TW201938210A - Composite material and method for free forming bone substitute - Google Patents

Abstract

A method and a composite material used for free forming a bone substitute are provided. The composite material comprises a support cloth, and a partially hardened bone paste coated on the support cloth. The bone paste contains a mixture of calcium sulfate and calcium phosphate in a weight ratio of 1:1 to 1:4. The bone substitute can be made by laminating the composite material either on a bone model or not.

Description

Free forming method of bone substitute and composite material used by same

The present invention relates to a method and a composite material for a free-form bone substitute, which are manufactured by addition or subtraction, and in particular to a method and a composite material for a free-form bone substitute. Cross-reference to related applications

This application claims priority from provisional application serial number No. 64 / 470,897, filed on March 14, 2017. The entire contents of the above patent applications are incorporated herein by reference and form a part of this specification.

Many forming techniques are used to make ceramic products. The most popular technique is the embossing technique that requires a steel mold. In the manufacturing process, the processing powder (including ceramic powder mixed with a binder and a lubricant) is poured into a steel mold; the powder is then pressed together by applying an external load. Although the molding technology has good mass production capacity, its shape complexity is quite limited. In addition, the cost of steel molds used in compression technology is usually higher. For mass production, it is usually necessary to apply a hard coating on the inner surface of the steel mold, which further increases the cost of the steel mold.

In order to make complex shapes, injection molding technology is also used to make ceramic products, but it needs to add a lot of additives, such as binders, plasticizers and surfactants, to facilitate the injection molding technology. Moreover, the cost of the steel mold used for injection molding is very high. Due to the large amount of adhesives and plasticizers used, the time required to remove additives through a de-binding process is very long, sometimes even days.

Due to the development of many personalized products, the demand for rapid prototyping has also increased. For new product development, 5 to 10 prototypes may be sufficient for subsequent evaluations. But if a mold is needed, the cost of developing a new product can be very high. In addition, the process of preparing the mold is time consuming, which may slow down the development of new products.

To solve the above problems, an additive manufacturing process such as 3D printing has recently been developed. Additive manufacturing technology has achieved great success in manufacturing many plastic products. Almost all products of any shape and size can be manufactured using additive manufacturing techniques. Additive manufacturing technology has also used selective laser sintering technology in the manufacture of metal products. However, ceramic materials are not suitable for the production of ceramic articles using similar methods of the above-mentioned additive manufacturing. Therefore, there is a need for alternative methods of manufacturing ceramic prototypes, and in particular, methods of forming highly customized bone substitutes.

Accordingly, a free-form method of ceramic articles is provided to make prototypes of ceramic articles, such as bone substitutes. In this method, an adhesive or a binding agent is preferably not required.

According to an aspect, the above-mentioned free forming method includes the following steps. A first layer of bone paste is coated on the support cloth, where the bone paste consists essentially of a mixture of calcium sulfate and calcium phosphate. After the bone paste is dried, a partially hardened bone paste is formed as an intermediate. Wet the intermediate with an aqueous liquid to harden the partially hardened bone paste. After drying, a hardened bone paste is formed.

In one embodiment, the weight ratio of calcium sulfate to calcium phosphate is from 1: 1 to 1: 4.

In another embodiment, calcium sulfate comprises CaSO ₄ · 0.5 H ₂ O, CaSO ₄ · 2 H ₂ O, or any combination thereof; calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphates, Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <X <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O, or any combination thereof.

In yet another embodiment, the aqueous liquid is (PO ₄₎ and of NaH ₂ (PO _{4) 2} buffer solution containing Na ₂ H.

In yet another embodiment, the method further comprises sintering the hardened bone paste after the hardening step, and removing the support cloth to obtain a porous bone ceramic.

In yet another embodiment, the support cloth is woven with biodegradable fibers. The biodegradable fibers may be, for example, polylactide, poly (lactic-co-glycolic acid). , Poly (propylene fumarate), or any combination thereof.

In another embodiment, the above-mentioned forming step and the drying step are further included several times between the above-mentioned drying step and the hardening step, so that the intermediate has a laminated structure.

In yet another embodiment, each layer of bone paste in the intermediate is sequentially hardened according to the determined cross-sectional pattern of the bone substitute to obtain a hardened bone substitute.

In yet another embodiment, an unnecessary portion of the hardened bone paste in the intermediate is removed after the hardening step to form a hardened bone substitute.

In yet another embodiment, the support cloth covers the model of the bone substitute before the forming step.

In yet another embodiment, the above-mentioned forming step and drying step are repeated several times between the drying step and the hardening step so that the intermediate has a laminated structure.

In another aspect, composite materials for free-form bone substitutes are also provided. The composite material includes a support cloth and a layer of partially hardened bone paste applied on the support cloth. Partially hardened bone paste is basically composed of a mixture of calcium sulfate and calcium phosphate in a weight ratio of 1: 1 to 1: 4.

In yet another aspect, a bone substitute is provided. The material of the bone substitute includes a hardened bone substitute material consisting essentially of a mixed calcium sulfate and calcium phosphate in a weight ratio of 1: 1 to 1: 4 and a channel distributed in the hardened bone substitute material.

In some embodiments, fibers are present in the channels.

Composite material for free-form ceramic products and preparation method thereof

A composite material for a free-form ceramic article is provided. The composite material includes a support cloth woven from organic fibers and a partially hardened ceramic paste distributed on the support cloth. This composite material can be used as an intermediate and used in the free-form method described below to prepare ceramic articles.

The method for preparing the above composite material may be, for example, distributing the dried ceramic powder on a wet support cloth, such as steps 100-104 in the process flow chart shown in FIG. 1A. After that, a drying step is performed to obtain a partially hardened ceramic paste on the support cloth. Water can usually be used to wet the ceramic powder and support cloth, so by adding water or an aqueous solution, the dried ceramic paste can be softened again to facilitate the shaping of the ceramic paste.

In some embodiments, the material of the initial ceramic powder may be calcium sulfate, calcium phosphate, hydroxyapatite, calcium carbonate, calcium hydroxide, magnesium carbonate, strontium carbonate, kaolin, or a combination thereof. The above ceramic paste exhibits self-hardening ability, that is, a partially hardened ceramic paste can be hardened using an aqueous liquid such as water or other aqueous solution containing a hardener.

The organic fibers may be made of poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA), or poly (propylene glycol fumarate). (poly (propylene fumarate), PPF), polycaprolactone (PCL), polyethylene glycol (PEG), poly (α-hydroxy ester), poly ( N-isopropyl acrylamide (poly (N-isopropyl acrylamide), PNIPA), pluronic block copolymer, carboxymethyl cellulose (CMC), or any combination thereof. In some embodiments, the organic fibers may be biodegradable fibers, such as organic fibers made from PLA, PLGA, PPF, or any combination thereof.

Free-form method for ceramic products

basic method

In the basic method of free-forming ceramic products, the composite material can be directly hardened by adding the above-mentioned aqueous liquid. Unwanted parts can then be removed by some available subtraction means, such as cutting, drilling or grinding.

In addition, in some embodiments, the support cloth may further cover a model of a desired ceramic product, such as a model having a desired shape of a bone substitute, so that the ceramic paste can be directly obtained after the ceramic paste is hardened by an aqueous liquid. For details of the processing flow, see steps 200-212 in FIG. 1B.

The hardened ceramic product can be further sintered at a temperature higher than 600 ° C, and the support cloth is removed to form a porous ceramic product, which has a channel left by the support cloth.

Subtractive manufacturing method

See Figure 1A. In some embodiments, if the thickness of the above-mentioned hardened composite material is not sufficient for the desired article, the wet composite material may also be stacked layer by layer before the hardening step to form an intermediate having a laminated structure, such as FIG. 1A Steps 106-110. The number of layers of composite material in a laminated structure is determined by the desired thickness of the desired ceramic article.

After the laminated structure is hardened in step 112 of FIG. 1A, some available subtractive processing methods (such as cutting, drilling, or grinding) can be used to remove the unnecessary parts to form the desired ceramic article in step 114 of FIG. 1A . Next, in step 116 of FIG. 1A, the processed laminated structure may be further sintered to form a porous ceramic article.

See Figure 1C. The stacked structure can also be formed by repeatedly performing steps 302-306a or 302-306b in FIG. 1C. The remaining steps in FIG. 1C are similar to the corresponding steps in FIG. 1A, so the related descriptions are omitted here.

Additive manufacturing method

In some embodiments, the size and shape of multiple cross sections of the ceramic article are identified sequentially. Next, during the lamination process, each layer of the ceramic paste can be sequentially hardened according to the determined cross-section of the desired ceramic product, such as steps 108b, 110 in FIG. 1A and steps 302, 304, 306b in FIG. 1C . That is, the hardening step in the basic method is performed only by applying an aqueous liquid to a defined cross section of each layer. Therefore, after the lamination process (steps 106, 108b, and 110 in FIG. 1A, or steps 302, 304, and 306b in FIG. 1C) and after removing the unhardened portion (step 114 in FIG. 1A and step 310 in FIG. 1C) ), Hardened ceramic products can be obtained.

Formation of bone substitutes

When the above ceramic product is used as a bone substitute, the initial ceramic powder used to prepare the above ceramic paste (ie, bone paste) can basically be a mixture of calcium sulfate and calcium phosphate, and the weight ratio of calcium sulfate to calcium phosphate is 1: 1 to 1: 4.

In some embodiments, the calcium sulfate comprises CaSO ₄ · 0.5 H ₂ O, CaSO ₄ · 2 H ₂ O, or any combination thereof. In other embodiments, anhydrous calcium sulfate may also be used. In still other embodiments, the calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate. phosphates), Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <x <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O, or any combination thereof. Among them, calcium sulfate is used to adjust the hardening rate of ceramic paste.

In addition, the above-mentioned aqueous liquid used to harden the bone paste is a buffer solution of water or sodium hydrogen phosphate Na ₂ H (PO ₄ ) / NaH ₂ (PO ₄ ) ₂ ). The concentration of sodium hydrogen phosphate in the buffer solution can be 0.1-1 M. Generally, the higher the concentration, the faster the hardening rate.

When a bone substitute needs to be implanted in the body, a hardened bone substitute or a sintered bone substitute can be used. If a hardened bone substitute is used instead of a sintered bone substitute, the support cloth should be woven with biodegradable fibers. If a sintered bone substitute is used, there are no restrictions on the fibers used to weave the support cloth.

In addition, a composite material with partially hardened bone paste on the support cloth can also be used as an implant because the partially hardened bone paste can harden after contacting the tissue fluid surrounding the implantation site.

The detailed explanations and examples of the ceramic powder / ceramic paste, the support cloth, and the moist liquid have been explained above, and therefore will not be repeated here.

Example 1 : Preparation of CaSO ₄ · 2 H ₂ O powder / fiber cloth composite

In this example, the ceramic used is CaSO ₄ · 2 H ₂ O powder, and the fiber cloth is a cotton cloth woven from cotton fibers having a diameter of about 100 μm. The distance between the two fibers is approximately 1,000 μm. The composite material can be prepared by wetting CaSO ₄ · 2 H ₂ O powder with a small amount of water and then coating wet CaSO ₄ · 2 H ₂ O powder on the fiber cloth. Composite materials can also be prepared by immersing a fiber cloth in water and then attaching CaSO ₄ · 2 H ₂ O powder to a wet cotton cloth. FIG. 2A is a photograph showing the appearance of the CaSO ₄ · 2 H ₂ O powder / fiber cloth composite material.

Finally, the wet composite material is dried in the air. FIG. 2B is a photograph showing a dry composite roll of CaSO ₄ · 2 H ₂ O powder / fiber cloth. As can be seen in Figure 2B, the dried composite is still soft, so that a roll of dried composite can be formed for easy storage.

Example 2 : Ceramic block made of CaSO ₄ · 2 H ₂ O powder / fiber cloth composite

In this example, the CaSO ₄ · 2 H ₂ O powder / fiber cloth composite of Example 1 was stacked layer by layer to form a ceramic block. First, the first layer of the composite material is hardened by miniaturizing with water. Next, the second layer of composite material is stacked on the first layer and then wetted. Repeat the above steps until the desired stack thickness of the composite material reaches the target. Subsequently, the stacked composite material is dried, for example, the drying temperature may be 60 ° C or higher to accelerate the drying process.

FIG. 3A is a photograph showing a ceramic plate formed after laminating 6 layers of CaSO ₄ · 2 H ₂ O powder / fiber cloth composite material. The self-hardening process takes only a few minutes. An external heating source can reduce the time required for drying. After grinding the edges of the specimen, the dimensions of the ceramic plate before sintering were 73 mm (length) × 28 mm (width) × 5.5 mm (thickness). The strength of the ceramic plate before sintering was measured using a three-point bending technique on a universal testing machine. The loading rate was 1 mm / min. The average value of the three-point bending strength of the ceramic plate before sintering was 5.6 ± 0.85 MPa, and the number of test samples was at least three.

The sample was then sintered in a furnace. The fibers were burned at a temperature of 600 ° C. The ceramic plate is then densified at a sintering temperature of 1050 ° C. The residence time at this temperature was 1 hour. FIG. 3B is a photograph showing the morphology of the sample before and after sintering. The length of the slab has been reduced by 15%, showing that the use of sintering technology can increase the density of ceramic plates. Three-point bending strength was then measured. The mean value of the bending strength is 1.6 MPa, and the number of test samples is at least three. Figure 2C shows a photograph showing the fracture surface of the sample after sintering. After burning out the fibers, continuous pores are formed. The distribution of calcium sulfate particles along the pores can be observed.

Example 3 : Preparation of the head of the humerus with CaSO ₄ · 2 H ₂ O powder / fiber cloth composite

To prepare the ceramic head of the humerus, the plastic head of the humerus is first used. Then apply the method in Example 2 to cover the plastic head on a ceramic / organic fiber composite layer by layer. That is, 2 to 3 layers of composite material are covered on the plastic head with the aid of a small amount of water while applying shear stress. The head of the humerus can then be prepared. Next, the plastic head can be removed by melting or thermal decomposition.

In this example, the plastic head described above can also be replaced with a wax head. Wax heads can be removed at temperatures above 300 ° C. FIG. 4 is a photograph showing a dried humerus head prepared in Example 3. FIG. This sample shows that ceramic articles with complex shapes can be prepared using the thin-film stacking technique, which is one of the additive manufacturing techniques.

Example 4 : Preparation of ceramic tube using CaSO ₄ · 2 H ₂ O powder / fiber cloth composite

Ceramic / organic fiber composite laminates can also be used to make ceramic tubulars. It is possible to produce tubulars with a length of more than 1000 mm and a diameter of more than 35 mm. Subtractive manufacturing techniques such as drilling, sawing, and grinding can be used. Using these techniques, ceramic products with any complex shape can be made. For example, Figure 5 shows a pre-sintered ceramic tube after cutting and drilling.

Example 5 : Self-hardening test of ceramic paste

The ceramic paste used and the results of the self-hardening test are listed in Table 1 below.

Table 1: Self-hardening test

As described above, calcium sulfate dihydrate (CaSO ₄ · 2 H ₂ O), calcium sulfate hemihydrate (CaSO ₄ · 0.5 H ₂ O), tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ), and one or more of the above Powder mixtures can be used as ceramic pastes for ceramic / organic fiber composites. Ceramic paste can be mixed with organic fibers to form a composite material. Both additive manufacturing and subtractive manufacturing can be used to make ceramics with complex shapes by spraying water on the composite material. Self-hardening can occur in minutes to days. Since the hardening time is only a few minutes, ceramic / organic fiber composites can be used for rapid prototyping.

Example 6 : Measuring the biaxial stress of a sintered ceramic disc

The ceramic paste is molded to form a cylindrical disk and then sintered. The sintered cylindrical disk has a diameter of about 20 mm and a thickness of about 3 mm. The geometrical weight-volume method was used to measure the density of the sintered cylindrical disc. A biaxial loading fixture and a one-ball-on-three-balls fixture were used to measure the biaxial strength of the sintered cylindrical disc. Equation (1) is also used to calculate the probability of failure. Probability of destruction = [n _th / (total number of samples + 0.5)] (1) n _th is the order of intensity values from low to high (see WH Tuan, M J. Lai, MC Lin, CC Chan and SC Chiu, " Mechanical properties of alumina as a function of grain size ", Mater. Chemistry and Physics, 36 (3-4), 246-251 (1994)). The ceramic and biaxial stress strength results tested are listed in Table 2 below. The curve of failure probability versus biaxial stress intensity is shown in Figure 6.

Table 2: Measurement of biaxial stress intensity ^a CaSO ₄ : SiO ₂ = 99: 1 weight ratio ^b CaSO ₄ : Ca ₃ (PO ₄ ) ₂ = 1: 1 weight ratio ^c CaSO ₄ : Ca ₃ (PO ₄ ) ₂ = 1: 4 weight ratio

Generally, the greater the biaxial stress intensity, the better the specimen resists external loads. Therefore, it can be seen that Ca ₃ (PO ₄ ) ₂ has the largest biaxial stress intensity in the test sample. This means that the mechanical strength of Ca ₃ (PO ₄ ) _{2 is} the best in the test sample. However, according to FIG. 6, the intensity value of the mixture of CaSO ₄ and Ca ₃ (PO ₄ ) ₂ is smaller in the degree of dispersion. This means that the reliability of the CaSO ₄ and Ca ₃ (PO ₄ ) ₂ mixture is better than that of Ca ₃ (PO ₄ ) ₂ alone. Therefore, adding CaSO _{4 to} Ca ₃ (PO ₄ ) ₂ not only reduces the self-hardening time, but also improves reliability. At the same time, the addition of Ca ₃ (PO ₄ ) ₂ can also increase the biaxial stress strength of CaSO ₄ . Therefore, a mixture of CaSO ₄ and Ca ₃ (PO ₄ ) ₂ is very suitable as a material for bone substitute.

Therefore, compared with traditional bone cement, bone substitutes, etc., a mixture of CaSO ₄ and Ca ₃ (PO ₄ ) ₂ (hereinafter referred to as “bone substitute composite material” ") The advantages include:

1. The bone substitute composites in this manual are bioabsorbable or biodegradable materials, so there is no need for a second operation after implantation.

2. The self-hardening process is an exothermic reaction. Therefore, the temperature of the bone substitute composite material reaches a maximum of about 42-46 ° C during the self-hardening process. This temperature is lower than the hardening process of commercial bone cement using poly (methyl methacrylate, PMMA) and its curing agent as an adhesive or binding agent (about 70-80 ° C) . As a result, the tissues surrounding the bone substitute implantation site are not severely injured by the heat released from the sclerosis process.

3. No adhesive or binding agent is required in the bone substitute composite of this specification, and only an aqueous liquid is required to harden the ceramic paste.

4. Composite materials can be made by subtractive manufacturing or additive manufacturing.

100, 102, 106, 108a, 108b, 110, 112, 114, 116‧‧‧ steps

200, 202, 204, 206, 208, 210, 212‧‧‧ steps

300, 302, 304, 306a, 306b, 308, 310, 312‧‧‧ steps

1A-1C show a process flow chart of a free-form method of a ceramic product. FIG. 2A is a photograph showing the morphology of a CaSO ₄ · 2 H ₂ O powder / fiber cloth composite material. FIG. 2B shows a photograph of the CaSO ₄ · 2 H ₂ O powder / fiber cloth composite roll after drying. FIG. 3A shows a photograph of a ceramic plate after laminating 6 layers of CaSO ₄ · 2 H ₂ O powder / fiber cloth composite material. FIG. 3B shows photographs of the appearance of the sample before sintering (the former sample) and after sintering (the latter sample). Figure 3C shows a photograph of the fracture surface of the sample after sintering. FIG. 4 shows a photograph of the head of the sintered humerus prepared in Example 3. FIG. FIG. 5 is a photograph showing the ceramic tube after cutting and drilling before sintering. FIG. 6 is a graph showing the probability of failure of a test sample versus biaxial stress.

Claims (20)

A method for freely forming a bone substitute, comprising: forming a first layer of bone paste on a support cloth, wherein the bone paste is mainly composed of a mixture of calcium sulfate and calcium phosphate; and drying the bone paste to form a partially hardened bone paste, said Partially hardened bone paste is used as an intermediate; hardening the partially hardened bone paste is to use an aqueous liquid to wet the intermediate, and then dry the intermediate to form a hardened bone paste. The method of freely forming a bone substitute according to claim 1, wherein a weight ratio of the calcium sulfate to the calcium phosphate is 1: 1 to 1: 4. The method of freely shaping a bone substitute according to claim 1, wherein the calcium sulfate comprises CaSO ₄ · 0.5 H ₂ O, CaSO ₄ · 2 H ₂ O, or any combination thereof; and the calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate, Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <x <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O or any combination thereof. The bone substitute free forming method according to claim 3, wherein the aqueous liquid is a buffer solution containing Na ₂ H (PO ₄ ) and NaH ₂ (PO ₄ ) ₂ . The method of freely forming a bone substitute according to claim 1, further comprising sintering the hardened bone paste after the hardening step to remove the support cloth and obtain a porous bone ceramic. The method for freely forming a bone substitute according to claim 1, wherein the supporting cloth is woven from biodegradable fibers selected from polylactic acid, poly (lactic-co-glycolic acid) ), Poly (propylene glycol fumarate), and any combination thereof. The method for freely forming a bone substitute according to claim 1, further comprising repeating the forming step and the drying step several times between the drying step and the hardening step, so that the intermediate has a laminated structure. . The bone substitute free-formation method according to claim 7, wherein each layer of the bone paste in the intermediate is sequentially hardened layer by layer according to the determined cross-sectional pattern of the bone substitute to obtain a hardened bone substitute. The method of freely forming a bone substitute according to claim 8, further comprising sintering the hardened bone substitute after the hardening step. The method of freely forming a bone substitute according to claim 7, further comprising removing an unnecessary portion of the hardened bone paste of the intermediate after the hardening step to form a hardened bone substitute. The method of freely forming a bone substitute according to claim 10, further comprising sintering the hardened bone substitute after the hardening step. The method of freely forming a bone substitute according to claim 1, wherein the support cloth covers a model of the bone substitute before the forming step. The method for freely forming a bone substitute according to claim 12, further comprising repeating the forming step and the drying step several times between the drying step and the hardening step, so that the intermediate has a laminated structure. . The bone substitute free forming method according to claim 13, further comprising sintering the intermediate body after the hardening step. A composite material for a free-forming bone substitute, comprising: a support cloth; and a layer of partially hardened bone paste coated on the support cloth, wherein the partially hardened bone paste is basically composed of a weight ratio of 1: 1 Mixture of calcium sulfate and calcium phosphate to 1: 4. The composite material for a free-form bone substitute according to claim 15, wherein the calcium sulfate comprises CaSO ₄ · 0.5 H ₂ O, CaSO ₄ · 2 H ₂ O, or any combination thereof; and the calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate, Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <x <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O or any combination thereof. A bone substitute, wherein the material of the bone substitute comprises: a hardened bone substitute material, which is basically composed of calcium sulfate and calcium phosphate mixed in a weight ratio of 1: 1 to 1: 4; and channels, distributed in The hardened bone replacement material. The bone substitute of claim 15, wherein the calcium sulfate comprises anhydrous calcium sulfate; and the calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate, Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <x <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O, or any combination thereof. The bone substitute according to claim 17, further comprising fibers located in the channel. The bone substitute of claim 19, wherein the calcium sulfate comprises CaSO ₄ · 0.5 H ₂ O, CaSO ₄ · 2 H ₂ O, or any combination thereof; and the calcium phosphate comprises Ca (H ₂ PO ₄ ) ₂ , CaHPO ₄ , Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ , Ca ₃ (PO ₄ ) ₂ , amorphous calcium phosphate, Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 <x <1), Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , Ca ₁₀ (PO ₄ ) ₆ F ₂ , Ca ₁₀ (PO ₄ ) ₆ O, Ca ₄ (PO ₄ ) ₂ O Or any combination thereof.