CN113559316A - Self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time - Google Patents

Self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time Download PDF

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CN113559316A
CN113559316A CN202010351431.8A CN202010351431A CN113559316A CN 113559316 A CN113559316 A CN 113559316A CN 202010351431 A CN202010351431 A CN 202010351431A CN 113559316 A CN113559316 A CN 113559316A
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setting time
calcium
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calcium phosphate
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董良润
刘思羽
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Suzhou Xinhelong Medical Devices Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
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Abstract

The invention discloses a self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time, which comprises a solid powder system and a hardening liquid system. Wherein the hardening liquid system is free of water (containing H)+、OH‑) Calcium ion, and phosphate ion (including PO)4 3‑、HPO4 2‑、H2PO4 ‑) Besides, at least one or more of MnIons, wherein n is +1, +2, +3 or-1, -2, -3. The invention has the following advantages: (1) the adjustable ranges of initial setting time (initial setting time) and final setting time (complete setting time) are wider; and (2) the pH value can be adjusted in a wider range.

Description

Self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time
Technical Field
The invention relates to a bone filling material, in particular to self-curing calcium phosphate bone cement with independently adjustable initial setting time and final setting time.
Background
Early Calcium Phosphate Cement (CPC) technology has the rapid hardening time of cement as the most important research factor. However, feedback from recent CPC users (surgeons) suggests that an ideal CPC should have the following characteristics: (1) the CPC powder and the liquid are easily mixed to form a paste with good fluidity and can be easily transferred into a syringe; (2) the CPC has good injectability and can be easily injected into a bone defect part through an injection needle sleeve; (3) after injection into a bone defect site, the CPC paste needs to have a sufficiently long "working" time during which it maintains a good shapeable state so that it can be shaped and remodeled without damaging the quality and strength of the paste and the set artificial bone; and (4) after the "operation" time has elapsed, the CPC cement hardens rapidly to suture the wound incision. During the entire procedure, the CPC cement slurry must be stable and harden in a "wet" condition without breaking down or being flushed by body fluids into the body cavity.
Currently on the market, most commercial CPC products use aqueous sodium phosphate as a sclerosant component. These hardening fluids generally provide a shorter "working" time, but a longer hardening time. For example, the hyseal product of the histox company, the physician must complete the mixing, injection and molding of the cement within 5 minutes, but the hardening of the bone cement requires an additional 15 minutes or so.
The sodium phosphate hydraulic cements in various commercial calcium phosphate cement products have a neutral pH.
Recently, a new CPC cement uses a calcium phosphate solution as a hardening fluid instead of the sodium phosphate solution which has been conventionally used. In some cases, the CPC has a short hardening time, but the "working" time cannot be adjusted. In other cases, some products reach a sufficiently long "on" time, but the final set time cannot be controlled. These CPC bone cements have the disadvantage that the cement hardening fluid is too acidic, i.e. has a pH of 2.5 or less. However, in clinical need, different site applications require different initial setting times and different final setting times of calcium phosphate cements, for example, spinal cements require a sufficiently long "working" time for CPC cement due to the complexity of its operation, but harden rapidly once injected into the spine. However, the demand for the CPC cement for dental use is different, and the initial setting time and the final setting time of the CPC cement for dental use are both required to be fast due to the secretion of a large amount of saliva in the oral environment.
Since the measurement method of the "working" time of the bone cement has not been standardized, the variable varies greatly depending on the measurement method. Therefore, in the present invention, we will use the initial setting time (initial setting time) of the bone cement as a parameter for evaluating the "working" time of the bone cement. This indicator of initial setting time is acceptable because initial setting is an indicator of the "no-form" or "no-form" evaluation of the cement paste. While the cement reaches sufficient strength to suture the wound, the time required is the final setting time.
Disclosure of Invention
The invention aims to solve the defects of regulation and control of the initial setting time and the final setting time, and provides the self-curing calcium phosphate cement with the initial setting time and the final setting time capable of being independently regulated.
The above object of the present invention is achieved by the following technical means: a self-setting calcium phosphate cement with independently adjustable initial setting time and final setting time comprises a hardening liquid system and a solid powder system, wherein the hardening liquid system is except water (containing H)+、OH-) Calcium ion, and phosphate ion (including PO)4 3-、HPO4 2-、H2PO4 -) Besides, at least one or more of MnIons; the solid powder system comprises at least one calcium-containing compound selected from the group consisting of calcium dihydrogen phosphate monohydrate (MCPM), calcium dihydrogen phosphate anhydrous (MCPA), calcium hydrogen phosphate anhydrous (DCPA), calcium hydrogen phosphate dihydrate (DCPD), alpha-tricalcium phosphate (alpha-TCP), beta-tricalcium phosphate (beta-TCP), amorphous tricalcium phosphate (ACP), calcium tetraphosphate (TTCP), calcium oxide (CaO), calcium hydroxide Ca (OH)2Calcium carbonate, calcium Octaphosphate (OCP), and the like.
Further, M in the hardening liquid systemnThe ions can be one or more anions or cations, wherein n is +1, +2, +3 or-1, -2, -3. Including Na+、K+、Mg+、Sr+、Zn2+、Fe2+、Fe3+、Mn2+And the like. Similarly, the chloride ion may also be replaced by other anions, such as F-、NO3 -、SO4 2-、HSO4 -、CO3 -、HCO3 -Acetate radicalIons, oxalate ions, citrate ions, lactate ions, amino acid ions, and other organic acid anions, and the like.
Further, the other organic acid radical ion is anion H (CH) of organic small molecule or organic high molecular acid2)x-(P)p-(K)y(x =0, 1, 2, 3, … 100000, P is N, O, P element, P is 0, 1, 2, 3, … …, 100000, K = COOH, SO3H、PO3H2，y=1、2、3、…、100000）。
Further, the solid powder system further comprises a source of carbonate ions to form carbonated apatite in the CPC bone cement product, the source of carbonate ions being calcium carbonate, sodium bicarbonate, magnesium carbonate, magnesium bicarbonate, potassium carbonate, potassium bicarbonate, strontium carbonate, strontium bicarbonate, ferrous carbonate, zinc carbonate, or a combination thereof.
Further, the carbonate ion source should be used in an amount sufficient to form a carbonate content of 0% to 30% in the CPC cured product.
Further, the solid powder system also includes citric acid, sodium citrate, or a combination thereof, in an amount sufficient to produce a citrate concentration of 0mol/L to 5mol/L when the solid and hardened liquid system are mixed.
Further, the hardening liquid system also comprises citrate ions with the concentration of 0mol/L to 5 mol/L.
Further, the sclerosant fluid system further comprises from 0% to 10% of a liquid thickener selected from xanthan gum, guar gum, carbomer, crepe carrageenan, hydroxyethyl cellulose, carboxymethyl cellulose, salts of the above thickeners, or combinations thereof, to improve the cohesiveness of the paste.
Further, the bone cement also comprises one or more additives such as pore-forming agents, antibiotics or other medicines, radiopaque fillers, reinforcing fillers and reinforcing fibers, and bone induction additives.
Compared with the prior art, the invention has the advantages that: the invention has the following advantages: (1) the adjustable range of initial setting time (initial setting time) and final setting time (complete setting time) is wider; and (2) the pH value can be adjusted in a wider range.
Detailed Description
The present invention will be described in more detail with reference to examples.
The invention relates to a self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time, which comprises a hardening liquid system and a solid powder system, wherein the hardening liquid system is except water (containing H)+、OH-) Calcium ion, and phosphate ion (including PO)4 3-、HPO4 2-、H2PO4 -) Besides, at least one or more of MnIons; the solid powder system comprises at least one calcium-containing compound selected from the group consisting of calcium dihydrogen phosphate monohydrate (MCPM), calcium dihydrogen phosphate anhydrous (MCPA), calcium hydrogen phosphate anhydrous (DCPA), calcium hydrogen phosphate dihydrate (DCPD), alpha-tricalcium phosphate (alpha-TCP), beta-tricalcium phosphate (beta-TCP), amorphous tricalcium phosphate (ACP), calcium tetraphosphate (TTCP), calcium oxide (CaO), calcium hydroxide Ca (OH)2Calcium carbonate, calcium Octaphosphate (OCP), and the like.
Further, M in the hardening liquid systemnThe ions can be one or more anions or cations, wherein n is +1, +2, +3 or-1, -2, -3. Including Na+、K+、Mg+、Sr+、Zn2+、Fe2+、Fe3+、Mn2+And the like. Similarly, the chloride ion may also be replaced by other anions, such as F-、NO3 -、SO4 2-、HSO4 -、CO3 -、HCO3 -Acetate ion, oxalate ion, citrate ion, lactate ion, amino acid ion, and other organic acid anions, and the like.
Further, the other organic acid radical ion is anion H (CH) of organic small molecule or organic high molecular acid2)x-(P)p-(K)y（x=0、1、2、3、…100000, P is N, O, P element, P is 0, 1, 2, 3, … …, 100000, K = COOH, SO3H、PO3H2，y=1、2、3、…、100000）。
Further, the solid powder system further comprises a source of carbonate ions to form carbonated apatite in the CPC bone cement product, the source of carbonate ions being calcium carbonate, sodium bicarbonate, magnesium carbonate, magnesium bicarbonate, potassium carbonate, potassium bicarbonate, strontium carbonate, strontium bicarbonate, ferrous carbonate, zinc carbonate, or a combination thereof.
Further, the carbonate ion source should be used in an amount sufficient to form a carbonate content of 0% to 30% in the CPC cured product.
Further, the solid powder system also includes citric acid, sodium citrate, or a combination thereof, in an amount sufficient to produce a citrate concentration of 0mol/L to 5mol/L when the solid and hardened liquid system are mixed.
Further, the hardening liquid system also comprises citrate ions with the concentration of 0mol/L to 5 mol/L.
Further, the sclerosant fluid system further comprises from 0% to 10% of a liquid thickener selected from xanthan gum, guar gum, carbomer, crepe carrageenan, hydroxyethyl cellulose, carboxymethyl cellulose, salts of the above thickeners, or combinations thereof, to improve the cohesiveness of the paste.
Further, the bone cement also comprises one or more additives such as pore-forming agents, antibiotics or other medicines, radiopaque fillers, reinforcing fillers and reinforcing fibers, and bone induction additives.
The invention principle of the invention is as follows: based on the clinical application scene, the curing reaction of calcium phosphate cement CPC can only be carried out in the water solution environment. Early inventions clearly showed that the concentration of calcium and phosphate ions, as well as the pH of the solution, significantly affected the rate of hardening. When sodium phosphate solution is used as the hardening liquid (i.e., Na-P-H)2O system), the concentration of phosphate ions and the pH of the solution can be flexibly adjusted, but the lack of calcium ions limits further control of the hardening time. On the other hand, whenWhen a calcium phosphate solution is used as the hardening liquid, the concentrations of calcium ions and phosphate ions can be controlled, but the pH of the solution depends on the ratio of calcium ions to phosphate ions in the solution. This limitation can be demonstrated by preparing any calcium phosphate solution by dissolving any proportion of calcium hydroxide and phosphoric acid solution in water. When the amount of calcium hydroxide added is much greater than the amount of phosphoric acid, the solution becomes alkaline, whereas when sodium hydroxide is added much less than the phosphoric acid, the solution becomes acidic. Thus, in another Ca-P-water (i.e., Ca-P-H)2O), the pH of the solution cannot be further independently adjusted if the concentrations of calcium ions and phosphate ions are given in the hardening liquid consisting of the ternary system.
In order to completely and independently control the concentration of calcium ions and phosphate ions and the pH value of the solution, the invention discloses a four-component hardening liquid system calcium-phosphorus-M-water (Ca-P-M-H) for calcium phosphate cement2O). Wherein the hardening liquid system is free of water (containing H)+、OH-) Calcium ion, and phosphate ion (including PO)4 3-、HPO4 2-、H2PO4 -) Besides, at least one or more of MnIons, wherein n is ± 1, ± 2, ± 3. When the novel hardening liquid is used, the calcium ion concentration, the phosphate ion concentration and the pH of the solution can be independently controlled according to clinical needs.
As with any solution, the total charge of the cation must be equal to the total charge of the anion. For such a four component system, if MnWhen the ion is a cation (i.e., n = +1, +2, + 3), charge balance can be represented by the formula [1 ]]And (4) showing.
2[Ca2+]+n[Mn]+[H+]=[H2PO4 -]+2[HPO4 2-]+3[PO4 3-]+[OH-] [1]
For example, if M is Na+When ionized, it was observed that the presence of sodium ions at a given pH provided a three-component system Ca-P-H with a phosphate ion concentration higher than the same calcium ion concentration2O, because of the presence of the four componentsIn the system, the positive charge of the sodium ions must be balanced by additional phosphate ions.
If M isnWhen the ion is an anion (i.e., n = -1, -2, -3), the bone cement hardening liquid contains a high calcium ion concentration and a low phosphate ion concentration. The corresponding charge balance is given by the formula [2 ]]To represent
2[Ca2+]+[H+]=n[Mn]+[H2PO4 -]+2[HPO4 2-]+3[PO4 3-]+[OH-] [2]
In this sclerosant solution system, the concentrations of calcium ions and phosphate ions as well as the solution pH can be adjusted independently, also for reasons of charge balance, the calcium ion concentration being generally higher than the calcium concentration in the corresponding three component system. For example, if M is Cl-When ionized, it was observed that, at a given pH, the presence of chloride ions resulted in a three-component system Ca-P-H having a phosphate ion concentration lower than the same calcium ion concentration2O, since in the four component system the negative charge of the chloride ion must be balanced by the additional calcium ion.
In the hardening liquid system, M can be one or more non-calcium and non-phosphorus ions, can be one or more cations or anions at the same time, and can also be the coexistence of anions and cations. If non-calcium, non-phosphorus anions or cations are included, the sclerosant fluid system may be represented as Ca-P-Xx+-Yy--H2And O. In this case, the charge balance of the hardening liquid system can be represented by the formula [3 ]]And (4) showing.
2[Ca2+]+x[Xx+]+[H+]=y[Yy-][H2PO4 -]+2[HPO4 2-]+3[PO4 3-]+[OH-] [3]
By applying the multi-component system, the aim of independently controlling the concentration and the pH value of calcium ions and phosphate ions in the CPC hardening liquid can be completely fulfilled, and the aim of completely controlling the hardening reaction rate of the CPC bone cement can be fulfilled by independently controlling the variables, so that the initial setting time and the final setting time of CPC can be flexibly controlled according to clinical requirements.
It should be noted that if sodium chloride is added to the CPC sclerosant solution, the net effect of independently controlling the calcium and phosphate ions and the pH of the solution as described above does not occur because the sodium and chloride ions are at the same concentration.
Furthermore, in order to obtain the above-mentioned effect, the above-mentioned sodium ion may be replaced with any other cation, regardless of charge, such as Na, as long as the cation does not cause toxicity or other undesirable side effects+、K+、Mg+、Sr+、Zn2+、Fe2+、Fe3+、Mn2 +And the like. Similarly, the chloride ion may also be replaced by other anions, such as F-、NO3 -、SO4 2-、HSO4 -、CO3 -、HCO3 -Acetate ion, oxalate ion, citrate ion, and other organic acid anions.
By completely independent adjustment of calcium ions, phosphate ions, other anions or cations, and independent adjustment of powder composition, the initial setting time, final setting time, and the relative proportions of the two can be independently adjusted according to clinical needs. In clinical applications, the development of CPC with a larger initial setting time/final setting time ratio (IST/FST ratio) has its outstanding advantages in spinal repair because of the complexity of the surgery, longer initial setting time is more convenient for the physician to have sufficient time for mixing, injecting, and shaping, while leakage of CPC in the medullary cavity is avoided, and the CPC is required to be rapidly hardened after injection into the spinal column. On the other hand, different hardening characteristics are required for the CPC for dental implant in oral cavity, because the hardening of the CPC can be influenced by the large saliva secretion of the oral cavity, but the CPC is relatively more convenient to use and operate in oral cavity, so that the CPC with quick hardening (i.e. the initial setting time and the final setting time are both short) is more suitable for oral cavity requirements.
Preparing materials:
the CPC hardening liquid system is prepared by the following method: dissolving calcium compound, phosphoric acid or phosphate compound, and other ionic compounds (such as sodium salt and chloride) in water at a given ratio, and adjusting pH of the solution to 1-12 with acid or alkali.
The experimental method comprises the following steps:
initial setting time and final setting time test: the curing time (initial setting time and final setting time) is tested by a Gillmore double cement needle according to the ASTM C266-04 standard, and the concrete method is as follows: mixing 0.3g powder sample with 0.1mL solidifying solution to obtain paste, injecting into a circular hole mold with thickness of 3mm and diameter of 6mm, and adding into a container 37oAnd C, keeping the temperature in a water bath, and vertically placing Gillmore initial setting cement needles (the total weight is 113.4g, the tail end diameter of the cement needles is 2.12 mm) or final setting cement needles (the total weight is 453.6g, the tail end diameter of the cement needles is 1.06 mm) on the surface of the sample during measurement respectively until no obvious visible indentation is observed on the surface by naked eyes so as to determine the initial setting time and the final setting time. The time interval from the moment the powder and the solidification liquid start to contact to the initial setting point and the final setting point is the initial setting time or the final setting time (in minutes). The experiment was repeated three times in total and the average initial setting time and final setting time were calculated.
Examples of the invention
Typical composition of CPC powder system and hardening liquid system
Figure DEST_PATH_IMAGE002
Example 1-CPC powder contains equimolar amounts of TTCP (calcium tetraphosphate) and DCPA (calcium hydrogen phosphate). The hardening liquid contains 2.39mol/L of sodium ions and 2.06mol/L of phosphate ions, and the pH of the solution is = 6.06. The hardening time test results showed an Initial Setting Time (IST) of 9.05 ± 0.15 minutes (n ═ 3) and a Final Setting Time (FST) of 23.7 ± 0.1 minutes. The problem with this CPC is that the final setting time is long but the ratio initial setting time/final setting time (i.e. IST/FST) is small, 0.38, which indicates that the "working" time for CPC is only a fraction of the longer hardening time, i.e. the shapeability time is too short.
Example 2-CPC powder was the same as example 1. The hardening liquid contains 0.35mol/L of calcium ions, 1.947mol/L of phosphate ions and 2.075mol/L of sodium ions, and the pH of the solution is = 5.75. The hardening time test results are IST =6.60 ± 0.10 min (n = 3) and FST =15.1 ± 0.3 min, the IST/FST ratio = 0.45. The small change of the composition of the CPC hardening liquid greatly shortens the IST and the FST, improves the IST/FST ratio, namely shortens the hardening time of the CPC, and increases the proportion of the plastic forming time in the hardening time.
Example 3-CPC powder was the same as example 1. The hardening liquid contained 0.17mol/L of calcium ions, 1.87mol/L of phosphate ions, and 1.63mol/L of sodium ions, and the pH of the solution was 2.63. The hardening time test results are IST =4.34 ± 0.07 min (n = 3) and FST =7.22 ± 0.09 min, IST/FST ratio = 0.60. The results show that further adjustment of the sclerosant composition results in shorter IST and FST, i.e.faster initial setting time and final setting time, and a significant increase in the IST/FST ratio to 0.60. The "run" time in this example is a major portion of the total time for the CPC to completely harden.
Example 4-CPC powder was the same as example 1. The hardening liquid contains 0.08mol/L of calcium ions, 1.43mol/L of phosphate ions and 0.53mol/L of sodium ions, and the pH of the solution is = 1.40. The hardening time test results are IST =4.03 ± 0.26 (n = 3) minutes, FST =6.53 ± 0.32 (n = 3) minutes, and IST/FST ratio = 0.61. The results show that the final setting time for CPC is only 6.53 minutes, maintaining sufficient "working" time. This example shows that excellent curing properties can be obtained using solutions with relatively low concentrations of sodium and calcium ions. Although the initial pH of the solution is relatively low, the pH rises rapidly to near natural after mixing of the powder and liquid.
Example 5-CPC powder was alpha-TCP (alpha-tricalcium phosphate) and the sclerosant solution contained the same composition as in example 2. The hardening time test results are IST =8.32 ± 0.21 minutes (n = 3) and FST =19.8 ± 0.44 minutes (n = 3), the IST/FST ratio = 0.42. The results showed that the initial setting time and the final setting time were both increased with the same four-component system curing liquid using different CPC solid powder systems, but the ratio of the initial setting time to the final setting time did not change much.
Example 6-CPC powders are alpha-TCP (alpha-tricalcium phosphate) and CaCO3(calcium carbonate) the composition of the hardening liquid was the same as in example 2, in a mixture of 3:1 molar ratio. The hardening time test results are IST =6.71 ± 0.13 min (n = 3) and FST =20.3 ± 0.58 min (n = 3), the IST/FST ratio = 0.33. This experiment was conductedThe results show that CaCO was added to the CPC powder when the same hardening liquid was used3The initial setting time of CPC can be shortened, but the final setting time is not greatly influenced.
Example 7-CPC powder DCPA (dicalcium phosphate) and CaCO3(calcium carbonate) in a molar ratio of 3: 2. The hardening liquid contains 0.21mol/L of calcium ions, 0.50mol/L of phosphate ions and 0.50mol/L of sodium ions. The hardening time test results are IST =18.2 ± 0.62 min (n = 3) and FST =60.5 ± 2.57 min (n = 3), the IST/FST ratio = 0.33. By changing the composition of the CPC solid powder and using a thinner sclerosant solution concentration, the initial setting time and the final setting time become significantly longer, especially the final setting time is as long as 1 hour, which is far from meeting the clinical requirement of cherry blossom within 30 minutes.
Example 8-CPC powder was beta-TCP (beta-tricalcium phosphate) and the sclerosant solution contained the same composition as in example 2. The hardening time test results are IST =11.2 ± 0.32 min (n = 3) and FST =31.1 ± 1.10 min (n = 3), the IST/FST ratio = 0.36. The results show that, in contrast to examples 5 and 2, the hardening time of β -TCP is much slower than that of α -TCP and also slower than that of DCPA + TTCP powder of example 2, probably because of the slower dissolution rate of β -TCP.
Example 9-CPC powder is MCPM + CaCO3The hardening liquid contains 1.87mol/L calcium ions, 0.17mol/L phosphate ions and 1.63mol/L chloride ions according to a mixture of a molar ratio of 3: 7. The hardening time test results are IST =18.2 ± 0.97 min (n = 3) and FST =48.0 ± 1.69 min, the IST/FST ratio = 0.38. The results show that the introduction of chloride ions makes the phosphate ions far lower than the calcium ion concentration, so that the initial setting time and the final setting time are long, the final setting time is close to 50 minutes, and the requirement of complete hardening within half an hour in clinic is not met.
Example 10-CPC powder is ACP + CaCO3The hardening liquid was the same as in example 4 in a mixture of 3:1 molar ratio. The hardening time test results are IST =7.12 ± 0.44 minutes (n = 3), FST =12.5 ± 0.62 minutes (n = 3), and IST/FST ratio = 0.57. This system gives a sufficiently long "working" time and has a fast final set hardening time, the final set time of CPC being only 12.5 minutes, is very suitable for repairing the open bone defects of limbs and skull.
Example 11-the concentration of each ion in the CPC powder and the sclerosant solution was consistent with the ratio of example 4, the only change being to change the sodium ions to potassium ions in the sclerosant solution of example 4. The hardening time test results are IST =6.20 ± 0.42 min (n = 3), FST =13.0 ± 0.73 min (n = 3), and IST/FST ratio = 0.48. The results showed that the hardening time tended to be longer when the sodium ions were replaced with potassium ions in the hardening liquid, and the initial setting time increased slightly, but the final setting time almost doubled.
Example 12-CPC powder As in example 1, the hardening liquid contained 0.73mol/L of calcium ions, 0.08mol/L of phosphate ions, and 0.2mol/L of chloride ions. The hardening time test results are IST =18.4 ± 0.78 min (n = 3) and FST =35.2 ± 1.24 min, IST/FST ratio = 0.52. The results show that the introduction of chloride ions into the hardening liquid lengthens both the initial setting time and the final setting time.
EXAMPLE 13 CPC powder the main constituents were the same as the CPC powder of example 1, with the addition of NaHCO in a molar percentage of 10%3The mixture consists of TTCP + DCPA + NaHCO3The hardening liquid was the same as in example 3. The hardening time test results are IST =12.4 ± 0.57 min (n = 3) and FST =17.1 ± 0.89 min, IST/FST ratio = 0.73. The resulting CPC of this example has the highest IST/FST ratio, i.e., the greatest ratio of initial set time to final set time, i.e., the longest "on the fly" time relative to a given final set time. This hardening time is of great clinical significance and is more suitable for more complex spinal repair procedures. Due to the complexity of spinal repair, relatively long procedure times are generally required clinically, the CPC gives the physician sufficient length of procedure time to shape, and once injected into the body, the CPC rapidly hardens. The reason why the CPC has a long initial setting and a fast final setting is that the CPC not only independently adjusts calcium, phosphorus and sodium ions in the hardening liquid, but also has the advantage that sodium ions and bicarbonate ions are introduced into the powder to doubly control the hardening time.
Example 14-CPC powder was a mixture of MCP, TCP, and TTCP in a molar ratio of 1:1:4, and the hardening liquid was changed to calcium ions for strontium ions, and contained strontium ions 0.17mol/L, phosphate ions 1.87mol/L, and sodium ions 1.63 mol/L. The hardening time test results are IST =5.42 ± 0.27 min (n = 3) and FST =12.6 ± 0.47 min, the IST/FST ratio = 0.43. The results show that further adjustment of the sclerosant composition results in shorter IST and FST, i.e.faster initial setting time and final setting time, and a significant increase in the IST/FST ratio to 0.60. The "run" time in this example is a major portion of the total time for the CPC to completely harden. The initial setting time and final setting time are both extended relative to calcium ion hardening fluids of the same composition, which may result in slower hardening of strontium-doped CPC due to the larger ionic radius of the strontium ions and the greater solubility of the strontium-hybridized hydroxyapatite. Of course, changes in powder composition are also another factor that affects the hardening time.
Example 15-CPC powder is a mixture of DCP, CaO, TCP in a molar ratio of 1:1:1.3, and the hardening liquid is the same as in example 4. The hardening time test results are IST =2.86 ± 0.23 min (n = 3), FST =4.26 ± 0.32 min (n = 3), and IST/FST ratio = 0.67. The system obtains a system with a high IST/FST ratio and short initial setting time and final setting time, is very suitable for fast hardening CPC planted in the oral cavity, and is necessary for fast hardening bone cement under the condition of large saliva secretion.
Example 16-CPC powder is MCP, DCPA, TTCP, CaCO mixed in equimolar amounts3The hardening liquid contains thinner ions, wherein calcium ions are 0.03mol/L, phosphate ions are 0.27mol/L, sodium ions are 0.31mol/L, and the pH of the solution is = 1.40. The results of the hardening time test were IST =10.2 ± 1.04 minutes (n = 3), FST =21.3 ± 1.63 minutes (n = 3), and IST/FST ratio =0.46, the range and ratio of the hardening time also being well suited for the filling of open bone defects in the extremities. The results show that the hardening time can be more effectively controlled to the range of clinical requirements by independently adjusting each component of the hardening liquid and the powder. It is worth noting that while the hardening liquid components can be adjusted completely independently by the technology of this patent, thereby adjusting the hardening time at will, the multi-component solid powder provides a richer means for the hardening time and product performance control. According to the unique technology of the patent, the ratio of each component in the hardening liquid and the powder is combinedThe regulation can develop a series of novel calcium phosphate bone cements (injection type artificial bones) which are suitable for different wound sites and different clinical requirements and have different hardening time, mechanical strength and degradation rate.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present invention or directly or indirectly applied to other related technical fields are included in the scope of the present invention.

Claims (9)

1. A self-curing calcium phosphate cement with independently adjustable initial setting time and final setting time is characterized in that: comprises a hardening liquid system and a solid powder system, wherein the hardening liquid system is except water (containing H)+、OH-) Calcium ion, and phosphate ion (including PO)4 3-、HPO4 2-、H2PO4 -) Besides, at least one or more of MnIons; the solid powder system comprises at least one calcium-containing compound selected from the group consisting of calcium dihydrogen phosphate monohydrate (MCPM), calcium dihydrogen phosphate anhydrous (MCPA), calcium hydrogen phosphate anhydrous (DCPA), calcium hydrogen phosphate dihydrate (DCPD), alpha-tricalcium phosphate (alpha-TCP), beta-tricalcium phosphate (beta-TCP), amorphous tricalcium phosphate (ACP), calcium tetraphosphate (TTCP), calcium oxide (CaO), calcium hydroxide Ca (OH)2Calcium carbonate, calcium Octaphosphate (OCP), and the like.
2. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: m in the hardening liquid systemnThe ion is one or more anions or cations, wherein n is +1, +2, +3 or-1, -2, -3; including Na+、K+、Mg+、Sr+、Zn2+、Fe2+、Fe3+、Mn2+(ii) a Similarly, the chloride ion may also be replaced by other anions, such as F-、NO3 -、SO4 2-、HSO4 -、CO3 -、HCO3 -Acetate ion, oxalate ion, citrate ion, lactate ion, amino acid ion, and other organic acid anions.
3. The self-setting calcium phosphate cement of claim 2, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the other organic acid radical ions are anions H (CH) of organic small molecules or organic high molecular acids2)x-(P)p-(K)y(x =0, 1, 2, 3, … 100000, P is N, O, P element, P is 0, 1, 2, 3, … …, 100000, K = COOH, SO3H、PO3H2，y=1、2、3、…、100000）。
4. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the solid powder system further comprises a source of carbonate ions for the purpose of forming carbonated apatite in the CPC bone cement product, the source of carbonate ions being calcium carbonate, sodium bicarbonate, magnesium carbonate, magnesium bicarbonate, potassium carbonate, potassium bicarbonate, strontium carbonate, strontium bicarbonate, ferrous carbonate, zinc carbonate, or a combination thereof.
5. The self-setting calcium phosphate cement with independently adjustable initial setting time and final setting time as claimed in claim 4, wherein: the carbonate ion source should be used in an amount sufficient to form a carbonate content of 0% to 30% in the CPC cured product.
6. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the solid powder system also includes citric acid, sodium citrate, or a combination thereof, in an amount sufficient to produce a citrate concentration of 0mol/L to 5mol/L when the solid and hardened liquid system are mixed.
7. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the hardening liquid system also comprises citrate ions with the concentration of 0mol/L to 5 mol/L.
8. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the sclerosant fluid system further comprises 0% to 10% of a liquid thickener selected from xanthan gum, guar gum, carbomer, crepe carrageenan, hydroxyethyl cellulose, carboxymethyl cellulose, salts of the foregoing thickeners, or combinations thereof, to improve the cohesiveness of the paste.
9. The self-setting calcium phosphate cement of claim 1, wherein the initial setting time and the final setting time are independently adjustable, and the self-setting calcium phosphate cement is characterized in that: the bone cement further comprises one or more additives such as pore formers, antibiotics or other drugs, radiopaque fillers, reinforcing fillers and fibers, and osteoinductive additives.
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TW201321033A (en) * 2011-11-28 2013-06-01 Univ Nat Cheng Kung Calcium-based bone cement formula with extended setting time
CN108273128A (en) * 2018-02-09 2018-07-13 山东大学深圳研究院 Self-cured calcium phosphate bone-rehabilitating material
CN109381740A (en) * 2018-06-29 2019-02-26 广州润虹医药科技股份有限公司 A kind of self-curable calcium phosphate bone cement that strontium ion mediates

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Publication number Priority date Publication date Assignee Title
CN101057979A (en) * 2007-04-03 2007-10-24 暨南大学 Injectable self-curable calcium phosphate bone tissue repairing material and its preparation method and application
TW201321033A (en) * 2011-11-28 2013-06-01 Univ Nat Cheng Kung Calcium-based bone cement formula with extended setting time
CN108273128A (en) * 2018-02-09 2018-07-13 山东大学深圳研究院 Self-cured calcium phosphate bone-rehabilitating material
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