Gradient curing calcium silicate and calcium phosphate bone tissue filling and repairing material

Abstract

The invention discloses a gradient curing calcium silicate and calcium phosphate bone tissue filling and repairing material, and relates to the technical field of bone filling and repairing materials. The invention comprises a powder and a liquid, the powder at least comprises: a calcium silicate component selected from tricalcium silicate, dicalcium silicate or a combination thereof; a phosphate ester compound selected from the group consisting of phosphoserine, phosphothreonine, phospholysine, or a combination thereof; a calcium / magnesium-based compound or ceramic; the liquid is a water-containing medium, and is prepared through the steps of raw material preparation, pretreatment, mixing, paste forming and the like. According to the invention, excessive use of high-pH materials is reduced or avoided, pH abnormity in the initial hydration stage of the system material is delayed, inflammatory response can be effectively alleviated, stimulation to surrounding tissues is remarkably reduced, the risk of postoperative complications is reduced, and through a porous structure formed by gradient curing and a gradual gelling curing mechanism, the system has a good application prospect. The filling capacity and the bone cell growth space of the material are improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of filling and repairing materials, and particularly relates to a gradient-curing calcium silicate and calcium phosphate bone tissue filling and repairing material. Background Art

[0002] With the global population aging and lifestyle changes, the incidence of fractures, osteoporosis and other skeletal diseases has increased significantly. Although traditional treatment methods such as metal internal fixation and bone transplantation are effective, they also have problems such as complex surgery, long recovery time and many complications. Therefore, developing an efficient, safe and easy-to-use bone repair material has become an urgent need in the medical field.

[0003] Although traditional filling and repairing materials such as calcium phosphate cement (CPC) have certain bioactivity, their curing speed is too fast, the operation time is short, and the strength after curing is insufficient, making it difficult to meet complex clinical needs. In addition, some filling and repairing materials may cause local inflammatory reactions or other side effects, limiting their wide application. In particular, filling and repairing materials containing too many high pH components (such as tetracalcium phosphate) will produce a high alkaline environment during the hydration process, which may cause damage to the surrounding tissues.

[0004] Therefore, we provide a gradient-curing calcium silicate and calcium phosphate bone tissue filling and repairing material and its preparation method to solve the above problems. Summary of the Invention

[0005] To solve the above technical problems, the present invention is realized through the following technical solutions:

[0006] The present invention provides a gradient-curing calcium silicate and calcium phosphate bone tissue filling and repairing material, which includes two parts: powder and liquid. The powder at least contains:

[0007] Calcium silicate components, selected from tricalcium silicate, dicalcium silicate or a combination thereof;

[0008] Phosphate ester compounds, selected from phosphoserine, phosphothreonine, phospholysine or a combination thereof;

[0009] Calcium / magnesium compounds or ceramics, mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof;

[0010] The liquid is an aqueous medium.

[0011] The present invention is further configured such that the proportion of the calcium silicate components is 10%-50%, the proportion of the phosphate ester compounds is 10%-60%, and the proportion of the calcium / magnesium compounds or ceramics is 20%-70%.

[0012] The present invention is further configured such that the calcium / magnesium compound or ceramic is mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof, accounting for more than 80% of the composition, and the remaining 20% is selected from one or a combination of bioactive glass, calcined animal hydroxyapatite bone, synthetic hydroxyapatite, calcium sulfate, hemihydrate calcium sulfate, calcium / magnesium carbonate, calcium / magnesium hydroxide, calcium / magnesium hydrogen phosphate, magnesium phosphate, magnesium / calcium oxide, calcium chloride, and tetracalcium aluminoferrite;

[0013] A gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material further includes:

[0014] Degradable fibers or particles, such as PGA, PLGA, PLCL, polylactic acid, collagen, silk fibroin, gelatin, chitosan, or sodium hyaluronate, etc., with a proportion of 0.1% - 10%;

[0015] Additives, such as imaging agents, antibiotics, drugs, etc., with a proportion of 0.1% - 5%.

[0016] The present invention is further configured such that the inorganic powder is a pore-forming or non-pore-forming particle, and after mixing, it is heat-treated at 300 - 500 °C to transform part of the crystal phase into an amorphous state, while removing moisture and other volatile substances and maintaining the biological activity of the material, with a particle size range of 1 - 500 μm.

[0017] The present invention is further configured such that the liquid is an aqueous medium with a mass of 12% - 50% of the powder, selected from purified water, distilled water, normal saline, water for injection, polyvalent metal salt solution, blood or bioceramic leaching solution, and soluble solutions of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide, etc.

[0018] A preparation method of a gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material includes the following steps:

[0019] (1) Prepare calcium silicate components, phosphate compounds, calcium / magnesium compounds or ceramics, and other components;

[0020] (2) Perform heat treatment on the components other than organic substances;

[0021] (3) Mix the above components in proportion to form a dry powder mixture;

[0022] (4) Add an appropriate amount of aqueous medium to the dry powder mixture and stir evenly until a paste is formed and cured.

[0023] The present invention is further configured such that the initial powder (10 - 80 μm) cures in two steps when encountering water:

[0024] (1) The acid ester compound and calcium silicate form porous particles (100 - 1500 μm) while stirring in 10 - 60 seconds when encountering an aqueous liquid;

[0025] (2) After the phosphate compound and the powder mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof encounter an aqueous liquid, they gradually gel and solidify after 90 seconds.

[0026] The present invention has the following beneficial effects:

[0027] 1. By reducing or avoiding the use of excessive high-pH materials, the present invention delays the abnormal pH appearance in the initial stage of the hydration of the system materials, controls the pH value close to the physiological level. Since the pH value of calcium silicate is relatively mild and the material itself has good biocompatibility, it can effectively reduce the inflammatory reaction, significantly reduce the irritation to the surrounding tissues, and reduce the risk of postoperative complications; at the same time, without using high-pH materials or alginate to buffer the gelling reaction, the reaction rate is reduced, providing a longer operation window period (usually 8 - 20 minutes), enabling the doctor to have sufficient time to precisely adjust the position and shape of the filling and repair materials to ensure the best surgical effect.

[0028] 2. When the filling and repairing material provided by the present invention is in use, the curing process of the initial powder (with a particle size between 10 - 80 μm) after contacting water is divided into two stages. First, within 10 - 60 seconds after contacting the aqueous liquid, the acid ester compound and calcium silicate react rapidly. While stirring, porous particles (with a particle size range of 100 - 1500 μm) are formed. The formed porous particles can significantly increase the overall volume of the mixture, enabling the material to more effectively fill larger bone defect areas. The porous structure provides additional growth space and attachment points for osteoblasts, which is beneficial to the ingrowth and development of new bone tissue, and accelerates the fracture healing or bone defect repair process. Then, after 90 seconds, the phosphate ester compound and the powder mainly composed of tetracalcium phosphate and tricalcium phosphate begin to gradually gel and solidify. During this process, the subsequently formed adhesive glue wraps the previously formed porous particles, finally forming a stable solid structure. By wrapping and fixing the porous particles, the mechanical strength and stability of the overall material are increased, making it more capable of withstanding physiological loads and not easily broken. The presence of the porous particles increases the porosity inside the material, which not only helps to maintain an appropriate degradation rate but also promotes body fluid penetration, thereby accelerating the release of active ingredients in the material and supporting faster bone regeneration. Since these two-step curing processes occur simultaneously but are distinguishable, it provides a relatively flexible operation time window, allowing the surgeon to have sufficient time to adjust the position and shape of the filling material to ensure the best surgical effect. In addition, the filling and repairing material can be formulated according to specific clinical needs to meet the requirements of different application scenarios. For example, the consistency and curing speed of the paste can be adjusted by changing the type of liquid medium (such as using normal saline or bioceramic extract), or the proportion of additives (such as adding antibiotics to prevent infection) can be adjusted to achieve specific functional requirements. The reaction of calcium silicate and phosphate ester to form porous particles first can effectively increase the volume of the mixture, increase pores, and enhance the degradation rate.

[0029] Of course, it is not necessary for any product implementing the present invention to simultaneously achieve all the above-mentioned advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for describing the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0031] Figure 1 It is a schematic diagram of the preparation process of a gradient-curing calcium silicate and calcium phosphate bone tissue filling and repairing material.

[0032] Figure 2 It is a schematic diagram of the reaction of individual phosphate ester and calcium silicate with water to form porous particles.

[0033] Figure 3 Schematic diagram of a dry powder mixture formed by mixing phosphate ester, calcium silicate and calcium phosphate.

[0034] Figure 4 Schematic diagram of the gelling of the dry powder mixture.

[0035] Figure 5 Schematic diagram of the solidification of the dry powder mixture when encountering water. Specific implementation mode

[0036] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0037] Embodiment

[0038] The present invention relates to a gradient-curing calcium silicate and calcium phosphate bone tissue filling and repairing material, which includes two parts: powder and liquid. The powder at least includes:

[0039] Calcium silicate components, selected from tricalcium silicate, dicalcium silicate or a combination thereof;

[0040] Phosphate ester compounds, selected from phosphoserine, phosphothreonine, phospholysine or a combination thereof;

[0041] Calcium / magnesium compounds or ceramics, mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof;

[0042] The proportion of the calcium silicate components is 10%-50%, the proportion of the phosphate ester compounds is 10%-60%, and the proportion of the calcium / magnesium compounds or ceramics is 20%-70%;

[0043] The liquid is an aqueous medium, and the liquid is an aqueous medium with a mass of 12%-50% of the powder, selected from purified water, distilled water, physiological saline, water for injection, polyvalent metal salt solution, blood or biological ceramic extract, and soluble solutions of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc.;

[0044] Among them, tricalcium silicate and dicalcium silicate are one of the main components of Portland cement and have excellent biological activity. When these components come into contact with body fluids, they will undergo a hydration reaction to generate carbonated hydroxyapatite, which is the main inorganic component of human bones, thereby endowing the filling and repair material with good biological activity and osteoconductivity. The phosphate compound can increase the hydrophilicity and cell adhesion of the filling and repair material, help improve the binding force between the material and the host tissue, and promote cell proliferation and differentiation at the same time. The phosphate compound can also regulate the degradation rate of the material to ensure that it is gradually replaced by new bone tissue in the body. Bioactive glass is a special ceramic material that can quickly react with body fluids to form a layer of HCA layer similar to human bones on the surface, promoting the regeneration and integration of bone tissue. Bioactive glass particles, bioactive glass microspheres and filamentous bioactive glass of types 45S5, 58S, magnesium-containing, strontium-containing, etc. have been widely studied and applied due to their excellent biological activity. The presence of bioactive glass can also enhance the compressive strength of the material and improve the ability of blood vessel formation around the new tissue;

[0045] The liquid medium is not only a key component for activating the powder components. The liquid medium is used for pH adjustment and also for adjusting the consistency of the paste to ensure its easy operation and adaptability to different surgical environments. In particular, using normal saline or bioceramic extract can simulate the in vivo environment and further enhance the biocompatibility and activity of the material.

[0046] The calcium / magnesium compound or ceramic is mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof, accounting for more than 80% of this component. The remaining 20% is selected from one or a combination of bioactive glass, calcined animal hydroxyapatite bone, synthetic hydroxyapatite, calcium sulfate, hemihydrate calcium sulfate, calcium / magnesium carbonate, calcium / magnesium hydroxide, calcium / magnesium hydrogen phosphate, magnesium phosphate, magnesium / calcium oxide, calcium chloride, and tetracalcium ferroaluminate;

[0047] A gradient-curing calcium silicate and calcium phosphate bone tissue filling and repair material further includes:

[0048] Degradable fibers or particles, such as PGA, PLGA, PLCL, polylactic acid, collagen, silk fibroin, gelatin, chitosan or sodium hyaluronate, etc., account for 0.1%-10%; and additives, such as imaging agents, antibiotics, drugs, etc., account for 0.1%-5%;

[0049] Among them, calcium / magnesium compounds or ceramics not only enhance the initial mechanical strength of the filling and repair materials, but also can release ions by slow dissolution to stimulate the growth and differentiation of bone cells. For example, the calcium ions released during the dissolution of calcium sulfate can promote the activities of osteoblasts; the degradable polymers can be gradually degraded into harmless substances in the body, while providing a temporary support structure, which is conducive to the ingrowth of new bone tissue. These polymers can also act as carriers to carry drugs or other bioactive molecules to achieve the sustained-release function; the imaging agent is used for intraoperative positioning; the antibiotic is used to prevent infection; gelatin, chitosan or hyaluronic acid solution, etc. can improve the processing properties of the materials, such as fluidity, viscosity, etc., or endow additional functions, such as anti-inflammatory properties; hyaluronic acid, as a natural polysaccharide, can provide lubrication and reduce frictional damage during the operation.

[0050] As Figure 1 shown, a preparation method of a gradient-cured calcium silicate and calcium phosphate bone tissue filling and repair material includes the following steps:

[0051] Raw material preparation: Accurately weigh various required components according to the formula to ensure that the proportion of each component is within the specified range to guarantee the performance consistency and reliability of the final product.

[0052] Pretreatment: Perform heat treatment on all components except organic matter at 300 - 500 °C to remove moisture and other volatile impurities, and maintain the biological activity of the materials. The particle size of the heat-treated powder should be controlled within the range of 1 - 500 μm to ensure the best mixing uniformity and mechanical properties. This step can also eliminate possible microbial contamination and improve the safety of the materials.

[0053] Mixing: Mix the pretreated powder components evenly according to the designed proportion to form a dry powder mixture. On this basis, add an appropriate amount of degradable fibers or particles and additives, and continue to stir until a uniformly distributed mixture is obtained. To ensure uniform mixing, equipment such as a high-shear mixer or a ball mill is used.

[0054] Paste formation: Slowly add a selected aqueous medium to the dry powder mixture while continuously stirring until a paste with appropriate fluidity and plasticity is formed. This paste has a certain time window for doctors to operate and then quickly solidifies, which is suitable for clinical surgical applications. To control the solidification speed, the type and dosage of the aqueous medium can be adjusted as needed.

[0055] Once the paste contacts body fluids, it will quickly initiate a bioactive response, forming a layer of carbonated hydroxyapatite on the material surface, promoting bonding with human bone tissue and supporting epitaxial growth, thereby achieving excellent repair effects.

[0056] Specifically, the initial powder (10 - 80 μm) solidifies in two steps when encountering water:

[0057] (1) The acid ester compound and calcium silicate form porous particles (100 - 1500 μm) while being stirred for 10 - 60 seconds when encountering an aqueous liquid.

[0058] (2) After the phosphate ester compound and the powder mainly composed of tetracalcium phosphate, tricalcium phosphate or their combination encounter an aqueous liquid, they gradually gel and solidify after 90 seconds.

[0059] Since the above two steps are carried out simultaneously, the component that forms the adhesive later will wrap and solidify the component that forms particles first. The part that forms porous particles first can increase the porosity and volume of the component that forms the adhesive later. As a filling material, it can fill larger bone defect areas, and can increase the degradation rate and provide space for osteoblast growth.

[0060] To further study the effects of the phosphate ester ratio and heat treatment on the product, three groups of samples were taken, with phosphate esters being 10%, 30%, and 60% respectively, and they were divided into two groups to react under heat treatment and non - heat treatment conditions.

[0061] It is known from experiments that calcium silicate and calcium phosphate compete to react with the phosphate ester in the system, and calcium silicate reacts faster with the phosphate ester. Phosphate ester / (calcium silicate / calcium / magnesium compounds or ceramics) = (10%, 30%, 60% of phosphate ester) / (the remaining amount prepared in a 1:1 ratio in 2), specifically referring to the following table (Appendix 1):

[0062]

[0063] (Appendix 1)

[0064] This filling and repairing material is applicable to the repair of various types of bone defects, including but not limited to:

[0065] Fracture fixation: In the case of open fractures or complex fractures, using the filling and repairing material of the present invention can effectively fill the bone defect area, provide immediate fixation and support, and at the same time promote the formation of new bone;

[0066] Spinal fusion: The filling and repairing material of the present invention can be used in spinal fusion surgery to fill the gap after disc removal, promote bone fusion between adjacent vertebral bodies, and reduce the incidence of postoperative complications;

[0067] Filling of defects around dental implants: For bone defects around dental implants, the filling and repairing material can precisely fill these tiny spaces, enhance the stability of the implant, and promote the regeneration of the surrounding bone tissue.

[0068] In the description of this specification, the descriptions referring to terms such as "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0069] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material, characterized in that: It comprises two parts, powder and liquid, wherein the powder at least comprises: Calcium silicate component selected from tricalcium silicate, dicalcium silicate or a combination thereof; a phosphate compound selected from phosphoserine, phosphothreonine, phospholysine or a combination thereof; Calcium / magnesium compounds or ceramics, mainly tetracalcium phosphate, tricalcium phosphate or a combination thereof; The liquid is an aqueous medium.

2. A gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 1, characterized in that: The calcium silicate components account for 10%-50%, the phosphate compounds account for 10%-60%, and the calcium / magnesium compounds or ceramics account for 20%-70%.

3. The gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 1, characterized in that: The calcium / magnesium compound or ceramic is mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof, accounting for more than 80% of the present component, and the remaining 20% ​​is selected from one or a combination of bioactive glass, calcined animal hydroxyapatite bones, synthetic hydroxyapatite, calcium sulfate, hemihydrate calcium sulfate, calcium carbonate / magnesium, calcium / magnesium hydroxide, calcium hydrogen phosphate / magnesium, magnesium phosphate, magnesium oxide / calcium, calcium chloride, and tetracalcium aluminoferrate.

4. The gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 1, characterized in that: Also includes: Degradable fibers or particles, such as PGA, PLGA, PLCL, polylactic acid, collagen, silk fibroin, gelatin, chitosan or sodium hyaluronate, accounting for 0.1%-10%; Additives, such as developers, antibiotics, drugs, etc., account for 0.1%-5%.

5. The gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 1, characterized in that: The inorganic powder is a pore-forming or non-pore-forming particle, which is mixed and then subjected to a heat treatment at 300-500° C. to transform part of the crystalline phase into an amorphous state, while removing moisture and other volatile substances and maintaining the biological activity of the material. The particle size range is 1-500 μm.

6. The gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 1, characterized in that: The liquid is an aqueous medium accounting for 12% to 50% of the mass of the powder, and is selected from purified water, distilled water, physiological saline, water for injection, multivalent metal salt solution, blood or bioceramic extract, and soluble solutions of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

7. The method for preparing the gradient-cured calcium silicate and calcium phosphate bone tissue filling and repairing material according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) preparing calcium silicate components, phosphate compounds, calcium / magnesium compounds or ceramics and other components; (2) heat treatment of components other than organic matter; (3) mixing the above ingredients in proportion to form a dry powder mixture; (4) Add an appropriate amount of aqueous medium to the dry powder mixture, stir evenly until a paste is formed, and then solidify.

8. The method for preparing the gradient solidified calcium silicate and calcium phosphate bone tissue filling and repairing material according to claim 7, characterized in that: The initial powder (10-80 μm) solidifies in two steps after encountering the aqueous liquid: (1) The acid ester compound and calcium silicate are mixed with an aqueous liquid and stirred for 10-60 seconds to form porous particles (100-1500 μm); (2) When the phosphate compound and the powder mainly composed of tetracalcium phosphate, tricalcium phosphate or a combination thereof meet with a water-containing liquid, they gradually gel and solidify after 90 seconds.

Images