of starch, sugar, glycerin, blood, bone marrow, autograft material, allograft material, fibrin clot and fibrin matrix, or suspension The material is a gel-forming binder, such as collagen derivatives, cellulose derivatives, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, fibrin, and biological adhesives such as cryoprecipitates.

In another object of the invention, the suspension material is a biological agent such as a growth factor,
It further consists of antibiotics, strontium salts, fluoride salts, magnesium salts, sodium salts, bone morphogenetic factors, chemotherapeutic agents, analgesics, bisphosphonates and bone growth agents. In certain embodiments, the growth factor is platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), insulin-related growth factor-I (IGF-I), insulin-related growth factor-II (IGF-II). ), Fibroblast growth factor (FGF), beta-2-microglobulin (BDGF II)
And a bone morphogenetic protein (BMP). In a particular embodiment, the antibiotic is selected from the group consisting of tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycosides such as tobramycin and gentamicin.

In another particular embodiment, the bone morphogenetic factor is a demineralized bone protein,
It is selected from the group consisting of demineralized bone matrix (DBM), bone protein (BP), bone morphogenetic protein (BMP), osteonectin, osteocalcin and osteogenin. In a further specific embodiment, the chemotherapeutic agent is selected from the group consisting of cisplatinum, ifosfamide, methotrexate and doxorubicin hydrochloride. In a more specific embodiment, the analgesic agent is selected from the group consisting of lidocaine hydrochloride, bipivacaine hydrochloride, and nonsteroidal anti-inflammatory drugs such as ketorolac tromethamine. In another object of the invention, the composition further comprises a coagulation factor composition. In a particular embodiment, the clotting factor composition comprises fibrinogen, thrombin and factor X.
Including III.

In a further object of the present invention there is a method of treating a bone defect comprising applying a shaped particle to a bone defect, the shaped particle comprising at least a central portion and a tapered end protruding from the central portion. A first shaped particle consisting of four particles [wherein the protrusion defines a void space between adjacent ends, each end having a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape; And having the interstitial space of one of the particles receives at least one end of the adjacent particles, facilitating the interlocking of adjacent particles in the array of shaped particles]; A second shaped particle consisting of at least two non-exposed ends and at least three curved ends protruding from the central portion [wherein the protrusion defines a void space between adjacent ends; , The base each end is attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receives at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array. ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. Easy to do].

In another object of the present invention there is a method of treating a bone defect comprising combining shaped particles with a suspension material and applying the combination to the bone defect,
The particle comprises a first shaped particle comprising a central portion and at least four tapered ends projecting from the central portion [wherein the protrusion defines a void space between adjacent ends, each end being defined by the central portion. Having a base attached to, opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle in the array of shaped particles. Facilitating the interlocking of adjacent particles]; second shaped particles consisting of a central portion, at least two non-curved ends and at least three curved ends protruding from said central portion [by said protrusions] An interstitial space between adjacent ends is defined, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. Easy to do].

In another object of the present invention there is a kit for the treatment of bone defects comprising a suspension material and first polymorphic particles and second polymorphic particles, said first and second polymorphic particles comprising: The particles are shaped for use in an array of interdigitated particles, the particles having a first shaped particle consisting of a central portion and at least four tapered ends projecting from the central portion [adjacent by the protrusions. Defining an interstitial space between the ends, each end having a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape; Accepting at least one end of the particles to facilitate the assembly of adjacent particles in the array of shaped particles]; a central portion and at least two non-curved ends and a protrusion from the central portion A second shaped particle consisting of at least three of the curved ends [wherein the protrusion defines a void space between adjacent ends, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. Easy to do].

In particular embodiments, the kit further comprises a biological agent. In another specific embodiment, the kit further comprises a coagulation factor composition, eg, a composition consisting of fibrinogen, thrombin and factor XIII. In another embodiment, the kit further comprises the first multiparticulate and second multiparticulate bowl containers and a delivery device. In a particular embodiment, the delivery device is a spoon,
It is selected from the group consisting of spatula, dipper, forceps, forceps, knife, hemostat, syringe, pipette, cup and dipper. In another particular embodiment, a bowl container is used to mix the first and second multiparticulates and the suspension material. In another specific embodiment, a bowl container is used to mix the first and second multiparticulates, the suspension material and the biological agent.

In another embodiment, a central portion and at least two non-curved ends,
Consisting of at least three of the curved ends projecting from the central part [the protrusion defines a void space between adjacent ends, each end being a base attached to the central part, an opposing point, a length and Having a circular cross-sectional shape, the interstitial spaces of one of the particles receiving at least one end of the adjacent particles, facilitating the interlocking of adjacent particles in the array. There are shaped particles used to treat bone defects shaped for use in an array of interlocking particles.

In another embodiment, calcium sulphate dihydrate shaped particles comprising the steps of making shaped particles of calcium sulfate dihydrate; heating the particles; and applying water to the particles. There is a way. In a further embodiment, shaped particles of calcium sulphate dihydrate are made; heating the particles of calcium sulphate dihydrate in the presence of pressure and moisture to convert the particles to alpha-calcium sulphate hemihydrate. To produce shaped particles of calcium sulphate dihydrate comprising the steps of: converting all or all; and applying water to the particles to convert the α-calcium sulphate hemihydrate to the calcium sulphate dihydrate. There is a way to do it.

Other further objects, features and advantages will be apparent and will be finally more readily understood by reading the following specification and by referring to the accompanying drawings, which form a part thereof. Let's do it. Also, the exemplification of the presently preferred embodiments of the invention is provided for the purpose of disclosure.

The term “bone defect” as used herein is defined as a bone defect, such as a fracture, fracture, gap, pathological bone, bone loss, fragile or soft bone, injury, disease or degeneration. Such defects may be the result of disease, surgical intervention, deformity or trauma. Degeneration can be the result of progressive aging. Pathological bones include bone diseases such as osteoporosis, Paget's disease, fibrous dysplasia, dysplasia, periodontal disease, osteopenia, osteopetrosis, primary hyperparathyroidism, hypoalkaline phosphatase disease. , Fibrous dysplasia, osteogenesis imperfecta, myeloma bone disease and bone malignancy. Bone defects may be due to disease or constitution, such as diseases that adversely affect bone indirectly. Furthermore, the bone malignancy being treated may be a primary bone malignancy or metastases from another tissue or part of the body.

The term “ceramic” as used herein is defined as a non-metallic, non-organic engineering material. Examples of such materials are hydroxyapatite, calcium sulfate, alumina or silica. As used herein, the term "gypsum" refers to calcium sulfate (C) in the stable dihydrate state.
aSO ₄ 2H ₂ O), natural minerals, synthetically derived equivalents and water of calcium sulfate hemihydrate (CaSO ₄ 1 / 2H ₂ O) (calcined gypsum) or hard gypsum calcium sulfate. Includes dihydrate materials formed by summing. Gypsum can be obtained from commercially available sources.

As used herein, the term “tapered” is defined to refer to the ends of shaped particles where the width of one end is different from the width of another end. Thus, the end taper is either outward from the center of the particle or inward toward the center of the particle. An object of the present invention is a shaped particle as part of a three dimensional combinatorial array of particles utilized in a bone graft.

The skilled artisan is aware that particles are utilized in guided implants where the implant actively promotes bone growth, either directly or indirectly. In addition, or in the alternative, the particles can be used for transfer implants where the implant has a transfer to bone growth but does not actively or directly promote it. In certain embodiments, the transfer implant is ceramic,
Utilizing shaped particles made from polymeric, glass materials, polymeric / glass, or polymeric / ceramic materials. In another particular embodiment, particles for transfer implantation are augmented with biological agents. The material of the particles is a biocompatible ceramic or glass that is not resorbed or broken down in the body, as the bone heals, fills the bone gaps or improves the bone defect. Is. The particles are of a suitable size such that some of the individual granules are often used to fill larger voids while being used to fill smaller voids. The three-dimensional structure allows the granules to fill the volume and interlock with each other. In addition, the particles can combine with the bone. The combination allows the particles to support some mechanical force while maintaining stability and aiding bone healing. Unlike commercially available products, the interlocking features allow the particles to resist some shear stress. It also helps resist migration from the implant site. The particles can meet unusual bone defect shapes and sizes without necessarily having to carve larger chunks into similar shapes / sizes. The combined particles also provide the entire implant with the ability to mechanically behave in a single mass rather than current granular products. The shape is a filled volume that is beneficial for bone healing, but instead open, interconnected (interc
onnected) such that the collection of these particles does not agglomerate into a solid with porosity.
The shape of the array of particles and / or shaped particles preferably allows for the fabrication or prediction of a particular porosity. For example, particles may be 40-80% due to aggregate formation.
Can be shaped to have a design that allows for porosity of

The purpose of having shaped particles is twofold. First, the mating ability provides resistance to shear stress and helps increase stability when the implant is packed into the defect. Second, porosity needs to be maintained when the shaped particles are combined. It is known in the art that new bone growth can migrate into pores in the 100-400 micron size range. The target total porosity is in the range of 20% -80%, which means that the array of interdigitated shaped particles of the present invention maintains 20-80% open space of a particular volume of array. . It is important that the implant material provide adequate porosity and allow implantation from the host bone.
Instead, the material must either resorb or degrade to allow bone replacement. A preferred embodiment is a combination of both of these properties.

The tapered shape of the ends of the shaped particles improves manufacturability, maximizes the open space between the ends, and provides mechanical stability, eg, a central body that places a load in excess of the mass of the material. The thicker arms, which are closer together, increase the mechanical stability of the preferred shaped particles of FIG.

The shaped particles of the present invention are illustrated in the figures. FIG. 1 shows shaped particles (10) having ends (20), and in the preferred embodiment the particles have six ends. In a preferred embodiment, at least three ends are in a common plane. The end tapers outwardly along the length of the end (30), so that the end base (40) is wider than the end tip (50). In a preferred embodiment,
The distal tip (50) is rounded. The particles have interstitial spaces (60) between adjacent ends (20). In a preferred embodiment, the tip (50) of the end (20).
The radius of curvature of the is about 0.5 mm and the radius of curvature of the adjacent distal interstitial spaces (60) is about 0.5 mm.

The preferred width of the overall particles is about 3-10 mm, preferably 4-8 mm, most preferably 6 mm. The most preferred width of the base (40) of the distal end (20) is about 1.85 mm and the preferred width of the distal tip (50) is about 1.19.
mm, and the preferred length (30) of the end (20) is about 3 mm. In the preferred embodiment, the angles between either of the adjacent ends (20) are approximately equal.
The skilled artisan knows that shaped particles larger than these dimensions or smaller than these dimensions can be used depending on the application and bone defect involved. Rather than 1, it is preferred to keep the size of the particles small with respect to the wound site so that many particles can fill the defect.

FIG. 2 illustrates an array of shaped particles of the invention in which the ends (20) of adjacent particles (10) are combined. 3A to 3D show different views of a particular embodiment in which a shaped particle (100) with five arms is the object of the present invention. In a preferred embodiment of a shaped particle with five arms, at least three ends are in one plane. End (
110) tapers inwardly along its length (120) such that the base (130) of the end (110) is narrower than the tip (141) of the end (110). An interstitial space (150) exists between adjacent ends. In a particular embodiment, the tip (141) of the end (110) is rounded.

3B to 3D, in a particular embodiment, two located approximately 180 degrees from each other.
The tips (158 and 159) of the two ends (160 and 170, respectively)
It is typically shown to be more conical in shape than the tip (141) of the end (110). The ends (160 and 170) taper outwardly and the bases (161 and 171 respectively) are wider than the tips (158 and 159).

4A to 4D show different views of a particular embodiment in which a shaped particle (300) with six arms is the object of the present invention. In a preferred embodiment, at least three ends are in one plane. The end (310) is its length (320)
Tapered inwardly along, the base (330) of the end (310) is narrower than the tip (340) of the end (310). Gap space (350
) Is present between adjacent ends. The tip (340) has a generally flat surface. 4B to 4D, the tip of the two ends (370 and 380, respectively) (
360 and 361) are generally more conical in shape than the tip (340) of the end (310) and have been shown to lie approximately 180 degrees relative to each other in the particle (300).

5A to 5D illustrate different views of a particular embodiment in which a six-armed shaped particle (400) is the subject of the present invention. In a preferred embodiment, at least three ends are in one plane. The end (410) is its length (420)
Tapering inward along the base of the distal end (410) (430),
It is narrower than the tip (440) of the end (410). An interstitial space (450) exists between adjacent ends. The tip (440) of the terminus (410) has a generally rounded surface. 5B to 5D, the tips (460 and 461) of the two ends (470 and 480, respectively) are usually more conical in shape than the tip (440) and are located 180 degrees from each other in the particle (400). Has been shown to do.

The shaped particles shown in FIGS. 4 and 5 are preferably made from polymers, polymer / ceramic composites or polymer / glass composites. The taper into the ends (310 and 410) allows these shaped particles to snap into adjacent particles. 6A to 6D illustrate different views of a particular embodiment of the present invention. The shaped particle (500) resembles two combined rings located at about 90 degrees to each other. The interstitial space (510) allows the assembly of adjacent particle rings (520) or curved protrusions. The preferred composition materials of this structure are polymers, polymer / glass composites or polymer / ceramic composites. In the preferred embodiment, the structure is relatively conformal as compared to the ceramic-based structure. The preferred diameter of the whole particle (500) is about 6 mm, and the ring of structure (520)
The preferred diameter of the component is about 1 mm. The maximum number of rings is such that it is not greater than 50% of the surface area of the enclosed sphere-otherwise the parts do not mate with each other or nest. This is used as a starting point, after which the diameter of the solid structure of the ring (eg about 1 mm) becomes a factor. As the diameter decreases, the number of possible rings increases.

In the numerical relationship of the radius of a “spherical” particle, r, the thickness or diameter of the ring, d and the number of rings, n, the surface area of the sphere is 4πr ² and the surface area of the interlocked ring is 2π.
It is rdn. The goal is to have a ring surface area of 50% or less of the spherical surface area. The numerical relationship can be described as 2πrdn ≦ 0.50 (4πr ² ) or 2πrdn ≦ 2πr ² or dn ≦ r.

7A to 7D illustrate particular embodiments of the present invention in which shaped particles (600) are similar to propellers. The interstitial space (610) allows the interlocking of the ends (620) of the particles. The length (615) of the end (620) is usually curved, as in a propeller arm. The composition material of this structure is a ceramic, polymer, bioglass, polymer / ceramic composite or polymer / glass composite. In the preferred embodiment, the structure is relatively conformal as compared to the ceramic-based structure. The preferred diameter of the whole particles (600) is about 6 mm and the end of the structure (620
The preferred diameter of the component) is about 1 mm. The ends (630 and 631), as shown in detail in FIG. 7D, are usually conical in shape and the length of the ends (65
0 and 651, respectively) with wider bases (640 and 641, respectively) tapering to thinner tips (660 and 661, respectively). The ends (630 and 631) are located approximately 180 degrees with respect to each other.

8A to 8D illustrate different views of a particular embodiment in which a six-armed shaped particle (700) is the subject of the present invention. In a preferred embodiment of a six-armed shaped particle, at least three ends are in one plane. The distal end (710) tapers inwardly along its length (720) such that the base (730) of the distal end (710) is narrower than the tip (741) of the distal end (710). An interstitial space (750) exists between adjacent ends. In a particular embodiment, the tip (741) is rounded. 8B-8D, in a particular embodiment, the tips (702 and 704) of the two ends (760 and 770, respectively) located approximately 180 degrees relative to each other have a tip (74) that is normally shaped distal (710).
It is shown to be more conical than 1). The ends (760 and 770) where the bases (761 and 771, respectively) are wider than the tips (702 and 704, respectively) are tapered outwards.

Skilled artisans will appreciate that several factors, including the volume-to-volume surface ratio of the shaped particles of the present invention, dictate the size of the particles required and the intended application of the bone graft to define degradation rate, strength and manufacturability. I know it has an impact.

Example 1-Shaped Particle Testing The shaped particle evaluation was based on two tests designed to address particle combination and clinical-type case applications. A) "Slump" test-Measure the ability of large numbers of transplanted bone granules to maintain their height before and after vibration. B) Push-thru test-resistance to push-through of aggregate formation of transplanted bone granules through a cylindrical defect in a porous foam mass, a laboratory model used as human cancellous bone. To measure. The goal is to determine which design gives the most combination, an improvement comparable to the commercially available tablet-shaped products.

Equipment: A) "Slump" test tablets, 28 mL shaped particle design, 28 mL each 100 mL graduated cylinder (EXAX, No. 200025) Scale (Mettler Toledo, AT261) Vibration, Electric Brush (Ideal)・ Industry Electric Maker (Id
eal Industries, Electric Marker) Funnel (half-angle 28 °) Cup-like container (half-angle 12 °, base diameter 1.125 ″) Annular stand height gauge (Mitutuyo, No. 192-112) Base plate ( 1x6x6 inch cold rolled steel) Clock with second hand

B) Push-through test tablets, 50 mL shaped particle design, 50 mL each, Tinius-Olsen screw drive mechanical test mechanism and # 2000.
Recorder Porous foam (General Plastics Manufacturing Company, FR3703) Polyethylene Plunger and Stopper Image Pro Plus Software (Media Cybernetics (Media
Cybernetics), V3.0.1)

Three different shaped particles of the present invention (shaped particles with 6 arms bulbously spread at the ends of the arms in the XY plane (FIG. 8); Shaped particles with 5 arms spread out (Fig. 3); Shaped particles with 6 arms that taper straight to the end of the arm in all directions (Fig. 1); and similar to commercially available products One tabletted shape.The shaped particle design was made using the clay formulation "50-dry." The SLA mold was used to form the design mold. All ingredients were made the same except that slightly different processing parameters were used to ensure removal.

1. A stereo lithographic model (SLA) was made from the mold for each of the three designs. 2. The SLA mold was washed and dried. 3. A lubricant was applied to the SLA type surface. Excess was removed with a clean cloth and compressed air, A. Two lubricants from Slide Products Inc. (Wheeling, IL) were used: 42612N.
44712G. B. Pam (registered trademark) (International Home Food (
International Home Foods, Parsippany, NJ (Parsippany)
), NJ) was used as another lubricant.

4. Clay formulation 50-Dry (81.6% gypsum, 1.1% carboxymethylcellulose, 4.1% glycerin, 13% water) rolled into a sheet large enough to cover the cavities in the mold (about 1 mm thick). )・ Gypsum: FG-200, BPB, Newarks, UK ・ Carboxymethylcellulose: 7HF, Hercules, Wilmington, Delaware ・ Glycerin, USP: GX-195-1, EM Science, Gibbstown (Gi
bbstown), New Jersey.

5. The mold halves were closed together and molded using a force of about 4000 lbs. 6. The mold was heated in a microwave oven to dry the water from the parts. A. Shaped particles with 6 arms bulbously spread at the ends of the arms in the XY plane, heated at about 30% force for 4 minutes. B. Shaped particle X with 5 arms bulging at the ends of the arms in the XY plane, heated at about 30% force for 4:25 minutes. C. Straight, tapered arm, heated at about 30% power for 3:50 minutes,
Shaped particle with 6 arms.

7. The mold was allowed to cool for about 1 minute. 8. The parts were removed from the mold and the flushing was trimmed using an Exacto knife. 9. The parts were dried in a vacuum dessicator for several hours before further testing.

Slump Test Since it is non-destructive, the slump test was performed first. Equal volume (28 mL)
Each shaped particle design and tablet sample of 1 were measured using a 100 mL graduated cylinder. These equal volumes were calibrated to determine the bulk of the material present. The test begins by injecting the entire volume of the individual shaped particle design into the original container. Use either a funnel (28 ° half angle) or a cup-like container (12 ° half angle with a 1.125 inch flat base) to contain the original bone particles for implantation, including the shaped bone particles. Provided. The container was then inverted and placed on the base whereby the vibration was applied for 5 seconds using an electric vibrating brush. The shaped bone graft particles that were shaped using vibration were stabilized in a container of choice and pre-packaged in their shape.

Following the shaking, the container was carefully removed. The height gauge was used to measure the initial height of the deposit. Vibration was then applied to the base plate to further stabilize the deposition. The height gauge was used again to measure this new height. The highest particles / tablets were used as height in all cases. This test was repeated 10 times for each design with each of two containers (funnel and cup-like container). From the data, height differences and height percentage changes (relative to the initial height of the deposit) were calculated.

Table 1 shows the bulk data collected for the three shaped particle designs and tablet shapes. The bulkiness shown was for 28 mL of particles and measured in a 100 mL graduated cylinder. One data point was collected for each design. Bulk and bulk by volume are important and are related to dissolution time and porosity of agglomerated granules. If all parameters are equal (material, density, surface area vs.
If the bulk is larger for each volume, the porosity of the lump will be lower,
The duration before dissolution is expected to be longer. The dissolution rate determines how much material disappears per unit time, but may be influenced by the surface area-to-volume ratio and the material.

[0060]

[Table 1]

Table 2 shows the summarized results of the slump test performed on each of the different sample shapes using the funnel as the initial shape. Each sample was measured 10 times. It has been proposed that maximizing the initial height and post-vibration height and minimizing changes in height and rate changes in height are ideal cases. The optimal values for the shaped particle design test for each parameter are in bold. The tablets did not form a deposit when the support vessel was removed (tablets could only be 1 or 2 layers high), indicating poor quality of combination as compared to the other samples.

[0062]

[Table 2]

[0063]

[Table I]

[0064]

[Table II]

[0065]

[Table III]

[0066]

[Table IV]

Table 3 shows the summary results of the slump test performed using the cup-like container as the initial form. As a result of slump tests using a funnel as our container, maximizing our height and post-vibration height and minimizing changes in height and percentage changes in height were ideal cases. Optimal values for the shaped particle design tested in each column are in bold.

[0068]

[Table 3]

[0069] The actual test data are as follows.

[Table V]

[0070]

[Table VI]

[0071]

[Table VII]

The data from the two slump tests were consistent. From tests using a funnel for support and the shape of the original stack, a simple tapered six-armed shaped particle looked better than the other designs. In a test using a cup-like container,
Shaped particles with six arms having bulbous arms in the XY plane,
It looked like a better design.

Push-Through Test The push-through test is based on Tinius-Olsen (Willow Groe).
ve), Pennsylvania) was a mechanical test performed using a screw-driven mechanical test mechanism. Once tested using this procedure, sample parts and defects in the porous mass are considered to be ineffective for damaged and rubbed tests.

A polyethylene stopper was pre-punched in a porous foam mass, 0.750.
"Place at the bottom of the hole (penetration). Then add the volume of shaped particles (approximately 8 mL) to the hole,
The top plunger was inserted. The correct amount of shaped particles was added when the plunger was positioned so that the full mark was just above the level of the top of the porous foam. The test mass with the plunger, stopper and shaped particles was then transferred to the testing mechanism. The part to be tested is positioned so that the stopper is above the solid mass and temporarily prevents the shaped particles and stopper from spoiling. A 10 pound preload force is then applied at a rate of 0.1 inch / minute. The preload is then removed and the stopper is placed over the opening so that the plunger can press against the shaped particles and the main resistance comes from the partial forces between the shaped particles and the shaped particles and the wall. Position it. Further resistance is expected between the stopper / plunger and the wall, which is small and will be uniform in all tests performed. Reapply the load at a rate of 0.1 in / min until the resistance load drops to zero and the granules are clear of the test mass. load/
Data is recorded using a displacement graph. This test was repeated 5 times for each of the 3 shaped particle designs and 3 times for the tablet shape.

The data was analyzed using Image Pro Plus software (Media Cybernetics) to determine the area under the curve. The assumption was made that the load and the exclusion axis were on the same scale (exclusion), which means that the value calculated as the area under the curve is not truly energy. The value of the area under the load exclusion curve is useful for comparing with each other and indicates relatively which design requires more energy to force the granules through the mass. Table 4 shows the summary results for the push-through test for each of the different geometries.

[0076]

[Table 4]

Maximizing the area under the load / exclusion curve was ideal-meaning the maximum energy required to exceed the resistance of mating and friction. The maximum value is shown for the shaped particles with 6 arms in which all arms are tapered, and is shown in bold in the table.

The difference in push-through resistance between this design and each of the other three designs was statistically significant (Student's t-test, two tails, non-uniform variables, p <0.05). I understood. Observations during testing showed that all three shaped particle designs resist push-through as well-interrupted by themselves and by the granules in combination with the walls of the foam mass, almost the entire thickness of the test mass. Resist the movement of the plunger across the ground.
The tablet shape did not provide much resistance and only had the short travel distance required before all the granules fell from the bottom of the test mass.

The granules tested were listed to reduce the bulk per 28 mL volume: tablet shape, 6-arm shaped particles with tapered arms, 5 arm shaped particles and X-. A shaped particle with 6 arms flared in a bulb at the ends of the arms in the Y plane. The conclusions of the slump test and push-through test are as follows. Different designs of slump tests were inconclusive. Testing with a funnel (28 ° half angle) showed that the 6-arm shaped particles with tapered arms were the best. Testing with a cup-like container (12 ° half angle, 1.125 ″ base) showed that the best shape was a shaped particle with six arms bulbously flared at the ends of the arms in the XY plane. It was also found to be qualitatively poorer than any of the shaped particle designs, failing to combine and failing to retain most of the original stack height.

Push-through testing showed that the six-armed shaped particles with tapered arms all provided the most resistance to pushing the granules through the porous foam test mass. Both other shaped particle designs require about 1/3 less energy to push the granules into the same mass. 6 tablets with tapered arms
About 3% of the energy required to push through shaped particles with one arm
Only need. All of the shaped particle designs were observed to resist push-through until the plunger exited the test mass almost completely. The tablet shape was ruined after the plunger had moved through the lump a short distance.

[0081] Example 2-Characteristics of shaped particles   In a preferred embodiment, the material of the ceramic component of the bone graft system of the present invention is sulfuric acid.
It is calcium. Other materials that can be used include calcium salts; hydro
Xiapatite, calcium phosphate; bioactive glass, vitreous-based glass (
(As may be used for maxio-cranio applications);
Lucium, calcium-based minerals; various calcium phosphates, and calci
Contains um-rich minerals, tricalcium phosphate and orthophosphate;
Apatite / wollastonite glass-ceramic, calci often used for laser applications
Umsilicates; resorbable polymers such as polysaccharides, polyglycolates,
Lylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone, polyp
Ropylene fumarate (all of these are made into blends or copolymers,
Desired properties); and resorbable polymer composites and
Includes glass or ceramic fillers. The main component of bioactive glass is C
aO, SiO₂And P₂O_FiveAnd its minor component is Na₂O, MgO, Al ₂ O₃, B₂O₃And CaF₂Is a possible material.

In a particular embodiment, the shaped particles of the present invention are colored to make them more discernible.
In another particular embodiment, the differently shaped particles of the invention are displayed in different colors to better distinguish the particles. In another particular embodiment, the particles are coated or an agent such as green fluorescent protein or blue fluorescent protein,
Inclusion in them makes them fluorescent and thus more recognizable.

The circular cross-section of the ends or arms of the shaped particles of the present invention is useful for resistance purposes, since an equal response to load occurs regardless of the application of the load near the periphery. is there. In contrast, commercially available products and US Pat. 5,6
The oval shape, as used in U.S. Pat. No. 76,700, is a measure of the load when the load is applied in the direction of the oval's shorter width lexical direction, as compared to the oval's longer width axis. Reduces resistance.

Example 3-Suspension Material It is an object of the present invention to utilize a suspension material for suspending the shaped particles of the present invention to make it easier to apply to bone defects. . The suspension material can be used as a further component of a bone substitute bone substitute system for treating bone defects. Suspension materials are liquids, putties, doughs or gel phase ingredients which can be mixed with the shaped particles described above, either before use or during prepacking. Suspension material has two possible functions: 1) acting as a binder, improving handling by forming a putty-like material that can be embodied, and / or 2) acting as a biological tool and healing. Infectious disease control, bone growth or other healing or supplementing by adding biological agents can: The suspension material provides a standard suspension of particles within the material, or the attachment of particles or the particles in such a way that the material is smaller in volume in the array than the volume of the particles themselves. Provides a bond.

Suspension materials respond to time, temperature, the presence of body fluids, or other external stimuli that may provide energy, such as ultraviolet radiation, magnetic radiation, electromotive force (EMF), radio waves or ultrasound. It can then be cured or uncured. In certain embodiments, the suspension material degrades when implanted. Conceptually, carbohydrates,
It is derived from natural products such as starches or glycerin. It should have sufficient viscosity to help the granules adhere to each other and improve surgical handling. Coating calcium salts with this type of material of the preferred embodiment of the shaped particles of the present invention also reduces their affinity for sticking to soft tissue and removes unwanted moieties from the site of application. make it easier. The fibrinogen / thrombin / factor XIII combination also provides for the use of liquids or gels of suitable viscosity as binders. The liquid may also be an artificial material that can be implanted in situ, for example calcium sulphate (calcined gypsum). In another embodiment, the binding agent comprises a carrier of various agents including but not limited to growth factors, bone morphogenetic proteins, fibrinogen / thrombin, antibiotics or some other therapeutic agent (see Example 6). Can act as.

In a particular embodiment, the suspension material is blood, bone marrow, autograft material or allograft material. These materials are preferably derived from patients treated with bone defects. Instead, they are preferably derived from the donor and have no source of disease transmission. In the present invention, suspension materials compatible with all artificial materials (calcium phosphate, calcium sulfate, bioactive glass and resorbable polymers) are used. Examples of suspension materials are mixed with artificial or natural products (autograft or allograft) selected by the clinician to produce a "paste" for application to bone defects such as bone gap filling. It is a mixed gel that can be. The suspension material must have a suitable viscosity and thickness to agglomerate the particles for easy application at the implantation site. Once agglomerated, the paste can be manipulated by hand or transferred to the defect site using a tool such as a chew, spoon or syringe.

The suspension material may also reduce selective sticking to soft tissue. This attachment to soft tissue can be caused by a number of factors. Calcium phosphates are known for their affinity for many proteins, as shown by their use in chromatographic columns for protein isolation. Thus, their surface chemistry contributes to their selective attachment to the soft tissue at the surgical site, which is often covered with blood and protein-containing body fluids. Second, many of these commercially available products have a rough surface that mechanically attaches to soft tissue, such as coral-derived products that contain many interconnected tubes that create a very rough surface when fractured. Have. Suspension materials can minimize both effects. In the first case, the suspension material alters the surface chemistry and thus reduces the particle "affinity" for the protein. Second, the suspension material satisfies the coarse character, thereby reducing the particle "ability" to mechanically adhere to the tissue.

The suspension material of the present invention comprises a biocompatible polymer, and in certain embodiments, the polymer is bioresorbable. The polymer must be implantable in the animal without causing unexpected side effects. The polymer may be a homopolymer or a copolymer, preferably amorphous. A particular example is a polyester, a polymer whose units are derived from hydroxycarboxylic acids. Another example is poly (
Lactic acid), which results from polymerizing a mixture of L- and D-lactide in a proportion such that poly (lactic acid) is amorphous. Another example is a copolymer consisting of units derived from lactic acid and glycolic acid.

The biocompatible polymer may or may not be degradable depending on the proposed use. Degradable polymers that are non-toxic and implantable into organisms such as humans are preferred, examples include polyglycolic acid or polylactic acid. Other materials that have been shown to be useful in this invention based on their biocompatibility and their ability to modify their viscosity and stickiness include: polyvinylpyrrolidone, chitosin, glycerol, Carboxymethyl cellulose, methyl cellulose, carrageenan, hyaluronic acid, collagen-hydroxyapatite-hyaluronic acid complex, alginates, glucose, starches, cellulose gum or any combination of the above listed items. The skilled artisan will know that the collagen or collagen derivative is preferably treated prior to use in the present invention to render it non-immunoreactive, or alternatively a recombinant form of collagen can be used. ing.

A binder is a material that promotes in particle agglomeration due to the tackiness of the binder, both in cohesive (with itself) and adhesive (with particles) properties. The final composition (binder plus particles) is still flexible and flexible so that the defect can be completely filled. It is possible to use calcined gypsum or a settling calcium phosphate cement system as the binder, which eventually becomes a hard constituent. This improves the direct structural bearing capacity under a significantly compressed load pattern. Thus, the binder may or may not be cured. In the preferred embodiment, the binder is cured.

Examples of suitable physiological materials contained in the suspension material are saline, various starches,
Hydrogels, polyvinylpyrrolidine, other polymeric materials, polysaccharides, organic oils or liquids, all of which are well known and used in the art. Materials that are biocompatible, ie, cause minimal tissue reaction, and are removed or metabolized without cytotoxicity are preferred. A biologically compatible aqueous solution of sugars such as glucose or starch can be used. Certain lipids can also be used. In this connection, highly compatible materials include esters of hyaluronic acid such as ethyl hyaluronate and polyvinylpyrrolidone (PVP). PVP is usually empirical formula _{[CHCH 2) 2 N (CH} 2) 3 CO] [ In the formula, n equals 25 to 500] n or having type, otherwise Plasdone (Plasdone) (R) (G
AF Corporation, New York, New York).

Another biocompatible material is the patient's own plasma. Blood is removed from the patient, centrifuged (or without) to remove cells, mixed with an appropriate volume of particles, and the mixture applied to the desired location. In a preferred embodiment, the suspension material is: carboxymethyl cellulose (
Glycerol USP (up to 20 weight percent); and purified water USP (up to 88.75 weight percent). The advantages of utilizing the suspension material of the present invention, an improvement over currently available products derived from human tissue, include improved handling; lower cost; no risk of disease; easier storage; longer Shelf life; easy disposal of any excess material; compatibility with known artefacts; and unlimited supply.

Example 4-Polymer Shaped Particles In another object of the present invention, the shaped particles of the present invention are a polymeric phase. The material can be derived from a wide variety of bioabsorbable, biocompatible polymers that resorb or degrade over time. These polymers may be ceramic or glass filled to enhance osteoconduction of the polymer alone. The polymer, or composite, allows for the adjustment of mechanical properties such as endurance and stiffness, as well as the rate of degradation. The function of this component provides compatibility with the implant bone system consisting of this material as well as the ceramic and suspension material phases described above. In a preferred embodiment, the polymeric shaped particles combine with the ceramic-based particles and still maintain a certain volume of the combination with open, interconnected porosity. The polymeric granules also protect the ceramic component from brittle fractures under compression and act as a cushion while the system is compressed to fill bone defects. To achieve these properties, polymeric shaped particles are envisioned to be largely artificial in their behavior with a small portion of elastic response. This ensures that the polymeric shaped particles shrink without too much bounce, but they serve as a buffer between the ceramic granules. Polymeric / composite granules are also used without ceramic granules in some applications, where the ability to densify the material is very important, such as compression implantation techniques commonly used today in whole body joint repair. I can imagine that. There are no current ceramic shaped particle systems suitable for compaction as they are finely divided by this technique. In a preferred embodiment, the polymeric shaped particles have a bubble shape that terminates in a bubble shape that can provide a "snap fit" for adjacent interdigitated polymeric shaped particles, such as the particles illustrated in FIGS. 4 and 5. As the end of.

Example 5-Implanted Bone System The three components of the present invention, which together provide a ceramic bone-shaped particle, a suspension material and a polymeric shaped particle, of the present invention provide three components of the bone grafting system during the implantation procedure. In addition, it offers the clinician several options. When defects are involved and do not provide much mechanical or structural support, the most basic opinion is to use only ceramic granules. When adding the suspension material, the clinician can act on the granules outside the bone defect site to shape the aggregate. Suspension materials also offer the potential to incorporate infection control or active agents to promote bone healing and growth. The addition of polymeric shaped particles to ceramic shaped particles provides the clinician with the ability to compress the implant to the deficit site. This is useful when more structural support and stability is required for the implant and is more suitable for larger volume loss. The system also includes allograft materials, such as flakes, masses, putties and gels), or in addition or in the alternative, autograft materials.

In a particular embodiment, the system comprises polymorphic particles, where the particles are of different shapes. The different shapes included are illustrated in the figures herein or have variants of these shapes. Additionally or alternatively, these multiparticulates consist of different materials. As can be seen from currently available products, a typical approach towards the range of properties required from bone graft material is to provide multiple bone graft materials, each intended for a particular type of indication. . If the clinician requires a mix of properties or attributes, the clinician may mix the currently available products from different manufacturers to get the desired set of attributes, or already designed to have the correct set of attributes. Must be changed to another product that has been designated. Thus, in the present invention, a system of products is provided which can be used in the system independently or mixed with other components. The list of possible constituents includes bioceramic components that have osteoconducting properties and are available as shaped particles; suspension materials that facilitate primarily in the delivery of shaped particles;
Conformant shaped particles with improved mechanical properties that mimic the fit of allograft cancellous bone; may act as a carrier with suspension materials, but provide some enhancement to bone healing, as well as: Fibrin matrix acting as a carrier for (see Example 7); antibiotics, cancer treatment, osteoporosis therapy, or other bone minerals that may affect the overall effectiveness of the transplanted bone material due to complications related to the implantation procedure. Of dysplasia; growth factors, bone morphogenetic proteins or protein fragments that further enhance bone healing and / or have a specific high affinity for fibrin matrix (these factors include mesenchymal stem cell development, bone Growth and regeneration of blasts / osteoclasts / osteocytes, promotion of mitogenesis and repopulation by osteoblasts / osteoclasts / osteocytes Utilizes a wide variety of different pathways depending on the end result affecting toxic agents, angiogenic agents, etc .; useful for bone healing, such as osteoblasts, osteoclasts and / or osteocytes Also included are cells that can be delivered using a fibrin matrix that is; allogeneic bone and bone products; and other biological agents.

In a preferred embodiment, these components are compatible with autologous transplantation. It is generally known that clinicians prefer to use autologous transplantation over existing artificial ones because it is the tissue being tested to be comparable. Clinicians, for the purposes of the present invention, mix with autologous transplants and / or blood to meet the missing aspects or properties of the currently available products (first to obtain a biological activity aspect).

This implantable bone system invention provides several improvements over current implantable bone substitutes: all components are resorbable / degradable in vivo (the present products provided are resorbable / Including both degradable and permanent structures); the interlocking structure increases the mechanical endurance and stability of the granular structure (especially shear) compared to the current design of irregular and regular, unassembled structures Under stress); individual shaped particles (especially ceramics) become denser and therefore less fragile and less fragile than the current porous (ceramic) structure, which is friable and weak, and open and interconnected porosity Maintained associative structure; dense shaped particles do not adhere to soft tissue as do the currently available porous ceramic structures; the offering as shaped particles allows clinicians a greater range of defect support. The current product provides granular and lump morphology; the multi-component system allows clinicians to obtain bone grafts for their patients without having to utilize many different product offerings. (Current products do not offer this flexible, systematic approach); the addition of antibiotics to the system allows clinicians to transplant earlier if infection is a concern. As well as the addition of biological agents capable of accelerating the bone healing process to the components of the system of the present invention provide superior mechanical properties to such molecules over current delivery systems (collagen sponges). Providing Support: Providing.

A key advantage of the system of the present invention is that it eliminates the need to develop a specific product for each specific indication. Clinicians need to provide the desired mix of attributes,
The components of the system can be mixed / matched, and thus each patient has the ability to tailor or design a bone graft product to meet their unique needs and specific complications. This results in lower cost to the patient and only the product used is billed. Flexibility in pharmaceutical options to match infectious agents is also an advantage of the present invention. In the case of antibiotics, the clinician can select the appropriate antibiotic based on the culture results from the wound. For some currently available products, the clinician has no choice but the antibiotic (tobramycin).

Also provided are products that are easier to store and have lower distribution costs than products that directly incorporate bioactive proteins, cells, or pharmaceuticals. These "active" ingredients have specific storage conditions and a limited shelf life. Once the products are premixed,
There is a risk that the manufacturer has to treat the end-of-life whole product rather than the "active" ingredient, which has a shorter shelf life. This allows you to
The problems created by the potential interaction between the "active" ingredients and the device are also eliminated.

Furthermore, if the bone graft already contains pharmaceuticals or bioactive proteins or cells, then the product may be overdosed, limiting its use in treating larger defects. Similar problems arise with treating small defects where doses are too low to produce beneficial results. Appropriate doses can be used in all cases, provided the clinician has the ability to determine doses.

Example 6-Addition of Biological Agent to the System In a preferred embodiment of the present invention, the biological agent is included in the suspension material. Examples are antibiotics, growth factors, fibrin (see Example 7), bone morphogenetic factors, bone growth agents, chemotherapeutic agents, analgesics, bisphosphonates, strontium salts, fluoride salts, magnesium salts and sodium salts. including.

In contrast to the oral administration of high doses of antibiotics to an organism, the present invention allows for the inclusion of antibiotics within the suspension material of a composition for topical administration. This reduces the amount of antibiotics needed to treat the infection or prophalaxis. Administration of the antibiotic by suspension material in the composition also reduces the diffusion of the antibiotic, especially when the antibiotic is included in the fibrin matrix (see Example 7). Alternatively, the particles of the present invention can be coated with an antibiotic and / or contained within a particle or suspension material. Examples of antibiotics are tetracycline hydrochloride, vancomycin, cephalosporins and aminoglycosides such as tobramycin and gentamicin.

Growth factors can be included in suspension materials for topical application to promote bone growth. Examples of growth factors that can be included are platelet-derived growth factor (PDGF
), Transforming growth factor β (TGF-β), insulin-related growth factor-I (IGF
-I), insulin-related growth factor-II (IGF-II), fibroblast growth factor (FGF), beta-2-microglobulin (BDGF II) and bone morphogenetic protein (BMP). The particles of the invention may be coated with growth factors and / or included in the particles or suspension material.

Bone morphogenetic factors may include growth factors, the activity of which is demineralized bone protein or DBM (demineralization), which in fact contains numerous components such as osteonectin, osteocalcin and osteogenin. Mineralized bone matrix), especially so-called BP protein (bone protein) or BMP (bone morphogenetic protein)
It is specific to bone tissue containing. The agent can coat the shaped particles of the present invention and / or be included within the particle or suspension material.

In certain embodiments, a bone growth agent can be included within the suspension material of the composition of the present invention. For example, the nucleic acid sequence encoding the amino acid sequence or the amino acid sequence itself can be included in the suspension material of the present invention in which the amino acid sequence promotes bone growth or healing. As an example, leptin is known to inhibit bone formation (Ducy et al., 2000). Nucleic acid or amino acid sequences that affect the leptin, leptin ortholog or leptin receptor in the opposite direction can be included in the composition. As a specific example, the antisense leptin nucleic acid within the composition of the present invention is transferred to a bone defect site to inhibit leptin amino acid formation, and thereby the inhibitory effect leptin has on bone regeneration or growth. Avoid Another example is a leptin antagonist or leptin receptor antagonist.

The nucleic acid sequence is delivered within a nucleic acid vector, where the vector is contained within a delivery vehicle. Examples of such delivery vehicles are liposomes, lipids or cells. In a particular embodiment, the nucleic acid is transferred by carrier-assisted lipofection (Subramanian et al.,
1999), facilitates delivery. In this method, the cationic peptide is M9
Attached to the amino acid sequence, the cation binds to the negatively charged nucleic acid. Then M9
Binds to nuclear transport proteins such as transportin,
The NA / protein complex crosses the cell membrane. The amino acid sequence is delivered in the delivery vehicle. An example of such a delivery vehicle is a liposome. Delivery of amino acid sequences can utilize protein transduction regions, an example of which is the HIV virus TAT protein (Schwarze et al., 1999).

In a preferred embodiment, the biological agents of the invention have a high affinity for the fibrin matrix (see Example 7). In certain embodiments, the particles of the invention can include a biological agent therein or thereon, either by degrading and eluting from the particles, or by diffusion. The biological agent may be an analgesic. Examples of such analgesics are lidocaine hydrochloride, bipivacaine hydrochloride, and nonsteroidal anti-inflammatory drugs such as ketorolac tromethamine.

Other biological agents that may be in suspension material or included on or in the particles of the invention include chemotherapeutic agents such as cisplatinum, ifosfamide, methotrexate and doxorubicin hydrochloride. Is. The skilled technician knows which chemotherapeutic agent is suitable for bone malignancy. Another biological agent that may be in suspension material or included on or in the particles of the invention is bisphosphonate. Examples of bisphosphonates are alendronate, clodronate, etidronate, ibandronate, (3-amino-1-hydroxypropylidene) -1,1-bisphosphonate (APD), dichloro. Methylene bisphosphonates, amino bisphosphonates, zolendronates and pamidronates. The biological agent may be in purified form, a commercially available partially purified form, or, in a preferred embodiment, a recombinant form.
It is preferred that there is no drug for impurities or contaminants.

Example 7-Addition of Fibrinogen to the Composition Advantageously, in the composition of shaped particles and suspension material, include any agent or agent that induces, enhances or enhances bone growth. is there. In a particular embodiment,
The composition further comprises fibrinogen which is cleaved by thrombin to give fibrin. In a more preferred embodiment, Factor XIII is also included in the cross-linked fibrin, conferring more structural integrity. Fibrin is known in the art to cause angiogenesis (vessel growth) and, in embodiments of the present invention, acts as an agitator of bone growth. For example, it is preferable to mimic signals normally present in bone breakage to promote regrowth. Fibrin is known to tend to bind growth factors that promote this regrowth.

For the purposes of the present invention, the inclusion of fibrin in the composition has two components: 1) promoting bone growth; and 2) acting as a delivery vehicle. The fibrin matrix is produced by reacting three coagulation factors-fibrinogen, thrombin and factor XIII. These proteins are
It can be manufactured using recombinant technology that avoids the problems associated with pooled blood products and self-produced products. Currently, proteins are supplied in a frozen state ready to thaw and mix. However, developments in the freeze-drying process have allowed the final product to be either frozen or stored at room temperature and reconstituted just prior to use. In a preferred embodiment, the coagulation factor is recombinant in form.

Only fibrinogen and thrombin need to produce the simplest form of the fibrin matrix. However, the addition of Factor XIII provides the ability to crosslink fibrin fibrils and strengthen the matrix. A specific mixture of the three proteins is provided to produce the appropriate reaction time, degradation rate and elution rate of the biological agent. The modification can be performed by changing the fibrin component. One expected modification is that instead of or in addition to the fibrin component,
The use of hyaluronic acid or collagen gel. Another variation is the inclusion of additional coagulation factors in the fibrin matrix. Further examples of coagulation factors are:
Although known and used in the art, in particular embodiments, they are coagulation factors associated with bone disorders.

The coagulation factor may be in purified, commercially available, partially purified or recombinant form. In certain embodiments, thrombin alone is used with the patient's own blood or bone marrow aspirate to produce the fibrin matrix. In certain embodiments, the biological agents described above are contained within a fibrin matrix.

Example 8-Method of Making Calcium Sulfate-Based Shaped Particles In another object of the present invention, an improved method of making calcium sulfate-based shaped particles is provided. Calcium sulphate materials are generally not very strong when formed using conventional forming techniques. Calcined gypsum (CaSO ₄ .1 / 2H ₂ O; calcium sulfate hemihydrate) is mixed with water and the following reaction is performed: CaSO ₄ .1 / 2H ₂ O + 1 1 / 2H ₂ O → CaSO ₄ .2H ₂ O By this, gypsum (CaSO ₄ 2H ₂ O; calcium sulfate dihydrate) can be formed. However, excess water is needed to increase porosity and weaken the material in order to obtain a pourable slurry. In addition, the high surface area to volume ratio of the porous component can increase the dissolution rate of the material in an aqueous environment.

Another option is to utilize a gypsum material, which is formed into a shape by compression of a slurry package. Since the gypsum is already fully hydrated, the material will not undergo the above reaction. If water is used in the process, it simply dries to the final form of porosity again. With this method invention, the material can be formed using techniques that can provide the desired ingredient shape and reasonable density in the dry ingredients. The second method of heat treatment and hydration is then used to adapt the final material properties, ie to increase durability and decrease dissolution rate. It is possible to adjust these properties by adjusting the method of formation and subsequent dehydration / rehydration. In a particular embodiment, the heating step is carried out at a pressure greater than ambient pressure, eg, 120-150 degrees Celsius or 25-50 PSI in an autoclave. Skilled technicians
It is known that the calcium sulphate composition of the present invention may be α or β depending on the heat and pressure used and either form may be used or produced in the present invention.

In the method, the gypsum is subjected to a heat treatment and a hydration method after being formed into a shape (
By compression, pouring, injection or other means known in the art). Similarly, the method is performed on calcined gypsum features formed by some of the non-water based methods (ie, die compaction). The intent of this second process is to adjust the durability and dissolution of the gypsum used in bone graft applications. By proper adjustment of the second process, it is possible to adapt the material properties of the components.

Steps in the method: 1) converting the shaped gypsum into shaped calcined gypsum using heat (about 150 ° C.), CaSO ₄ .2H ₂ O → CaSO ₄ .1 / 2H ₂ O + 1 1 / 2H ₂ O 2) Returning the shaped calcined gypsum to gypsum, promoting recrystallization, improving strength and dissolution characteristics, CaSO ₄ .2H ₂ O + excess H ₂ O → CaSO ₄ .2H ₂ O + excess H ₂ O 3) excess water Dry the ingredients.

Alternatively, an example of a product in which this second processing is useful is a stronger gypsum, which is more resistant to dissolution by water, such as in controlled release applications, consumer products and mold making. It is applied. It is an object of the present invention to combine the known substeps of converting gypsum powder to calcined gypsum powder (calcination) and rehydration of calcined gypsum powder to return the material to gypsum to produce a stronger gypsum.

In the present invention, calcium sulfate capable of hydration reaction can be used. This includes gypsum formed in the exhaust gas desulfurization method, gypsum formed as a by-product of neutralization of waste sulfuric acid, gypsum formed as a by-product in the phosphoric acid regeneration method, and calcined gypsum (especially, Such gypsum products include gypsum hemihydrate formed by refining known gypsum products by known recrystallization methods and calcining the purified gypsum. In a preferred embodiment, gypsum is commercially available. Skilled artisans know that application of water to particles in the rehydration process helps to tailor material properties including strength, dissolution rate and density.

Example 9-Forming Shaped Particles This method involves the following general steps: The clay-gypsum powder is mixed with processing aids (eg, binders and lubricants) and water and moistened to form a clay plastic. 2. The clay is shaped into the desired shape by forming operations such as compression, rolling, extrusion or injection. 3. Put the clay in a mold, or in contact with the mold, green enough to be handled (
green) Make shape with durability. Curing immediately after formation is also good for maintaining particle shape and resistance. 4. The pieces may then be moved to the next processing step or packaging.

The following are preferred specific embodiments of this method: Clay-gypsum powder makes up about 75-85 w / c (weight percent); carboxymethyl cellulose or other binder material about 0-5 w / c; water about 10-25 w / c.
. 2. Compress the clay-using a split type, apply gypsum clay with an applied load (about 3000 lbs-
Force) compress down. 3. Put the clay in a mold-heat the mold containing gypsum clay. Heat the parts to a temperature of about 100 ° C in about 5 minutes. Curing is performed by dehydration. 4. Remove the piece from the mold.

It is usually preferred that the ceramic material of the shaped particles of the present invention is not too hard, not too sticky, or too dry. There are many materials suitable for use as binders, including carboxymethyl cellulose, hydroxypropyl methyl cellulose or polyacrylates. The shaping method of the present invention includes compression in a split mold, injection molding and extrusion. The "hardening" action of clay is either a simple dehydration, or a more complex reaction that is mitigated by a combination of binders, water and gypsum, coordinated by external stimuli such as heat, irradiation or chemical addition. It

All patents and publications mentioned in this specification are indicative of the level of ordinary skill in the art to which this invention pertains. All patents and publications, to the same extent, are hereby incorporated by reference, as if each individual publication was explicitly and individually indicated to be incorporated by reference. Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, AF, Beil,
FT, Shen, J., Vinson, C., Rueger, JM, and Karsenty, G. 2000. Leptin inhibits bone formation by hypothalamic relay: central regulation of bone mass. Cell 100:
197-207. Schwarze, SR, Ho, A., Vocero-Akbani, A. and SF Dowdy, 1999. In vivo protein transduction: Delivery of biologically active proteins to mice. Science 285: 1
569-1572. Subramanian, A., Ranganathan, P. and SL Diamond, 1999. Nuclear targeting peptide backbone lipofection of non-dividing mammalian cells. Nature Biotechnology 17: 8
73-877.

Those of ordinary skill in the art will readily appreciate that the present invention is well adapted to attain the ends and advantages as well as those inherent therein.
Particles, compositions, processes, methods, kits, procedures and techniques described herein are currently
It represents preferred embodiments and is intended to be representative and not limiting in scope. Modifications and other uses herein will occur to those skilled in the art, which are encompassed within the spirit of the invention or are defined by the scope of the claims which are not yet determined.

[Brief description of drawings]

FIG. 1 is a diagram of a preferred six-armed shaped particle of the present invention.

FIG. 2 is a diagram of an array of combined six-armed shaped particles of the present invention.

3A-3D are diagrams of five-armed shaped particles of the present invention. FIG. 3A is a top view of the particles. FIG. 3B is a diagram of particles from a high lateral reference. FIG. 3C is a front view of the particles. FIG. 3D is a right side view of the particles.

4A to 4D are views of a six-armed shaped particle with a flat tip of the present invention. FIG. 4A is a top view of the particles. FIG. 4B is a diagram of particles from a high lateral reference. FIG. 4C is a front view of the particles. FIG. 4D is a right side view of the particles.

5A-5D are diagrams of six-arm shaped particles with a rounded tip of the present invention. FIG. 5A is a top view of the particles. FIG. 5B is a diagram of particles from a high lateral reference. FIG. 5C is a front view of the particles. FIG. 5D is a right side view of the particles.

6A to 6D are diagrams of shaped particles having a combined ring structure of the present invention. FIG. 6A is a top view of the particles. FIG. 6B is a diagram of particles from a high lateral reference. FIG. 6C is a front view of the particles. FIG. 6D is a right side view of the particles.

7A-7D are different views of a six-armed shaped particle having a propeller-like structure of the present invention.

8A-8D are views of a six-armed shaped particle of the present invention. FIG. 8A is a top view of the particles. FIG. 8B is a diagram of particles from a high lateral reference. FIG. 8C is a front view of the particles. FIG. 8D is a right side view of the particles.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Kaiser, William, Bee.             Men, Tennessee 38104, United States             Fiss, South Rembert 603 (72) Inventor Kinan, Keith, Em.             38135, Bar, Tennessee, United States             Tret, Oak Road 3372 (72) Inventor Shriver, Jeff             38108, Col, Tennessee, United States             Dova, The Riverge Drive 9382 F-term (reference) 4C081 AB04 BB08 CA021 CA161                       CD022 CD032 CD122 CD172                       CD18 CE02 CF011 DA11                 4C097 AA01 BB01 CC01 DD01 DD05                       DD07 EE02 EE08 SC10

Claims (63)

[Claims] 1. A central portion; and at least four tapered ends projecting from the central portion, the protrusions defining a void space between adjacent ends, each end attached to the central portion. A base, an opposing point, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles receives at least one terminus of the adjacent particle and allows the mating of adjacent particles in the array. A shaped particle used to treat a bone defect, wherein the shaped particle is shaped for use in an array of interdigitated particles. 2. The at least three ends are located in one plane.
Particles. 3. The particle of claim 1, wherein the particle has 6 ends. 4. The particle of claim 1, wherein said particle comprises a material selected from the group consisting of ceramics, bioactive glasses, polymers, polymer / ceramic composites and polymer / glass composites. 5. The particles of claim 1, wherein the ceramic comprises a calcium salt. 6. The particle of claim 5, wherein the calcium salt is selected from the group consisting of calcium sulfate, calcium carbonate, calcium phosphate and calcium tartrate. 7. The particle of claim 6, wherein the particle comprises calcium sulfate. 8. The particle of claim 7, wherein the calcium sulfate is in the form of gypsum. 9. The particle of claim 6, wherein said particle comprises bioactive glass. 10. The particle of claim 4, wherein the particle comprises a polymer. 11. The particle of claim 10, wherein the polymer is selected from the group consisting of polypropylene, polylactic acid, polyglycolic acid and polycaprolactone. 12. The particle comprising a polymer / ceramic composite.
Particles. 13. The particle of claim 4, wherein the particle comprises a polymer / glass composite. 14. The particle of claim 1, wherein the particle has a diameter of about 3-10 millimeters. 15. The particle having a diameter of about 4-8 millimeters.
Particles. 16. The particle of claim 1, wherein the particle has a diameter of about 6 millimeters. 17. The array of claim 1, wherein the array comprises multiparticulates. 18. The array of claim 17, wherein the multiparticulates are a mixture of particles of different materials. 19. The particle of claim 18, wherein the different material is selected from the group consisting of ceramics, calcium salts, bioactive glasses, polymers, polymer / ceramic composites and polymer / glass composites. 20. The particle of claim 1, wherein said treatment of a bone defect is selected from the group consisting of bone augmentation, bone repair, bone replacement, bone improvement, bone strengthening and bone healing. 21. The bone defect is selected from the group consisting of fracture, breakage, bone loss, soft bone, fragile bone, hole in bone, gap in bone, bone disease and degeneration of bone. 20 bone defects. 22. The disease is osteoporosis, Paget's disease, fibrous dysplasia,
From osteodystrophy, periodontal disease, osteopenia, osteopetrosis, primary hyperparathyroidism, hypoalkaline phosphatase, fibrous dysplasia, osteogenesis imperfecta, myeloma bone disease and bone malignancy 22. The disease of claim 21 selected from the group consisting of: 23. The array of claim 1, wherein the combination of the adjacent particles in the array defines an appropriate porosity to allow implantation from a host bone. 24. The array of claim 23, wherein the porosity is between about 40% and about 80%. 25. The array of claim 23, wherein the porosity is between about 60% and about 80%. 26. The shaped particle comprises a central portion and at least four tapered ends projecting from the central portion, the protrusion defining a void space between adjacent ends, each end being defined by the central portion. A base attached to the portion, an opposing point, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles receives at least one end of the adjacent particle and the array of shaped particles An array of shaped particles, wherein the array of shaped particles provides for treating a bone defect, wherein the array of shaped particles comprises a plurality of shaped particles. 27. A first shaped particle, the array comprising a central portion and at least four tapered ends projecting from the central portion [wherein the protrusion defines a void space between adjacent ends; The ends have a base attached to the central portion, opposing points, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles receives at least one end of the adjacent particles and is shaped. Facilitating the interlocking of adjacent particles in the array of particles]; a second shape comprising a central portion, at least two non-curved ends and at least three curved ends protruding from the central portion. Particles [the protrusions define interstitial spaces between adjacent ends, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved protrusions [wherein the protrusions define the interstitial space between adjacent protrusions, and the protrusions combine adjacent particles in the array. An array of shaped particles consisting of a large number of shaped particles consisting of one or more shaped particles from the group consisting of: 28. A polycyclic structure having at least four curved projections, the projections defining interstitial spaces between adjacent projections, the projections facilitating the interlocking of adjacent particles in the array. A shaped particle used to treat a bone defect shaped such that the particle is used in an array of interdigitated particles. 29. The shaped particle of claim 28, wherein the angles between the curved protrusions are equal. 30. The shaped particle of claim 28, wherein the particle comprises a material selected from the group consisting of polymers, polymer / ceramic composites, and polymer / glass composites. 31. The polymer of claim 30, wherein the polymer is selected from the group consisting of polypropylene, polylactic acid, polyglycolic acid and polycaprolactone. 32. A first shaped particle comprising a central portion and at least four tapered ends projecting from the central portion [wherein the projection defines a void space between adjacent ends, each end being defined by the central portion. An array of shaped particles having a base attached to a portion, an opposing point, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles receives at least one end of the adjacent particle. The second shaped particle comprising a central portion, at least two non-curved ends, and at least three curved ends protruding from the central portion [the protrusions]. Defines a void space between adjacent ends, each end having a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. A shaped particle from the group consisting of: and a suspension material, the composition being used to treat a bone defect. 33. The suspension material is starch, sugar, glycerin, blood, bone marrow,
33. The suspension material of claim 32 selected from the group consisting of autograft material, allograft material, fibrin clot and fibrin matrix. 34. The suspension material is a gel-forming binder.
Suspension material of 3. 35. The binding agent comprises a collagen derivative, a cellulose derivative, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, fibrin clot, a fibrin matrix, and a biological adhesive such as a cryoprecipitate. 35. The binder of claim 34 selected from the group. 36. The suspension material of claim 32, wherein the material further comprises a biological agent. 37. The group wherein the drug comprises a growth factor, an antibiotic, a strontium salt, a fluoride salt, a magnesium salt, a sodium salt, a bone morphogenetic factor, a chemotherapeutic agent, an analgesic, a bisphosphonate and a bone growth agent. 37. The biological agent of claim 36 selected from 38. The growth factor is platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), insulin-related growth factor-I (IGF-I), insulin-related growth factor-II (IGF-). II), fibroblast growth factor (FGF)
, Beta-2-microglobulin (BDGF II) and bone morphogenetic protein (
38. The growth factor of claim 37 selected from the group consisting of BMP). 39. The antibiotic of claim 37, wherein said antibiotic is selected from the group consisting of tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycosides such as tobramycin and gentamicin. 40. The factor is a demineralized bone protein, demineralized bone matrix (DBM), bone protein (BP), bone morphogenetic protein (BMP)
38. The bone morphogenetic factor of claim 37 selected from the group consisting of :, osteonectin, osteocalcin and osteogenin. 41. The chemotherapeutic agent of claim 37, wherein said agent is selected from the group consisting of cisplatinum, ifosfamide, methotrexate and doxorubicin hydrochloride. 42. The analgesic of claim 37, wherein said analgesic is selected from the group consisting of lidocaine hydrochloride, bipivacaine hydrochloride and non-steroidal anti-inflammatory drugs such as ketorolac tromethamine. 43. The composition of claim 32, further comprising a coagulation factor composition. 44. The coagulation factor composition of claim 43, wherein said coagulation factor composition consists of fibrinogen, thrombin and factor XIII. 45. A first shaped particle, wherein the shaped particle comprises a central portion and at least four tapered ends projecting from the central portion [wherein the protrusion defines a void space between adjacent ends; The ends have a base attached to the central portion, opposing points, a length and a circular cross-sectional shape, wherein the interstitial space of one of the particles receives at least one end of the adjacent particles and is shaped. Facilitating the interlocking of adjacent particles in the array of particles]; a second shape comprising a central portion, at least two non-curved ends and at least three curved ends protruding from the central portion. Particles [the protrusions define interstitial spaces between adjacent ends, each end being a base attached to the central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. And a method for treating a bone defect, which comprises the step of applying the shaped particle to the bone defect. 46. A step of combining shaped particles with a suspension material, the first shaped particles comprising: a central portion and at least four tapered ends projecting from the central portion (adjacent by the protrusions). Defining an interstitial space between the ends, each end having a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape; Accepting at least one end of the particles to facilitate the assembly of adjacent particles in the array of shaped particles); a central portion, at least two non-curved ends, and a curvature protruding from the central portion. Shaped particles comprising at least three of said ends, said protrusion defining a void space between adjacent ends, each end being a base attached to said central portion,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array And a third shaped particle consisting of a polycyclic structure having at least four curved projections, the projections defining interstitial spaces between adjacent projections, which projections combine adjacent particles in the array. Selected from the group consisting of:], and applying the combination to a bone defect. 47. A suspension material and first polymorphic particles and second polymorphic particles, wherein the first and second particles are shaped for use in an array of interdigitated particles. A first shaped particle comprising a central portion and at least four tapered ends projecting from the central portion [wherein the protrusion defines a void space between adjacent ends, each end being defined by With a base attached to the central portion, opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receives at least one end of the adjacent particle, and Facilitating the assembly of adjacent particles in an array]; a second shaped particle comprising a central portion, at least two non-curved ends, and at least three curved ends protruding from the central portion. [Interstitial space between the terminal adjacent the said projections are defined, each end is attached to the central portion base,
Having opposite points, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, facilitating the mating of adjacent particles in the array ]; And a third shaped particle consisting of a polycyclic structure having at least four curved projections [wherein the projections define the interstitial space between adjacent projections, and the projections combine adjacent particles in the array. A bone defect treatment kit selected from the group consisting of: 48. The kit of claim 47, wherein the first polymorphic particles and the second polymorphic particles are of different materials. 49. The kit of claim 48, wherein the different materials are selected from the group consisting of ceramics, calcium sulfate, bioactive glass, polymers, polymer / ceramic composites and polymer / glass composites. 50. The kit of claim 47, further comprising a biological agent. 51. The kit of claim 47, further comprising allograft material. 52. The kit of claim 47, further comprising a clotting factor composition. 53. The coagulation factor composition of claim 52, wherein the coagulation factor composition comprises fibrinogen, thrombin and factor XIII. 54. The kit of claim 47, further comprising a bowl container for the first and second multiparticulates and a delivery device. 55. The delivery device of claim 54, wherein said delivery device is selected from the group consisting of a spoon, spatula, tuck, tweezers, forceps, knife, hemostat, syringe, pipette, cup and dipper. 56. The bowl container of claim 54, wherein said bowl is used to mix said first multiparticulate and second multiparticulate and said suspension material. 57. The kit of claim 50, further comprising a bowl container for said first multiparticulate and a second multiparticulate and a delivery device. 58. The delivery device of claim 57, wherein said delivery device is selected from the group consisting of a spoon, spatula, tuck, tweezers, forceps, knife, hemostat, syringe, pipette, cup and dipper. 59. The bowl container of claim 59, wherein said bowl is used to mix said first multiparticulate and second multiparticulate, said suspension material and said biological agent. 60. A central portion, at least two of the non-curved ends, and at least three of the curved ends protruding from the central portion [wherein the protrusion defines a void space between adjacent ends, Each end has a base attached to the central portion, an opposing point, a length and a circular cross-sectional shape, the interstitial space of one of the particles receiving at least one end of the adjacent particle, Facilitating the assembly of adjacent particles in the array], wherein the particles are shaped for use in an array of interdigitated particles,
Shaped particles used to treat bone defects. 61. A method of making shaped particles of calcium sulfate dihydrate comprising the steps of making shaped particles of calcium sulfate dihydrate; heating the particles; and applying water to the particles. 62. Forming shaped particles of calcium sulfate dihydrate; heating the particles of calcium sulfate dihydrate in the presence of pressure and humidity to form α-
Calcium sulphate 2 comprising partially or wholly converting to calcium sulphate hemihydrate; and applying water to the particles to convert the α-calcium sulphate hemihydrate to the calcium sulphate dihydrate. Method for producing shaped particles of hydrate. 63. Forming shaped particles of calcium sulfate dihydrate; heating the particles of calcium sulfate dihydrate in the presence of pressure and moisture to form β
Calcium sulphate consisting of partly or wholly converting to calcium sulphate hemihydrate; and applying water to the particles to convert the β-calcium sulphate hemihydrate to the calcium sulphate dihydrate. A method for producing shaped particles of a dihydrate.