TWI327071B - Composite bone graft substitute cement and articles produced therefrom - Google Patents

Description

1327071 IX. Description of the Invention: [Technical Field] The present invention is directed to a particulate composition suitable for forming a bone graft replacement adhesive immediately after mixing with an aqueous phase solution, and a bone graft replacement adhesive thus obtained Agents, a bone graft replacement kit comprising the particulate composition, a method of making and replacing (4) a bone graft replacement kit, and an article made from the bone graft replacing the adhesive.

[Prior Art] Bone structure defects, such as wounds, diseases, or surgery, may occur in many cases. In many surgical fields, effective repair of bone defects, such as the upper jaw, the bones, the ossicles, and plastic surgery, is required.泎 A variety of natural and synthetic materials and compositions have been used to promote the treatment of bone defects. As with the use of compositions to repair other forms of tissue, the biological and mechanical properties of bone repair materials are key to determining the effectiveness and stability of this (IV) use. Page 丨 should not

(4) In addition to blood, it is the second common transplant material. The autografted μ has long been considered to be the most effective when repairing (4), because it has aggregate function and non-generating secretory (four) H implants (four) the bone is not in all cases, and this side = finger hair (d) and cause serious shortcomings of the wound. The (4) allogeneic shift causes the problem of the second surgical position 'but there are certain disadvantages. For example, allograft bone = has lower bone compatibility and yield than autologous bone, and produces less vascular remodeling of 1327071 at the bone defect site. And generally cause a large immune response. There is also a risk of certain disease metastases when using allogeneic bone grafts. In order to avoid the problems associated with autografting and allograft bone, field-related research has been established to use synthetic bone substitute materials in natural bone sites. For example, a number of compositions and materials including bone matrix for removing minerals, calcium phosphate and calcium sulfate have been proposed. Adhesives including calcium sulphate have a long history as an alternative to bone grafting. Modern surgical grade calcium sulphate adhesives provide high initial strength, good handling properties, and can be completely replaced by bone in many applications. However, calcium sulphate binders have the property of being relatively resorbed by the body relatively quickly, which is undesirable in certain applications. Among bone graft materials, hydroxyapatite is one of the most commonly used calcium phosphate compounds. Its structure is similar to that of bone minerals and has good biocompatibility. However, oxonite has a very low resorption rate which is not suitable for some applications. Other calcium phosphate materials, such as beta-tricalcium phosphate, have been used in this field, which have a faster resorption rate compared to hydroxyapatite but have lower mechanical strength. Attempts have also been made to utilize certain calcium phosphate materials which are coagulated in situ, such as an anhydrous compound of tetracalcium phosphate and dicalcium phosphate or a mixture of dihydrate compounds which, after mixing with an aqueous phase solution, react to form hydroxyapatite. Synthetic bone repair materials currently available do not have the desirable properties for all bone graft applications. As mentioned above, some of the compositions have a resorption rate that is too slow or too fast. In addition, many bone grafting adhesives are difficult to implant because they are not capable of coagulation or injection. Other disadvantages 7 1327071 is like inappropriate strength or difficult to add to bioactive agents for controlled release. For these reasons, it is necessary in the art to have a bone graft adhesive composition having a desired resorption rate and having high mechanical strength, easy handling, and adhesion growth of bone cells. SUMMARY OF THE INVENTION The present invention provides a particulate composition suitable for forming a bone graft replacement adhesive immediately after mixing with an aqueous phase solution, and a hardened bone graft replacement adhesive thus prepared. The present invention is also related to a method of making a bone graft replacement kit comprising the particulate composition, and manufacturing and using the bone graft replacement kit. The particulate composition of the present invention comprises a calcium sulphate hemihydrate powder which is combined with a calcium phosphate stone-forming calcium phosphate mixture. After the particulate composition is mixed with an aqueous mixed solution, a hardened biphasic binder comprising a brushite and a sulfated dihydrate compound is formed. The sulfated dihydrate provides good mechanical strength, and due to its relatively rapid resorption rate, it can be rapidly replaced by bone tissue in the formed adhesive, however, with a binder comprising only calcium sulfate dihydrate. In contrast to the composition, the brushite is used to reduce the overall resorption rate of the binder. The specific embodiment of the bone substitute adhesive of the present invention has high mechanical strength, such as high compressive strength and diameter tensile strength, condenses into a hardening composition in a reasonable period of time, and promotes high quality bone at the bone defect site. Developed with acceptable operational characteristics. In one aspect, the present invention provides a particulate composition comprising a mixture comprising a sulfuric acid momahydrate powder having a bimodal particle distribution and an intermediate particle size of from about 5 to about 20 microns, and forming a transmissive structure 8 1327071 The composition of the acid composition of the stone 35. The formation of the (tetra) stone __ mixed «mono-hydrophobic compound powder and powder. The Bu=three-about powder has a recording size of less than about 20 micro(four). The concentration of the sulfuric compound powder is up to about fifty percent by weight, more preferably at least about seventy percent, and most preferably at least about 50% by weight of the total weight of the particulate composition. Seventy-five percent of the weight. Calcium formation

The concentration of the composition of the stone (iv) acid is about three to thirty percent by weight based on the total weight of the particulate composition. The β-disc acid powder portion of the particulate composition is preferably a modal particle distribution including a particle mold of 30 to 70 volumes for the ρ_ scaly acid __ volume and #, J The state is about 2 〇 to 6 〇 microns, and about 20 to 70 volumes of the particle mode is about to buckle to the Sichuan micron. In another embodiment, the bimodal particle distribution comprises about a percent of the total volume of tricalcium sulphate # & 4- 4 ten to /, fifteen volumes of micro

The particle abnormity is about 4.0 to 5.5 microns, and about 35 to 50 volume of the particle mode is about sixty to seventy microns. "The portion of the sulphate hydrolysate of the particulate composition, including the sulphur sulphur_half-size & matter, and having a bimodal particle distribution, including the total volume of the sulphur-hemihydrate _ About 30 to 60 volumes of secret granules are sorrowful! 〇 to 3 〇 microns, and about 40 to 70 volumes of particle modality is about 2 〇 to 3 〇 microns. And z from the particle '' and the mixture of the mixture may additionally include (3 - phosphate tri-mammite, the second of which has an intermediate particle size of 75f75 μm, such as about 75 to 〇 00 μm, the β- The concentration of the tricalcium phosphate fine particles is up to about twenty percent by weight, and more preferably up to about twelve percent by weight, based on the total weight of the particulate composition 1327071. An additive may be additionally included, such as a catalyst suitable for catalytically converting the calcium sulfate hemihydrate to calcium sulfate dihydrate. An example of such a catalyst is calcium sulfate dihydrate fine particles coated with sucrose. The composition may include a bioactive agent such as a bone-loss bone, a growth factor, an antibiotic, an insecticide, a chemotherapeutic agent, an anti-viral agent, an analgesic anti-inflammatory drug, and an osteoinductive or osteoconductive guide. Functional material. The mineral-depleted bone matrix is a preferred bioactive agent. In one embodiment, the particulate composition of the present invention is carried out in an amount of from about 3 to about 25 minutes with an aqueous phase solution. After mixing, it immediately condenses into a hard block. Therefore, in another aspect of the present invention, there is provided a bone graft replacing adhesive having a paste formed by mixing the particulate composition of the present invention with an aqueous phase solution. The bone graft replacement adhesive may include β-tricalcium phosphate fine particles (if present) and a reaction product formed by mixing the particulate composition of the present invention with an aqueous phase solution, the reaction product including calcium sulfate dihydrate And the calcium phosphate stone. The bone graft substitute adhesive can be cast into a predetermined shape such as a spherical shape, a fine particle shape, a wedge shape, a block shape and a dish shape, and is shaped into a shape required for application time, or does not need to be first. Shaped or shaped, and simply injected or delivered to the site of bone defects. The adhesive of the present invention can also be integrated into any different orthopedic implant device, typically in the form of an external drape, or It is a filling material for the porous outer layer of such a device to promote bone ingrowth in the implanted device region. The monthly graft replacement adhesive is preferably:: medium:: at least, the granule composition and the water phase are at least large... 10,000 Pa is preferably at least 6; the more ambiguous is at least 5 MPa, = Having a diameter tensile strength of at least about 9 MPa, preferably at least /, having a pressure of 1 MPa. A preferred embodiment of the replacement adhesive also has a high degree of composition of the particulate with the water. The phase solution is mixed and has at least about 15 million whites, compressive strength after the line-hour curing. More preferably, it has an anti-repetitive strength of at least about 4 GPa. In addition, the bone graft replaces the binder. A preferred embodiment has an anti-(four) degree of at least about 5 Q MPa, more preferably at least about 80, after mixing the microparticles with the aqueous phase solution for 24 hours in ambient air. The compressive strength of 10,000 Pa.—The replacement of the bone graft (4) is better (4) 彳 also has the average dissolution rate expressed as the average weight loss per day, which is combined with the use of a sulfuric acid (4) particle assembly (4) (4) Under average dissolved ratio, at least less than 25% 'the average Dissolve the branch in steam at 37 ° C. The use of the immersion length is 3.3 亳, and the outer diameter (〇D) is (8 =:=:=% is better, the average dissolution rate is at least low and - In addition to the Gamma view, the present invention provides a bone graft replacement kit, which is used to package (4) a container of the present invention, a written container of a method, and a mixing device for describing the nest. := "Through sets can additionally include - a mixture of nuclear aqueous phase fluid and the particulate composition, and 6 to send the bone graft to replace the adhesive to the bone defect, an injection device (eg, a syringe) . Another point of view, such as the 兮方在夫在, provides a way to deal with bone defects. Applying the above described bone graft replacement to the site of the bone defect. As explained above, the bone graft replaces the adhesive to be applied in a pre-formed form, which is immediately shaped according to the size and shape of the bone defect. Become the desired shape 'or do not need to pre-shape 9 = 'primary device or other device that carries the composition, directly applied to the bone defect site. In another aspect of the present invention, a method and method for forming the microparticles of the present invention is provided. Generally, the method comprises mixing or mixing each of the powder components of the particulate composition to form a homogeneous mixture. Therefore, the method for forming a composition of the έ 微粒 particles in the conjugate example includes the glycerin tri-per powder, the sulphuric acid semi-aqueous compound powder (which can be selectively catalyzed by the above-mentioned catalyst), The monocalcium phosphate monohydrated t-powder powder is mixed with the β-thanoic acid three-grain fine particles (if present). The mixing of the different blister or fine granules is preferably carried out immediately prior to mixing the particulate composition with the water 12 1327071 phase solution. Preferably, the mixture of the particles is included in the rod, and the θ human mixture comprises sterile water: 7 can be::: into the: sticky: the acid can be glycolic acid or secret: acid:: It is preferred to neutralize the acid to an intermediate pH of about 6.5-7.5. In another aspect of the present invention, the bone graft replacement adhesive of the present invention and the set are formed to form a transparent stone. The phosphoric acid is saturated (1; r's at the end of the second embodiment with the serotonin mono-monohydrate powder) not "quasi-agent: is pre-existing (for example, placed in the sleeve (four) distractor tear (four) _. in another = = in order to avoid the two related above-mentioned discussion of the mixed solution of the organic acid component to form a crystalline powder (for example, 'become a neutral salt form like a metal salt), unlike in the liquid The other component of the set of particles in the powder form. The use of the acid component in the form of a powder avoids the change of the acid caused by the gamma-raying of the composition when the g is destroyed, and the introduction of the bone shift (four) generation of the adhesive lag is increased. 'Materials, the present invention provides a method for storing a stable set of ten sets, the set comprising a particulate composition and an aqueous phase The liquid is suitable for immediate formation of a bone graft replacement adhesive after mixing, wherein the kit comprises a tannic acid powder which reacts in the presence of water and a slow acid to form a calcium transdermal solution, the method comprising: strontium monocalcium phosphate a monohydrate powder and a tricalcium phosphate powder are packaged in the separation container of the set; and (1) in the form of a crystalline powder or dissolved in the aqueous phase solution, the condition of the carboxyl group In order to dissolve the carboxylic acid in the heart = it is added after the aqueous phase solution is sterilized: Γ, ,. The kit may additionally include a sulphate compound powder step 5 1-2 to additionally include The sulfuric acid mother's semi-aqueous compound powder is sealed in 2 Ril-Μ's is mixed with the dish sour mono-monohydrate compound powder spoon: 匕 (4) - or both sides. m, the method will (4) lightly γ The set of components is irradiated for sterilization. The exemplary examples of the acid-lowering neutral salt which can be used as a powder include ethanol (tetra), potassium, potassium, and lactic acid clock. To - in the container 'either packaged to contain the acid a container of the compound powder, or a medium containing the (tetra) acid, and a bone graft replacement kit, a) a first container enclosing the powder of the q-single calcium monohydrate; ii) „ P owes a second container of calcium powder; iii) is enclosed in a separate volume = or with a single acid monohydrate powder and (iv) acid three! Bow powder =- $ The mixture of sulfuric acid is about half-hydrate powder; w) sealed in __. , the aqueous phase solution of the cereal towel; and v) dissolved in the aqueous phase solution or in the form of a powder in the form of a powder (4), the (4) crystalline powder is enclosed: a knife is in the middle or with the acid The monohydrate powder, β_disc = each powder and the sulfuric acid compound powder, any one or more of the conditions - when the oxo acid is dissolved in the aqueous phase solution, ', 疋, proceed The aqueous phase solution is added to the solution after radiation sterilization. In some embodiments, the acid crystal powder is sealed in a 13207701 container, and thus the aqueous phase solution and the monocalcium phosphate monohydrate powder, the β-tricalcium phosphate powder, and the sulfuric acid Before the one or more of the calcium hemihydrate powders are mixed, the aqueous phase solution may be mixed to restore the carboxylic acid crystal powder to a carboxylic acid. The calcium sulphate hemihydrate powder may additionally comprise a mixture in the form of a mixture suitable for catalytically converting the calcium sulphate hemihydrate to a calcium sulphate dihydrate. In addition, the kit may additionally be present in a separate container or mixed with any one or more of the monocalcium phosphate monohydrate powder, the beta-tricalcium phosphate powder, and the calcium sulfate hemihydrate powder. --squaric acid triamed fine particles. A bioactive agent may also be included in the kit, enclosed in a separate container, or with the monocalcium phosphate monohydrate powder, the beta-tricalcium phosphate powder, and the calcium sulfate hemihydrate powder. Any one or more of them are mixed. In yet another embodiment, a bone graft replacement kit is provided, comprising: i) a first container enclosing a powder of monocalcium phosphate monohydrate; ii) a second container enclosing a powder of beta-tricalcium phosphate, The beta-tricalcium phosphate powder has an intermediate particle size of less than about 20 microns; iii) is enclosed in a separate vessel or mixed with one or both of the monocalcium phosphate monohydrate powder and the beta-tricalcium phosphate powder. A-sulfate mother hemihydrate powder having a bimodal particle distribution and an intermediate particle size of from about 5 to about 20 microns; iv) an aqueous phase solution enclosed in a separate vessel; ν) a carboxylic acid in the form of a crystalline powder, the carboxylic acid crystalline powder being in the form of a neutral alkali metal salt; vi) a calcium sulphate hemihydrate suitable for use in the alpha-calcium sulphate hemihydrate powder a catalyst which is catalytically converted to calcium sulfate dihydrate 15 1327071; and vii) is present in the separation vessel or P-mixed with the bis(10) oleic acid monohydrolysate powder - or both Filling the acid with three fine particles, The fine particles have a particle size of at least 75 μm. [Embodiment]

The invention will now be described more fully hereinafter with reference to the accompanying drawings. The present invention may be embodied in many different forms and should not be construed as limiting: Embodiments set forth hereinafter; rather, these embodiments are also provided so that they will satisfy the applicable statutory requirements. When used specifically in the context of the claims, unless the context clearly dictates otherwise, the singular "a" or "the" includes the plural.

The present invention provides a particulate composition which, after mixing with an aqueous phase solution, is hardened or coagulated to form a bone graft replacement adhesive. The particulate composition comprises a calcium sulphate hemihydrate (CSH) powder and a calcium phosphate mixture comprising a monocalcium phosphate monohydrate (MCPM) powder and a beta tricalcium phosphate (p_TCp) powder to form a brushite. The use of the particulate composition of the present invention produces a bone graft replacement adhesive comprising calcium sulfate dihydrate (CSD) which is a reaction product between calcium sulfate hemihydrate (CSH) and water. The calcium sulphate:water compound (CSD) component of the binder provides good mechanical strength of the binder, promotes bone growth, and provides a relatively fast resorption rate in living organisms, thus a porous medium in the binder It can be established immediately after implantation. Therefore, the calcium sulfate dihydrate (CSD) component of the binder can be rapidly replaced by bone tissue which grows inward into the implantation site. 16 < S ) 1327071 The two calcium phosphate components react immediately after mixing with an aqueous phase solution to form brushite. In contrast to binders comprising only calcium sulfate dihydrate (CSD), the brushite in the binder will slow the absorption rate of the bone grafting replacement binder. Thus, the dual phase bone grafting alternative adhesive of the present invention provides a dual resorption rate as defined by the calcium sulphate dihydrate (CSD) component and the permeable wall stone component. In addition to the lower resorption rate, the microparticle composition embodiment of the present invention can also provide a bone graft replacement adhesive which has high mechanical strength, good handling properties, and reasonable setting time. Moreover, certain embodiments of the bone graft replacement adhesive of the present invention have the ability to produce south quality bone when used to treat bone defects. The calcium sulphate hemihydrate (CSH) powder used in the present invention preferably has a bimodal particle distribution. As understood in the art, the bimodal particle distribution represents two peaks in the graphical representation of the particle size for the volume percentage of each size particle. Figure 1 depicts an exemplary bimodal particle distribution. In a preferred embodiment, the bimodal particulate particle distribution of the calcium sulphate hemihydrate (CSH) powder is about thirty to six percent for the total volume of the calcium sulphate hemihydrate (CSH) powder. The ten volume particle mode is about 1.0 to 3.0 microns, and about 40 to 70 volumes of particle mode is about 20 to 30 microns. In yet another embodiment, the bimodal particle distribution comprises from about forty to sixty percent of the particle mode of about 1.0 to 2.0 microns, and about forty to sixty percent of the particle mode. The state is about 20 to 25 microns. The calcium sulphate hemihydrate (CSH) powder preferably has an intermediate particle size of from about 5 to about 20 microns, 17 1327071 more preferably from about 8 to about 15 microns, and most preferably from about 1 to about 5 microns. . As used herein, the intermediate particle size, i.e., the particle size that divides the particle distribution into two halves, so that the half particle volume in the distribution is above the intermediate size and the other half is below it. The intermediate particle size is obtained by using the high-resolution laser domain method (4) for line (four) interpolation. More specifically, the laser diffraction method is performed using fixed-frequency parallel light having a wavelength of 632 8 nm and having a power of 5 milliwatts. Laser diffraction measurements were taken through an array of 32 channels (10) | The pellets are delivered to the measurement system through a relatively constant mass flow rate which utilizes an optimum dispersion medium for the air stream generated by a pressure of -3.5 bar. A commercially available machine for laser diffraction particle analysis is the ASIS Clansthal-Zellerfdd, Germany) dispersion unit. The 〇ASIS system is used in the dry form via the VIBRI mode HDD200 and RODOS. § The use of the mysterious VIBRI mode has a 75% feedback rate gap. The pressure of -3.5 bar is the particle size of the calcium sulphate hemihydrate produced by the 4 mm syringe. It is preferred to use a lens (0.25/0.45...87·5 μm) for the tricalcium phosphate component. In other words, the R4 lens (0.5/1·8.·..350 microns) is preferred (both from Sympatec). The particulate composition of the present invention preferably comprises calcium sulphate hemihydrate (CSH) powder in a total amount of at least about fifty percent by weight, preferably at least about one hundred, for the total weight of the particulate composition. A weight of seventy percent, and more preferably a weight of at least seventy-five percent. In certain embodiments, the total amount of the calcium sulphate hemihydrate (CSH) powder is at least about eight hundred and twenty-seven hundred and twenty-seven, and at least about eighty-five percent or at least ninety percent. weight. Generally, the sulfuric acid semi-aqueous compound (CSH) powder is present in a total amount of at least about 70% by weight to about 99% by weight, preferably at least about 70% by weight. The weight is about 90% by weight. The calcium sulphate hemihydrate (CSH) powder is preferably a-calcium sulphate hemihydrate, which has a calcium sulfate dihydrate (CSD) immediately after coagulation as compared with the β-sulfate word hemihydrate. Higher mechanical strength. The calcium sulphate hemihydrate (CSH) portion of the particulate composition is important for providing the mechanical strength of the bone graft replacement adhesive, which at the same time has the ability to coagulate or harden in a relatively short period of time. As is known in the art, the sulfuric acid semi-aqueous compound (CSH) is a form in which the sulfuric acid i-bend is combined with a 1 / 2 water molecule (CaS04. 1/2H20) and reacts with water to form a calcium sulfate dihydrate ( CaS04.2H20). It is considered that calcium sulfate dihydrate (CSD) is present in the bone graft replacement adhesive of the present invention to provide rapid bone tissue regeneration at the bone defect site. The calcium sulfate hemihydrate (CSH) powder can be formed by dehydration from the form of a dihydrate by heating. According to the method of heating, α-calcium sulfate hemihydrate or β-calcium sulfate hemihydrate can be obtained. These two forms have differences in crystal and particle morphology. The preferred alpha-calcium sulfate hemihydrate has a relatively high density and generally has a large hexagonal rod-like primary crystal which is well formed into a compact form with distinct edges. In a preferred embodiment, the calcium sulphate hemihydrate (CSH) powder is produced by the procedure disclosed in U.S. Pat. No. 2,616,789, the disclosure of which is incorporated herein by reference. This treatment is related to the immersion of calcium sulfate dihydrate into a solution of water and an inorganic salt. Preferred salts include magnesium gasification, calcium chloride and sodium chloride. However, it is also possible to use other inorganic salts which do not depart from the present invention, such as ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium sulfate, calcium bromide, calcium iodide, magnesium bromide, iodide. Magnesium, magnesium sulphate, sodium bromide, sodium hydride, sodium nitrate, gasification clock, potassium bromide, potassium telluride, potassium nitrate, gasification bismuth, bismuth sulphate, barium sulfate, zinc hydride, bromination Zinc, molybdenum zinc, zinc nitrate, zinc sulfate, copper chloride, desert copper, copper sulphate, copper sulphate, and mixtures thereof. Preferred salts are those which have biologically suitable properties and any which can be used in their anhydrous and aqueous forms. The salts referred to are expected to contain both anhydrous and aqueous forms. The sulfated dihydrate is heated to about boiling point with atmospheric pressure until the majority of the calcium sulfate dihydrate is converted to calcium sulfate hemihydrate (CSH). The calcium sulphate hemihydrate (CSH) formed has a structure different from that of other sulphuric acid parent hemihydrate (CSH) obtained by other hot water treatment methods, and has a lower water carrying capacity after grinding. In particular, the sulfuric acid mother hemihydrate (CSH) structure produced by this method has the characteristics of thick, short, and rod-like crystals. In one embodiment, the calcium sulphate hemihydrate (CSH) powder additionally comprises a catalyst having the ability to catalytically convert calcium sulphate hemihydrate (CSH) to a dihydrate form, thereby allowing the resulting bone graft to be replaced by a bond. The agent condenses more quickly. Although not bound by the theory of operation, it is believed that the catalyst particles act as a nucleation site for the conversion of the sulfuric acid mother hemihydrate compound (CSH) to the calcium sulfate dihydrate compound. 20 1327071 Examples of catalysts include calcium sulfate dihydrate, potassium sulfate, and sodium sulfate or other ionic salts. A preferred catalyst is a crystalline sulphate dihydrate compound (available from U.S. Gypsum) which utilizes sucrose (available from VWR Scientific Products). The treatment of suspending the sucrose to stabilize the calcium sulphate dihydrate is described in U.S. Pat. No. 3,573,947, which is hereby incorporated by reference in its entirety. The catalyst is generally present in a total amount of up to about one percent by weight based on the total weight of the particulate composition. In certain embodiments, the particulate composition comprises between about 0.001 and 0.5 percent by weight of the catalyst, more typically between about 0.01 to 0.3 percent. Mixtures of two or more catalysts can also be used. The calcium phosphate portion of the particulate composition of the present invention comprises a powder of monocalcium phosphate monohydrate (MCPM, Ca(H2P04)2 · H20) and a powder of β-tricalcium phosphate (β-TCP, Ca3(P04)2). As is understood in the art, the main reaction product of monocalcium phosphate monohydrate (MCPM) and beta-tricalcium phosphate (β-TCP) is brushite, which is also known as phosphoric acid. Calcium dihydrate (DCPD, CaHP04.2Η20). The brushite-forming powder may also participate in other reactions which form a specific calcium phosphate form, such as hydrogen and oxygen, which has better thermodynamic stability than dicalcium phosphate dihydrate (DCPD). Apatite, octacalcium phosphate, etc. Some of the β-tricalcium phosphate (β-TCP) powder amount that is reacted may also remain in the binder. Preferably, the beta-tricalcium phosphate (β-TCP) powder has an intermediate particle size of less than about 20 microns, more preferably less than about 18 microns of intermediate particles 21 1327071, most preferably less than about 15 microns. Intermediate particle size. In general, the beta-tricalcium phosphate (P-tcp) powder will have an intermediate particle size of from about 1 micron to about 2 meters. The size of the β-thanoic acid per (p_Tcp) powder may affect the total amount of the permeate formed in the (iv) implanted adhesive towel. It is believed that the smaller size of β-tricalcium phosphate (β·ταρ) will result in an increase in the formation rate of the permeable stone, while the larger particle size will result in a lower rate of formation. In general, in order to increase the reaction rate of the brushite, it is preferred to use a smaller size of β-tricalcium phosphate ((3_Tcp) particles. The particle composition of the β-tricalcium phosphate (p_Tcp) powder portion is preferred. Is a bimodal particle distribution comprising, for the total volume of the p_wei three-contact, 'about 30 to 70 volumes of particle mode is about 2.0 to 6. G micron' and about 100 The particle mode of thirty to seventy volumes is about 40 to 70 microns. In one embodiment, the tri-calcium phosphate (p_Tcp) powder has a bimodal particle distribution, including for the beta-phosphate In terms of the total volume of the three ends, about 50 to 65 volumes of the particle mode is about 4.0 to 5.5 microns, and about 35 to 50 volumes of the particle mode is about 6 inches. Up to 70 microns. The monocalcium phosphate monohydrate (MCPM) powder is relatively soluble in water, and its particle size is relatively unimportant.—Generally, the disc acid monohydrolysate (MCpM) The powder has a particle size that laughs at about Z meters; however, without departing from the invention He can use its particle size. As is appreciated, monocalcium phosphate monohydrate compound, ΡΜ) _ as a single gavage (MCP) in hydrated form. When the “time meal” water compound (MCPM) shellfish covers the acid single dance 22 1327071 (MCP), it is a simple anhydrous form of monocalcium phosphate monohydrate (MCPM) and releases the same number in solution. Calcium and phosphate ions. However, if monocalcium phosphate monohydrate (MCPM) is replaced by monocalcium phosphate (MCP), the total amount of water used to form the bone graft replacement binder must be increased to treat monocalcium phosphate ( Water molecules lost by MCP) (if you want to accurately produce the same dissolved product formed with the use of acid-filled monohydrate (MCPM).) φ As mentioned above, the bone graft of the present invention replaces the adhesive. The brushite component is used to reduce the bioresorption rate of the bone graft replacement adhesive in comparison with the calcium sulfate binder. The reduced resorption rate then allows the bone graft to be replaced by a binder. Long-term structural support of bone defect sites, which can assist in the treatment of certain applications. Although not bound by any particular theory of operation, it is believed that the bone graft replacement of the present invention After application to the living organism, the mixture can become a matrix of a dish with a high porosity because the calcium sulfate component of the mixture has a faster resorption rate. During the natural treatment process, the acid is # The remaining pore matrix will provide a good scaffold for bone ingrowth. The total amount of phosphate monocalcium monohydrate (MCPM) powder and beta-tricalcium phosphate (β-TCP) powder is present in the particulate composition. It can be mainly changed according to the total amount of brushite used in the bone graft replacement adhesive. Generally, the calcium phosphate stone forming calcium phosphate composition (in other words, the monocalcium phosphate monohydrate (MCPM) powder) The total amount of the combination with the β-tricalcium phosphate (β-TCP) powder is about 3 to 30% by weight, preferably about 10 to 23% by weight based on the total weight of the particulate composition. 1327071 The weight of one tenth and the best is about 15%. The relative amount of the scaly monocalcium monohydrate (MCPM) and P-tricalcium phosphate (|3_TCP) can be based on the The molecular equivalent in the spheroid formation reaction, The stoichiometric relationship is selected. In one embodiment, the concentration of the monocalcium phosphate monohydrate (MCPM) powder is about three to seven percent by weight based on the total weight of the particulate composition, and the beta-phosphate The total amount of tricalcium (P_TCp) is about 3 to 72 to 8.67 by weight.

It has been found that the monocalcium phosphate monohydrate (MCPM) and P. tricalcium phosphate (β-TCP) powder may react prematurely during storage in residual moisture to form brushite and/or triclinite. An unexpected anhydrous compound similar to brushite. Therefore, it will form in a homogeneous mixture

The amount of permeated (tetra) stone that is immediately produced after mixing the particulate composition with the aqueous phase mixing solution to form the bone-shifting (four) generation binder, which may be followed by a Undesirable ways to alter the nature of the bone graft replacement adhesive. Therefore, in a preferred embodiment, the two calcium phosphate powders are not enclosed together in a dry environment and are tightly sealed for moisture, that is, separately packaged in the storage compartment. In the case of the second embodiment, the two calcium phosphate powders are separately packaged, wherein each powder = 疋 is not separately packaged together with other components of the particulate composition of the present invention, and - and/or various other components (for example, sulfuric acid) About half-water compound (C just private) mixed. 3 « Finance, this hair-like (four) secret also contains most of the β-phosphorus brewing: calcium (β-TCP) fine particles, which have ten particle sizes with acid three Intermediate particle size of the feed (β-TCP) powder.

24 S 1327071 generally has a particle size of about 75 to _micron, preferably about 100 to 400 microns, and more preferably about 40 microns. The fine particles are used to form a substrate, a second + / haiyue spear bud plant instead of a binder. In general, the concentration of Yanhai β_phosphate three mothers (β-TCP) fine particles is the most for the total weight of the particulate composition.

The weight of ten is preferably from the total weight of the particulate composition to about 15% by weight, and more preferably about 12% by weight. In the preferred embodiment, the concentration of the β__3 (β-TCP) fine particles is about 8 to 12 percent by weight. The β-phosphorus triamma (β·τα>) fine particles can be used to relatively purify the second phase in the final bond, which is utilized for the use of the phosphate mono-monohydrate (mcpm) and phosphoric acid #5 (β- The TCP (four) stone formed by the powder reaction provides a lower resorption rate. Thus, the presence of the fine particles can further alter the resorption curve of the formed monthly graft replacement adhesive. The (tetra) acid three (p_τ(7) fine particles and the p_disc acid (β-TCP) powder used in the present invention can utilize both commercially available β-acid-breaking three #5 (β_τα>). The powder is formed as a starting material, such as the bismuth tris(5-TCP) powder available from Plasma B1 〇tal Ltd. (Derbyshire, UK). In the embodiment, the particulate composition The β-disc acid tri-(β_τα>) component is a first-order spheroidal commercially available β-packaging diamma (β-TCP) powder, which is humidified and ground to an intermediate particle size of less than 1.0 μm, and then passed through a The transitioner drains the formed rips to remove the grinding media. Thereafter, the solid block of tricalcium phosphate (p_TCp) can utilize any of the different techniques known in the art, from any

25 < S 1327071 Separation of other liquid components, such as centrifugation, gravity separation, overpressure, and preparation. The dried mass can then be processed through a (iv) sieve to produce two separate beta triphosphate (P_TCP) components having different intermediate particle sizes. The P-tricalcium phosphate (β-TCP) dry cake is subjected to general grinding before or during sieving to break the cake. In a preferred embodiment, the screen system produces a green (in other words, unfired) 鲅•P•tricalcium phosphate (P_TCP) component having an intermediate particle size of from about 125 to about 355 microns, and additionally has A green (green) state tricalcium phosphate () component of about 75 to about 3 Γ 5 micron intermediate particle size. Thereafter, the sintering treatment of the two dicalcium phosphate (?-TCP) components is carried out by heating in a furnace, and the density is increased by this method. In one embodiment, the furnace treatment comprises heat treatment of a tri-calcium phosphate (卩_Tcp) component which is carried out on an alumina plate at a temperature of about 1100 to 1200 Celsius for three hours. Generally, the temperature is adjusted upward to a desired sintering temperature at a temperature of about 5 to 6 degrees Celsius per minute, and the temperature is adjusted downward during the cooling. After the sintering treatment, the encrypted β-tricalcium phosphate (p_TCp) having a green state of about 125 to about 355 μm in size can be used as the fine particle component of the particulate composition. A green (green, in other words, unburned) sintered beta-salt-tricycle (β-TCP) component having a particle size of about 75 to about 355 micrometers can be ground by ball milling for about one to four An hour is formed to form a beta-acid-filled diammine (β-TCP) powder having an intermediate particle size of less than about 20 microns, which can then be used in the particulate composition described above. 26 1327071 The aqueous phase component to be mixed with the particulate composition of the present invention is selected to provide the composition with a desired hardness and hardening or setting time. Generally, the aqueous phase solution is provided in a desired total amount to achieve a liquid powder ratio (L/p) of at least about 0.21, preferably at least about 〇 21, and more preferably at least about 〇.23. A preferred liquid powder ratio (L/P) range is between about 0.2 and about 0.3, more preferably between about 〇 2 and about 〇 25. Examples of suitable water content components include water (eg, distilled water) and solutions thereof, and may optionally include one or more additives selected from the group consisting of sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, ethylene. Amine tetraacetic acid (EDTA), ammonium sulfate, ammonium acetate and sodium acetate. In a preferred embodiment, the water mixed solution used is a saline solution or a solution. A demonstration aqueous phase solution is a 9% aqueous solution of sodium chloride which is available from DeerftdcUL or elsewhere. In one implementation, the aqueous phase solution additionally contains - or a plurality of organic carboxylic acid-containing compositions (hereinafter referred to as carboxylic acid or carboxylic acid components) and does not contain a hydroxide group, and is appropriately The value (for example, using an acid such as a hydroxide oxy group, neutralizing to about 6.5 to about 75, the acid dicebox, and the example of the viscous acid includes the glycolic acid milk = the original). In one embodiment, the mixed solution

27 1327071 The solution was a 0.6 molar (M) solution of glycolic acid which was neutralized to pH 7.0 using sodium hydroxide. The compositions of the compositions referred to herein are included with the salt form. Under the second example, as shown in the example 3, has been found to be in progress? "The month of sterilizing sterilization" makes the sulphuric acid component in the 3H aqueous phase solution may be due to the use of Xingchang radiation: the formation of acid deterioration, resulting in non-bone graft replacement of adhesive properties, such as in the adhesive setting time ,, drift, and. Thus, in a preferred embodiment, the carboxylic acid composition discussed above incorporates the aqueous phase two: the liquid 'packaged together with other particulate components of the set as a crystalline column such as 'free acid and salt form', Or a plurality of other powders, the knives form a mixture or are present in a separate container, and Μ is present at = t. Powder form _ ingredients can avoid _ γ assist in the acid degradation of the index after the second = bacteria. Alternatively, the (tetra) carboxylic acid component is added to the aqueous phase solution after the radiation is introduced, and therefore "y is present in the solution and is not exposed to sterilized Korean radiation. In the implementation of the 'Finance', the financial institution makes the (4) Lin Li to _ metal salt base neutralized in the solution of about 6.5 to about 7.5, and then ^ with the solvent (for example, water) bursting square eight 曰 #太&gt ; ..., the way of the knife is a crystalline powder. The two are separated into a salt form, such as a metal salt or a salt removal. The present invention uses hydrazines: the presence of hydrazine to demonstrate a dry crystalline powder comprising sodium glycolate, sodium alkoxide. The powdery form can be added: granules... after 4:! The microparticle heart that forms the bone graft substitute adhesive, the sulphuric acid hemihydrate (cafe) component or the scale

28 S /υ/ι 酉夂 dance ingredients. However, in some embodiments, the powdered (tetra) salt is stored in a separate container so that it can be recovered by the aqueous phase solution before the solution is mixed with other particulate components of the composition. The bone graft replacement adhesive of the present invention may additionally comprise other additives known in the art. The additive may be added to the particulate composition of the present invention or the aqueous phase mixed solution in a solid or liquid manner. An example of an additive for a sulfuric acid composition is a plasticizer designed to change the composition and setting time. This plasticizer can delay the coagulation of the calcium sulphate hemihydrate sigma paste, thereby increasing the time for which the composition is used to set the tray-water phase solution for subsequent mixing. The model plastic (4) contains oil and other polyols, vinyl alcohol, stearic acid, glacial sugar, and cellulose. Burnt cellulose is a particularly preferred plasticizer. What is the demonstration of burnt cellulose? Hydroxypropyl propyl cellulose, methyl fiber = ethyl cellulose, hydroxide ethyl cellulose, hydroxide propyl cellulose, 虱 propyl propyl methyl cellulose, methyl cellulose , lysine acetate and mixtures thereof or salts. Exemplary supplements also include bioactive agents. As used herein, singular, linear active agent means any component that provides a medium, _, composition, substance or mixture of proven pharmacological effects in a living organism tube. Examples of bioactive agents include, but are not limited to, peptides, proteins, enzymes, small molecule agents, dyes, lipids, nucleosides, oligonucleotides = polynuclear (10) 'nucleic acids, cells, viruses, vesicles, microparticle discs Glue shell particles. It may provide a local or systemic image of the patient __: specifically, the bioactive agent preferably has a (four) guiding function or

29 < S 1327071 Bone guiding functional materials, antibiotics, chemotherapeutics, insecticides (eg, antifungal and antiparasitic agents), antiviral drugs, anti-inflammatory drugs and analgesics. Exemplary antibiotics include ciprofloxacin, tetracycline, tetracycline, tetracycline, cephalosporin, aminoglycocides (eg, tambamycin, kanamycin, neomycin, red mold) , vancomycin, 'gantamycin and its derivatives), subtilin, ubiquitin, N-dimercaptomycin, chloramphenicol, and derivatives thereof. Exemplary chemotherapeutic agents include Lushun Platinum, fluoropyrimidinedione (5-FU), cancer or dexamethasone, ifosfamide, methotrexate, and doxorubicin hydrochloride. Exemplary analgesics include lidocaine hydrochloride, bupivacaine, and nonsteroidal anti-inflammatory drugs such as triptolide. Exemplary antiviral drugs include gangcyclovir, dovdine, amantadine, adenosine, ribaravin, flufluramine, acyclovir, di-deoxyuridine, filtration Sexual viral components or gene product antibodies, cytokines, and interleukins. The demonstration anti-parasitic agent is a spray. Demonstration anti-inflammatory drugs include (X-1-antitrypsin and (X-1-antichymotrypsin. • Available anti-fungal agents include Taifuken as described in US Pat. No. 3,717,655.. Ketoconazole, oxytetracycline, griseofulvin, neomycin sulphate, miconazole, in the hope of its derivatives, which are fully integrated into the reference of the invention herein; such as the linear dichlorobenzene of Howard Bis-hexane; and more particularly as described in U.S. Pat. No. 3,228,828, such as brominated dubronfin, gasified dubronfin, fluorinated dubronfin, gasified benzodiazepine, gasification ten Cis isomers of hexaalkylpyrimidine, ampicillin, 1-(3-cycloallyl)-3,5,7-triaza-1-azaindene adamantane chloride (available from The quaternary ammonium of the Dow Chemical Company under the trademark Dowicil 200, and its ternary ammonium analogs of 30 analogs, which are fully integrated herein as references for the present invention; as described in Us Pat. Nos. 2,170,111; 2,115,250 and 2,229,024 Cetyltrimethylammonium bromide, gasified benzylammonium sulphonate and benzyl benzalkonium hydride, which are fully integrated herein as a reference for the present invention Dedicated; like 3,4,4,_ trichloro-symmetrical diphenylurea, tri-gas, diphenylurea, trichlorocarbanilide, trigastric, and 3,4,5-dimethoxyphenethylamine Ureas and salicylamines; such as dioxins, tetrasgen, hexahydro and 2,4,4,-trichloro-2,-hydroxydiphenyl ether hydroxy hydroxy stupid; as in US Pat. Nos , 2,710,277 and 2,977,315 describe organotin and halogen antibacterial agents such as zinc pyrithione, silver sulfadiazine, silver uracil, iodine and iodoform derived from a nonionic surfactant, which are fully integrated herein as References; and polyvinylpyrrolidone as described in u s. pat. N 〇 s 2, 706, 701; 2, 826, 532 and 2, 900, 305, which is hereby fully incorporated by reference in its entirety herein. "Includes any cellular product that regulates the growth or differentiation of other cells, particularly for the regulation of connective tissue precursor cells. Growth factors used in accordance with the invention include, but are not limited to, fibroblast growth factor (FGF) (eg, FGF-丨,, FGF-4); platelet-derived growth factor (pD) GF) (eg, pDGF_ab, PDGF_BB, PDGF_AA); bone forming proteins (BMPs) (eg, any of BMP-1 to BMίM8); osteogenic proteins (〇p) (eg 'OP-hOM or OP_3); transformation Growth factor·α, transforming growth factor-β (eg, β-β2 or p3); LIM mineralized protein (LMps); osteoinductive factor (10); angiopoietin; endothelin; growth differentiation factor, anti-back Morphogenetic protein _ 丨 (ADMP- 〗); endothelin, liver 1327071 cell growth factor and keratinocyte growth factor; osteogenic (osteogenesis protein-3) •, liver fat growth factor (HBGFs) (for example, HBGF- 1 and HBGF2); the hedgehog family, containing Indian, sonic and desert hedgehog proteins; interleukin (IL) (eg, IL-1 to IL-6); colony stimulating factor (CSF) (eg, CSF-1) , G-CSF and GM-CSF); epithelial growth factors (EGFs); and insulin-like growth factor (IGF) (eg, IGF-1 and IGF-II); removal of mineral bone matrix (DBM); cytokines; bone formation Protein and osteogenin, comprising homologs of the above proteins. Microparticle removal mineral bone matrix (DBM) is a preferred bone guiding function additive. The bioactive agent can also be an antibody. For example, suitable antibodies include STRO-1, SH-2, SH-3, SH-4, SB-10, SB-20 and antibodies to the phytase. These antibodies are in Haynesworth et al., Bone (1992), 13:69-80; Bruder, S. et al., Trans Ortho Res Soc (1996), 21:574; Haynesworth, SE, et al., Bone ( 1992), 13:69-80 i Stewart, K., et al, J Bone Miner Res (1996), 11 (Suppl.): S142; Flemming JE, et al., in “Embryonic Human Skin. Developmental Dynamics,” 212: 119-132, (1998); and Bruder SP, et al., Bone (1997), 21(3): 225-235, all of which are hereby fully incorporated herein by reference. Other examples of bioactive agents include bone marrow, platelet concentrate, blood, allograft bone, sparse bone fragments, synthetic or naturally derived mineral flakes such as calcium phosphate or calcium carbonate, mesenchymal stem cells, and ginger sulfate. Thick slabs, fragments and/or spheres of the bow. The bone graft replacement adhesive of the invention of 32 can be made by using the phase 2 and the device of the present invention to form the particulate composition with the water phase: (for example, vacuum) without causing the mixture to form a water. Knife,,,. Mix at a temperature that is frozen or apparently evaporated. After mixing, the viscosity of the mixture is generally changed according to the additive added thereto. "The second generation = the degree of hardness of the paste will be... The material can be converted to a wheel trap like a syringe" Fracture: it to the target, standing in the 'for example' to fill the bone deficiency': Lu Er r'. In some embodiments t' the material can be injected through a standard needle of 10 ^ 〇 to, for example, 1 G cm. The bone graft replacement adhesive of the present invention 2 will generally be in the range of from about 3 to about 25 minutes; the second is about 1 to about 20 minutes, as defined by the Vicat = head titration setting. . The invention has a === said to have a distinct 1 pack of life in about 3 ° to about 6 minutes, and the condensation of the material may occur in different environments, 5 milk, water, living organisms, or in various Occurs under test tube conditions. The hardened bone movement (four) difficult to seam (four) is: the raw material, especially the specific diameter of the tensile strength and the pressure resistance in the case of mixing the particulate composition with the aqueous phase solution, the surrounding work enthalpy - hour After curing, the diameter tensile strength 'is preferably at least 5 megapascals or optimally at least 6 megapascals. Further preferred embodiment of the contact agent has at least about 800 and at least 9 hundred If tensile strength after 24 hours of curing of the particulate composition with; = 1327071 =: 1 gas, preferably at 24 hours. After curing, it has a white direct tensile strength ' or optimally at least 1 million kPa. The preferred embodiment of the strong acoustic two-shifting alternative adhesive also has a high degree of compression resistance. (4) After the maintenance of the surrounding hour, it has a strength of at least about 15 MPa, and more preferably Having at least about 40:2: a preferred embodiment of a graft replacement adhesive in which the particulate "dihydrate phase bath is mixed and allowed to stand in ambient air for 24 hours, having an anti-four degree of at least about 5 GPa More preferably, it has a compressive strength of up to >, about 80 MPa. ', this time shift (four) generation bonding (four) New 4 at least bone graft replacement adhesive, in contrast to calcium, : In certain preferred embodiments, the adhesion of the present invention = = not = the average dissolution rate of the mother's day (four) loss average weight percentage, the sulfuric acid tilting composition of the micro (four) product (four) silk compound, the flat i dissolution rate compared to , at least less than 25%, the average degree of solution is distilled into the water, measured by a immersion length of 3 3 milligrams of 37 to 4.8 millimeters of the ball. What is more, this; 0. The alternative dissolution agent has an average dissolution rate of less than 3% of the sulfur surface, and most preferably less than 35%. In some embodiments, ', can be = 40% or more. The preferred dissolution range indicated by the following test procedure is lower than the average loss weight percentage, = about (10)' is preferably about 7%. Up to about 13%. The average dissolution rate determined by the use of every two 34,132,7071 is calculated using the data of τ, 2、, 1, 2, 3, and 4 days. 代套: 明一一个=本广^ · The composition is enclosed in the above description. The α is sealed with the separation surface of the innocent aqueous phase solution: the bone graft replacement kit containing the description of the use of the kit is preferably included. Mixing with the aqueous phase solution to form the bone grafting adhesive, and then vacuuming the mixing device. In addition, the set generally transports the bone grafting adhesive to the bone defect site, in the device (eg 'needle and syringe'. In general, bacteria: will use (four) to carry out the particle composition and the no: human. In the case of the <5, the 5 rpm contains one for the sulphuric acid mother half ^] 2 (10) Η) a container of powder, one for β•phosphate tris(10)_Tcp ”f′ and “one for (tetra) acid Single water-splitting compound (mcpm: the final combination in the other - Example # 'This set contains two containers for the German composition, the first contains ρ·_^ (p_Tcp) (four), part of The sulfuric acid aqueous compound (CSH) component, and the second component contains a supplemental (tetra) aqueous compound (10) PM) powder and a part of the sulfur axis semi-hydrated mouth (CSH) component. In another embodiment, the scalar single mom is as previously mentioned 'in some embodiments, the fourth component is separated into different containers. == Bioreaction: There are many kinds of package configurations to achieve this project. of

35 1327071 The water compound (MCPM) powder itself is encapsulated in a separate container, and the β-tricalcium phosphate (β-TCP) powder is packaged together with the calcium sulfate hemihydrate (CSH) powder. In any of the above embodiments, any of the powder containers may additionally comprise the carboxylate-based component crystalline powder and/or the β-tricalcium phosphate (β-TCP) fine particles, or the components may be separately packaged. Into its own container. When a catalyst suitable for catalytically converting the calcium sulphate hemihydrate (CSH) to calcium sulphate dihydrate (CSD) is present, it is typically mixed with the calcium sulphate hemihydrate (CSH) powder. In a preferred embodiment, the kit includes a first container enclosing the powdered mono-monohydrate (MCPM) powder, and a second container enclosing the remaining particulate drug mixture, the mixture being like the calcium sulfate Hemihydrate (CSH) powder, calcium sulfate hemihydrate (CSH) catalyst, the β-tricalcium phosphate (β-TCP) powder, the β-tricalcium phosphate (β-TCP) fine particles, and the carboxylic acid crystal One or more of the powders. In a preferred embodiment, the carboxylic acid in powder form is isolated and packaged so that it can be reconstituted in the aqueous phase solution prior to mixing the solution with the remaining particulate components, if desired. However, as previously mentioned, if the carboxylic acid is added after the radiation sterilization of the kit of aqueous components, the aqueous phase solution of the kit may also comprise a tickotropic component in the form of a solution. It is important to use all of the aqueous phase solution packaged into the kit to ensure a consistent set time. In one embodiment, the aqueous phase solution is encapsulated in a highly dehydrated container, such as a glass syringe or other glass container, which may make it less likely to retain the amount of residual solution that might otherwise form the bone graft instead of bonding. The performance characteristics of the agent change. 36 1327071 The invention also provides a method for the treatment of bone dragons. The method of the present invention relates to the application of a bone graft replacement adhesive to the site of the bone defect as described above. The bone graft replacement adhesive can be applied in a flowable form, such as through an injection bag, after the particulate composition disk is mixed with the aqueous phase solution prior to coagulation of the composition. Alternatively, the bone grafting adhesive can be used in a hardened form of pre-washing, which is spherical, fine-grained, wedge-shaped, block-shaped and dished, 疋^' or 疋, and has a binder block. A form of random shape fragments formed by smaller pieces that are broken by mechanical failure. In another f: the bone graft adhesive J can be formed prior to application: the mixture is manually shaped into the desired shape of the desired defect portion.疋, -Special bones A whole set of corrections (4) Storage and wealth management "integration." The bone graft is replaced by (10). In this embodiment, the bone graft is a mixed material. The bones in the area are born inward. - external fistula implant device Zhouyuan generation device C, for example, limited-toothed surgical implant including knee joint replacement device and patella device), mirror sacral device (for example, restriction, semi- and femoral components), elbow joint replacement The upper humerus device, the wrist joint replaces the y upper thigh device, the joint device), the shoulder device, the 2- and 3-part passive key device, and the spinal device (for example, 37 <S> 丄327071 thoracolumbar spine fixation Device, cervical spinal fixation device and spinal fusion cage), finger/finger device and backbone device. The invention will be further described using subsequent non-limiting examples. Example 1 of the experiment describes the use of the bone graft of the present invention in place of a binder in a living organism and specifically describes the reduced resorption rate (compared to the composition of sulfuric acid) of the composition of the present invention, good mechanical properties, and Accepted condensation time. Example 2 describes the function of an embodiment of the composition of the present invention which, in contrast to a conventional sulphate (CaS〇4) spheroid, increases the rejuvenated bone mass = total, strength and stiffness. Example 3 describes the deteriorating effect of sputum injection of glycolic acid in solution and the effect of this deterioration on the setting time of the 4th generation of the bone graft. Example 4 describes the substitution in the micro-use of glycolate, which reduces the effect of light shots on the potency of the implant, without sacrificing other advantages of specific manipulation and mechanical strength properties.

II knot time H: Use a 1 mm diameter, 5 cm length Fischer's needle to set 3 (8) grams, all settings are in accordance with 仏TM >, "here fully integrated as a reference for the invention., *, The sample size of the sputum should be generated by using the 破 # ^ ^ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于 用于, the amount of square centimeters, drop down to about 20 ml of 7 not block; the sample should be sloppy and removed, in addition to the 兮... teeth up ° Hai Fei's needle at 5 An aqueous phase; the valley liquid is in contact with the particulate composition

After 38 1327071, the material was not disturbed after 1 minute. The polyethylene cup should have a size such that the block has a short, flat cylindrical shape with a height of from about 1/4 inch to about 3/8 inch. According to the Fischer's needle titration test, the setting time is defined as the time point at which the aqueous phase solution contacts the particulate composition, and after the dripping from the upper surface of the sample, the Fischer's needle does not pass through a sample of the adhesive 50. The total time elapsed between % height time points. The needle is only affected by gravity due to its own weight and falls along a line of advance perpendicular to the top and bottom flat faces of the cylindrical sample block. The needle was dropped every 30 seconds after the first drop. The needle should not drip more than 6 times during this test. If after the 6th drip, the needle continues to pass more than 50% of the sample, the test must be repeated with fresh material, a new clean polyethylene cup, and a clean fee without a residue. In particular, avoid the materials remaining in previous tests. Polyethylene cups, mixing equipment, and material handling equipment should not be reused. All materials and equipment used during the test should be maintained between 21 and 27 degrees Celsius and stored in an environment with a relative humidity between 20 and 50%. Compressive Strength Measurement The compressive strength of a material is determined by the test method described below. A sample was cast using a stainless steel split model with eight sample loading capabilities having dimensions as specified by ASTM F451 (outer diameter of 6 mm X length of 12 mm) and is fully integrated herein as a reference for the present invention. The split model is located on a glass plate having a vertical upright cylindrical space and a sample well. The material is mixed and then loaded into a device that delivers the material to the sample chamber of 39 1327071, so a backfilling method can be utilized, typically a syringe with a jamshidi-type needle can be used. Each sample well is filled from the bottom to the top with a back fill. It is customary to overfill the model so that too much material will protrude above the size of the split , type, which ensures that all trapped air can be replaced in the sample well. Need to maintain the model down to the glass during casting

Above, avoid material protruding outwardly from the bottom of the sample cell between the glass sheet and the mold. After filling each sample cell, the other glass plate was manually pushed onto the excess material on top of the pole type to create a waterproof sheet that spans the top of the sample and the model itself. The size of the plate is such that it does not cause additional stress or create a stressed environment during the feeding of the material. Within two minutes of contact of the aqueous phase solution with the particulate component, all of the sample was cast and the wet sheet was established.

The sample was taken out of the mold 30 minutes after the aqueous phase solution was contacted with the particulate component. First, move m water from the split model containing the surface of the sample; I page, regardless of the lower glass plate used for the cleaning and casting!! The model 'is built on the lower surface of the model - waterproof and thin, " Children can use the razor to scrape off the waterproof sheet and form a flat, monthly surface. The split model was separated and the sample was removed. The eight samples are especially σα. Hai is removed within 32 ^ after contact with the particulate component. After removing the sample, it should be cured in air at room temperature (with a relative humidity of H ρ / 纟 ' Monument day T.

S 40 1327071 A material test was conducted at a predetermined time after the aqueous solution of the sea was contacted with the particulate component. In general, the test is conducted at hours and 24 hours. The test was conducted on a pressure test apparatus in accordance with ASTM F451, which is fully integrated herein as a reference for the present invention. The pressure test equipment is located on a mechanical test frame with the ability to perform displacement control and monitors displacement and force through data acquisition at 50 Hz or faster.

The samples were tested on the pressure test frame separately. The sample is located between the flats, with the cylindrical surface of the far sample facing the platform. The pressure test frame containing the sample is compressed at a rate of 0 333 mph per second until damage occurs. The forces and displacements during the test will be monitored and specially noted to destroy the maximum force at the time of production. Proper damage will create a fissure that spans the height of the sample. The maximum pressure at the time of destruction will be recorded. Destruction is defined as the sudden drop in load, the difference from the initial slope of the load formed by the load of the sample, the spring, and/or the force recorded immediately after the visual destruction of the sample.

The compressive strength in megapascals will be calculated as follows: (Pmax) / (eR2); where Pmax is the breaking load in Newtons, the knife is about 3.14, and R is the sample in millimeters Radius (3 mm). It is important that the wreckage of all equipment, especially the care material of interest, be cleaned when preparing for compressive strength samples. Straight tensile strength is measured by the following test methods. Polyurethane plastic 丨 吋 cube closure unit with a density of λ pounds per cubic foot (as available from General Plastics ManufJturing 1327071

Company, Tacoma, WA's Last-A-Foam®) has an outer diameter cylindrical space of approximately 5/8 inch (15.8 mm) and a nick for removal from the side as a sample model. The approximately 5/8 inch outer diameter cylindrical space is drilled vertically to the other side of the cube using a 5/8 inch drill bit with a reduced pressure. The space is along the length of the cube and is aligned to the center, so when the cylindrical space is created in the cube by drilling, the two drilled faces of the cube share the same centerline. The opposite faces from the remaining four complete sides serve as the open side of the final sample; these sides can be removed through the score. Each of these sides has two engraved scores on top of each other that can be removed immediately prior to testing without affecting the integrity of the sample. The score should be along the full length of the cube and can be separated using an exposed portion of greater than 5% of the sample height. Generally, the score is established by a vertical banding. The first "f 2c picture description - the type shows the fine diameter tensile work (four) π. The = top and bottom of the model 20 is shown. Figure 2b provides the model. The first and second figures provide the front and rear views of the model 2G It shows that it does not have a cylindrical space of 3 耄 with an outer diameter of 16 mm. The = job is a kind of uniform _ thing, and «to the suitable for the 16 mm outer diameter cylindrical space of the shooting brother, you can use a 30 cm centimeters with a 1 cm opening: On the side of the score on the hand _ one of the mouth μ + end, holding the 5 hp type of the hand index finger is located in the circle. Once the material is injected into the index finger of the die, the shape of the injected material will be felt.

The 42 S finger is slowly removed, and then the paste protrudes from the side of the model f with a small amount of the space of the space. When the paste=Γ is carried out, the syringe is slowly pulled out from the front opening, and the submicron syringe performs another injection, and the additional material exceeds the front and rear openings of the size of the original plastic cube == and utilizes The spatula touches the model and iiH smoothes. Should be in the water phase and the granule composition ^ 2 ^ η # 〇ασ ^ t ^ 〇 far sample receiver in the model in the air flat maintenance, Jane and the rear side will be exposed to room temperature conditions (, two , under the air - the predetermined time, in general, the upper = open (four) lamella composition contact σ is also calculated from the beginning time of this s treatment. Test = in the ability to perform displacement control Τ: Τ: through 2 The data acquisition of ° or faster is used to monitor the sides of the two samples; only at that moment, the side is removed with a knife. The top plate of the model is maintained by applying a slight force with two fingers. , the damage of the model interface r, the knife is located in the area of the score -== face turn γ to open the mark; and in the same way == = the top and bottom of the model are left behind Maintain the sample, the surface: Bu can be freely rotated to align with the load key. This rotating platform does ensure that: 1327071 and the equivalent load of the sample contact point are divided by the rate of 亳米 transversely #古本,^. The yoke plus the mother minute f will break through the length of the sample and will form a complete negative force. For the two quantities, the displacement and the force are all positive values. The == the most = shows the first part of the material body of the plastic spring by I shrinking to the first part of the plastic body , the force will be repeated two::::2 to compress the plastic sample mouth, a#, from σ 酼 5 5 load will be converted to this; mT slope increases 'and maintain a fixed slope. The port load starts at the fixed slope. =:::= In the _ row, the sample 丄 = tube:, the unit diameter tensile strength will be calculated as the following equation: Load: H); where Pmax is Newton The unit of damage jU is 3.14, and L is the length of the sample in millimeters (25 * d Η is the height of the sample in millimeters (16 亳mb if one or more of the following occurs) In terms of tensile strength, the sample is considered to be unacceptable: the crack is not vertical, the crack is not the full length of the sample, the length of the sample is broken, or the pores are clearly visible in the material. & When the tensile strength sample is prepared, it should be cleaned of all the wreckage, especially Curing materials of interest. 44 (-5 honing rate The dissolution rate of the material is determined by the following test method. In the Ϊ type Γ casting, there is a 4.8 mm outer diameter and a 3.3 mm high round body. The 3.3 mm thick SiO2 sheet in the cylindrical space can be used as the: 1 column space with an outer diameter of 4.8 mm and a face tube of 3 3 ' ' =, and the remainder: oxidized stone eve sheet 11 A sheet of polyethylene sheet is placed on the table. A polyethylene mesh is placed on the sheet of polyethylene; the sheet has the same dimensions as the web (except for the production so that the web shields the page from the top) Piece. Then the net = outer). A smaller size cerium oxide model (except for any part of the thickness of the 垔 垔 都不 悬挂 悬挂 悬挂 悬挂 悬挂 悬挂 悬挂 任何 任何 任何 任何 任何 任何 任何 任何 任何 任何The two are mixed to form a paste of the hook. The paste is recorded to the top of the model so the material is inserted into the room. While the model is filled, the mesh allows emptying from the space = multiple application actions to ensure that the material completely penetrates the bottom I of the mold and protrudes from the mesh to the lower polyethylene page Chip. The final application of the top of the model was taken with a knife to remove most of the excess material, producing a smooth top surface of the sample. A top page of the model is then placed on top of the model with the first sheet of polyethylene sheets so that it completely covers the top of the model. The splicer gently rubs the finger and gently touches the piece. The intimate contact between the top polyethylene sheet and the sample was established. The page then treats the complete system, pages, meshes, models, and pages as integer /vj/i dimensions, flipping it so that the original top faces down. The system uses the hand, ', = and repeatedly taps on the table' so that any air trapped in the model can be replaced by the material; the system should not be tapped with excessive force or too many people. Once the majority of the air has been removed, the system is placed on the table with the side down, the sheet and the mesh side up. f is the top polyethylene sheet at the bottom and the web, and the smear is used to apply the material to the top of the sample (originally the bottom) because of the void formed by the gas (four). The transfer line of the model was finally painted except for most of the excess material. Then use the finger again to gently rub the page against the model. The intimate contact between the top and bottom polyethylene sheets and the sample was established. H) The first sheet of Ethylene has been directly attached to the sample and model (no mesh U: the remaining sample in the model will be carried out for a minimum of 8 hours. After 8 hours, it is convenient to remove the sample from the model by hand: : The way of Τ 品 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Causes 'defects generated after removal from the model, and/or physical damage caused by the sample αα itself. All non-defective samples are dispersed in a material-layer manner—non-assisted dry-weld 4: disc and sample Then, at least 40 degrees Celsius is removed from the oven at 40 degrees Celsius, and 3G minutes of cooling is performed in room temperature conditions (Celsius (four degrees), relative humidity 2G-5G%). One sample was tested for dissolution.

46 S 1327071 selected samples are paired with a clean cylindrical frit glass take-up ring of the following dimensions: a total height of 90.25 mm, a 4 mm frit glass base located 80 mm above the top of the ring (40 - 60 micron pores), 25 mm outer diameter and 22 mm inner diameter. Measure (0.01 mg) and record the mass of each extraction ring. Measure (0.01 mg) and record the mass of each sample. Each pair of samples and inserts has a dedicated polyethylene bottle (300 ml). The polyethylene bottle has a size such that the insert and the sample can be easily fed in and out of the polyethylene bottle, and after filling 275 ml of water, a water column which is more than bad is formed. The polyethylene bottle was filled with 275 ml of distilled water at room temperature (21-27 degrees Celsius). The sample is placed in its corresponding insert and the insert is sunk into the polyethylene bottle; care is taken to retain any portion of the material that is detached from the insert. The polyethylene bottle was capped and subjected to a 37 degree Celsius water bath to avoid any vibration and record time. After the sample was placed in water for 24 hours, the insert containing the sample was taken out. The amount of water is discharged from the insert through the base of the frit glass. The insert containing the sample will then be dried in an oven at 40 degrees Celsius for 4 hours or until completely dried (determined by weight). The ring containing the sample was then cooled for 30 minutes at room temperature (21-27 degrees Celsius; 20-50% relative humidity). The sphere-containing loop weighing was then carried out with an accuracy of 0.01 mg. The mass of the sample itself can be obtained by subtracting the known empty bottle quality from the combined mass. Subtracting this mass from the initial sample mass will give the mass of the dissolution loss. This mass loss can be divided by the initial mass of the sample and the result multiplied by 100 to form a mass percentage of the dissolution loss. 47 1327071 At this point, the ring containing the ball will be placed in a polyethylene bottle containing clean distilled water (275 ml) at room temperature (21-27 degrees Celsius) and the polyethylene bottle capped. Water bath. Repeat the weighing step after 24 hours of drying. Repeat these actions after soaking in clean distilled water for 24 hours until the end of the test or the material is completely dissolved. EXAMPLE 1 The diameter tensile strength, solubility properties, and estimates of new bone ingrowth in living organisms and residual material for bone graft adhesives will be compared to a commercially available calcium sulfate material. All experimental experimental groups are examples of the present invention comprising a sulfuric acid I-bar hemihydrate using a weight percentage of 74.906, a catalyst having a weight percentage of 0.094 (a sulphuric acid about dihydrate compound coated with sucrose), and a scale of 6.7 by weight. Acid mono-I bow water monohydrate, 8.3 weight percent β-packaged Sanma powder, weight percentage 10 β-tricalcium phosphate powder fine particles, and neutralization with sodium hydroxide solution having a pH of 10 for acid test A binder composed of an aqueous solution of 莫.6 molar glycolic acid having a value of 7·〇〇 (hereinafter referred to simply as "SR"). For all experiments, MIIG®X3 bone graft replacement (hereafter referred to as ''Χ3') (Wright Medical, Arlington, TN) sulfuric acid was used as the control group. The binder (SR) material was within 14 to 19 minutes. Coagulation, and the bone graft replacement (X3) material condenses within 7 to 10 minutes. In this study, an intermediate resorbed calcium sulfate, calcium phosphate composition binder was also evaluated and the material was dissolved. , compressive strength, and estimation of new bone ingrowth and residual material in living organisms. This material is also an embodiment of the invention comprising sulfur 48,138,071 calcium sulfate hemihydrate at a weight percentage of 84.999, 6.7 weight percent phosphoric acid A monocalcium monohydrate, a catalyst having a weight I of 8.3, a β-acid diamma powder, a catalyst having a weight percentage of 〇〇13 (a calcium sulfate dihydrate compound coated with a fine sugar), and an aqueous phase component. The intermediate material is condensed in 11 to 16 minutes. The compressive strength is measured for the vacuum mixed sample using the method set above. The sample (η = 6) will be carried out in the surrounding air! The sample (η 3 ) was cured in the surrounding air for 24 hours. It was loaded along the length of the sample at a fixed rate of 333 mm per second using the Lu (B) Bicmix test system. The compressive strength is calculated using Λ(Pmax)/(Tr*R2). The diameter of the vacuum-mixed sample is measured by the method set above. The side of the plastic block is removed before testing. The sample (n=4) was run at room temperature in the surrounding air! and in hours. The MTS 858 Bi〇nix test system was used to apply lateral force to the sample at a solid rate of 5 mm per second. Load to failure. Diameter tensile strength (DTS) is calculated using (2*Pmax)/(7i*L*H). The dissolution test uses a length of 3.3 mm and the outer diameter (〇D) is: 4.8 mm. The sample is placed in 2 ml of Celsius distilled water. The solution is renewed every day. Drying and weighing the sample every day for 30 days is carried out every five days. ^%. X-ray diffraction technology (XRD) is used to decide The residual weight.Results: Figure 3 shows the results of the diameter tensile strength (DTS). The analysis of the variance (AN〇VA) by software (SAS, Cary, NC). The adhesion of 49 1327071 in air curing (SR), between ! and 24 hours: see a significant difference (ρ < 〇 · 〇〇 1) 'But for bone graft replacement (called 5 and no obvious Μ (ρ = 〇. 508). φ The data in this air conservation can be seen: 贞 see that the adhesive (SR) in H, the reaction is not complete, but the monthly private plant replacement (X3) coagulation reaction has basically been completed. This result is predictable based on the difference in condensation time. The average, maximum and minimum compressive strength values of the intermediate material are then determined. The 1-hour maintenance time data has an average intensity of 19.4 MPa, a minimum intensity of 16.2 MPa, and a maximum intensity of 21.4 MPa. The 24-hour maintenance time data has (four) million (four) average intensity, a minimum intensity of 614 MPa and a maximum intensity of 77.3 MPa. Figure 4 shows the dissolution rate. The dissolution rate was estimated using a linear regression from day day to day 4 of the curve. The average binder (SR) dissolution rate was 10.7% per day' and the bone graft replacement (X3) dissolution rate was daily. The intermediate material has an average dissolution rate of 135% per day. After 95% of the bone graft replacement adhesive is dissolved, the 'residual binder (SRW X-ray diffraction (xrd) shows that it should be a known bioresorbable and osteoconductive material. A 6-week live Small-scale experimental studies in organisms were established under the Accreditation Agreement of the Animal Experimental Organisation Group (IACUC). In each of the three dogs, two sizes of 9 mm mm were counted at each position close to the tibia. Each part is not made up of a binder (s R ) large pill (M 5 cm ^ 3 ), a length of 3.3 mm X outer diameter (〇D) mixture (SR) sphere, and a length of 3·3 mm. 50 1327071 The 4.8 mm bone graft replacement (X3) spheroid is injected with an intermediate re-absorption sulphate mother, acid-filled #5 composition binder, and the implant will be sterilized using gamma-Han. Each dog One implant for each material was accepted. Treatment of the defect and reabsorption of the globule or large pill were estimated from X-rays obtained after 〇, 2 and 4 weeks, and exposure X-rays after 6 weeks. Newly formed bone and residual implants in defects The material is estimated by optical microscopy using the method of dyeing the basic dark red dye and the indole amide blue without removing calcium, embedded in the plastic tissue section. The new bone region and residual material in the defect are determined by the histomorphometry technique. In the study of living organisms, 'X-rays and tissue sections show that both spheres and large pills are replaced by newly formed osteoid, intertwined and thin layered bone, and have been in the previous implant site. A concentrated sheet is formed. After 6 weeks, the newly formed bone portion is 35.9 ± 6.1% for the implant implant (SR) globule defect, and is implanted for bone graft replacement (Χ3) globular The defect was 26.7 ± 10.0%. After 6 weeks, most of the implanted ball material had been absorbed, but compared with the bone graft replacement (Χ3) ball defect, implant bonding The defect of the agent (SR) globule has a lot of residual material. For the implanted binder (SR) large pill, the newly formed bone mass is 15.6±5.6% and has 29.9±11.9% residual implant material. Intermediate re-absorption of sulfur For the i-bow, the acid-filling mom composition binder large pill, the newly formed bone mass is 23.4±7.1% and has 19.3±8.0% residual implant material. For the large pill material, compared with the spherical material With a larger percentage of residual material and a smaller contact area implant volume ratio, it is expected to form fewer new bone 51 丄J厶/VJ / i mass fractions at an early stage. It has the characteristics of coagulation and strength, and its control group has pure characteristics. It can also be read as the second one to slow down the dissolution rate. In the early stage, the growth of bone in living organisms is the same as that of pure sulfuric acid. And, equal, or better than the pure calcium sulfate control group results. Example 2 Material method:

Under the accreditation agreement of the Animal Detectives Group (recognition (3) 匸), at 1 〇: the skinny adult male dog (25_32 kg) is close to the bilateral position of the money =, the construction of the ° ° ° boundary size axial pith defect (diameter 13 mm χ 50 mm), : Study of the 13th (n-5) and 26th (n=5) weeks. In the tibia, a 6 cm3 test material (according to the adhesive S曰R of Example 1) was omitted. On the opposite side of the opposite side of the makeup bone, an equal volume of sulfuric acid is added to the CaS〇4) sphere (〇SEOSET® pellets, Wright)

Progress: ^ ° Obtain X-ray photos at weeks G, 2, 6, 13 and 26. ^ The lunar lateral unnuclear (four) organization W. The new bone shell 4 knife and implanted residual material in this defect were quantified using standard counting techniques. This = also uses high-resolution contact X-rays for inspection. Take the test cylinder from each core of the trap (8 mm diameter χ 20 mΓ, / use unconstrained, no axial force test to determine its ultimate strength and modulus at 05 = m = speed per minute ( mGduius). The tissue shape and biomechanical measurement data were analyzed by Friedman and =^w_ey test. And Xiangping (four) and standard deviation showed 52#: The X-ray photos of the clinical and post-mortem test were clearly revealed. The difference between the resorption rate of the bone graft and the replacement of the new bone in the defect. At the 2nd week, the apparent calcium sulfate (CaSOd globular resorption) was started and was completed approximately at the 6th week. The resorbing rate of the adhesive (sr) also started at week 2, but some binders still existed at week 26. In all of the stained tissue sections, there were lesions from the bone and bone marrow along the fibrous tissue. Recovering defects, as well as relatively low volume residual implant materials. Defect treatment (39.4 ± 4.7%) with adhesive (SR), and defect treatment with conventional calcium sulfate (CaS〇4) spheres (〗 7 3±4 3 /) phase In comparison, there was twice the proportion of newly formed mineralized bone regions (p-0.025) at week 13. At the 26th week, bone had re-formed a normal structure, but with calcium sulfate (CaS〇4) In the case of globular defect treatment (11.2 ± 2.6%), the defect treatment with the adhesive (SR) still had more bone in the defect (18 gents 34%) (p = 〇〇 25). The residual matrix and β-phosphonium tricalcium (p_TCP) fine particles are mixed in the bone column. The surface of the material is not covered by the moon i which is later formed by the osteoclast-like cells, and some of them still contain tiny Particles. Defect treatment using a binder (SR) (29 ± 28.8% at week 13 and ±.6 ± 0.8% at week ,), with conventional calcium sulfate (caS〇4) spheres Defect treatment (17.3 ± 4.3%) compared (帛13周 and 26th weeks are 〇.〇%) 'The proportion of residual matrix area still having high vehicle intersection (ρ is 0.025 and 0.083, respectively). In the way of agent (SR) for defect treatment, the residual matrix decreases with time (p=〇〇47). Residual p_tricalcium phosphate 53 1327071 (β-TCP) fine-grained area The ratio also gradually decreased from the 13th week (3_6±1·0%) to the 26th week (〇.8±1.4%) (?=〇.〇16). 0-tricalcium phosphate (0-1^?) The maximum size of the granules decreased from 13 microns at 348 soils at week 13 to 296 ± 29 microns at week 26 (ρ=〇.〇〇8). At the 13th and 26th weeks, the use of binders (SR) The core bone samples obtained at the defect site for defect treatment are significantly stronger and harder than those obtained from defects treated with calcium sulfate (CaS〇4) spheres (Table D below). In comparison, a similar core bone column sample from 8 normal proximal tibia locations has an ultimate strength of 1.4 ± 0.66 MPa and a modulus of 117 ± 72 MPa. Table 1 Time (week) SR treatment of calcium sulphate ball treatment ultimate strength (MPa) 13 5.3 (2.6) * 0.90 (0.44) Ultimate strength (MPa) 26 2.2 (0.41) ** 0.47 (0.46) Modulus (MPa) 13 283 (217) 40.8 (35.6) Modulus (MPa) 26 150 (73) * 15.8 (23.6) *ρ=0.025, **p=〇.〇46 'The difference in spheres · Many based on calcium Materials with different resorption rates are successfully mixed to produce a binder with a design slow reabsorption curve. In this binder, most of the calcium sulphate and dicalcium phosphate dihydrate matrix are absorbed in the early 54 1327071 phase, which promotes bone formation deep into the adhesive large pill' while spreading the β-tricalcium phosphate (β -TCP) Fines provide a scaffold that binds to new bone and can be resorbed more slowly. The adhesives of this design had increased total bone mass, strength and stiffness at weeks 13 and 26 when compared to treatment with conventional calcium sulphate (CaS04) spheroids. The adhesive ensures that it is advantageous for clinical applications to use a strong, injectable, and highly biocompatible bone graft replacement. Example 3 Material 舆 Method: A 250 ml mixed solution of 0.6 mol of glycolic acid neutralized with sodium hydroxide was established, and the pH value was recorded using a pH meter after calibration. The solution can utilize glycolic acid in crystalline form (Alfa Aesar Part # A12511; Ward Hill, MA), 10 equivalents of sodium hydroxide solution (EMD Chemicals Part # SX0607N-6; Darmstadt, Germany) and USP water for rinsing (Baxter Healthcare Corporation Part # 2F7112;

Deerfield, IL) formed. The solution was then re-packed into two 125 ml portions. One of the bottles was sterilized by total gamma irradiation at a dose of 25-32 kilograms (kGy) while the other bottle was maintained at the control group without cockroaches. After solution sterilization, the acid test value of the sterilized and unsterilized solution was again checked and recorded using an acid tester. In this study, the same batch of the powder form adhesive (SR) used in Example 1 was used. Avoid differences between batches, and cause condensation time to differ from injection force. 55 Each bottle contains a gram of charge to three vials' and is grouped with. This cluster will be used as a control (10) powder for the three vials, and the group will be selected to represent each of the neutralized glycolic acids = _ from the 125 ml sterilized water; two true == f vials, and Three fills - gram = this table is dry. / η. The mixed Yang water bottle is sterilized by γ 姊. The 囷 water bottle will then be combined with the kit of bacteria powder units. υ 已经 已经 亥 亥 亥 — 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群 群Three solutions of a liter of sterile water bottle solution are filled. The other three ¥ 3 〇, gram of adhesive (called the powder of the heart of the liquid L open in the second sterilization. This means that the sterilized solution from the water bottle contains the unburned (four) end and the water bottle sterilization solution set of seals, The money is (4) set for the final sterilization. After the night ==_ is completed, the following test is carried out. All the dissolved ^ (four) _ amount will be checked and recorded by the acid recorder. f nine sets of single w unit It has unsterilized solution (four) and has two - water bottle sterilization solution and unit sterilization..., knife 1 - a solution with two water bottles sterilized (-times, watts:: times in the unit) and primary unit The sterilized powder) will be mixed in a straight 1-turn to form a uniform paste. Use a gram needle to determine the condensation of a 1/4 inch thick paste in a 25 ml plastic cup

56 S 13270/丄 » Junction time. In the powder, the standard of 6 cm π was measured; at the 3 and 5 minutes of the touch, it was determined from the sub-injector to determine the rate of 3 cm 4.4 mm which was injected into the six-denier Jamshidi needle. The output force is rewarded by using the data of __ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ And (4) see the axis in two different, but in the - cluster, the average acid Hi of the two bacteria solution twice off the acid value of 5 . It is 6.3, while the other solutions have about 5. For all clusters, the injection force is about 25 Newtons, and at ^8, it is 40 Newtons. , · Temple 17 Hai shot output I is large For the non-sterilized and one reduced bacteria group, there are - units in minutes of (four) minutes and two episodes. The set time for the two solution sterilization clusters was shifted to about 22 minutes. The end phase is measured: 里 =射 = will cause the pH value and the condensation time to degrade. II: Timing::: Erxian: Significant, but when added for radiation sterilization, τ will definitely cause some degradation in the 5H cluster. Example 4

Liquid, degree of gas oxygen _ Ο raw material solvent acid base drop;: meaning (GA) after gamma radiation sterilization on the material curve. =r...α) Bonding::== Pull strength:, shot = between = nature. Diameter resistance for each configuration ^_Submicroscope =:=:== Configure the comparison of the Kelvin setting time between unsterilized samples. ΓΤ 50 grams of glycolic acid (GA) (~1 stem from Dupont) was sterilized by light sputum. Prepare two parts of the same volume of ~1 moles of glycolic acid (ga,,, lu, sorghum, glycolic acid (GA, one of them has "radiation (4) (GA)' and the other - Unirradiated glycolic acid with the same batch number = A). In order to avoid the material conversion caused by liquid conversion and evaporation, 3_803 grams of glycolic acid (GA) was dissolved in a 250-liter beaker. This solution was previously produced. 500 pens of 〇.6 molar concentration of sodium hydroxide (NaOH) raw material solution in a volume of 500 ml flask, using distilled crane (DI) water to dilute 30 ml of 1 〇, equivalent concentration of sodium hydroxide (Na()H) is produced. This raw material solution is used to titrate glycolic acid (GA) solution. A 5Q ml dropper with a piston (0.1 ml) is used to increase the sodium hydroxide (NaC) in different increments. H) The raw material solution was directly dispensed into a flask containing the ~1 molar concentration of glycolic acid (GA) solution. During the titration,

58 1327071 «• Mycoglycolic acid (ga) solution is stirred with a magnetic stir bar covered with polytetraethylene and a plate. The total weight of the sodium hydroxide (Na〇H) raw material solution was monitored and recorded by titration. The pH value of the glycolic acid (GA) solution was also monitored and recorded with the gradually added sodium hydroxide (Na〇H) stock solution. The pH measurement is determined by a pH meter (VWR Scientific; Model 8000) and an electrode (VWR Scientific; p/N 14〇〇2_78〇). The electrode uses a standard buffer solution with a pH of 4 〇. Verify between 〇 and 7 ( (VWR Scientific; P/N 34170-130 and 34170-127, respectively). The titration was carried out by continuously increasing the raw material solution until a minimum change in pH was observed in the alkaline range. A titration curve (pH of the glycolic acid (GA) solution for milliliters of 0.6 molar concentration of sodium hydroxide (NaOH)) was plotted and compared with the effect of gamma irradiation of crystalline glycolic acid (ga). Using a 60 Hz PK Twin-Shell Yoke Scrambler (Patterson-Kelley Co.; East Stroudsburg, PA) in a 1 quart (qt) acrylic V-shell, the 300 gram adhesive (SR) described in Example 1 was used. The material (Configuration 1, with sodium glycolate (Na-GA) in solution) was stirred for 20 minutes. All of the pastes established using Configuration 1 were formed from a 0.6 molar solution of sodium glycolate (Na-GA) having a liquid to powder weight ratio (L/P) of 0.23. Prepare twenty-five parts of 15 cm cm of modified adhesive (SR) using a 60 Hz PK Twin-Shell Yoke scrambler in a 2 quart (qt) stainless steel acrylic V-shell with 20 minutes of material agitation. The material (configuration 2, including a sodium persalt 59 1327071 (Na-GA) powder having a weight percentage of 1.290 and a size of S 45 microns) is an injectable kit. α 〇 1 〇 gram of water is loaded to handle the loss of solution in the vial during delivery. This set of Huai: dish 'transfer sterilization (25-32 kGy dose). In this study, the group of the Dingsi group was made. The weight ratio (L/p) of the liquid of the configuration 2 to the powder is 〇. The difference in the weight ratio of this configuration is caused by the change of sodium glycolate (Na_GA) from solution to powder.

RESULTS: There was a slight Fischer's setting time shift in the Fischer's setting time results shown in Configuration 2. Except for the different Na-GA positions in the two configurations, only the remaining variables were those in which the set of 2 sets had been irradiated and the material of the arrangement 1 was not irradiated. To compare the two variables, the Kelvin setting time for each of the two additional samples was also used; however, the sample of configuration 2 was not sterilized.

• Perform two % gram powder configuration 丨 unit fee Kelvin condensation time test ° 3 yuan whole mixture is transferred to 5G ml polystyrene beaker, (VWRScienti 叱 P / Nl side - 015); The layers are layered and most of the air is removed by slightly tapping the beaker on the table top. The Keith's setting time for both samples is determined by the same method as described above. ^ At the same time, the two units of the configuration 2 powder were also tested, and the complete compound was also used to determine the Keith's setting time as mentioned before. Due to the lack of material mixture, only 3 gram powder was used for testing. 60 1327071 Configuration 1 The newly acquired data will be integrated with the results of the previous fee Kelvin test, so there is no other processing difference other than the volume. Configuration 2 The newly obtained data is used alone to compare with the results of Configuration 1. Figure 5 shows the production of glycolic acid (GA) from gamma sterilized and not sterilized in 7! The titration profile of the molar concentration of glycolic acid (ga) solution. The curves formed were not significantly different. As recorded in Figure 3, the sodium glycolate (Na_GA) solution used in the configuration of the i-set production, after the gamification is performed, shows the effect of (iv) the value of the deviation offset. There is no significant acid change in the solution produced by gamma irradiation of glycolic acid (ga). This result is a reduction in the effect of the ethanol-sub-degradation of the Y-irradiated Y-light, if not completely, by the manner in which the crystalline form of the ai is exposed. This is evidence that the configuration of sodium glycolate (Na-GA) crystals is less affected by gamma irradiation. Table 2 below shows the average 24 hour dry diameter tensile strength (DTS) test for each configuration. Both configurations have a diameter tensile strength (DTS) value close to 9, and each group becomes apparent. Although configuration 2 has a slightly higher average intensity value (1) 9 megapascals) 'There is no statistically significant difference between the two configurations ((iv) = the observed difference can be considered as an inherent difference in the test method. This 14 The final condensing adhesives in both configurations have the same mechanical strength. Table 2 ' ------- Hours DTS (MPa), η=6 Configuration ------- 61 s 1327071 1 8.80 [0.62 ] 2 9.29 [0.75] Table 3 shows the average dissolution test results for each configuration after four days. These two configurations have almost the same dissolution results, stupid in four days ~ your soil master π w%. ^^The similar measurement shown by the mother 禋 为 is a fruit, further proof that both systems form the same reaction chemistry and reaction level table 3_

4 days dissolution test (remaining weight percentage), η = 5 mean [standard deviation 1

View the condensed adhesive block through the diameter tensile strength (DU) gap surface produced by each configuration, through U ίI (SEM)

The final products are generally evaluated as _ phase, the average injection force and the amount of charge for each type of distribution, and the average value = 丨 = set; ^ the coefficient of variation of the measurement with fairly close injection force Both are less than 3% of the (10), _ king body thousand mean. The reproducibility of the two. The average shot of configuration 2 (4) has a good (2.6%) configuration. These results show a slight lower than the viscosity and flow characteristics of the paste from = 36.9 Newtons. , two configurations can get equal

< S > 62 configuration 1 average shot [standard deviation] '

Average condensation time (minutes:seconds) Standard deviation] 15:00 [〇〇:3〇1 17:40 [01:261 Level: Fee configuration 1 measurement data 罝 right 4. 4 〇 (minutes: seconds) Configuration 1 is 2:40 long. The data is compared to the lower =; C: 30' forms - and the configuration 2 is 26. The difference between the standard deviation and the standard deviation of configuration 2 is different. q 灭 置 的 的 的 的 的 的 费 费 置 费 费 费 费 费 费 费 费 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝 凝The offset was determined because of the change in the position of sodium glycolate (Na_GA). By mouth, table. The average fee for the 5 configuration is 5 Kelvin condensation time. The configuration of the summer results is integrated with the results of the two additional units and the three quantities previously presented. n=5 in Table 5 1; n=2 (minutes:seconds) in Configuration 2 [Standard Deviation 1 14:18 [01:02] Configuration -~~— 14:45 [00:211__ In this scenario, each Good match, -. The difference between the time λ averages is less than 3 〇 seconds, unlike before

63 <S illuminate the configuration of the 2 data obtained by j, '. fruit. This shows the reaction dynamics of the two configurations, which are similar to the similar Kelvin setting time, and further demonstrates the equality between the two configurations. The Freund's condensation time offset seen in the earlier blows of the *Pa.. d king is the result of gamma irradiation, &amp; 3 does not deviate from the difference between the two configurations. 4^!; = Configuration 2 caused an unexpected Fischer's condensate, two ~, target 13 consistent 'where the configuration of the form of stirring powder - a person in the same gamma dose range continuous irradiation of sodium glycolate (Na_GA) The solution, which causes an increase in the average fee Kelvin condensation time. Conclusion: (D two; two: between the production configuration, there is no statistically significant difference between the diameter tensile strength ^, 'glutinal solution rate and the output force value. j estimated the irradiation gi set 2 data, its (four) condensate There is a statistical difference value of time = 0.04) 'But there is no difference in the same score for the un-configured 2f material (P value = G.59). This difference is due to the difference in configuration' because if there is a change in position of sodium glycolate (Na_GA), a significant difference in the second Fey's setting time will also be formed. Therefore, this study is clearly configured in the form of paste and cohesive binders with equivalent chemical, physical, mechanical properties and types. Numerous modifications and other embodiments of the inventions set forth herein will be apparent to those skilled in the art. Therefore, it is understood that the invention is not limited to the specific embodiment disclosed, and its modifications and other embodiments are also contemplated, and in the scope of the appended claims. Although some specific techniques are used here. It is only used for the general term and description, and is not intended to be limiting. 1327071 [Simple Description of the Drawings] Therefore, after having a general description of the present invention, reference will now be made to the accompanying drawings, in which: Figure 1 illustrates a bimodal particle distribution pattern obtained from a high resolution laser diffraction mode. Concepts; Figures 2a, 2b and 2c provide a number of illustrations of an exemplary diameter tensile strength sample mold; Figure 3 depicts the diameter of the bone graft adhesive according to the present invention and the commercially available calcium sulfate binder. Comparison; Figure 4 is a graph showing the dissolution properties of an in-tube test of two bone grafting adhesives according to the present invention compared to commercially available calcium sulfate binders; and Figure 5 depicts the use of unirradiated and gamma-irradiated crystals. A solution titration curve formed by glycolic acid.

MIIG (X3) bone graft replacement NaOH sodium hydroxide SR adhesive [Main component symbol description] 20 model 30 cylindrical space C / S calcium sulfate C / P calcium phosphate DTS diameter tensile strength Μ Moer ml ml MPa million PA 65

Claims (1)

1327071 \/r. Patent application garden: !...... 1· - Particle composition HX Immediately after mixing with water, a bone graft replaces the adhesive, including: Z = hemihydrate powder It has a bimodal particle distribution and a concentration of the intercalating particulate water compound of about 20 microns is at least about 70% by weight of the total weight of the calcium acid + tile composition; (1) a dish of a monohydric acid compound powder; and iii) a powder of a β-citrate tris, a compound size. No, an intermediate micro 2 of less than about 20 μm, a particle composition of the patent application scope, Including (iv) three particles of acid having an intermediate particle size of at least about 75 microns. • A particulate composition according to claim 2, wherein a concentration of the (tetra) acid tri-n, and the 'field particles is up to about 20% by weight based on the total weight of the particulate composition. — The particulate composition of claim 3, wherein the β-squaric acid tri-granules have a 'thumbth' of 12% of the total weight of the particulate composition. 5. For example, the micro (four) composition of the patent scope 帛1, wherein the sulfuric acid crane hemihydrate is α-calcium sulfate hemihydrate. 6. The particulate composition of claim 1, wherein the sulfuric acid about hemihydrate powder has a bimodal particle distribution comprising - containing a mode of from about 1.0 to about 3.0 microns Microparticles and microparticles having a mode of from about 20 to about 30 micrometers, wherein the modality having a mode of from about 1 〇66 to about 3.0 micrometers is from about thirty to about sixty percent by volume of the total volume of the hydration, and The microparticles having a mode to about 30 micrometers are from about forty to about seventy percent by volume of the total volume of the sulfur gorge hemihydrate. 7. If applying for a full-time meal, the green color of the water-repellent compound powder is at least 75% by weight. 8. If the composition of the patent application is applied, the scale The combined concentration of the monohydrate powder and the «acid three ends is about three to thirty percent by weight based on the total weight of the fine particle composition. 9. The particulate composition of claim i wherein the bismuth citrate powder has a -bimodal particle size distribution comprising -containing from about 2. G to about 6. Micron modal particles and - particles having a mode of from about 40 to about 70 microns, the particles having a mode of from about 2.0 to about 6. G microns are about twenty of the total volume of the ρ·capric acid tri-shadow powder Up to about seventy percent by volume, and that has about 4 〇 to The particles of about 70 micrometers in modality are from about thirty to about seventy percent by volume of the total volume of the tricalcium phosphate powder. 10. The particulate composition of claim 1, further comprising a catalyst which reaches about one percent by weight of the total weight of the particulate composition, for catalytically converting the sulfuric acid hemihydrate to sulfuric acid feed water Compound. 11. The particulate composition of claim 10, wherein the catalyst is selected from the group consisting of calcium sulfate dihydrate microparticles, potassium sulfate microparticles, and sodium sulfate microparticles, wherein the catalyst can be selectively coated with sucrose. cover. 67 1327071 Biological activity 12. The particulate composition of claim 1 of the patent scope, including the ~ agent. 13. The particulate composition of claim 12, wherein the biological agent is selected from the group consisting of: a thin bone tablet, a growth factor active antibiotic, an insecticide, a chemotherapeutic agent, an antiviral virus drug And anti-inflammatory drugs. , painant agent 14. The particulate composition of claim a, wherein the biological agent is a bone matrix from which minerals are removed. The particle composition of claim 12, wherein the biological tongue agent is a growth factor selected from the group consisting of: fibroblast growth factor, platelet-derived growth factor, bone forming protein π raw Bone protein, transforming growth factor, LIM mineralized protein, osteoinductive factor, angiopoietin, endothelin; growth differentiation factor, anti-dorsal morphogenetic protein-1 (ADMP-1), endothelin, hepatic blister growth factor And keratinocyte growth factor, liver gluten growth factor, singular egg _ white matter, interleukin, colony stimulating factor, epidermal growth factor, insulin-like growth factor, cytokines, osteogenic protein and osteonectin. 16. The particulate composition of claim 1, comprising: i) an alpha-calcium sulfate hemihydrate powder having a bimodal particle distribution and an intermediate particle size of from about 5 to about 20 microns, wherein A concentration of the calcium sulphate hemihydrate is at least about seventy-five percent by weight of the total weight of the particulate composition, and that the calcium sulphate hemihydrate powder has a bimodal particulate distribution, the bimodal particulate The distribution includes particles having a mode of from about 1 mm to about 3.0 microns and particles having a mode of about 20 straight 68 to about 30 microns, the particles having a mode of about i ο to about 3 〇 microns being the calcium sulphate The total volume of the semi-aqueous compound powder is from about thirty to about sixty percent by volume 'and the microparticles having a mode of from about 2 Torr to about 3 〇 micrometers are from about forty to about seventy percent of the total volume of the calcium sulphate hemihydrate powder. Percentage by volume; ii) monocalcium phosphate monohydrate powder; iii) b tricalcium phosphate powder having an intermediate particle size of less than about 20 microns, the disco-single monohydrate powder and the tri-calcium sulfate a knot of powder The concentration is about ten to twenty percent by weight of the total weight of the particulate composition; ίν) beta-tricalcium phosphate fine particles having an intermediate particle size of from about 10 μm to about 400 μm and reaching a concentration of a weight of about 12% by weight of the total weight of the particulate composition; and ν) - a catalyst for catalytically converting calcium sulfate hemihydrate to a sulfuric acid about dihydrate compound, a concentration of the catalyst reaching the total particulate composition About one percent of the weight of the weight. 17. The particulate composition of claim 16 further comprising a bioactive agent selected from the group consisting of: a thin bone, a growth factor, an antibiotic, an insecticide, a chemistry Therapeutic agents, antiviral drugs, analgesics and anti-inflammatory drugs. a particulate composition for forming a bone graft replacement adhesive immediately after mixing with an aqueous phase solution, comprising: i) a calcium sulphate hemihydrate powder having a bimodal particle distribution and from about 5 to about An intermediate particle size of 20 microns, wherein the sulfur 691327071_hemihydrate powder comprises particles having a mode of from about 1Q to about 3G microns and particles having a mode of from about 20 to about 3 microns, which has about 1. The particles of G to about 3.G micron of the mold n are from about thirty to about sixty percent by volume of the total volume of the sulfuric acid hemihydrate powder, and the particles having a mode of from about 20 to about 30 microns are the sulfuric acid. The total volume of the calcium semi-hydrated s powder is from about forty to about seventy percent by volume. ii) squama mono-monohydrate monohydrate powder; in) beta-dicalcium phosphate powder having an intermediate of less than about 2 〇 microns Particle size; iv) - a catalyst for catalytically converting calcium sulphate hemihydrate to a sulphate dihydrate; and ν) a bone matrix for removing minerals. 19. The particulate composition of claim 18, wherein the ρ-squaric acid powder has a bimodal particle size distribution comprising particles having a mode of from about 10 to about 6.0 microns and having about 4 〇 to about % micron modal particles 'they having a mode of about 2.0 to about 6.0 microns, the granules being from about % to about a volume percent of the total volume of the β-supply acid powder: and having about 4 The modal particles that are entangled to about 7 micrometers are about 3 () to about 7 Q volume percent of the total volume of the beta bismuth. 20. The particulate composition of claim 4, wherein the sulfuric acid semi-hydrated 5 system is an alpha sulfuric acid hemihydrate. For example, the particle composition of the "Patent No. 18 of the patent range" is wherein the combined concentration of the single-sweet monohydrate powder and the β-phosphate is about three percent of the total weight of the money composition. Thirty-thickness β 70 1327071 22. A bone graft replacement adhesive comprising a reaction product formed by mixing a particulate composition according to any one of claims 1 to 21 with an aqueous phase solution, The reaction product comprises a sulfuric acid #5 dihydrate compound and a brushite phosphate. 23. The bone graft replacement adhesive according to claim 22, wherein the binder mixes the particulate composition with the aqueous phase solution and A one-dimensional tensile strength of at least about 4 million Pascals (MPa) after one hour of curing in ambient air. 24. A bone graft replacement adhesive according to claim 22, wherein the adhesive is The particulate composition is mixed with the aqueous phase solution and has a diameter tensile strength of at least about 8 MPa after 24 hours of curing in ambient air. 25. Bone graft replacement adhesive as claimed in claim 22 Wherein the binder has an average dissolution rate, which is expressed as an average percentage of weight loss per day, which is at least about 25% lower than the average dissolution rate of a binder formed by using a particulate composition composed of calcium sulfate. The average dissolution rate is measured by immersing a precipitate having a length of 3.3 mm and an outer diameter (OD) of 4.8 mm in a steam of 37 degrees Celsius. 26. The bone of claim 22 An alternative adhesive, wherein the aqueous solution comprises a dilute acid. 27. A bone graft replacement adhesive according to claim 26, wherein the carboxylic acid is a monohydroxycarboxylic acid. Bone graft replacement adhesive, wherein the 1327071 hydroxycarboxylic acid is glycolic acid. And - a bone graft replacement kit, which includes - or more _ in the seal of the application, the scope of the benefit! The benefits of the particulate composition described are for the separation vessel for encapsulation of a sterile aqueous phase solution and for a written instruction set describing a method of using a "seaset". 30. A method for improving the stability of a set of storage, the set comprising a microparticle, a compound and an aqueous phase solution for forming a bone graft during mixing - wherein the kit comprises two _ The final Wei Wei powder ^ water and the presence of nucleus can reflect the shape of money _ stone, the method package = (four) acid monohydrate compound powder and the separation container to the set; and the formula is dissolved in the water phase The solution is encapsulated into the set as follows, with the proviso that when the acid 3 is in the :: phase solution, it is added to the solution after the aqueous phase solution has been subjected to radiation reduction. 31t. The method of claim 30, wherein the nucleus is a neutral-type form&apos; which is selected from the group consisting of sodium glycolate, potassium glycolate, sodium lactate and potassium lactate. 32.=Please=Scope Item 30^ Method The components of this kit are used for sterilization. 33. A bone shifting alternative kit comprising: :) m which seals Weidan 26 monohydrated material powder; u) - the first valley is sealed with ρ·tricalcium phosphate powder; 72 1327071 ui) sulfuric acid The calcium hemihydrate powder is enclosed in a separate container or mixed with the monocalcium phosphate monohydrate powder and one or both of the powders; a water-phase solution enclosed in a separation vessel; and v) a carboxylic acid dissolved in the aqueous phase solution or in the form of a crystalline powder, the carboxylic acid crystalline powder being enclosed in a separate vessel or Mixing one or more of the phosphorus monocalcium monohydrate powder, the P-tricalcium phosphate powder and the sulfuric acid 5 hemihydrate powder, with the proviso that ♦ when the tickic acid is dissolved in the aqueous phase solution It is added to the solution after the water phase is sterilized by radiation. 34. A bone graft replacement kit according to claim 33, wherein the kit is sterilized by exposure to gamma light. 35. The bone graft replacement kit of claim 33, wherein the carboxylic acid is a neutral salt form selected from the group consisting of sodium glycolate, glycolic acid Potassium, sodium lactate and potassium lactate. 36. In the case of the bone graft replacement kit of claim 33, the acid powder is enclosed in a separate container, so the aqueous phase solution and the monocalcium phosphate monohydrate powder, ρ_phosphate Before mixing any one or more of the calcium powder and the calcium sulfate hemihydrate powder, it may be mixed with the aqueous phase solution to restore the carboxylic acid crystal powder to a carboxylic acid. 37. The bone graft replacement kit of claim 33, wherein the calcium sulphate hemihydrate powder further comprises a catalyst in the form of a mixture and for catalytically converting calcium sulphate hemihydrate to calcium sulphate dihydrate. 73 1327071 38. The bone graft replacement kit of claim 37, wherein the catalyst is selected from the group consisting of calcium sulfate dihydrate microparticles, potassium sulfate microparticles, and sodium sulfate microparticles, wherein the catalyst can Optionally covered with sucrose. 39. The bone graft replacement kit of claim 33, further comprising being present in a separate container, or with the monocalcium phosphate monohydrate powder, the beta-tricalcium phosphate powder and the calcium sulfate hemihydrate Any one or more of the mixed β-tricalcium phosphate fine particles. 40. The bone graft replacement kit of claim 33, further comprising a bioactive agent, enclosed in a separate container, or with the dish acid #5 monohydrate powder, β-disc acid three # 5 Mixing one or more of the powder and the sulfuric acid word hemihydrate powder. 41. The bone graft replacement kit of claim 40, wherein the bioactive agent is selected from the group consisting of: a thin bone tablet, a growth factor, an antibiotic, an insecticide, a chemotherapeutic agent, an antibiotic Transvaginal viral drugs, • antispasmodics and anti-inflammatory drugs. 74