MAGNESIUM PHOSPHATE BONE CEMENT

Abstract

A magnesium phosphate bone cement includes a powder agent and a liquid agent. A liquid-to-solid ratio of the liquid agent to the powder agent is 0.1-0.5 ml/g. The powder agent comprises following components: phosphate accounting for 32-70 wt %, magnesium oxide accounting for 28-65 wt %, and silicon-containing compound accounting for 1-15 wt %. Preferably, the powder agent further comprises ammonium dihydrogen phosphate, and degradable and adhesion-promoting material, wherein the ammonium dihydrogen phosphate accounts for 5-30 wt % of a total weight of the phosphate.

Claims

1. A magnesium phosphate bone cement, comprising a powder agent and a liquid agent, wherein, a liquid-to-solid ratio of the liquid agent and the powder agent is 0.1-0.5 ml/g, and the powder agent comprises following components: TABLE-US-00013 phosphate 32-70 wt %; magnesium oxide 28-65 wt %; silicon-containing compound 1-15 wt %.

2. The magnesium phosphate bone cement according to claim 1, wherein, the phosphate comprises one of or a mixture of two or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, and calcium dihydrogen phosphate.

3. The magnesium phosphate bone cement according to claim 1, wherein, the phosphate comprises ammonium dihydrogen phosphate, and the ammonium dihydrogen phosphate accounts for 5-30 wt % of a total weight of the phosphate.

4. The magnesium phosphate bone cement according to claim 1, wherein, the powder agent further comprises a degradable and adhesion-promoting material.

5. The magnesium phosphate bone cement according to claim 4, wherein, the degradable and adhesion-promoting material comprises at least one of sugar, sugar derivative, beeswax, sodium hyaluronate, and bone glue.

6. The magnesium phosphate bone cement according to claim 1, wherein, the silicon-containing compound comprises silica and/or silicate.

7. The magnesium phosphate bone cement according to claim 6, wherein, the silicate comprises silicate glass, and the silicate glass comprises one of or a mixture of two or more of 45S5, 45S5.4F, 52S4.6, 55S4.3, 60S3.8, 42SF, 46SF, 49SF, 52SF, 55SF, and 60SF.

8. The magnesium phosphate bone cement according to claim 1, wherein, the magnesium phosphate bone cement comprises a retarder, and the retarder comprises one of or a mixture of two or more of boric acid, borate, citric acid, and citrate.

9. The magnesium phosphate bone cement according to claim 1, wherein, the phosphate further comprises calcium phosphate, and the calcium phosphate comprises either of or a mixture of -tricalcium phosphate and -tricalcium phosphate.

10. The magnesium phosphate bone cement according to claim 1, wherein, the liquid agent comprises one of or a mixture of two or more of deionized water, sodium chloride solution, and phosphoric acid solution.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to make the content of the present disclosure more clear and better understood, the present disclosure will be further described in more details with reference to the accompanying figures and embodiments, wherein,

[0038] FIG. 1 shows a large amount of bone-like hydroxyapatite deposition on the surface of the bone cement of the present disclosure when being soaked in the simulated body fluid (SBF);

[0039] FIG. 2 shows the change of compressive strength of the bone cement of the present disclosure after being soaked in the simulated body fluid (SBF) for different periods of time;

[0040] FIG. 3 shows a silicone gel layer produced on the surface of the bone cement of the present disclosure after being soaked in the simulated body fluid (SBF);

[0041] FIG. 4 is a Micro-CT image of the bone cement of the present disclosure one month after the bone cement being used in a fracture bonding surgery;

[0042] FIG. 5 is a Micro-CT image of the bone cement of the present disclosure three months after the bone cement being used in a fracture bonding surgery;

[0043] FIG. 6 is a Micro-CT image of the bone cement of the present disclosure six months after the bone cement being used in fracture bonding surgery.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] To make the objectives, technical solutions, and advantages of the present invention clearer, the present disclosure will be further described in more details with reference to the accompanying figures and embodiments.

[0045] The magnesium oxide of the present invention is obtained by calcining magnesium hydroxide and/or basic magnesium carbonate. The calcination temperature in the calcination process is 1200 C.-1600 C., and the calcination time is 1-6 hours. Preferably, the calcination temperature is 1400 C.-1500 C., and the calcination time is 3-4 hours. Different calcination processes affect the activity of magnesium oxide, thereby affecting the strength and the solidification time of the bone cement.

[0046] Exemplary formulations of the bone cement of the present invention are as follows:

[0047] Formulation a:

[0048] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00001 KH.sub.2PO.sub.4 45%; MgO 41%; SiO.sub.2 8%; Sucrose 4%; -Tcp 1%; Na.sub.2B.sub.4O.sub.7 1%;

[0049] The liquid agent is deionized water, and the liquid-to-solid ratio of the powder agent and the liquid agent is 0.2 ml/g.

[0050] Formula b:

[0051] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00002 Ca(H.sub.2PO.sub.4).sub.2 40%; MgO 45%; NH.sub.4H.sub.2PO.sub.4 5%; 45S5 5%; Glucose 4.5%; H.sub.3BO.sub.3 0.5%;

[0052] The liquid agent is physiological saline, and the liquid-solid ratio of the powder agent and the liquid agent is 0.22 ml/g.

[0053] Formula c:

[0054] Formulate powder agent in the following weight percentage (wt %):

TABLE-US-00003 NaH.sub.2PO.sub.4 40%; MgO 40%; NH.sub.4H.sub.2PO.sub.4 5%; Na.sub.2SiO.sub.3 8%; Bone glue 6%; Na.sub.3C.sub.6H.sub.5O.sub.7 1%;

[0055] The liquid agent is phosphoric acid solution, and the liquid-to-solid ratio of the powder agent and the liquid agent is 0.25 ml/g.

[0056] Formula d:

[0057] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00004 KH.sub.2PO.sub.4 35%; MgO 50%; NH.sub.4H.sub.2PO.sub.4 5%; 60S3.8 7%; Sucrose 2%; Na.sub.2B.sub.4O.sub.7 1%;

[0058] The liquid agent is deionized water, and the liquid-solid ratio of the powder agent and the liquid agent is 0.16 ml/g.

[0059] Formula e:

[0060] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00005 NaH.sub.2PO.sub.4 30%; MgO 51%; NH.sub.4H.sub.2PO.sub.4 8%; 46SF 10%; Sodium hyaluronate 0.5%; Na.sub.2B.sub.4O.sub.7 0.5%;

[0061] The liquid agent is physiological saline, and the liquid-solid ratio of the powder agent and the liquid agent is 0.32 ml/g.

[0062] Formula f:

[0063] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00006 KH.sub.2PO.sub.4 35%; MgO 39%; NH.sub.4H.sub.2PO.sub.4 8%; SiO.sub.2 8%; Sucrose 4%; Na.sub.2B.sub.4O.sub.7 1%;

[0064] The liquid agent is deionized water, and the liquid-solid ratio of the powder agent and the liquid agent is 0.19 ml/g.

[0065] Formula g:

[0066] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00007 Ca(H.sub.2PO.sub.4).sub.2 35%; MgO 45%; NH.sub.4H.sub.2PO.sub.4 10%; 45S5 8%; Beeswax 1.5%; H.sub.3BO.sub.3 0.5%;

[0067] The liquid agent is physiological saline, and the liquid-solid ratio of the powder agent and the liquid agent is 0.23 ml/g.

[0068] Formula h:

[0069] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00008 KH.sub.2PO.sub.4 36%; MgO 44%; NH.sub.4H.sub.2PO.sub.4 5%; Na.sub.2SiO.sub.3 8%; Maltose 6.5%; Na.sub.3C.sub.6H.sub.5O.sub.7 0.5%;

[0070] The liquid agent is phosphoric acid solution, and the liquid-to-solid ratio of the powder agent and the liquid agent is 0.28 ml/g.

[0071] Formulation i:

[0072] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00009 KH.sub.2PO.sub.4 45%; MgO 40%; NH.sub.4H.sub.2PO.sub.4 5%; 45S5 5%; Sucrose 4%; Na.sub.2B.sub.4O.sub.7 1%;

[0073] The liquid agent is deionized water, and the liquid-solid ratio of the powder agent and the liquid agent is 0.16 ml/g.

[0074] Formula j:

[0075] Formulate powder agent according to the following weight percentage (wt %):

TABLE-US-00010 NaH.sub.2PO.sub.4 30%; MgO 51%; NH.sub.4H.sub.2PO.sub.4 8%; 55SF 7%; Cellulose 3.5%; Na.sub.2B.sub.4O.sub.7 0.5%;

[0076] The liquid agent is physiological saline, and the liquid-solid ratio of the powder agent and the liquid agent is 0.3 ml/g.

[0077] The above exemplary formulations are some preferred formulation ratios of the present invention and are not intended to limit the present invention.

[0078] In one of the embodiments of the present invention, the powder agent and the liquid agent are blended according to formula a, and poured into a mold after being stirred for 3 minutes, and unloaded from the mold half an hour later, and then placed for 24 hours in an environment with temperature of 37 C. and humidity of 100%, where the average value of the measured compressive strength reaches 60 MPa. The solidified bone cement particles are soaked in the simulated body fluid (SBF). One day later, as shown in FIG. 1, a large amount of bone-like hydroxyapatite deposition is found on the surface of the bone cement particles, which indicates that the bone cement has a good biological activity. As shown in FIG. 2, after the bone cement particles are soaked for 12 weeks, the average value of the measured compressive strength is 16 MPa, which remains above the human cancellous bone strength.

[0079] In one of the embodiments of the present invention, the powder agent and the liquid agent are blended according to the formula d, and poured into a mold after being stirred for 2 minutes, and unloaded from the mold half an hour later, and then placed for 24 hours in an environment with temperature of 37 C. and humidity of 100%. The solidified bone cement is soaked in simulated body fluid (SBF), and as shown in FIG. 3, a porous silicone gel layer is formed on the surface one week later.

[0080] As a degradable bonding agent, the bone cement fixes and repairs comminuted fractures.

[0081] In one of the embodiments of the present invention, the powder agent and the liquid agent are blended according to formula h, and stirred for 3 minutes and then set aside. The experimental model is a pig shin bone fracture, and 60 fresh shin bones of pigs are serially numbered and divided into six groups A, B, C, D, E and F through CHISS software, and each group contains 10 bones. A square fracture section is produced inside each shin bone about 3 cm below the platform of the pig shin bone by a bone chisel, and the surface area of the square fracture section is trimmed to be 1 cm.sup.2, to facilitate the calculation of the adhesive strength after measurement. The well-blended bone cement is uniformly daubed on the cross-section of the fracture. After being fixed under pressure for 15 minutes, the groups A, B and C, and the groups D, E and F cure under the room temperature of 23 C. and 37 C. respectively and in the simulated body fluid. The compressive strength is measured after half an hour, two hours and 24 hours respectively. The results are as follows:

TABLE-US-00011 TABLE 1 Comparison of average values of compressive strength after the bone cement has solidified under different conditions (x s, N/cm.sup.2) Solidification conditions Solidi- Room 37 C., in fication temperature simulated t P time of 23 C. body fluid value value 0.5 h 98.31 14.96 91.33 9.10 1.26 0.224 2 h 117.33 22.93 114.28 12.19 0.37 0.715 24 h 118.78 20.01 119.59 20.96 0.09 0.931

[0082] As can be seen from the above comparison, there is no significant difference between the average values of compressive strength of the bone cement after solidification at room temperature and in the simulated body fluid for half an hour, two hours and 24 hours respectively, and better bonding strength can be achieved with solidification at room temperature at 23 C. for 2 h which is almost the same time of completing a clinical surgery. Therefore, the bone cement can be applied in clinical practice to directly bond and fix fractures.

[0083] In one of the embodiments of the present invention, 15 adult healthy pigs are selected for the experimental group to carry out the bone bonding tests in vivo, and a screw sized 4.0 mm4.0 cm for cancellous bone is used for internal fixation in control group.

[0084] One month, 3 months, and 6 months after the surgery, two knee joints of the animals are photographed with frontal and lateral X-rays and CT, and scanned by Micro-computed tomography (Micro-CT). As shown in FIGS. 4 to 6, there is no displacement of fracture in both pig experimental group and the control group. One month later, the appositions and the alignments of the fractures in the experimental group and the control group are good; the fracture line is clearly visible; and the fracture callus is normal and is calcified to form bridge fracture callus; and part of the bone trabecula penetrates the bone cement. Through comparing the images taken three months after the surgery with the images taken one month after the surgery, no displacements of the fractures are found; the fracture line is blurred; the bone cement is gradually absorbed and degraded; and the fracture has healed. As shown in the images taken six months after the surgery, the fracture line completely disappears; MPC is completely absorbed and degraded; and the fractures have completely healed.

[0085] The analyses for concentrations of serum phosphorus, serum magnesium, and serum calcium in pigs before the surgery and at three time points after the surgery are performed through the variance analysis of statistical method. The results are as follows:

TABLE-US-00012 TABLE 2 Variance Analysis for Concentrations of Serum Phosphorus, Serum Magnesium and Serum Calcium at Different Time Points (x s, mmol/L) Group 1 month 3 months 6 months before after after after F P item surgery surgery surgery surgery value value Serum 2.77 2.64 2.63 2.55 0.85 0.483 Phosphorus 0.16 0.15 0.25 0.39 concentra- tion Serum 0.94 0.90 0.92 0.94 0.26 0.853 Magnesium 0.11 0.13 0.10 0.10 concentra- tion Serum 2.44 2.45 2.46 2.41 0.25 0.862 Calcium 0.12 0.14 0.09 0.07 concentra- tion

[0086] The serum magnesium concentration has no significant changes before the surgery, one month after the surgery, 3 months after the surgery and 6 months after the surgery, which indicates that, during fracture healing, the bone cement implanted in the pigs doesn't have adverse effects on the serum electrolyte ions concentrations; the dissolution and absorption of the bone cement can be fully balanced during the normal metabolic process of the pigs. During the experiment, no abnormal reactions such as inflammation emerged in the domestic pigs, and no pigs died due to the implantation of bone cement. Therefore, it is believed that the bone cement of the present invention can be degraded and absorbed, and that the bone cement has a high biological safety and a good biocompatibility.

[0087] The bone cement is used to strengthen the fixation of screws.

[0088] In one of the embodiments of the present invention, the powder agent and the liquid agent are blended according to formulation i, and stirred for 3 minutes and then set aside. The bone cement of the present invention is used in the experimental group, and PMMA bone cement is used in the control group. The test method is as follows: divide 18 landraces pigs weighing 502 kg into two groups randomly; a screw track is provided at the humerus medialis epicondylus and parallel with the long axis of trochlea in the humerus; the diameter of the screw track is 8 mm; and insert a screw for cancellous bone, which is 6 mm in diameter and 40 mm in length; the rest is filled with and boned by the stirred bone cement. X-ray and CT scans were taken one month, 3 months, and 6 months after the surgery, to observe the absorption of the bone cement and the growth of new bone. The animals were killed at the time points of one month, 3 months and 6 months after the surgery, so as to take samples. Some specimens were used for analyzing the diameter of the screw track, and the other specimens were used for measuring biomechanical.

[0089] Radiography of X-ray and CT scans shows that the thickness of bone cement around the screw in the experimental group gradually becomes thinner at the time points of one month, 3 months and 6 months after the surgery, and the bone cement is tightly surrounded by new bone; i.e., as time goes on, the bone cement is gradually absorbed and is replaced by new bone; the thickness of the poly(methyl methacrylate) bone cement around the screw in the control group does not change significantly; i.e., the poly(methyl methacrylate) could not be decomposed and absorbed by the body. Histological analysis shows that the diameters of the screw track in the experimental group are 8.200.10 mm, 7.100.20 mm, and 6.130.06 mm for one month, 3 months, and 6 months respectively after the surgery. The diameters of the screw track at three time points are significantly different (P<0.05); in the control group, the diameters of the screw track are 8.230.05 mm, 8.100.04 mm, and 8.130.06 mm respectively, having no significant statistical difference (P>0.05). One month after the surgery, there is no significant difference between the diameters of the screw track in the experimental group and that in the control group (P>0.05). At two time points, 3 months and 6 months after the surgery, the diameter of the screw track in the experimental group is smaller than that in the control group, and there is a significant statistical difference (P<0.05).

[0090] Withdrawal forces are measured one month, three months and six months after the surgery. The maximum withdrawal forces in the experimental group are 4.960.43 kN, 3.970.26 kN, and 2.530.15 kN respectively, and the maximum withdrawal forces measured at three points have a statistical difference (P<0.05); the maximum withdrawal forces in the control group are 2.800.36 kN, 2.620.24 kN and 3.060.38 kN respectively, and the maximum withdrawal forces measured at three points have no significant statistical difference (P>0.05). The maximum withdrawal forces measured in the experimental group at two points, i.e., one month and 3 months after the surgery are greater than those measured one month and 3 months after the surgery in the control group, and there is a significant statistical difference (P<0.05); there is not a significant statistical difference between the maximum withdrawal force measured 6 months after the surgery in the experimental group and the maximum withdrawal force measured 6 months after the surgery in the control group (P>0.05).

[0091] The experimental results show that the bone cement of the present invention has a good biological safety and can effectively enhance the internal fixation strength. Within 3 months after the bone cement is implanted, the bone cement has a better reinforced fixation for the screw than PMMA does, and the bone cement can be mostly absorbed and decomposed within 6 months, and be replaced by autologous bone.

[0092] It is apparent that the above mentioned embodiments are only examples for clearly illustrating the present invention, but not intend to limit the embodiments of the present invention. It should be understood by the skilled in the art that various modifications and improvements can be made based on the description above. There is no need and no possibility to illustrate all embodiments, and all obvious modifications and improvements made on the basis of the present disclosure should be included in the protection scope of the present invention.