CN100503693C - 3-D porous frame material of poly-lactic acid-polyether block copolymer and its preparation method - Google Patents
3-D porous frame material of poly-lactic acid-polyether block copolymer and its preparation method Download PDFInfo
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- CN100503693C CN100503693C CNB031149391A CN03114939A CN100503693C CN 100503693 C CN100503693 C CN 100503693C CN B031149391 A CNB031149391 A CN B031149391A CN 03114939 A CN03114939 A CN 03114939A CN 100503693 C CN100503693 C CN 100503693C
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Abstract
A polylactic acid-polyester block copolymer used for cell-affinity 3D porous scaffold material in tissue engineering is prepared by copolymerization of D,L-lactide (D,L-LA) with polyether. The said 3D porous scaffold material is prepared from said block copolymer through preparing porous film by solvent casting and particle filter, and shaping by use of chloroform to adhere the porous film for particular shape. Its advantages are a certain hydrophilicity, high biocompatibility, and high porosity (90% or more).
Description
Technical field
The invention belongs to macromolecular material and biomedical engineering technology field, be specially a kind of three-dimensional porous rack material for tissue engineering and preparation method thereof with cellular affinity.
Background technology
Tissue engineering bracket material be meant can with organize active somatic cell combine and can implantable bioartificial the material of body, it is the basic boom of engineered tissue.Poly(lactic acid) is a kind of biodegradable aliphatic polyester, its degraded product is a lactic acid, nontoxic and can get rid of externally with human body metabolism, be widely used in the tissue engineering bracket material, but be restricted because of shortcomings such as its high hydrophobicity and pair cell affinity differences.Therefore, introduce soft segment by molecular designing, synthetic each analog copolymer based on poly(lactic acid) improves the cellular affinity of poly(lactic acid) and the focus that biocompatibility becomes research.Polyoxyethylene (PEO), polyoxyethylene glycol (PEG) are by the nontoxic polymer of drugs approved by FDA oral administration, because of the kindliness of its molecular chain, distinctive cellular affinity and the characteristics that can reduce the protein immunity, usually be used to poly(lactic acid) is carried out chemical modification.
Organize often to be the three-dimensional space configuration in vivo, appropriate nutrition condition and steric requirements are provided for the growth of cell, help the physiological function of organizing performance specific.Therefore, the timbering material that is used for the vitro tissue engineering need have necessary microstructure and certain porosity, to hold mesenchymal cell and to promote the performance of its function.External existing people has carried out extensive studies to the preparation of used in tissue engineering porous support, specifically can be divided into fibrage method (Mikos AG, Sarakinos G, LymanMD, et al.Preparation of poly (glycolic acid) bonded fiber structures for cell attachment andtransplantation.J Biomed Mater Res, 1993,27:183～189), solvent casting-particle filter drop method (MikosAG, Thorsen AJ, Czerwonka LA, et al Preparation and characterization of poly (L-lactic acid) foams.Polymer, 1994,35 (5): 1068～1077), phase separation method (Lo H, Ponticiello MS, Leong KW.Fabrication of controlled release biodegradable foams by phases eparation.TissueEngineering, 1995,1:15～28), Freeze Drying Technique (Whang K, Thornas CH, Healy KE, et al.Anovelmethod to fabricate bioadsorbable scaffolds.Polymer, 1995,36:837～842), gas foaming method (HarrisLD, Kim BS, Mooney DJ.Open pore biodegradable matrices formed with gas foaming.J BiomedMater Res, 1998,42:396～402).Domestic research still is in the starting stage, because the restriction of various conditions, the porous support materials that makes mostly is porous membrane, can't satisfy the needs of organizational project fully.The method that solvent casting-particle filter drop technology combines with lamination techniques is adopted in this research, has prepared the three-dimensional porous rack material for tissue engineering with certain space shape.
Summary of the invention
The objective of the invention is to three-dimensional porous rack material for tissue engineering that proposes a kind of good biocompatibility, controlled porosity and preparation method thereof.
The three-dimensional porous rack material for tissue engineering that the present invention proposes is a kind of by D, and the L-rac-Lactide (D, L-LA) and poly(lactic acid)-polyether block copolymer of obtaining of polyethers copolymerization.
Among the present invention, adopt the polyethers of different molecular weight, can obtain the poly(lactic acid)-polyether block copolymer of different molecular weight.Polyethers can adopt hydrophilic polymers such as polyoxyethylene glycol (PEG), polyoxyethylene (PEO), polytetrahydrofuran, then corresponding segmented copolymer PLA-PEG, PLA-PEO, PLA-polytetrahydrofuran etc.
Among the present invention, above-mentioned poly(lactic acid)-polyethers embedding multipolymer can be made into film, and the thickness of film is 0.1-2mm.Further, can above-mentioned thin-film material is superimposed, obtain plied timber, the superimposed formation of 3-8 layer film generally can be arranged, become needed three-dimensional stent material with certain space shape.
The present invention is as follows for the concrete preparation method of above-mentioned materials:
1, poly(lactic acid)-polyether block copolymer is synthetic
With D, L-LA, polyethers (as hydrophilic polymers such as polyoxyethylene glycol (PEG), polyoxyethylene (PEO), polytetrahydrofurans) are 300:1～3:1 by weight proportion, and add reaction flask as the stannous octoate of catalyzer, the mass ratio of catalyzer and reaction raw materials is: 0.01%～1%, inflated with nitrogen, vacuumize, 3-5 time repeatedly, seal then; Put into the salt bath, polymerization is 2～40 hours under 140 ℃～200 ℃ temperature; Polymerization finishes postcooling, takes out multipolymer, uses organic solvent dissolution, organic solvent can be ethyl acetate or acetone, chloroform etc., precipitation in normal heptane (methyl alcohol or water etc.), and use the distilled water repetitive scrubbing, vacuum-drying then obtains the poly(lactic acid)-polyether block copolymer of purifying.
2, the preparation of poly(lactic acid)-polyethers porous membrane
The concrete steps of preparation poly(lactic acid)-polyether block copolymer porous membrane are: (1) is dissolved in the poly(lactic acid)-polyether block copolymer of certain mass in the organic solvent, make 5%～30% solution, here organic solvent can be a chloroform, perhaps methylene dichloride, dioxane, tetrahydrofuran (THF) etc.; (2) will sieve grain diameter is that the pore-creating agent of 50～500 μ m joins in the block copolymer solution, the mass ratio of pore-creating agent and polymkeric substance is: 1:1～9:1, and mix, pore-creating agent can be sodium-chlor, sodium tartrate, Trisodium Citrate, yellow soda ash, sucrose etc. here; (3) three's mixture is watered cast from the aluminium foil, allow solvent volatilize naturally 12～48 hours; (4) vacuum-drying is 12～48 hours, to remove residual solvent; (5) above-mentioned substance is heated to 80 ℃～120 ℃, held time 10 minutes～2 hours, divest the single thin film that obtains containing pore-creating agent behind the aluminium foil; (6) single thin film is immersed in water is housed (can be deionized water, perhaps tap water, pure water etc.) beaker in, beaker is placed in the ultrasonic oscillator vibrates then, changed water once in per 6～8 hours, remove pore-creating agent, temperature is controlled at about 28 ℃-35 ℃; (7) allow the individual layer porous membrane seasoning 12～48 hours of removing pore-creating agent, in 28-35 ℃ of vacuum-drying 24～72 hours, it was standby to put into moisture eliminator then.
3, poly(lactic acid)-polyethers individual layer porous membrane is superimposed
Drawing a spot of organic solvent (as chloroform or methylene dichloride) with suction pipe drops on the writing paper, treat that solvent tiling back is placed on two synergetic individual layer porous membranes of desire on the writing paper with tweezers, push, make it fully moistening, allow two wet side fully contact then, make it to bond together fully.At last with its vacuum-drying 12～48 hours in 15～50 ℃ vacuum drying oven, used solvent when removing stack.In this way, can superpose out successively 3 to 8 layers multilayer porous film.As required, can prepare the three-dimensional porous rack material with poly(lactic acid)-copolyether of certain space shape such as square or circular, see shown in Figure 4 with blade or tapping and plugging machine.
Be that example is analyzed its molecular weight with the PLA-PEG multipolymer below, and the relation of porosity and pore-creating agent consumption.
1. the analysis of molecular weight of copolymer
Under identical polymerization temperature and polymerization time, the relation of PEG content is seen Fig. 1 in PLA-PEG block copolymer amount and the raw material.The polymerization temperature of test is 170 ℃, and polymerization time is 6 hours.
Fig. 1 shows that along with the increase of the PEG relative content that participates in copolymerization, molecular weight of copolymer descends gradually.The relative minimizing of this explanation lactide content causes PLA segment content decline in the segmented copolymer.
2. the relation of pore-creating agent content in porosity and the raw material
Under the identical situation of pore-creating agent (sodium-chlor) particle size, the porosity of PLA-PEG porous support materials is by the decision of the initial amount of pore-creating agent in the raw material, and is as shown in table 1.
Table 1: the relation of pore-creating agent initial amount in porosity and the raw material
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Pore-creating agent initial content (wt%) | 60 | 70 | 75 | 80 | 85 | 90 |
| Porosity (%) | 61.2 | 69.3 | 73.9 | 82.5 | 85.1 | 90.7 |
As known from Table 1, the content of the porosity of porous support materials and pore-creating agent (sodium-chlor) has good corresponding relationship.Porosity is substantially along with the increase of pore-creating agent content increases.Therefore, can control the size of porous support materials porosity by the content of pore-creating agent in the control raw material.The initial amount of pore-creating agent has the difference of a little in porosity that material is final and the raw material, and this mainly is because the transfer when casting of the mixture of polymers soln and pore-creating agent not exclusively causes.
3. the stack of individual layer porous membrane and sample preparation
Because the density of pore-creating agent and polymers soln varies in size, adopt the thickness of the individual layer porous membrane of solvent casting-particle filter drop technology preparation generally to be no more than 2mm.Tissue engineering bracket material generally all needs to have the space three-dimensional structure of definite shape, so the present invention has adopted lamination techniques to prepare to have certain thickness porous material.To the cross section scanning electron microscopic observation of stack place, the result as shown in Figure 3.Find that from figure stack does not have tangible depredation, pore structure still exists, and distribution uniform.
The experimental result of all the other poly(lactic acid)-polyether block copolymers is to above-mentioned similar.
Description of drawings
Fig. 1 is the relation diagram of PEG molecular weight in molecular weight of copolymer and the raw material.
Fig. 2 is porous membrane hole diagram.
Fig. 3 is a multilayered film material cross-sectional scans Electronic Speculum diagram.
Fig. 4 is a three-dimensional porous rack material photo in kind.
Embodiment
The invention is further illustrated by the following examples.
Embodiment 1, take by weighing 30gD, L-LA and 1gPEG (molecular weight is 6000) add reaction flask, drip the 0.023g stannous octoate as catalyzer.Inflated with nitrogen is 10 minutes then, vacuumizes 10 minutes, and inflated with nitrogen is 8 minutes once more, vacuumizes 8 minutes, then seals.The salt bath of putting into 170 ℃ at last reacts 6h.Reaction finishes postcooling, takes out multipolymer, uses acetic acid ethyl dissolution, precipitates in normal heptane, and with distilled water wash 4 times, puts into vacuum drying oven vacuum-drying 24h then, obtains the PLA-PEG segmented copolymer of purifying.Measure through GPC, the molecular weight of multipolymer is 4.1 ten thousand.
Embodiment 2, take by weighing 10gD, L-LA and 1gPEO (molecular weight is 5000) add reaction flask, drip the 0.016g stannous octoate as catalyzer.Inflated with nitrogen is 10 minutes then, vacuumizes 10 minutes, and inflated with nitrogen is 8 minutes once more, vacuumizes 8 minutes, then seals.The oil bath pan of putting into 150 ℃ at last reacts 2.5h.Reaction finishes postcooling, takes out multipolymer, with the methylene dichloride dissolving, precipitates in cold methanol, and with distilled water wash 3 times, puts into vacuum drying oven vacuum-drying 24h then, obtains the PLA-PEO segmented copolymer of purifying.Measure through GPC, the molecular weight of multipolymer is 4.52 ten thousand.
Embodiment 4, to get molecular weight be the chloroform that 4.1 ten thousand PLA-PEG segmented copolymer 0.6g is dissolved in 8ml, and adding the 2.4g particle diameter then is 100～120 purpose sodium chloride particles, and remaining step is identical with embodiment 3.The porosity of prepared porous membrane is 81.1%, as shown in Figure 2.
Embodiment 5, to get molecular weight be the chloroform that 5.3 ten thousand PLA-PEG segmented copolymer 0.6g is dissolved in 8ml, and adding the 2.4g particle diameter then is 80～100 order sodium tartrate particles, and remaining step is identical with embodiment 3.The porosity of prepared porous membrane is 80.8%.
Embodiment 7, to get three porositys be that (every thickness is 0.8～1.0mm) to carry out stackedly, and wherein every porous membrane is made circle with tapping and plugging machine for 80.8% pLA-PEG segmented copolymer porous membrane.At first drawing a spot of chloroform with dropper drips on writing paper, treat that its tiling back invests two synergetic porous membranes of desire on the writing paper, make lamination surface fully moistening, then two wet side are bonded together, and push gently so that it fully contacts with tweezers, the 3rd porous membrane in this way again superposes.Made disc three-dimensional porous rack material as shown in Figure 4.The sem photograph of stacked place cross section as shown in Figure 3.
Embodiment 8, to get six porositys be that (every thickness is 0.8～1.0mm) to carry out stackedly, and wherein every porous membrane is cut into the trilateral that varies in size with blade, and remaining step is identical with embodiment 6 for 82.5% PLA-PEG segmented copolymer porous membrane.Made nose shape three-dimensional porous rack material as shown in Figure 4.
Claims (6)
1, a kind of three-dimensional porous rack material for tissue engineering is characterized in that it being by D, L-LA and polyethers copolymerization and poly(lactic acid)-polyether block copolymer of obtaining, and wherein polyethers adopts polyoxyethylene glycol, PEO or polytetrahydrofuran; This timbering material is a film shape, and thickness is 0.1-2mm, constitutes by the 3-8 layer film is superimposed.
2, a kind of preparation method of three-dimensional porous rack material as claimed in claim 1 is characterized in that
(1) segmented copolymer such as poly(lactic acid)-polyethers is synthetic
With D, L-LA, polyethers are 300:1～3:1 by weight proportion, and add reaction flask as the stannous octoate of catalyzer, and the mass ratio of catalyzer and reaction raw materials is: 0.01%～1%, inflated with nitrogen, vacuumize, and 3-5 time repeatedly, seal then; Put into the salt bath, polymerization is 2～40 hours under 140 ℃～200 ℃ temperature; Polymerization finishes postcooling, takes out multipolymer, uses organic solvent dissolution, precipitates in normal heptane or methyl alcohol or water, and uses the distilled water repetitive scrubbing, and vacuum-drying then obtains the poly(lactic acid)-polyether block copolymer of purifying;
(2) preparation of poly(lactic acid)-polyethers porous membrane
1. poly(lactic acid)-polyether block copolymer is dissolved in the organic solvent, makes 5%～30% solution; The pore-creating agent that 2. will sieve grain diameter and be 50～500 μ m joins in the block copolymer solution, the mass ratio of pore-creating agent and polymkeric substance is: 1:1～9:1, and mix, pore-creating agent is a kind of of sodium-chlor, sodium tartrate, Trisodium Citrate, yellow soda ash, sucrose here; 3. three's mixture is watered and cast from the aluminium foil, allow solvent volatilize naturally 12～48 hours; 4. vacuum-drying is 12～48 hours, to remove residual solvent; 5. above-mentioned substance is heated to 80 ℃～120 ℃, held time 10 minutes～2 hours, divest the single thin film that obtains containing pore-creating agent behind the aluminium foil; 6. single thin film is immersed in the beaker that water is housed, beaker is placed in the ultrasonic oscillator vibrates then, changed water once in per 6～8 hours, remove pore-creating agent, temperature is controlled at 28-35 ℃; 7. allow the individual layer porous membrane seasoning 12～48 hours of removing pore-creating agent, in 28-35 ℃ of vacuum-drying 24～72 hours, it was standby to put into moisture eliminator then;
(3) poly(lactic acid)-polyethers individual layer porous membrane is superimposed
Draw organic solvent with suction pipe and drop on the writing paper, treat that solvent tiling back is placed on two synergetic individual layer porous membranes of desire on the writing paper with tweezers, push, make it fully moistening, allow two wet side fully contact then, make it to bond together fully; At last with its under 15～50 ℃ vacuum condition dry 12～48 hours, used solvent when removing stack; In this way, superpose out successively 3 to 8 layers porous-film.
3, preparation method according to claim 2 is characterized in that used polyethers is a kind of of polyoxyethylene glycol, polyoxyethylene, polytetrahydrofuran.
4, preparation method according to claim 2 is characterized in that organic solvent used in the synthetic segmented copolymer is a kind of of ethyl acetate, acetone, chloroform.
5, preparation method according to claim 2 is characterized in that preparing the used organic solvent of porous membrane and is a kind of of chloroform, methylene dichloride, dioxane, tetrahydrofuran (THF).
6, preparation method according to claim 2 is characterized in that the used organic solvent of superimposed porous membrane is chloroform or methylene dichloride.
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| CN100355405C (en) * | 2004-06-24 | 2007-12-19 | 同济大学 | Production of porous stand for tissue engineering |
| WO2007101443A1 (en) | 2006-03-09 | 2007-09-13 | Coloplast A/S | Degradable hydrophilic block copolymers with improved biocompatibility for soft tissue regeneration |
| CN101864062B (en) * | 2010-06-07 | 2012-05-23 | 中国科学院宁波材料技术与工程研究所 | Unsaturated polylactic acid block copolymer and preparation method thereof |
| CN113144286B (en) * | 2021-04-21 | 2022-12-09 | 四川大学华西医院 | Degradable self-supporting artificial bile duct and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6472210B1 (en) * | 1997-11-14 | 2002-10-29 | Bonetec Corporation | Polymer scaffold having microporous polymer struts defining interconnected macropores |
| US6476156B1 (en) * | 2000-02-14 | 2002-11-05 | Korea Institute Of Science And Technology | Biodegradable triblock copolymers and process for their preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6472210B1 (en) * | 1997-11-14 | 2002-10-29 | Bonetec Corporation | Polymer scaffold having microporous polymer struts defining interconnected macropores |
| US6476156B1 (en) * | 2000-02-14 | 2002-11-05 | Korea Institute Of Science And Technology | Biodegradable triblock copolymers and process for their preparation |
Non-Patent Citations (2)
| Title |
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| 聚丙交酯/聚乙二醇多嵌段共聚物的合成及其性能. 陈文娜，杨建，王身国等.高分子学报，第5期. 2002 * |
| 聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物的降解性能. 全大萍，高建文，廖凯荣等.功能高分子学报，第15卷第4期. 2002 * |
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