CN101864153B - Biodegradable material and preparation method and application thereof - Google Patents
Biodegradable material and preparation method and application thereof Download PDFInfo
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- CN101864153B CN101864153B CN200910049605.9A CN200910049605A CN101864153B CN 101864153 B CN101864153 B CN 101864153B CN 200910049605 A CN200910049605 A CN 200910049605A CN 101864153 B CN101864153 B CN 101864153B
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Abstract
The invention discloses a biodegradable material and a preparation method and application thereof. The biodegradable material comprises a degradable polyester macromolecular material and sodium polyphosphate; the molar ratio of corresponding monomer polymers of the degradable polyester macromolecular material and the sodium polyphosphate is 1:1-0.01; and the sodium polyphosphate is shown in a formula I, wherein n is more than or equal to 3, and is an integer.
Description
Technical field
The material that the present invention relates to synthetic, relates in particular to a kind of Biodegradable material and its production and use.
Background technology
Degradable polyester family macromolecule material is due to its good biocompatibility and suitable degradation rate, can be processed into that timbering material is applied to organizational project or as drug release carrier (excipient substance) and medical operation suture.For example, polyglycolic acid wherein, have another name called polyglycolic acid or PGA (polyglycolic acid, have another name called polyglycolide, PGA) successfully apply in the world at present PGA timbering material and successfully built in vitro and in vivo respectively the Various Tissues such as cartilage, tendon, skin, cornea, blood vessel.Especially in the structure of tendon and cartilage, with PGA staple fibre, at nude mice by subcutaneous, constructed tendon from tissue engineering sample tissue, in the model of chicken, construct again subsequently the tendon tissue with good biological mechanical property, sight and histological structure and biomechanical strength all approach normal tendon tissue substantially for they.Same timbering material has also constructed and has had the tissue engineering muscle tendinous tissue of biomechanical property and repair damaged accordingly in the model of pig.Ripe cartilaginous tissue also can successfully build in vitro by PGA in conjunction with mesenchymal stem cells MSCs (Bone Marrow StromalCells, BMSC), and can be in order to repair the cartilage defect in non-heavy burden district, pig joint; Or with PGA and autologous chondrocyte, build cartilaginous tissue, damaged in order to repair the full thick-layer of pig joint cartilage.
Yet, in above tissue construction process, several serious scientific phenomenas that cause because of this class material degradation have been there are, especially the material such as PGA, because its degradation speed is relatively very fast, the phenomenon of embodiment is more outstanding: (1) is in tendon builds, because the degradation production after material degradation is acid, if cannot discharge in time, the mixture that can cause cell and material causes aseptic inflammation reaction after in implantable bioartificial body.Thereby cause cicatrization and adhesion of tendon, therefore directly affected the repairing effect of tendon; (2) in the structure of cartilage, the seed cell of bone marrow stroma stem cell or other types and PGA mixture are in forming pseudocartilage tissue process, the accumulation due to acid product after material degradation often can be observed in centre, cannot discharge in time, cause the large-scale necrocytosis in central section, finally form the tissue block of hollow.The material disintegration that acid degradation product causes is one of principal element causing this phenomenon.In addition, also have in the world apparatus that relevant report points out PGA or PLA class in clinical study, the later stage often causes the Inflammatory response of organism to foreign object.
The people such as Hurrell once mentioned and used CaCO
3particle is sneaked in poly(lactic acid) (polylactic acid, PLA) support, in coming and the acid forming in degradation process, has alleviated to a certain extent acid autocatalysis and the disintegration phenomenon that causes.But on the one hand the existence of Ca, unfavorable to some tissue construction, cartilage especially, can affect the differentiation direction of seed cell; On the other hand, CaCO
3neutralization very weak, and effect cannot maintain, and discharges comparatively fast, cannot all play a role in the whole process of degraded, and after discharging because its solubleness is very low, be difficult to mediate.
Therefore, this area method of effectively controlling the acid degradation problem of this class material in the urgent need to address, especially needs to provide the new Biodegradable material for cell characteristics and particular organization's construct in vitro process.
Summary of the invention
The present invention aims to provide a kind of Biodegradable material.
Another object of the present invention is to provide the preparation method of described Biodegradable material.
The 3rd object of the present invention is to provide the purposes of described Biodegradable material.
The 4th object of the present invention is to provide the purposes of sodium polyphosphate.
In a first aspect of the present invention, a kind of Biodegradable material is provided, described Biodegradable material contains degradable polyester family macromolecule material and sodium polyphosphate; The corresponding polymer monomer mol ratio of described degradable polyester family macromolecule material and sodium polyphosphate is 1: 1-0.01; Described sodium polyphosphate is suc as formula shown in I:
formula I
Wherein n >=3, are integers.
In another preference, described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid, poly-acid anhydrides (polyanhydrides), poe (polyorthoesters) or polycarbonate (polycarbonate).
In another preference, described poly-alpha hydroxy acid is selected from poly(lactic acid) (PLA), polyglycolic acid (PGA), poly(lactic acid)/ethanol copolymer (PLGA) or polyhydroxybutyrate (PHB).
In another preference, the corresponding polymer monomer mol ratio of described degradable polyester family macromolecule material and sodium polyphosphate is 1: 1-0.1; Be preferably 1: 1-0.5; Be more preferably 1: 0.5-0.1.
In a second aspect of the present invention, a kind of preparation method of Biodegradable material as above is provided, described method comprises step:
(1) solution that contains polyester macromolecular material and the solution that contains sodium polyphosphate are evenly mixed, obtain mixing solutions; With
(2), by mixing solutions lyophilize, obtain Biodegradable material as above;
In described mixing solutions, the corresponding polymer monomer mol ratio of degradable polyester family macromolecule material and sodium polyphosphate is 1: 1-0.01; Described sodium polyphosphate is suc as formula shown in I:
formula I
Wherein n >=3, are integers.
In another preference, described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid, poly-acid anhydrides (polyanhydrides), poe (polyorthoesters) or polycarbonate (polycarbonate); Described poly-alpha hydroxy acid is selected from poly(lactic acid) (PLA), polyglycolic acid (PGA), poly(lactic acid)/ethanol copolymer (PLGA) or polyhydroxybutyrate (PHB).
In another preference, described method comprises step:
(a) Powdered polyglycolic acid or Powdered poly(lactic acid)/ethanol copolymer and Powdered sodium polyphosphate are evenly mixed, obtain mixed powder; With
(b) by mixed powder at 207-220 ℃ of melting 3-10 minute, obtain Biodegradable material as above;
In described mixed powder, the corresponding polymer monomer mol ratio of degradable polyester family macromolecule material and sodium polyphosphate is 1: 1-0.01; Described sodium polyphosphate is suc as formula shown in I:
formula I
Wherein n >=3, are integers.
In a third aspect of the present invention, a kind of purposes of Biodegradable material as above is provided, and described Biodegradable material is as the timbering material of tissue engineered implant, for the preparation of tissue engineered implant, for the preparation of sutures or for the preparation of the solid support material (excipient substance) of drug release.
In another preference, described tissue engineered implant comprises cartilage graft, tendon graft, blood vessel graft, corneal graft and skin graft.
In a fourth aspect of the present invention, provide a kind of purposes of sodium polyphosphate, the acidity that described sodium polyphosphate is used for and degradable polyester family macromolecule material produces in degradation process; Described sodium polyphosphate is suc as formula shown in I:
formula I
Wherein n >=3, are integers;
Described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid, poly-acid anhydrides (polyanhydrides), poe (polyorthoesters) or polycarbonate (polycarbonate).
Accordingly, technical scheme provided by the invention has been controlled the acid degradation problem of macromolecular material effectively, and the new Biodegradable material for cell characteristics and particular organization's construct in vitro process is especially provided.
Accompanying drawing explanation
Fig. 1 has shown the dsc analysis result of PGA.
Fig. 2 has shown that PGA and sodium polyphosphate mix a kind of cardinal principle pattern of rear compressing tablet material.
Fig. 3 shown in embodiment 2 PGA compressing tablet material is placed in to PBS solution solution pH value over time.
Fig. 4 shown in embodiment 3 PGA compressing tablet material is placed in to nutrient solution (DMEM) solution pH value over time.
Fig. 5 has shown that in embodiment 4, PGA compressing tablet material is implanted the histology changing conditions after 2 weeks; Wherein
G is cardinal principle situation; A, B, C and D are the situations at a, b, c and the d position observed respectively under high power lens; A is healthy tissues position, and b is tissue and material interface, and c is material internal, and d is material and organizational interface;
Fig. 5 (I) is the situation of independent PGA, and Fig. 5 (II) is the situation of the compressing tablet material that obtains after PGA and STP mix, and Fig. 5 (III) is the situation of the compressing tablet material that obtains after PGA and SPP mix, and Fig. 5 (IV) is the situation of independent PGA.
Fig. 6 has shown that in embodiment 4, PGA compressing tablet material is implanted the histology changing conditions after 4 weeks; Wherein
G is cardinal principle situation; A, B, C and D are the situations at a, b, c and the d position observed respectively under high power lens; A is healthy tissues position, and b is tissue and material interface, and c is material internal, and d is material and organizational interface;
Fig. 6 (I) is the situation of independent PGA, and Fig. 6 (II) is the situation of the compressing tablet material that obtains after PGA and STP mix, and Fig. 6 (III) is the situation of the compressing tablet material that obtains after PGA and SPP mix, and Fig. 6 (IV) is the situation of independent PGA.。
Embodiment
Contriver is through extensive and deep research, being surprised to find that can be by degradable polyester family macromolecule material and sodium polyphosphate (sodium polyphosphate, SPP) be mixed to form a kind of new Biodegradable material, wherein sodium polyphosphate has good biocompatibility as modified material, it neutralizes the acidic-group that degradable polyester family macromolecule material degradation produces when discharging, effectively by the liquid stable in medium within the scope of certain pH value.
For the solvent that can dissolve PGA, there are hypertoxic Special Circumstances, contriver has also creatively taked a kind of blend and the method for melting-pulverizing repeatedly, effectively sodium polyphosphate is mixed in PGA material equably, thereby form new Biodegradable material provided by the invention.
Definition
As used herein, " degradable polyester family macromolecule material " refers to the Biodegradable material that can expose C-terminal after a kind of ester linkage hydrolyzing.Such as but not limited to, poly-alpha hydroxy acid, poly-acid anhydrides (polyanhydrides), poe (polyorthoesters) and polycarbonate (polycarbonate); Described poly-alpha hydroxy acid is selected from poly(lactic acid) (PLA), polyglycolic acid (PGA), poly(lactic acid)/ethanol copolymer (PLGA) or polyhydroxybutyrate (PHB); Preferably GA content >=50% (monomer mole ratio), more preferably GA content >=75% in described PLGA.
Polyglycolic acid (PGA) structural formula is
shown in II:
formula II
As used herein, " sodium polyphosphate " refers to suc as formula the material shown in I:
formula I
Wherein n >=3, are integers; Preferably n is 3,4,5,6,7,8,9 or 10.
As used herein, " Tri sodium Phosphate (sodium triphosphate, STP) " molecular formula Na
5o
10p
3, molecular weight 368, structural formula is as shown in formula III:
formula III
As used herein, " mixing solutions " refers to and will be dissolved with the solution of degradable polyester family macromolecule material and be dissolved with the solution that the solution phase of sodium polyphosphate is mixed to get, and the volume ratio of two kinds of solution that mix is mutually 10: 1-30: 1; Preferably 30: 1.The solvent that dissolves degradable polyester family macromolecule material is selected from but is not limited to following: trichloromethane, ethyl acetate, tetrahydrofuran (THF), dimethyl formamide; The solvent that dissolves sodium polyphosphate is water.
As used herein, " mixed powder " refers to Powdered polyglycolic acid (PGA) or Powdered poly(lactic acid)/ethanol copolymer and the resulting powdery substance of the even mixing of Powdered sodium polyphosphate.。
Biodegradable material
The invention provides a kind of Biodegradable material, it contains degradable polyester family macromolecule material and sodium polyphosphate, and both corresponding polymer monomer mol ratios are 1: 1-0.01 is preferably 1: 1-0.1; Be more preferably 1: 0.5-0.1.
In the preferred a kind of Biodegradable material of the present invention, containing PGA or PLGA and sodium polyphosphate, is more preferably to contain PGA and sodium polyphosphate; The corresponding polymer monomer mol ratio of PGA and sodium polyphosphate is 1: 1-0.01 is preferably 1: 1-0.1; Be more preferably 1: 1-0.5 is 1: 0.5-0.1 best.
In another preferred embodiment of the present invention, a kind of Biodegradable material is provided, wherein contain PGA or PLGA and Tri sodium Phosphate, more preferably contain PGA and Tri sodium Phosphate; The corresponding polymer monomer mol ratio of PGA and Tri sodium Phosphate is 1: 1-0.01 is preferably 1: 1-0.1,1: 1-0.5; Be more preferably 1: 0.5-0.1; Be 1 best: 0.5-0.2.
The shape of Biodegradable material provided by the invention has no particular limits, and its end-use can be block, fibrous, Powdered, also can be according to using the required shape needing that is processed as.
Preparation method
Biodegradable material provided by the invention can prepare by following step:
(1) solution that contains polyester macromolecular material and the solution that contains sodium polyphosphate are mixed, and high-speed stirring (30,000rpm) obtain mixing solutions; With
(2), by mixing solutions lyophilize, obtain Biodegradable material provided by the invention;
In described mixing solutions, the corresponding polymer monomer mol ratio of degradable polyester family macromolecule material and sodium polyphosphate is 1: 1-0.01.
Can be by method well known in the art, mixing solutions is dry, preferred concentrating under reduced pressure is dry, lyophilize, more preferably lyophilize.
In a preference of the present invention, described Biodegradable material can obtain by certain methods:
1. PLGA is dissolved in chloroform soln and and the aqueous solution that contains sodium polyphosphate, high-speed stirring (30,000rpm) 10 minutes, prepare water in oil mixed emulsion;
2. by mixed emulsion quick freezing (80 ℃) 24 hours, then lyophilize 48 hours, Biodegradable material provided by the invention obtained.
In another preferred embodiment of the present invention, the preparation process of the described Biodegradable material that contains PGA and sodium polyphosphate is:
1. particulate state PGA being processed into Powdered and Powdered sodium polyphosphate with pulverizer evenly mixes, dries;
2. be placed in tabletting machine at high temperature fused state lower sheeting, at 207-220 ℃, keep 3-10 minute, the time of the general low maintenance of temperature is long, and vice versa; Be preferably 210-218 ℃ and keep 4-8 minute;
3. again with repeating step 2 after pulverizing, obtain the Biodegradable material of the PGA of containing provided by the invention and sodium polyphosphate.
Purposes
Biodegradable material provided by the invention can be as the timbering material of tissue engineered implant or for the preparation of tissue engineered implant; Described tissue engineered implant comprises cartilage graft, tendon graft, blood vessel graft, corneal graft, skin graft etc.
Described tissue engineered implant can be inoculated in seed cell on Biodegradable material provided by the invention, by external structure, obtains.
The present invention also provides the purposes of sodium polyphosphate, it can in and the acidity that produces in degradation process of degradable polyester family macromolecule material.Sodium polyphosphate can be effectively by the liquid stable in medium within the scope of certain pH value, and there is good biocompatibility.Sodium polyphosphate and degradable polyester family macromolecule material are bundled together, can be within the very first time end acidic-group that discharges of neutralization materials degraded.Therefore adopt sodium polyphosphate to carry out modified degradable polyester macromolecular material, to reach the neutralization of acid degradation product and to eliminate the local inflammation reaction causing because of acidity.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms use, each feature disclosing in specification sheets, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, adopt first polymer substance sodium polyphosphate come in and the acidic substance that produce of the degradable polyester family macromolecule material degradation such as PGA;
2, adopt first the technology of blend and repeatedly melting-pulverizing that sodium polyphosphate is evenly mixed in PGA material;
3, in coming in time by the form of drug release and the acidic-group that in support, degraded produces;
4, from the modification of the degradable polyester family macromolecule materials such as PGA itself, go out to send to suppress tissue to the non-bacterial inflammation of material and suppress the material disintegration phenomenon that the acid autocatalysis of material causes first;
5, first sodium polyphosphate is applied on tissue engineering bracket material.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, the same meaning that all specialties of using in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The polyglycolic acid using in the embodiment of the present invention (PGA) and sodium polyphosphate (sodiumpolyphosphate, SPP) are bought from Sigma, and Tri sodium Phosphate (sodium triphosphate, STP) is bought from Fluka.
Embodiment 1
Prepare Biodegradable material
1.PGA solid particulate is crossed liquid nitrogen, then with pulverizer, smashes, powdered;
2.STP and SPP salt particle grind with agate mortar respectively, make original particle more tiny evenly, powdered;
3. the PGA after pulverizing and STP, or PGA and SPP evenly mix and are placed in 120 ℃, baking oven and dry 6h;
4. by mixed PGA and STP, or PGA and SPP, be placed in tabletting machine and be shaped at high temperature fused state lower sheeting, make PGA-STP and PGA-SPP round sheet material.Parameter during compressing tablet is: be pressurized to 22Mpa, be heated to 215 ℃ simultaneously, and keep pressure and temperature 5min;
5. after the PGA-STP of above preparation and PGA-SPP sheet being put into liquid nitrogen quenching, again with pulverizer, pulverize;
6. PGA-STP and PGA-SPP powdered mixture are placed in to tabletting machine compression molding again, repeating step 4, obtain Biodegradable material;
7. room temperature is cooling, the Biodegradable material obtaining is placed in to drying receptacle, cryopreservation.
Known according to means of differential scanning calorimetry (DSC) analytical results (seeing Fig. 1), the Tm=207 ℃ of PGA.Therefore in the preparation process of above-described embodiment 1, need to be higher than this melt temperature, but excess Temperature makes its oxidation and accelerated degradation, and can not maintain original disk shape.When Heating temperature reaches 220 ℃, keep 5min to make its internal and external temperature even, processing material deformation is later very serious, is unfavorable for subsequent experimental operation.When Heating temperature is 215 ℃, material melting also can be remained stationary, and therefore selects 215 ℃ to be compressing tablet processing temperature and time with 5min.
Embodiment 2
PGA external degradation experiment one
As table 1 is tested grouping:
Table 1 external degradation experiment grouping
a
| Grouping | Composition | Consumption (gram) |
| 1 | PGA | 0.16 |
| 2 | PGA+STP | 0.16+0.102 |
| 3 | PGA+SPP | 0.16+0.141 |
| 4 | PGA+NaCl 1 | 0.16+0.102 |
| 5 | PGA+NaCl 2 | 0.16+0.141 |
1with the NaCl with STP equivalent verify PGA and STP particle mix after impact on degraded.
2with the NaCl with SPP equivalent verify PGA and SPP particle mix after impact on degraded.
athe monomer mole ratio of choosing PGA monomer and STP or SPP in experiment is 1: 0.5.
The material of group 1 and 2 obtains by the method in embodiment 1; Meanwhile, change STP or SPP into NaCl salt particle, and NaCl is done to the similar processing in embodiment 1, and PGA is to prepare material with the same terms of embodiment 1, as a control group.
PGA-STP and the PGA-SPP disk of group 1 and group 2 are placed in to 75% alcohol disinfecting 25min.Then use phosphate buffer soln (phosphate buffer saline, PBS, 0.1M) to rinse, with filter paper, unnecessary water is sopped up, be then placed in the PBS of 25ml, 37 ℃ standing, by pH meter results of regular determination pH value.Every group of 3 samples.
Result
1, the outward appearance of compressing tablet material
The diameter that 1-5 organizes different PGA compressing tablet materials is 10mm, and thickness is 2-3mm, sees Fig. 2.Between simple PGA and PGA+TTP or PPS etc., without obvious, distinguish.In experiment, keeping the amount of PGA in different compressing tablet materials constant is in order to guarantee that the acid that can produce in theory equates.Due in external degradation experiment, the capacity of PBS is far away higher than material volume, and therefore acid pile up effect is not clearly, so consider the impact that the thickness difference of material and simple PGA material causes after modification.Setting up PGA+NaCl group is in order to consider in the situation that particle mixes, may promote the degraded of PGA itself, because salt particle is very easily water-soluble, once salt particle dissolves so, can increase the specific surface area of PGA compressing tablet material, therefore also just increase the area contacting with water, and increased the amount of hydrolysis reaction.The amount of the salt particle adding in this case, is how many and the aggravation situation of hydrolysis reaction is directly proportional.Namely why set up two control groups consistent with our modification experiment group respectively.
2, external degradation experiment
As shown in Figure 3, the variation of pH value from degradation experiment, can find out, the degraded of simple PGA (1 group) has made the pH value of PBS solution around drop to 6.2 left and right in first week, second week pH value straight line drop between 3.5-4, after several weeks in downtrending slow down, in the time of five weeks, be down to approximately 3.3.Sneak into without after buffering or the neutral salt particle NaCl without neutralizing acid sexuality, during (4 groups and 5 groups) its degraded, the decline of pH value further aggravates, as Fig. 3, in degraded, made pH value drop to 3.5 in first week, reduce afterwards trend mild, slow decreasing was down to 3.1 left and right in the time of five weeks.Difference between 4 groups and 5 groups is little, may be because the amount difference of the salt particle adding is too little, so that result difference not statistically significant.As sneaked into surge capability, and can to a certain degree antacid salt particle (2 groups and 3 groups), the decline of its pH value improves significantly.In first week, the pH value of 2 groups and 3 groups is down to 6.5 left and right, and simple PGA (1 group) is more not obvious than maintaining of pH value.But 3 groups of PGA+SPP groups just have the remarkable decline of pH value at degraded second day, its decline degree and 4,5 groups identical, than 1 group of simple PGA degraded pH value, decline and go back soon.2 groups tentatively show obvious pH value surge capability.At the second weekend, the pH value of 2 and 3 groups is down to respectively 5.5 and 5.2, apparently higher than 1 group of simple PGA (approximately 3.75) of the same period.When the 5th weekend, be down to 4.2 for 2 groups, and 3 groups are down to 3.4 left and right.
Result shows, the decline of pH value during the adding or be conducive to alleviate PGA material degradation of buffering salt particle sodium polyphosphate.The neutralization of the salt particle of different polymerization degree is different, the neutralization of the SPP of high-polymerization degree is inferior to the STP of low polymerization degree, may be because particle sneaks into the wetting ability that has improved PGA material during modification, the distribution of SPP in PGA compressing tablet material do not have low-molecular-weight STP even, the effect that has caused the dissolving of the salt particle on nearly surface to increase PGA specific surface area is stronger, therefore stronger to the acceleration effect of PGA degraded.Simple salt particle sneak into the degraded that can significantly aggravate PGA, if but suitably the interpolation of the buffering salt particle of type still can improve the decline situation of pH value around.
Embodiment 3
PGA external degradation experiment two
Experimental procedure, sample preparation is the same with the external degradation of embodiment 2, and the corresponding monomer mole ratio of PGA and STP is 1: 1.PGAP and the PGA-STP disk of group 1 and group 2 are placed in to 75% alcohol disinfecting 25min.Then use phosphate buffer soln (phosphate buffer saline, PBS, 0.1M) to rinse, with filter paper, unnecessary water is sopped up, be then placed in the nutrient solution (DMEM) of 25ml, 37 ℃ standing, by pH meter results of regular determination pH value.
Experimental result:
As shown in Figure 4, the variation of pH value from the degradation experiment in nutrient solution (being also will use tissue construction due to nutrient solution), can find out, the degraded of simple PGA (1 group) has made the pH value of nutrient solution around drop to 7 once at first week, second week pH value straight line drop between 3.5-4, after time in downtrending slow down, maintain about 3.3.And PGA+STP group (2 groups) maintains 8 left and right in degraded in one week, second week maintains between 7-8, within maintaining 7-6.7 afterwards in experimental period point.Simple cultivation pH value is also always more than 8.
Degradation experiment grouping in table 2 vitro culture liquid
| Grouping | Composition | Consumption (gram) |
| 1 | PGA | 0.16 |
| 2 | PGA+STP | 0.16+0.204 |
| 3 | DMEM | / |
Embodiment 4
PGA body is implanted into experiment
As table 3 is tested grouping:
Table 3 body is implanted into experiment grouping
| Grouping | Composition | Consumption |
| 1 | PGA | 0.16 |
| 2 | PGA+STP | 0.16+0.102 |
| 3 | PGA+SPP | 0.16+0.141 |
| 4 | PGA* | 0.3 |
* thickness and PGA+STP, PGA+SPP are basic identical
1, material is prepared: PGA-STP and PGA-SPP disk that the method with described in embodiment 1 is obtained are placed in 75% alcohol disinfecting 25min.Then with 0.9%NaCl sterile saline, rinse, with filter paper, unnecessary water is sopped up.
2, animal model and surgical procedure: select healthy piggy, with the tincture of iodine and alcohol disinfecting Zhu Fu menisectomy district, cut skin, separated subcutis forms cavity, and bottom, chamber is more than 2cm apart from skin incision, puts into an implant, skin suture in each chamber.Four samples are implanted to same Tou Zhu subcutaneous tissue of abdomen, between implant at a distance of more than 8cm.
3, postoperative detection: establishing time point is 1w, 2w and 4w, each time point repeats 3 samples, i.e. three pigs.Postoperative 1w, draws materials respectively after 2w and 4w, with 4% paraformaldehyde, fixes, and paraffin embedding, makes 4 μ m slabs, does conventional hematoxylin-eosin (HE) dyeing, evaluates embedded material around and inner inflammation situation.
Result
Because experiment in body is that compressing tablet material is implanted under pigskin, be therefore the environment of a relative solid, accumulation acid in the degraded environment of relatively external liquid is more serious, and mediate, wants the many of difficulty, and the disintegration phenomenon of investigating so material is just necessary.Because thickness is one of acid major influence factors of piling up, therefore test in vivo in four groups, owing to having added simple PGA in 1 group of Thickness Ratio that modified material causes, want large for 2 and 3 groups, just set up 4 groups, its thickness is consistent with PGA+STP, the PGA+SPP of 2,3 groups.4,5 groups in embodiment 2 added NaCl neutrophil granule group and do not investigated the degraded situation in body, and reason is that the interpolation of NaCl salt particle also has extra impact to surrounding tissue.And be unfavorable for observing the degraded because of PGA, cause that local pH value declines, and the non-bacterial inflammatory reaction of the surrounding tissue causing.
According to histology pictures, implant after one week and find that 4 groups of situations are similar.And during second week, from external degradation experiment, see the time period that pH value sharply declines, as shown in Figure 5, from cardinal principle photo, 1 and 4 is that the shape that simple PGA organizes material maintains substantially, material internal does not have tissue to grow into substantially.But 2 and 3 groups have been difficult to distinguish surrounding tissue and material, have had the trend combining together.From the histology pictures of high power, observe healthy tissues position a, tissue and material interface b, material internal c and material and the d of organizational interface (b and d are similar), can find out, simple PGA 1 and 4 groups have obvious inflammatory reaction at interface, and material is middle except inflammatory cell, almost there is no healthy tissues.During section, finding has serious pus in the middle of 4 groups of PGA materials.Other groups do not have.Seldom, and centre also has healthy tissues to grow into 2 and 3 groups of inflammatory cells, and the consistency of tissue and material is better.The tissue compatible implementations of 2 groups has and is slightly better than 3 groups.Find out thus, the aseptic inflammation of modification group will obviously be less than simple PGA group, and simple PGA group is due to the acidity of material internal, organizes and is difficult to grow into.
While implanting 4 weeks, 1 and 4 group at implant site red color visible necrotic tissue, and material all has a large amount of pus while cutting.Material has lost original form, and tissue has obvious swelling, has the tissue of parcel one deck like fibrous capsule around, especially 4 groups at material.In 1 and 4 group, in the tissue directly contacting with material, there are a large amount of intensive inflammatory cells.Otherwise 2 and 3 modification groups incorporated well with surrounding tissue in the time of 4 weeks, especially 2 groups, without significantly inflammatory cell is intensive, tissue and material are also uniformly distributed.In the middle of material, without cavity, during incision, do not have pus to flow out yet.3 groups have a small amount of inflammatory cell to occur at local location, and material and tissue incorporate better, are uniformly distributed each other.2 and 3 groups all without significantly fibrous capsule appearance.
Conclusion:
By the method that the strong buffer reagent sodium polyphosphate of polymer is pulverized by melting repeatedly, sneak in PGA material, can effectively alleviate the pH value decline of the surrounding liquid that PGA degraded causes, can be effectively by media stabilize within the scope of certain pH value.By subcutaneous implantation in body, test, also confirmed to remove modification PGA with this type of salt particle, do not affect the original biocompatibility of PGA, and inflammation surrounding tissue being caused can also effectively eliminate material degradation time impact, and can eliminate material disintegration or hollow phenomenon.If become the timbering material of used in tissue engineering also can eliminate corresponding disadvantageous effect with the PGA Raw material processing after modification.
Do not affecting under the prerequisite of the original biocompatibility of PGA, PGA is being carried out to the acid product that modification produces in neutralization materials degradation process with in time, constantly, thereby eliminating the inflammatory reaction that the acid product because of material degradation causes.Timely and the persistence of modification is extremely important.Because from the degradation process of PGA, it is a hydrolytic process, and ester linkage breaking, forms the oligomer that acidic-group carboxyl is end, and then be degraded to monomeric glycolic acid.And the existence of acidic ending group has self-catalysis to hydrolysis reaction in oligomer, accelerated the speed of degraded.Meanwhile, the accumulation of the acid product in stock support and between polymer chain will be early than pH value in solution decline around.As tissue engineering bracket material, seed cell is directly to contact with material, the various active protein class materials of acidic micro-environment meeting coup injury cell, cell matrix and the emiocytosis of material surface.So the acid degradation product of PGA material should be controlled from the beginning and regulate, and last till the whole process of degraded.What therefore, the present invention proposed is to adopt the technology of medicine parcel that the strong buffer reagent sodium polyphosphate of a kind of polymer (sodium polyphosphate, SPP) is introduced in PGA material.When discharging, neutralize the acidic-group that PGA degraded produces.
The foregoing is only preferred embodiment of the present invention, not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is to be broadly defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.
Claims (11)
1. a Biodegradable material, is characterized in that, it consists of degradable polyester family macromolecule material and sodium polyphosphate; The corresponding polymer monomer mol ratio of described degradable polyester family macromolecule material and sodium polyphosphate is 1:1-0.1; Described sodium polyphosphate is suc as formula shown in I:
Wherein n >=3, are integers.
2. Biodegradable material as claimed in claim 1, is characterized in that, described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid or poe.
3. Biodegradable material as claimed in claim 2, is characterized in that, described poly-alpha hydroxy acid is selected from poly(lactic acid) (PLA), polyglycolic acid (PGA), poly(lactic acid)/ethanol copolymer (PLGA) or polyhydroxybutyrate (PHB).
4. Biodegradable material as claimed in claim 1, is characterized in that, the corresponding polymer monomer mol ratio of described degradable polyester family macromolecule material and sodium polyphosphate is 1:1-0.5.
5. Biodegradable material as claimed in claim 1, is characterized in that, the corresponding polymer monomer mol ratio of described degradable polyester family macromolecule material and sodium polyphosphate is 1:0.5-0.1.
6. a preparation method for the Biodegradable material as described in as arbitrary in claim 1-5, is characterized in that, described method comprises step:
(1) solution that contains degradable polyester family macromolecule material and the solution that contains sodium polyphosphate are evenly mixed, obtain mixing solutions; With
(2), by mixing solutions lyophilize, obtain the Biodegradable material as described in as arbitrary in claim 1-5;
In described mixing solutions, the corresponding polymer monomer mol ratio of degradable polyester family macromolecule material and sodium polyphosphate is 1:1-0.1; Described sodium polyphosphate is suc as formula shown in I:
Wherein n >=3, are integers.
7. preparation method as claimed in claim 6, is characterized in that, described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid or poe; Described poly-alpha hydroxy acid is selected from poly(lactic acid) (PLA), polyglycolic acid (PGA), poly(lactic acid)/ethanol copolymer (PLGA) or polyhydroxybutyrate (PHB).
8. a preparation method for the Biodegradable material as described in as arbitrary in claim 1-5, is characterized in that, described method comprises step:
(a) Powdered polyglycolic acid or Powdered poly(lactic acid)/ethanol copolymer and Powdered sodium polyphosphate are evenly mixed, obtain mixed powder; With
(b) by mixed powder at 207-220 ℃ of melting 3-10 minute, obtain the Biodegradable material as described in as arbitrary in claim 1-5;
In described mixed powder, the corresponding polymer monomer mol ratio of polyglycolic acid or poly(lactic acid)/ethanol copolymer and sodium polyphosphate is 1:1-0.1; Described sodium polyphosphate is suc as formula shown in I:
Wherein n >=3, are integers.
9. the purposes of the Biodegradable material as described in as arbitrary in claim 1-5, it is characterized in that, as the timbering material of tissue engineered implant, for the preparation of tissue engineered implant, for the preparation of sutures or for the preparation of the solid support material of drug release.
10. purposes as claimed in claim 9, is characterized in that, described tissue engineered implant comprises cartilage graft, tendon graft, blood vessel graft, corneal graft and skin graft.
The purposes of 11. 1 kinds of sodium polyphosphates, is characterized in that, for and the acidity that produces in degradation process of degradable polyester family macromolecule material; Described sodium polyphosphate is suc as formula shown in I:
Wherein n >=3, are integers;
Described degradable polyester family macromolecule material is selected from poly-alpha hydroxy acid or poe.
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