CN102133429A - Method for in-situ preparing nanometer hydroxyapatite/natural polymer composite material - Google Patents
Method for in-situ preparing nanometer hydroxyapatite/natural polymer composite material Download PDFInfo
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Abstract
The invention discloses a method for in-situ preparing nanometer hydroxyapatite/natural polymer composite materials. The method comprises the following steps: firstly, adding HA (Hyaluronic Acid) into water, stirring to form lacte suspension, adding HNO3 drop by drop until the HA is dissolved completely, regulating the PH value to be 1-3 to obtain liquid A; secondly, dissolving natural polymer into HNO3 solution to obtain liquid B; thirdly, under the stirring, pouring the liquid A into the liquid B and mixing uniformly; and stirring continuously under the temperature being 4-40 DEG C, simultaneously regulating the pH value of the mixture to be 11-13 so as to form white gel, and conducting aging process on the white gel, and then freezing the white gel to be dry, thus obtaining the nanometer hydroxyapatite/natural polymer composite materials. In the method, the reaction time is short, the mineralization speed is quick, the reaction condition is moderate, and the mechanical strength of the hydroxyapatite/natural polymer composite material is obviously enhanced.
Description
Technical field
The present invention relates to field of biomedical materials, be specifically related to a kind of method of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material.
Background technology
Human body hard tissue (as bone and tooth) is a kind of organic/inorganic nano hybrid, and inorganic matter wherein mainly is nano-grade hydroxy apatite (HA).Therefore, from bionic angle, the hard tissue material that research has " bionic structure " is the important directions of current biomedical material development.
Biomineralization is template based on bionical principle with the macromole, induces the growth of mineral crystal by self assembly or self-organizing, duplicates the nano combined and gradient-structure of natural bone tissue.It mainly is simulated body fluid mineralising method, hydrosol method, coprecipitation and emulsion process etc. that present external mineralising prepares the HA composite process, but these mineralising methods all are the outer surface formation one deck mineralized layers at material, differ greatly with the natural bone tissue form.Mineralising in the nature bone has two important step, at first be that free phosphoric acid calcium salt and nanometre collagen are compound, the fixed amorphous state calcium phosphate of the macromolecular material of this liquid state (ACP) is adsorbed in procollagen and the space then, as deposition, dimension and the structure of the precursor of HA regulation and control calcium phosphate, finally form the complex of degree of depth mineralising.
Polysaccharide such as natural macromolecular material such as chitin, chitosan and derivant thereof, collagen, sodium alginate and albumen are organic principles main in the occurring in nature bioplex, play an important role in biomineralization as macromolecular template, and it provides the molecular recognition point of height with the interaction between the inorganic mineral crystal.And therefore these materials are that macromolecular template carries out the effective ways that biomineralization is the simulation natural tissues with the natural macromolecular material owing to have excellent biological compatibility and biodegradability etc. are subjected to numerous researcheres in Tissue Engineering Study favor.
Summary of the invention
Primary and foremost purpose of the present invention is to overcome the shortcoming of prior art with not enough, the method of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material that a kind of response time is short, mineralization velocity is fast, reaction condition is gentle is provided, this method is that calcium phosphorus source provides accurate calcium-phosphorus ratio (1.67) with HA, with the natural macromolecular material is the macromole host material, in sour environment, form homogeneous phase solution, change mutually by Sol-Gel, with " bottum-up " mode in-situ construction nanometer HA/ natural polymer composite porous support material.
Another object of the present invention provides the composite that said method obtains, and this composite is porous matrix material with the natural macromolecular material, and its inside has nanometer hydroxyapatite with the surface through mineralising.
A further object of the present invention is to provide the application of above-mentioned composite.
Purpose of the present invention is achieved through the following technical solutions:
A kind of method of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material may further comprise the steps:
(1) nanometer hydroxyapatite (HA) is added to the water, stirs and make its formation milk-white coloured suspension, dropwise add HNO
3Dissolve fully to HA, regulate its pH to 1-3, obtain A liquid;
(2) natural macromolecular material is dissolved in HNO
3Solution obtains B liquid;
(3) under agitation A liquid is poured in the B liquid into mix homogeneously; Mixed liquor constantly stirs down at 4-40 ℃, regulates pH value simultaneously to 11-13, forms white gels, and this moment, inorganic matter formed synthos (being called mineralization process), and ageing is handled again, and lyophilizing then obtains nanometer hydroxyapatite/natural high molecular composite material.
In the step (1), the concentration of nanometer hydroxyapatite is 0.1-0.75g/100mL in the A liquid; Described adjusting pH to 2;
In the step (2), the concentration of natural macromolecular material is 1-7g/100mL in the B liquid;
The described HNO of step (2)
3The volumetric concentration of solution is 1%;
In the step (3), the mass ratio of nanometer hydroxyapatite and natural macromolecular material is 1: 2-1: 4;
It is that white gels with gained places under 40-70 ℃ (preferred 60 ℃) and leaves standstill 4-8h that the described ageing of step (3) is handled;
Described natural macromolecular material comprises chitin, chitosan, collagen, polypeptide, sodium alginate, protein etc. and derivant and complex;
In said method, mineralising is carried out under the weak base condition, and described pH value is respectively 11-13.
In said method, adding HA is for accurate calcium-phosphorus ratio (1.67) is provided in mineralization process.
By nanometer hydroxyapatite/natural high molecular composite material that method for preparing obtains, therefore nanometer hydroxyapatite and natural macromolecular material mix homogeneously can reach degree of depth mineralising.The compressive strength of material is 50-80Mpa, satisfies the clinical requirement of non-weight bearing area.
Nanometer hydroxyapatite/the natural high molecular composite material that is obtained by method for preparing can be used as engineering material of bone tissue.
Ultimate principle of the present invention is as follows:
When system pH greater than 6 the time, natural macromolecular materials such as chitosan, collagen can be precipitated out from its solution, natural polymer and Ca
2+Complexing power is stronger, can form macromolecule-metallo-chelate, and when pH value was 9-11, complexing power was the strongest.So in alkaline solution, in coprecipitation process, natural polymer and calcium ion generation complex reaction, making HA is the avtive spot growth with natural polymer Semi-polarity group, this has just effectively overcome HA problem pockety in matrix, and nanometer HA is evenly adhered on natural polymer, form effective hybrid composite.
The present invention has following advantage and effect with respect to prior art:
(1) preparation method response time weak point of the present invention, mineralization velocity is fast.According to producing gel immediately, natural polymer and phosphate symbiosis behind the inventive method adding ammonia adjusting pH value.The ageing processing can promote that phosphate transfection turns to hydroxyapatite crystal, and prolongs with digestion time, and hydroxyapatite crystal is grown up gradually.
(2) natural polymer and hydroxyapatite symbiosis.In alkaline solution, in coprecipitation process, natural polymer and calcium ion generation complex reaction, making HA is the avtive spot growth with natural polymer Semi-polarity group, this phosphate is combining of molecule aspect with chitosan, not only make natural polymer submounts surfaces externally and internally cover with phosphate, the timbering material of gained is the homogeneous material of a kind of phosphate and chitosan " symbiosis ".
(3) reaction system mild condition.Reaction medium is a dilute nitric acid solution in the inventive method, and pH is regulated by ammonia, and is harmless to natural polymer.The codeposition process is at room temperature carried out, and ageing process carries out under 60 ℃, can not cause the degraded and the degeneration of material; The pH value of system is alkalescence, also can not cause the degraded and the dissolving of material.
(4) reaction method and reaction system operation and control easily.Related chemical reagent is common reagent in the inventive method, obtains easily; Whole operation process simple possible.
(5) cost is low.All related in the inventive method reagent are common chemical reagent, and are cheap; And the entire reaction condition is relatively gentleer, has avoided the input of high-energy source.
(6) the hybrid compound support frame material that obtains of the present invention, not only in preparation process, make up the supporting structure that portals, and mineralising forms the nanometer hydroxyapatite crystallization and combines with natural macromolecular material closely, not only all deposit fine and close mineralized layer on the inside and outside surface of timbering material, and also formed the hybrid composite of homogenizing in the inside of support, so the mechanical strength of material significantly strengthens.
Description of drawings
Fig. 1 is the XRD figure of HA/CS (1/4) compound rest of different ageing preparation under the pH=11; Wherein: (a)-(d) be respectively ageing 0,4,8 and 12h; (e) pure HA; (f) pure CS.
Fig. 2 is the pH=11 SEM photo of the HA/CS compound rest of preparation down; Wherein: (a1) pure CS support, 100 *; (a2) ageing 0h, 40000 *; (b1) ageing 4h, 200 *; (b2) ageing 4h, 10000 *; (c1) ageing 8h, 600 *; (c2) ageing 8h, 10000 *; (d1) ageing 12h, 500 *; (d2) ageing 12h, 10000 *.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment and accompanying drawing, but embodiments of the present invention are not limited thereto.
Embodiment 1: the preparation of nanometer hydroxyapatite/chitosan (HA/CS) composite
The HA powder is added in the deionized water, and it is the 0.75g/100mL milk-white coloured suspension that high-speed stirred forms HA concentration, dropwise adds HNO
3Dissolve fully to HA, dropping ammonia is regulated pH to 3 again, obtains A liquid.According to the HA/CS mass ratio is that 1/4 ratio takes by weighing chitosan (CS) powder, and it is dissolved in 1% HNO
3Aqueous solution, continuous stirring obtains transparent chitosan solution fully after the filtration, be B liquid.Under magnetic agitation, A liquid is slowly poured in the B liquid into mix homogeneously.Under 40 ℃, mixed liquor dropwise adds ammonia under vigorous stirring to regulate pH value be 11 to form white gels, and ageing (under 70 ℃) 4h, is washed till neutral and secondary lyophilizing at lyophilizing then, obtains porous compound support frame material.
Prepared nanometer hydroxyapatite/chitosan compound support frame material is tested and analyzed.
Nanometer hydroxyapatite/chitosan composite is made 5.0mm * 5.0mm * 5.0mm sample, on Tianjin, island universal testing machine (AG-1), carry out the compressive strength test, loading velocity 5mm/min, compressive strength is the data of 50% o'clock gained of distortion, its compressive strength and modulus of compressibility are respectively 59.3 ± 0.045KPa and 148.25 ± 0.112KPa, and (compressive strength and modulus of compressibility are respectively 39.1 ± 0.073KPa and 97.75 ± 0.183KPa) to be higher than the pure chitosan mechanical strength far away.
The XRD of nanometer hydroxyapatite/chitosan composite characterizes as Fig. 1, and (Fig. 1 a) the crystalline phase composition of sample had multiple synthos when ageing was not handled.(Fig. 1 b) was converted into the HA with certain degree of crystallinity when digestion time was 4h.
SEM photo such as Fig. 2 of nanometer hydroxyapatite/chitosan compound rest change mutually and the ageing processing obtains the porosity height, and the porous support that hole is more regular circle and runs through mutually helps the discharge of cell migration, nutrition transmission and metabolite.During digestion time 4h (Fig. 2 b1,2b2), the hole of support is more even, and hole wall is thinner, along with the prolongation of digestion time, and hole wall thickening, the regularity variation of support.
Embodiment 2: the preparation of nano hydroxyapatite/collagen (HA/COL) composite
The HA powder is added in the deionized water, and it is the 0.5g/100mL milk-white coloured suspension that high-speed stirred forms HA concentration, dropwise adds HNO
3Dissolve fully to HA, dropping ammonia is regulated pH to 1 again, obtains A liquid.According to the HA/COL mass ratio is that 1/2 ratio takes by weighing collagen (COL), and it is dissolved in 1% HNO
3Aqueous solution is B liquid.Under magnetic agitation, A liquid is slowly poured in the B liquid into mix homogeneously.Under 4 ℃, stir and dropwise to add ammonia down to regulate pH value be 12 to form white gels, ageing (under 40 ℃) 5h, is washed till neutral and secondary lyophilizing at lyophilizing then, obtains porous nano hydroxyapatite/collagen (HA/COL) composite.
Utilize above-mentioned method of testing to test and analyze to nano hydroxyapatite/collagen (HA/COL) composite, its compressive strength and modulus of compressibility are respectively 55.6 ± 0.321KPa and 132.63 ± 0.214KPa, and (compressive strength and modulus of compressibility are respectively 25.6 ± 0.021KPa and 80.0 ± 0.035KPa) far above pure collagen mechanical strength.
Scanning electron microscopic observation, the porosity of material is higher, macropore diameter average out to 150 μ m, hole wall is thinner, and layer mineral combines closely with collagen.
Embodiment 3: the preparation of nanometer hydroxyapatite/sodium alginate composite (HA/SA)
The HA powder is added in the deionized water, and it is the 0.1g/100mL milk-white coloured suspension that high-speed stirred forms HA concentration, dropwise adds HNO
3Dissolve fully to HA, dropping ammonia is regulated pH to 2 again, obtains A liquid.According to the HA/SA mass ratio is that 1/3 ratio takes by weighing sodium alginate (SA), and it is dissolved in 1% HNO
3Aqueous solution is B liquid.Under magnetic agitation, A liquid is slowly poured in the B liquid into mix homogeneously.Under 20 ℃, stir and dropwise to add ammonia down to regulate pH value be 13 to form white gels, ageing (under 60 ℃) 8h, is washed till neutral and secondary lyophilizing at lyophilizing then, obtains porous nano hydroxyapatite/sodium alginate composite (HA/SA) composite.
Utilize above-mentioned method of testing to test and analyze to nanometer hydroxyapatite/sodium alginate composite (HA/SA), its compressive strength and modulus of compressibility are respectively 78.6 ± 0.0.521KPa and 194 ± 0.123KPa, and (compressive strength and modulus of compressibility are respectively 65.1 ± 0.012KPa and 124 ± 0.201KPa) to be higher than pure sodium alginate gel mechanical strength.
Scanning electron microscopic observation, the porosity of material is higher, macropore diameter average out to 148 μ m, hole wall is thinner, and layer mineral combines closely with collagen.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (8)
1. the method for an in-situ preparing nanometer hydroxyapatite/natural high molecular composite material is characterized in that may further comprise the steps:
(1) nanometer hydroxyapatite is added to the water, stirs and form milk-white coloured suspension, dropwise add HNO
3Dissolve fully to nanometer hydroxyapatite, regulate its pH value, obtain A liquid to 1-3;
(2) natural macromolecular material is dissolved in HNO
3Solution obtains B liquid;
(3) stirring is poured A liquid in the B liquid into mix homogeneously down; Mixed liquor constantly stirs down at 4-40 ℃, regulates pH value simultaneously to 11-13, forms white gels, and ageing is handled again, and lyophilizing then obtains nanometer hydroxyapatite/natural high molecular composite material.
2. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1, it is characterized in that: the concentration of nanometer hydroxyapatite is 0.1-0.75g/100mL in the described A liquid of step (1); Described pH value is 2.
3. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1, it is characterized in that: the described HNO of step (2)
3The volumetric concentration of solution is 1%.
4. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1, it is characterized in that: the mass ratio of described nanometer hydroxyapatite and natural macromolecular material is 1: 2-1: 4.
5. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1, it is characterized in that: it is that white gels is left standstill 4-8h under 40-70 ℃ that the described ageing of step (3) is handled.
6. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 5, it is characterized in that: it is that white gels is left standstill 4-8h under 60 ℃ that the described ageing of step (3) is handled.
7. according to the method for the described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1, it is characterized in that: described natural macromolecular material is a kind of in chitin, chitosan, collagen, polypeptide or the sodium alginate.
8. nanometer hydroxyapatite/natural high molecular composite material of preparing of the method for each described a kind of in-situ preparing nanometer hydroxyapatite/natural high molecular composite material of claim 1-7.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784757A (en) * | 2015-04-15 | 2015-07-22 | 华中科技大学 | Nano-apatite composite material and preparation method thereof |
| CN110339403A (en) * | 2019-07-15 | 2019-10-18 | 四川大学 | Spherical nano hydroxyapatite/natural polymer biomimetic scaffolds and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1654543A (en) * | 2005-01-27 | 2005-08-17 | 浙江大学 | Biodegradable calcium phosphate/collagen composite materials for medical use and method for preparation thereof |
| CN1799647A (en) * | 2005-12-13 | 2006-07-12 | 天津大学 | Nanometer hydroxyapatite/chitosan/gelatin porous scaffold material and preparation method thereof |
| CN101032430A (en) * | 2007-04-13 | 2007-09-12 | 中国人民解放军第三军医大学第一附属医院 | Method for preparing integrated frame fabrication of cartilage of tissue-engineered bone having function interface |
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- 2011-03-22 CN CN2011100691472A patent/CN102133429A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1654543A (en) * | 2005-01-27 | 2005-08-17 | 浙江大学 | Biodegradable calcium phosphate/collagen composite materials for medical use and method for preparation thereof |
| CN1799647A (en) * | 2005-12-13 | 2006-07-12 | 天津大学 | Nanometer hydroxyapatite/chitosan/gelatin porous scaffold material and preparation method thereof |
| CN101032430A (en) * | 2007-04-13 | 2007-09-12 | 中国人民解放军第三军医大学第一附属医院 | Method for preparing integrated frame fabrication of cartilage of tissue-engineered bone having function interface |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784757A (en) * | 2015-04-15 | 2015-07-22 | 华中科技大学 | Nano-apatite composite material and preparation method thereof |
| CN110339403A (en) * | 2019-07-15 | 2019-10-18 | 四川大学 | Spherical nano hydroxyapatite/natural polymer biomimetic scaffolds and preparation method |
| CN110339403B (en) * | 2019-07-15 | 2020-06-12 | 四川大学 | Spherical nano hydroxyapatite/natural polymer bionic scaffold and preparation method thereof |
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Application publication date: 20110727 |