CN101428152A

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Publication number: CN101428152A
Application number: CNA2008102047825A
Authority: CN
Inventors: 常江; 郇志广
Original assignee: Shanghai Institute of Ceramics of CAS
Current assignee: Shanghai Institute of Ceramics of CAS
Priority date: 2008-12-17
Filing date: 2008-12-17
Publication date: 2009-05-13

Abstract

The invention relates to a dicalcium silicate compounded self-setting material as well as the preparation method and the application thereof, in particular to a human body hard tissue defect filling and recovery material, and belongs to the field of medical biomaterials. The invention is a paste comprising mixing liquid and dicalcium silicate/calcium sulfate hemihydrate which are mixed with each other at a mass ratio of 0.5-1.5:1, and the mixing liquid is selected from one of deionized water, a simulated body fluid, an inorganic salt solution, or an organic matter solution. Compared with the prior materials, the invention has the characteristics of excellent biological activity, random moulding, self-setting, non-cytoxicity, progressive degradation and adjustable degradation rate, and can achieve the effect of inducing the generation of bone-like apatite. Moreover, the material provided by the invention has better self-setting performance than pure calcium silicon-based or calcium sulfate self-setting bone recovery materials, the preparation method is simple.

Description

Composite self-curing material of dicalcium silicate and its production and application

Invention field

The present invention relates to composite self-curing material of dicalcium silicate and its production and application, relate to the damaged filling renovation material of human body hard tissue, belong to the biomaterial for medical purpose field.

Background technology

In body bone tissue and the treatment of tooth defect repair, can carry out calcium phosphate bone cement in defect and fill repairing and treating.At present, people are also by the minimally-invasive treatment means, with packing material be designed to injectable and in vivo the pastel of self-curing carry out injection for curing, both avoided the cumbersome procedure of traditional operation, alleviated patient's misery, greatly reduce medical expense again.

(Chow etc., JDent Res 1984 since the eighties in 20th century, people such as Chow proposed the notion of calcium phosphate bone cement (CPC); 63:200), many scholars develop the CPC bone cement packing material of a series of different phosphate acid calcium salt combinations in succession, this class material has excellent biological compatibility and self-curing characteristic, and can conduct growth in osteogenic cell migration and the osseous tissue, but this repair process creeping substitution (as bone conduction) (the J BiomedMater Res:Appl Biomater 1998 that only is osseous tissue in material surface with good biocompatibility and the micropore in essence; 43:451-461), material itself is biologically active not, can not produce active stimulate and promote bone tissue restoration (Hench etc., Life Chem Rep 1996 to the skeletonization stem cell; 13:187-241).Secondly, this class material cured speed is too fast, is easy to generate " filter is pressed " phenomenon in minimally-invasive treatment, is difficult for injection.

Over nearly 30 years, The experimental results shows, the bioactive materials of some calcic-silicon, as

Bioactivity glass and A-W glass ceramics, in simulated body fluid and human body, all can induce class bone carbonated hydroxyapatite (CHA) deposition, and also verified this class bioactive materials of in vivo test has good and the ability osseous tissue bonding (Hench etc., J Biomed Mater Res Symp 1971; 36:117-141; Kokubo etc., Biomaterials 1991; 12:155-163).Recent years, many scholars' reports, the calcium that the bioactive materials of many calcic-silicon components discharges, silicon ion can with osteoblast effect, active cell gene expression, promote cell proliferation and differentiation (Xynos etc., Biomed Biophys Res Commun 2000; 276:461-465; Xynos etc., J Biomed Mater Res 2001; 55:151-157; Phan etc., J BiomedMater Res 2003; 67A:1001-1008; Gough etc., Biomaterials 2004; 25:2039-2046).This shows that inducing class bone CHA to generate and promoting human body osteocyte propagation, break up is the common trait of some calcic-silicon components bioactive materials, this provides scientific basis for developing new biologically active self-curing material.

Dicalcium silicate (Ca₂SiO₄, C₂S) be one of main component in the Portland cement, that the pastel that adds an amount of distiller liquor preparation has is moulding arbitrarily, characteristics such as curing voluntarily.When the dicalcium silicate powder body contacts with water, the dissolving of microgranule top layer is also followed ion migration, and calcium-silicate hydrate (C-S-H) gel deposition with nano-pore structure is at the powder body microparticle surfaces, and calcium hydroxide crystal grain is in hydrate gel capillary porose area nucleation and grow up simultaneously; Carrying out along with reaction, the sclerosis of calcium-silicate hydrate gel polymerisation, formation has the block materials (Barnes work, Structure and performance of cements.London:Applied Science Publishers.1983) of certain micropore and intensity.With bioactivity glass and ceramic-like seemingly, dicalcium silicate also has superior bioactive (Gou etc., J Eur Ceram Soc 2002; 24:93-99).In addition, up-to-date studies show that, dicalcium silicate not only has superior bioactive, and the silicon ion that also has appropriateness discharges and degradation property (Gou etc., J Biomed Mater Res Part B:Appl Biomater2005; 73B:244-251), be a kind of novel damaged filling restoration bioactive material of the human body bone/tooth with applications well prospect.But this material still exists some defectives on using, and this is mainly reflected in following two aspects: at first, this material cured speed is slower, and setting time is longer; Secondly, this material short term strength is lower.

Calcium sulfate self-curing bone cement (Calcium Sulfate Cements, CSCs) as the damaged packing material of a kind of bone the applicating history in more than 100 year has been arranged, its correlational study the earliest can be traced back to 1892 (Henry etc., Clinical Pharmaco-kinetics 1995; 29:36-45).Half-H 2 O calcium sulphate (CaSO₄1/2H₂O, Calcium Sulfate Hemihydrate plaster) is calcium sulphate dihydrate (CaSO₄2H₂O, Calcium Sulfate Dihydrate, CSD) the resulting a kind of flat crystal of thermal dehydration, when mixing with water, it can with the water generation dihydrate gypsum that reacts rapidly, reaction equation is:

CaSO₄·1/2H₂O+3/2H₂O→CaSO₄·2H₂O

This also is reaction mechanism (A J Lewry, J Mater Sci 1994 that the semi-hydrated gypsum aquation is solidified; 29:5279-5284).In clinical practice, this material has characteristics and the excellent biological compatibility that structural support is provided for defect, and this class material also has good bone conductibility after implantation.But, this material still exists some defectives on using, this is mainly reflected in the following aspects: at first, though this material solidification speed is fast, the defect structural support can be provided at short notice, but bone cement slurry syringeability is poor, and lacks the ability that the reparation position is provided long-term structural support; Secondly,, do not have biological activity, osteanagenesis is not had facilitation though this material has excellent biological compatibility and bone conductibility.The 3rd, clinical research shows, this material degradation in vivo excessive velocities causes repairing the position easily and big quantity of fluid occurs and ooze out, and in degradation process a large amount of SO that discharge₄^2-, in addition, also there is metabolic problem in this material.

Based on above-mentioned dicalcium silicate and half-H 2 O calcium sulphate characteristics separately, the imagination that the present invention proposes be dicalcium silicate and half-H 2 O calcium sulphate can be carried out compound, to obtain the compound self-curing material of dicalcium silicate/half-H 2 O calcium sulphate.With respect to simple dicalcium silicate or calcium sulfate bone cement, the advantage that dicalcium silicate/the half-H 2 O calcium sulphate composite bone cement mainly possesses is: (1) has and the similar rapid solidification ability of calcium sulfate bone cement; (2) similar to dicalcium silicate, its mechanical strength has the advantages that to improve with the hydration time prolongation; (3) possesses biological activity; (4) utilize the dicalcium silicate degradability different, adjust the degradation property of composite by the relative scale of two kinds of components in the control composite, to adapt to wider clinical application with calcium sulfate.Thereby be guided out design of the present invention.

Summary of the invention

The purpose of this invention is to provide a kind of bioactive beta-dicalcium silicate/half-H 2 O calcium sulphate (C₂S/plaster) preparation method of compound self-curing material and purposes.Characteristics that it is higher with the long-term mechanical strength of dicalcium silicate, biological activity is good and half-H 2 O calcium sulphate rapid solidification, biocompatibility is good and the characteristics with bone conductibility combine, and prepares a kind of novel biological activity human body bone and the damaged filling renovation material of tooth; Be suitable for the self-curing material used in orthopaedics, the department of stomatology and the minimally-invasive treatment by adjusting the ratio of the content of half-H 2 O calcium sulphate in the composite material powder, can preparing.

Based on the foregoing invention purpose, the invention provides and a kind ofly carry out dicalcium silicate and half-H 2 O calcium sulphate compound, with water or various solution is the in-situ solidifying bioactive materials of distiller liquor preparation, and the present invention also provides in-situ solidifying bioactive beta-dicalcium silicate/half-H 2 O calcium sulphate preparation methods and in the purposes of the damaged filling of bone/tooth, minimally-invasive treatment.

Dicalcium silicate of the present invention/existing superior bioactive of half-H 2 O calcium sulphate self-curing material and biocompatibility, again can be as required, be prepared into dough shape or injectable cement material easily, satisfy the clinical multiple treatment needs that carry out bone, the operation of tooth defect repair.

The used compound self-curing material powder body of the present invention is the mixed powder that dicalcium silicate and half-H 2 O calcium sulphate are formed, and wherein dicalcium silicate is to be primary raw material with lime nitrate and Ludox, adopts the powder body of sol-gel process preparation; Half-H 2 O calcium sulphate is to be raw material with the calcium sulphate dihydrate, adopts the powder body of hygrometric state or dry state heating preparation.Material of the present invention is characterised in that compound self-curing material powder body mesosilicic acid dicalcium quality percentage composition 5-95wt.%.The diameter of particle of various compositions is defined as 1-300 μ m in the composite, and proportion of composing can adjust accordingly as required.

Technical scheme of the present invention is as described below:

The used dicalcium silicate powder body of the present invention is to be raw material with Ludox, lime nitrate, citric acid and ethylene glycol, and with nitric acid as catalyst, adopt sol-gel process to prepare gel and it is carried out drying, afterwards to the resulting powder body of its high-temperature calcination.

The used half-H 2 O calcium sulphate powder granule of the present invention is the heating calcium sulphate dihydrate, and the control heating condition makes it decompose resulting powder body.

The used dicalcium silicate powder granule of the present invention is defined as the granular materials of diameter 1-300 μ m, and the half-H 2 O calcium sulphate powder granule is defined as the micro particulate materials of diameter 1-300 μ m.

Dicalcium silicate of the present invention/half-H 2 O calcium sulphate composite granule is to mix resulting powder body by sulfate hemihydrate calcium content 5-95wt.% with the dicalcium silicate powder machinery.

The pastel that the used defect of human body bone repair materials of the present invention is mainly sized mixing and is prepared into by dicalcium silicate/half-H 2 O calcium sulphate composite granule and distiller liquor, the content of half-H 2 O calcium sulphate is 5-95wt.% (mass ratio) in the composite.

Used dicalcium silicate/half-H 2 O calcium sulphate self-curing material the using method of the present invention promptly obtains being used for the dicalcium silicate/half-H 2 O calcium sulphate self-curing material of defect of human body bone reparation for being that the ratio of 0.5-1.5:1 fully is in harmonious proportion 0.5-1 minute with dicalcium silicate/half-H 2 O calcium sulphate composite granule and distiller liquor in liquid-solid mass ratio.

Preferred liquid-solid ratio (distiller liquor/composite granule) is: 0.5-1.5:1 (mass ratio).

The used distiller liquor of the present invention is a kind of in deionized water, inorganic salt (carbonate, calcium chloride, phosphate etc.) solution, organic solution (gelatin, chitosan, hyaluronic acid etc.) and the simulated body fluid.After above-mentioned dicalcium silicate/half-H 2 O calcium sulphate composite granule and distiller liquor mixing, be in harmonious proportion 0.5-1 minute, obtain can be used as the corresponding bone cement pastel sample of repairing defect of human body bone filling reparation.

The mensuration of compound self-curing material injectivity and setting time:

Pack into the nozzle inside diameter (D) that has of 15mL capacity of sample is the syringe of 2.0mm syringe needle, its injectivity is tested; Press the ISO9597-1989E proposed standard, adopt Vicat to test at the presetting period (I) and the final setting time (F) of above-mentioned bone cement pastel.

The relation of table 1 dicalcium silicate/half-H 2 O calcium sulphate pastel setting time and its sulfate hemihydrate calcium content (liquid-solid ratio=1.2:1)

Sulfate hemihydrate calcium content (wt.%)	Presetting period (min)	Final setting time (min)
Sulfate hemihydrate calcium content (wt.%)	Presetting period (min)	Final setting time (min)	0	100	280
10	80	200	0	100	280
10	80	200	30	22	50
50	12	30	30	22	50
50	12	30	70	10	23

90	8	14
90	8	14	100	7	10

The result of table 1 shows that the setting time of the aforesaid dicalcium silicate of the present invention/half-H 2 O calcium sulphate pastel shortens with the raising of sulfate hemihydrate calcium content in the composite.The result of Fig. 2 shows that in the scope of half-H 2 O calcium sulphate mass content at 5-50wt.%, dicalcium silicate/half-H 2 O calcium sulphate pastel can be injected.Mechanical strength be injected and be taken into account to the paste material that sulfate hemihydrate calcium content of the present invention is 5-50wt.% can, is suitable for Minimally Invasive Surgery; The sulfate hemihydrate calcium content is the characteristics that the dough material of 50-95wt.% has rapid solidification, can solve the problem that the damaged filling of large volume bone is repaired.

The biological activity test of compound self-curing material:

Dicalcium silicate/half-H 2 O calcium sulphate curing materials is adopted in-vitro simulated body fluid (SBF) immersion test (Kokubo etc., J Biomed Mater Res 1990; 24:721-734) carry out biological activity test, and the back sample surfaces carries out X-ray diffraction (XRD) and scanning electron microscope (SEM) characterizes to soaking.As shown in Figure 3 and Figure 4, dicalcium silicate of the present invention/half-H 2 O calcium sulphate curing materials surface energy induces osteoid apatite to generate, and shows that dicalcium silicate of the present invention/half-H 2 O calcium sulphate curing materials has superior bioactive.The XRD figure spectrum is gone back the display material surface and is contained calcium carbonate, and this is one of dicalcium silicate self-curing material hydrated product---and calcium hydroxide transforms into calcium carbonate with the carbonate reaction in the simulation physiological environment, calcium carbonate helps osteocyte activity and mineralising.

The external degradation property testing of compound self-curing material:

Adopt Ringer ' s solution to carry out the external degradation property testing to the compound self-curing material of dicalcium silicate/half-H 2 O calcium sulphate, detect the degradability of this composite with the dicalcium silicate/mass loss ratio of half-H 2 O calcium sulphate curing materials after soaking Ringer ' s solution certain hour.As shown in Figure 5, the degradation rate of dicalcium silicate/half-H 2 O calcium sulphate composite improves with the raising of sulfate hemihydrate calcium content in the composition.The result of Fig. 4 shows, can adjust the degradability that the content of half-H 2 O calcium sulphate in dicalcium silicate/half-H 2 O calcium sulphate composite is regulated composite according to the needs of different therapentic parts in clinical practice.

In view of the above, compound self-curing material of the present invention is a kind of novel defect of human body bone repair materials, this material has good biology performance, can deposit class bone carbonated hydroxyapatite and progressively degraded in human body simulation body fluid, the content that degradation rate can be by adjusting half-H 2 O calcium sulphate in this material is to satisfy the requirement of different therapentic parts in addition.

According to foregoing, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention, universal knowledege and technological means according to this area, in dicalcium silicate/half-H 2 O calcium sulphate composite granule particulate material and distiller liquor, add the other biological compatibility and curative drug component, all belong to modification, replacement and the change of the various ways that content of the present invention comprises, all belong to scope of the present invention.

Description of drawings

XRD figure spectrum (the sulfate hemihydrate calcium content: 20wt.%) of Fig. 1 dicalcium silicate/half-H 2 O calcium sulphate bone cement material maintenance after 7 days.

The syringeability curve of Fig. 2 dicalcium silicate/half-H 2 O calcium sulphate pastel; Liquid-solid ratio=1.2:1 (sulfate hemihydrate calcium content: 0-50wt.%).

Fig. 3 maintenance dicalcium silicate after 7 days/XRD figure spectrum (sulfate hemihydrate calcium content: 40%wt.%) when the half-H 2 O calcium sulphate curedcomposite material soaks 4 days in SBF; Liquid-solid ratio=1.2:1.

Fig. 4 maintenance dicalcium silicate after 7 days/surface topography (sulfate hemihydrate calcium content: 40wt.%) when the half-H 2 O calcium sulphate cured composite material soaks 4 days in SBF; Liquid-solid ratio=1.2:1; Fig. 4-A, 5000 times of amplifications; Fig. 4-B, 30000 times of amplifications.

Fig. 5 maintenance dicalcium silicate after 7 days/half-H 2 O calcium sulphate cured composite material soaks the degradability curve in Ringer ' s solution; Liquid-solid ratio=1.2:1.

The specific embodiment

Further illustrate content of the present invention below in conjunction with example, but these examples do not limit the scope of the invention, all technology that realizes based on foregoing of the present invention and the material of preparation all belong to protection scope of the present invention.

Embodiment 1

1) distiller liquor preparation

Take by weighing 1.0g analytical pure sodium bicarbonate and be dissolved in the sodium bicarbonate solution that obtains 1.0wt.% in the 99.0mL deionized water, sterilization is enclosed in the sterilized bottle, and is standby.

2) preparation of the compound self-curing material of dicalcium silicate/half-H 2 O calcium sulphate:

Be dicalcium silicate/half-H 2 O calcium sulphate composite powder of 30wt.% and distiller liquor in liquid-solid mass ratio with the sulfate hemihydrate calcium content be that the ratio of 1.2:1 fully is in harmonious proportion 0.5-1 minute, promptly obtain can be used for the compound self-curing material of dicalcium silicate/half-H 2 O calcium sulphate of minimally-invasive treatment.This self-curing material can promptly reach initial set in the injection defect about 20 minutes, the self-curing material slurry is injectable in 15 minutes, self-curing material comprcssive strength can reach 9.6 ∽ 36.0MPa, and degradation rate has good biological activity simultaneously more than 60% after 21 days.

Embodiment 2

1) distiller liquor preparation

2) preparation of the damaged packing material of the compound bone of dicalcium silicate/half-H 2 O calcium sulphate:

Be dicalcium silicate/half-H 2 O calcium sulphate composite powder of 60wt.% and distiller liquor in liquid-solid mass ratio with the sulfate hemihydrate calcium content be that the ratio of 1.2:1 fully is in harmonious proportion 0.5-1 minute, inject mould, maintenance is moved back dicalcium silicate/half-H 2 O calcium sulphate composite bead or sequin (C that mould promptly obtains being used for the damaged filling of bone more than 7 days afterwards under 37 ℃ and 100% damp condition₂S/plaster Pellets).The comprcssive strength of this bead or sequin can reach 7.0 ∽ 9.0MPa, and degradation rate can reach more than 80% after 21 days, has good biological activity simultaneously.

Embodiment 3

1) preparation of distiller liquor

With simulated body fluid as distiller liquor, the ion concentration of simulated body fluid such as table 2 (pH=7.25-7.4):

Table 2

Ionic species	Na⁺	K⁺	Mg²⁺	Ca²⁺	Cl^-	HCO₃^-	HPO₄^2-
Ionic species	Na⁺	K⁺	Mg²⁺	Ca²⁺	Cl^-	HCO₃^-	HPO₄^2-	Ion concentration (mmol/L)	142.0	5.0	1.5	2.5	148.8	4.2	1.0

2) preparation of dicalcium silicate/half-H 2 O calcium sulphate composite degradable material

Be dicalcium silicate/half-H 2 O calcium sulphate composite powder of 5-95wt.% and distiller liquor in liquid-solid mass ratio with the sulfate hemihydrate calcium content be that the ratio of 0.8-1.2:1 fully is in harmonious proportion 0.5-1 minute, inject mould, maintenance is moved back dicalcium silicate/half-H 2 O calcium sulphate composite bead (C that mould promptly obtains being used for the damaged filling of bone more than 7 days afterwards under 37 ℃ and 100% damp condition₂S/plaster Pellets).The comprcssive strength of this bead can reach 7.3 ∽ 37.2MPa, and degradation rate can reach more than 60% after 21 days, has good biological activity simultaneously.

Embodiment 4

1) preparation of distiller liquor

Gelatin (Gelatin) is dissolved in fully by the concentration of 0.1g/ml in 40 ℃ the deionized water, promptly obtains aqueous gelatin solution as distiller liquor.

2) preparation of the compound self-curing material of dicalcium silicate/half-H 2 O calcium sulphate

Be dicalcium silicate/half-H 2 O calcium sulphate composite powder of 5-95wt.% and distiller liquor in liquid-solid mass ratio with the sulfate hemihydrate calcium content be that the ratio of 1.0-1.2:1 fully is in harmonious proportion 0.5-1 minute, promptly obtain can be used for the dicalcium silicate/half-H 2 O calcium sulphate/gelatin-compounded self-curing material of minimally-invasive treatment.This self-curing material can promptly reach initial set in the injection defect about 20 minutes, the self-curing material slurry is injectable in 15 minutes, self-curing material comprcssive strength can reach 7.0 ∽ 36.0MPa, and degradation rate has good biological activity simultaneously more than 60% after 21 days.

Reference example (1,2,3,4) to the elaboration of the compound self-curing material performance of dicalcium silicate/half-H 2 O calcium sulphate, user can be adjusted the mass ratio of the content of half-H 2 O calcium sulphate in dicalcium silicate/half-H 2 O calcium sulphate composite powder and distiller liquor and composite powder to reach the therapeutic effect of the best according to different clinical needs and in this description.

Claims

1, composite self-curing material of dicalcium silicate, it is characterized in that the pastel formed by distiller liquor and dicalcium silicate/half-H 2 O calcium sulphate, the mass ratio of distiller liquor and dicalcium silicate/half-H 2 O calcium sulphate is 0.5-1.5:1, selected distiller liquor be in deionized water, simulated body fluid, inorganic salt solution or the organic solution any one.

2, by the described composite self-curing material of dicalcium silicate of claim 1, it is characterized in that dicalcium silicate/half-H 2 O calcium sulphate composite granule mesosilicic acid two calcium contents 5-95wt.%.

3, by the described composite self-curing material of dicalcium silicate of claim 1, the particle diameter that it is characterized in that dicalcium silicate is 1-300 μ m.

4, by the described composite self-curing material of dicalcium silicate of claim 1, the particle diameter that it is characterized in that half-H 2 O calcium sulphate is 1-300 μ m.

5, by claim 1 or 2 or 3 or 4 described composite self-curing material of dicalcium silicate, it is characterized in that inorganic salt as distiller liquor be in carbonate, calcium chloride or the phosphate any one.

6, by claim 1 or 2 or 3 or 4 described composite self-curing material of dicalcium silicate, it is characterized in that organic solution as distiller liquor be in gelatin, chitosan or the hyaluronic acid solution any one

7, the preparation method of composite self-curing material of dicalcium silicate comprises the steps:

(1) be that 5-95wt.% carries out mechanical mixture with two kinds of powder body of dicalcium silicate/half-H 2 O calcium sulphate by dicalcium silicate content, incorporation time was controlled at 2-6 hour;

(2) be that the ratio of 0.5-1.5:1 fully is in harmonious proportion 0.5-1 minute with above-mentioned synthetic dicalcium silicate/half-H 2 O calcium sulphate composite granule and distiller liquor in liquid-solid mass ratio.

8, composite self-curing material of dicalcium silicate is used for the tissue defect repair.