CN1176978C - Degradable chemically crosslinked aquagel and its prepn - Google Patents
Degradable chemically crosslinked aquagel and its prepnInfo
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- CN1176978C CN1176978C CNB011264780A CN01126478A CN1176978C CN 1176978 C CN1176978 C CN 1176978C CN B011264780 A CNB011264780 A CN B011264780A CN 01126478 A CN01126478 A CN 01126478A CN 1176978 C CN1176978 C CN 1176978C
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- chemically crosslinked
- macromonomer
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- hydrogel
- degradable
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Abstract
The present invention relates to chemically crosslinked hydrogel having degradability and a preparation method thereof. The hydrogel belongs to the technical field of high molecular materials. The hydrogel is formed in a water phase at the body temperature (or the normal temperature) by a macromolecular monomer technology by adopting a hydrophilic or partially hydrophilic macromolecule or an oligomer as a main body combined with a degradable oligomer. The hydrogel is insoluble in water (chemically crosslinked), but the hydrogel is controllably degradable. The hydrogel can be widely suitable for the biologic material fields of cell culture brackets for tissue engineering, or drug controlled release carriers, etc.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to a kind of chemically crosslinked aquagel and preparation method thereof with degradation characteristic.
Technical background
Degraded product with polymkeric substance of degradation characteristic is low-molecular weight compound or finally is metabolized to micromolecular compound such as CO
2And H
2O etc.If degraded product is water-soluble, then can directly excrete or be absorbed by body by various metabolic processes; If degraded product is water insoluble and molecular weight is bigger, then can further degrade by lysosome, thereby may cause the aseptic inflammation reaction by the phagolysis of scavenger cell, have certain toxicity.
Biodegradable polymer be widely used in medical field (as suture, nail, reparation shaping and medical courses in general etc.) and as pharmaceutical carrier realize medicine in vivo the sustained release of privileged site do in order to reach therapeutic purpose.Current research and the most widely used biodegradable polymer are aliphatic polyesters, as poly-D, and L-rac-Lactide (PDLLA), poly-L-rac-Lactide (PLLA), poly-glycollide (PGA), polycaprolactone (PCL) and their multipolymer.Chinese invention patent (publication number CN1271742A) synthesizes glycollide-L-rac-Lactide-caprolactone terpolymer, and this multipolymer has good biological degradability, mechanical property and can regulate the performance of biodegradation rate.Chinese invention patent (publication number CN1272384A) adopts phase disengagement method to prepare chitosan/gelatin porous cytoskeleton material, good biocompatibility, and using in fields such as organizational projects can be moulding in advance, but above-mentioned biomaterial does not have syringeability.
Hydrogel has excellent biological compatibility, research at present and the most widely used be the multipolymer (PEPO) of polyoxyethylene glycol (PEG) or polyoxyethylene (PEO) and polyoxytrimethylene (PPO), (～10KDa) polyoxyethylene glycol (PEG) or PEPO excrete by kidney after dissolving in vivo lower molecular weight easily, nontoxic, no antigen and immunogenicity have been widely used in biologic medical and biotechnology field.Suitable hydrogel preparation method can will not become polymer substance and the cell or the medicament mixed of gel in advance, form gel after being injected into human body or animal body then, naturally cell or medicine are fixed, thereby be also referred to as the syringeability hydrogel, be generally a kind of physical cross-linking hydrogel.Even be not the characteristics of utilizing its syringeability, this gellike also have biocompatibility good, be convenient to operation, abundant advantages such as fixed cell or medicine, thereby earn widespread respect in medical treatment and medicine sustained release field.U.S.'s patent of invention 6,129,761 has been reported and has been added linking agent such as divalent cation forms hydrogel in the polysaccharide compound of modification such as hyaluronic acid, the alginates aqueous solution, served as the cell culturing bracket effect in organizational project.But physical cross-linking hydrogel, its dissolving or degradation property are difficult to control, when being used for occasion such as vitro tissue cultivation, can't implement experiment because of being dissolved in water.(Macromolecules, 1993,26 such as A.S.Sawhney, 581[U.S.]) prepared the big monomer of polyoxyethylene glycol (PEG), cause by ultraviolet or visible light that it is crosslinked, form chemically crosslinked aquagel, and the possibility of this hydrogel as medicine sustained release carrier further has been discussed.But adopt light-initiated need be injected into intravital occasion for organizational project etc. the time and inconvenient; For bigger gel, illumination and the crosslinking reaction that is caused also are difficult to accomplish evenly.
Summary of the invention
The objective of the invention is to propose a kind of degradable chemically crosslinked aquagel and preparation method thereof with good biocompatibility, water-absorbent, permeability.
The degradable chemically crosslinked aquagel that the present invention proposes, be to be made of by chemically crosslinked wetting ability or part wetting ability macromole or oligomer and degradable group, be polymer network structure, its degradation rate does not rely on the condition of the gel that forms, independent controlled, its chemical structural formula is:
In the formula
Expression is in the segment between the arbitrary form chemically crosslinked point.
The multipolymer of the arbitrary form that (Y '-X ') expression is made up of X ' and Y ', X ' is wetting ability or part wetting ability macromole or oligomer, Y ' is degradable unit or its oligomer.
In the chemically crosslinked aquagel of the present invention, wetting ability or part wetting ability macromole or oligomer X ' are main body, account for 51%-99.5% (weight percent), and degradable unit or its oligomer Y ' account for 49%-0.5% (weight percent).Water in the chemically crosslinked aquagel is a pure water, or buffered soln, or the body fluid of animals and plants or human body, or tissue culture medium, or other is not based on the solvent medium of organic solvent.
The present invention use the macromonomer technology prepared above-mentioned chemically crosslinked, the degradable polymer hydrogel.Its preparation method is a chemically crosslinked macromonomer centre portions for adopting polyethers wetting ability with good biocompatibility or part wetting ability macromole or oligomer X, gets multipolymer Y-X-Y by ring-opening polymerization method and biodegradable aliphatic polyester Y copolymerization; But connect two key reactive group Z of chemically crosslinked then at these copolymer molecule main chain two ends, get macromonomer Z-Y-X-Y-Z; The solution of preparation macromonomer causes crosslinking reaction by water soluble oxidized reduction initiator, forms chemically crosslinked aquagel.This hydrogel does not dissolve in water under normal temperature (body temperature), but can controlledly progressively degrade, and is applicable to fields such as used in tissue engineering cell culturing bracket and medicine sustained release carrier.
In the aforesaid method, wetting ability or part wetting ability macromole or oligomer X as chemically crosslinked macromonomer centre portions generally can adopt the not too high polyoxyethylene glycol of molecular weight (PEO), and molecular weight perhaps adopts the PEPO segmented copolymer from 100-100000.Biodegradable aliphatic polyester Y can adopt oligomerization L-rac-Lactide (PLLA), oligomerization DL-rac-Lactide (PDLLA), oligomerization glycollide (PGA), oligomerization caprolactone (PCL), ε-alkyl to replace any in the caprolactone and their any type of multipolymers.But chemically crosslinked group Z can adopt acrylate, methacrylic ester, or the derivative of other esters of acrylic acid.X and polymerisate are that the molar ratio between the monomer of Y is 0.5: 99.5-99.5: 0.5.
In the aforesaid method, the condition of X and Y ring opening copolymer is: under 0.1mmHg vacuum and the catalyst action, and 120 ℃-200 ℃ of temperature of reaction, reaction times 3-50 hour; Preferable temperature of reaction is 140 ℃-160 ℃, and the reaction times is 15-24 hour, and getting reaction product is Y-X-Y.Wherein, catalyzer can adopt stannous iso caprylate, and its consumption is the 0.1%-5% of the oh group mole number of X, and preferable consumption is 0.5%-1.5%; Also available hydrolith of catalyzer or zinc powder, the mol ratio of the oh group of its consumption and X is 0.2: 0.8-0.8: between 0.2, preferable consumption is 0.4 for the mol ratio with the oh group of X: 0.6-0.6: 0.4.
In the aforesaid method, copolymerization product Y-X-Y is dissolved in methylene dichloride or the chloroform, this Y-X-Y solution and Z reaction (Z can be introduced by acrylate chloride, methacrylic chloride or other acrylate chloride derivative).The mol ratio of the consumption of Z and the oh group of Y-X-Y is 4: 1-10: between 1.Adding and Z equimolar amount triethylamine in above-mentioned Y-X-Y solution earlier is added dropwise to Z under stirring and nitrogen protection, (0-5 ℃) reaction is 10-12 hour in ice bath, reacts 10-12 hour down in room temperature (about 20 ℃) then.React finish after-filtration, precipitation, the collecting precipitation thing, vacuum-drying obtains macromonomer Z-Y-X-Y-Z.
In the aforesaid method, the weight concentration of the solution of macromonomer Z-Y-X-Y-Z is 5-85%, and its solvent can be water, or damping fluid, human body or animal and plant body body fluid, or tissue culture medium, or other is not based on one or more mixture of the solvent medium of organic solvent.The water soluble oxidized reduction initiator that adds in this macromonomer solution can be a persulphate, as Potassium Persulphate or ammonium persulphate etc., the consumption of initiator accounts for the 0.01-8% of macromonomer solution weight, causes crosslinking reaction under 1-80 ℃ of condition, forms hydrogel.
The present invention has following characteristics:
1, the hydrogel of the present invention's proposition is not dissolved in water (chemically crosslinked), but can be in normal temperature and aqueous phase degraded.Because adopt the centre portions as macromonomer such as polyoxyethylene glycol or PEPO segmented copolymer, biocompatibility is good.
2, the hydrogel degradation speed in vivo of the present invention preparation can be different with chemical constitution by control copolyester kind, factors such as the length of polyester chain and cross-linking density regulate.
3, the hydrogel of the present invention's preparation uses nontoxicity, commercial stannous iso caprylate or hydrolith or zinc powder to be catalyzer, and equipment is simple.The chemical property that adopts acrylate chloride or methacrylic chloride or other acrylate chloride derivative to come modified copolymer with the copolymer reaction of polyoxyethylene glycol or PEPO and aliphatic polyester, post-reaction treatment is simple.Help large-scale industrial production.
4, the present invention adds water soluble oxidized reduction initiator in the macromonomer aqueous solution, and utilize and cause crosslinking reaction under body temperature or the normal temperature, thus fixed packet tolerant (cell or medicine).
5, degradable chemically crosslinked aquagel of the present invention is realized in normal temperature, normal pressure, the aqueous solution, and can adopt injecting method, thermal initiation crosslinking reaction in external mold or in the body, the thing that can be processed into various complicated shapes is used for medical science, organizational project or others, and is simple to operation.
6, chemically crosslinked aquagel of the present invention has good water-absorbent, permeability, biocompatibility, is the macromolecule hydrogel of the novel synthetic of a class, has wide biomedical applications.
Embodiment
The embodiment that the invention is further illustrated by the following examples, but be not limited to these embodiment.
Embodiment 1, the reactant molar ratio is PEG10K: the L-rac-Lactide: stannous octoate=1: 32: 0.02 (last " notes " are seen in the explanation of code names such as relevant PEG10K), mixing the back vacuumized 6 hours at 60 ℃, to remove volatile matter, use rare gas element (nitrogen or argon gas) displacement then for several times, seal ampoul tube down in vacuum (0.1mmHg) at last.Copolyreaction is 24 hours under 140 ℃ of conditions.The dichloromethane solution of copolymerization product and acrylate chloride (mol ratio is 1: 10) reaction, the reaction after-filtration, filtrate is precipitated in anhydrous diethyl ether (10～0 ℃), collecting precipitation, vacuum-drying gets macromonomer PEG10K-L32.In weight concentration is this macromonomer phosphate buffer soln (PBS) of 30%, add weight concentration and be 2% redox initiator ammonium persulphate, 37 ℃ of following chemically crosslinkeds, obtain hydrogel.Hydrogel reaches swelling equilibrium in 37 ℃, PBS solution after, water-intake rate is 98%, and the volume swelling ratio is 3.7.
Embodiment 2, identical with embodiment 1 operation, the reactant molar ratio is PEG8K: 6-caprolactone: D, L-rac-Lactide: stannous octoate=1: 2: 2: 0.02, get macromonomer PEG10K-CL2-DL2.In weight concentration is that to add weight concentration in this macromonomer PBS solution of 40% be 2% redox initiator ammonium persulphate, 37 ℃ of following chemically crosslinkeds, obtains hydrogel.Hydrogel reaches swelling equilibrium in 37 ℃, PBS solution after, water-intake rate is 92%, and the volume swelling ratio is 3.5.
Embodiment 3, identical with embodiment 1 operation, reactant molar ratio are PEO-PPO-PEO (block length is than being EO: PO: EO=99: 65: 99): glycollide: stannous octoate=1: 8: 0.02 gets macromonomer PEO-PPO-PEO-G8.Weight concentration be this macromonomer PBS solution of 30% to add weight concentration be 1% redox initiator Potassium Persulphate, 37 ℃ of following chemically crosslinkeds, obtain hydrogel.Hydrogel reaches swelling equilibrium in 37 ℃, PBS solution after, water-intake rate is 80%, and the volume swelling ratio is 2.4.
Embodiment 4, identical with embodiment 1 operation, the reactant molar ratio is PEG6K: D, L-rac-Lactide: CaH
2=1: 8: 2, temperature of reaction was 160 ℃, and the time is 15 hours, got macromonomer PEG6K-DL8.In weight concentration is that to add weight concentration in this macromonomer PBS solution of 25% be 1% redox initiator ammonium persulphate, adopt RS75 type Rheometrics rheometer, under 37 ℃, constant humidity, carry out mechanical test (frequency 1Hz, stress 10N), after chemical crosslink reaction takes place, its static modulus of elasticity is that 203KPa[compares: the PBS solution physical cross-linking hydrogel of 30wt%PEPO triblock copolymer (block length is than being EO: PO: EO=99: 65: 99), static modulus of elasticity is 31KPa].
Above-mentioned chemically crosslinked aquagel carries out the external degradation experiment under PH7.4 phosphate buffer solution and 37 ℃ of conditions, weightlessness is represented degradation speed behind the water gel degradation, and the result is as shown in table 1.
Table 1 PEG6K-DL8 chemically crosslinked aquagel external degradation performance
Degradation time (my god) 02 12 19 25 33
Hydrogel weightlessness (%) 0 0.5 44 84 95 99
Annotate: PEG2K, PEG6K, PEG8K, PEG10K represent that respectively molecular weight is 2000,6000,8000 and 10,000 polyoxyethylene glycol.
Gn represents that peg molecule chain two ends on average all are connected to n oxyacetic acid ester units;
Ln represents that peg molecule chain two ends on average all are connected to n L-lactic acid copolymerization units;
DLn represents that peg molecule chain two ends on average all are connected to n D, L-lactic acid copolymerization units;
CLn represents that peg molecule chain two ends on average all are connected to n caprolactone copolymerization units.
Claims (11)
1, a kind of degradable chemically crosslinked aquagel, it is characterized in that forming the polymer chemistry cross-linked network structure by wetting ability or part wetting ability macromole or oligomer and degradable group, its degradation rate does not rely on the condition of the gel that forms, and independent controlled, its chemical structural formula is abbreviated as:
In the formula:
Expression is in the segment between the arbitrary form chemically crosslinked point;
The multipolymer of the arbitrary form that (Y '-X ') expression is made up of X ' and Y ';
X ' is wetting ability or part wetting ability macromole or oligomer; Y ' is degradable unit or its oligomer.
2, chemically crosslinked aquagel according to claim 1, it is characterized in that wetting ability or part wetting ability macromole or oligomer X ' are main body in this chemically crosslinked aquagel, weight content is 51%～99.5%, and degradable unit or oligomer Y ' weight content in this chemically crosslinked aquagel is 49%～0.5%.
3, chemically crosslinked aquagel according to claim 1 is characterized in that wherein water is that pure water or buffered soln or body fluid or tissue culture medium or other be not based on the solvent medium of organic solvent.
4, a kind of preparation method of degradable chemically crosslinked aquagel as claimed in claim 1, use the macromonomer technology, it is characterized in that adopting the polyethers X that contains the polyoxyethylene glycol repeating unit is chemically crosslinked macromonomer centre portions, gets multipolymer Y-X-Y by ring-opening polymerization method and biodegradable aliphatic polyester Y copolymerization; But connect the group Z of double bond containing chemically crosslinked then at these copolymer molecule main chain two ends, get macromonomer Z-Y-X-Y-Z; The solution of preparation macromonomer causes crosslinking reaction by water soluble oxidized reduction initiator, forms chemically crosslinked aquagel; Wherein, Y is any type of multipolymer of any and above-mentioned each base polymer in poly DL-lactide, poly-L-rac-Lactide, poly-glycollide, poly-epsilon-caprolactone, the ε-alkyl replacement caprolactone; Z is the derivative of acrylate, methacrylic ester or other acrylate.
5, the preparation method of hydrogel according to claim 4, it is characterized in that form the macromonomer centre portions X be polyoxyethylene glycol, molecular weight from 2000 to 10000 perhaps is polyoxyethylene and polyoxypropylene copolymer.
6, the preparation method of hydrogel according to claim 4 is characterized in that the copolymerization unit molar ratio of prepared macromonomer is X: polymerisate is that the monomer of Y is 0.5: 99.5-99.5: 0.5.
7, the preparation method of hydrogel according to claim 4 is characterized in that the catalyzer that copolyreaction is adopted is a stannous iso caprylate, and its consumption is the 0.1-5% of the oh group mole number of X, and temperature of reaction is 120-160 ℃, and the reaction times is 3-50 hour.
8, the preparation method of hydrogel according to claim 4, it is characterized in that the catalyzer that copolyreaction is adopted is hydrolith or zinc powder, the mol ratio of the oh group of its consumption and X is 0.2: 0.8-0.8: 0.2, and temperature of reaction is 120-160 ℃, the reaction times is 3-50 hour.
9, the preparation method of hydrogel according to claim 4 is characterized in that the mol ratio of the oh group of the consumption of Z and Y-X-Y is 4: 1-10: between 1.
10, the preparation method of hydrogel according to claim 4, the weight concentration that it is characterized in that macromonomer solution is 5-85%, its solvent be water, damping fluid, human body or movingly plant body fluid, tissue culture medium, not based on one or more mixture of the solvent medium of organic solvent.
11, the preparation method of hydrogel according to claim 10 is characterized in that the water soluble oxidized reduction initiator that adds is a persulphate, and consumption is the 0.01-8% of macromonomer solution weight, and the crosslinking reaction temperature is 1-80 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348127A (en) * | 2015-12-08 | 2016-02-24 | 温州金源化工有限公司 | Preparation method of quinacridone intermediate |
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| ATE458773T1 (en) * | 2006-03-09 | 2010-03-15 | Coloplast As | DEGRADABLE COPOLYMERS WITH A HYDROPHILIC BLOCK WITH IMPROVED BIOCOMPATIBILITY FOR SOFT TISSUE REGENERATION |
| CN102070784A (en) * | 2010-12-08 | 2011-05-25 | 苏州同科生物材料有限公司 | pH-responsive degradable hydrogel and preparation method thereof |
| CN105062019B (en) * | 2015-08-18 | 2016-11-30 | 九江学院 | A kind of temperature sensitive reversible degradable polyester hydrogel of transparent type with PhastGel ability and preparation method thereof |
| US11178934B2 (en) * | 2018-07-18 | 2021-11-23 | Bolt Threads Inc. | Resilin material footwear and fabrication methods |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348127A (en) * | 2015-12-08 | 2016-02-24 | 温州金源化工有限公司 | Preparation method of quinacridone intermediate |
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