CN101371933A - Biodegradable hydrogel with temperature sensitivity and production method and use thereof - Google Patents
Biodegradable hydrogel with temperature sensitivity and production method and use thereof Download PDFInfo
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- CN101371933A CN101371933A CNA2008100484860A CN200810048486A CN101371933A CN 101371933 A CN101371933 A CN 101371933A CN A2008100484860 A CNA2008100484860 A CN A2008100484860A CN 200810048486 A CN200810048486 A CN 200810048486A CN 101371933 A CN101371933 A CN 101371933A
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Abstract
The invention relates to a hydrogel which is temperature-sensitive and biodegradable simultaneously, the hydrogel is prepared by the following method: hydroxyethyl methacrylate-polycaprolactone is obtained by the reaction of hydroxyethyl methacrylate and epsilon-caprolactone; the hydroxyethyl methacrylate-polycaprolactone reacts with carbonyldiimidazole, hydroxyethyl methacrylate-polycaprolactone-imidazole is obtained by rotary evaporation; the hydroxyethyl methacrylate-polycaprolactone-imidazole and Alpha-(1->6)-D-glucan are dissolved in dimethyl sulfoxide, p-dimethylaminopyridine is added, mixture which is obtained by the reaction at room temperature is settled in isopropyl alcohol, hydroxyethyl methacrylate-polycaprolactone-g-Alpha-(1->6)-D-glucan is obtained by vacuum drying; N-isopropylacrylamide and the hydroxyethyl methacrylate-polycaprolactone-g-Alpha-(1->6)-D-glucan are dissolved in phosphorous acid buffer solution with pH of 7.4, then ammonium persulfate and N,N,N',N'-tetramethylethylenediamine are added, the hydrogel is obtained by the reaction at room temperature; dialysis is carried out on the obtained hydrogel by phosphorous acid buffer solution, thereby obtaining the temperature-sensitive and biodegradable hydrogel.
Description
Technical field
The present invention relates to a kind of Biodegradable hydrogel with temperature sensitivity and its production and use.Belong to chemical field, also belong to field of biology.
Background technology
The eighties in last century, Tanaka has reported that poly-N-N-isopropylacrylamide hydrogel has temperature sensitive property feature (J.Chem.Phys.1987,81:1392), swelling at low temperatures, at high temperature shrink, be characterized in existing a temperature transition zone---low critical phase transition temperature (LCST), when hydrogel gel swelling when being lower than this temperature, surpass this temperature then volume shrink rapidly.Though this class hydrogel has good temperature sensitivity, can not degrade fully in vivo.
Summary of the invention
The purpose of this invention is to provide a kind of hydrogel that had not only had the temperature sensitivity feature but also had biodegradation character, and preparation method is simple, resulting hydrogel good biocompatibility is suitable for as external medicine sustained release or tissue engineering bracket material.
Technical scheme provided by the invention is: a kind of Biodegradable hydrogel with temperature sensitivity, made by purgation: (1) is that hydroxyethyl methylacrylate (HEMA) and the ε-caprolactone (CL) of 1:1-1:10 is in nitrogen atmosphere with mol ratio, with the catalysis of stannous octoate, 100-120 ℃ were reacted 3-12 hours; Post reaction mixture is dissolved in oxolane, precipitation, and precipitate is dissolved in ethyl acetate, uses dried over mgso, and concentrating under reduced pressure obtains hydroxyethyl methylacrylate-polycaprolactone (PCL-HEMA) then; Hydroxyethyl methylacrylate-the polycaprolactone and the carbonyl dimidazoles (CDI) that obtain are dissolved in oxolane with mol ratio 1:1-1:2, in nitrogen atmosphere, reacted 16-24 hours, and obtained hydroxyethyl methylacrylate-polycaprolactone-imidazoles (HEMA-PCL-CI) by rotary evaporation; α-(1 → the 6)-D-glucosan (Dextran) that with above-mentioned product hydroxyethyl methylacrylate-polycaprolactone-imidazoles and weight average molecular weight is 15000-25000 is dissolved in the dimethyl sulfoxine (DMSO) with the mol ratio of 20:1-30:1, add with hydroxyethyl methylacrylate-polycaprolactone-imidazoles equimolar right-dimethylamino naphthyridine (DMAP), reacted 3-4 days under the room temperature, the mixture that obtains precipitates in isopropyl alcohol, use washed with isopropyl alcohol then, vacuum drying obtains polycaprolactone-g-α-(1 → 6)-D-glucosan (Dex-PCL-HEMA); (2) N-N-isopropylacrylamide and hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan is dissolved in the phosphate buffer of pH=7.4, the N that adds Ammonium persulfate. and catalytic amount then, N, N ', N '-tetramethylethylenediamine reacts under the room temperature and obtained hydrogel in 12-24 hours; The hydrogel that obtains is at room temperature dialysed with phosphate buffer, obtain Biodegradable hydrogel with temperature sensitivity.
The consumption mass ratio of above-mentioned N-N-isopropylacrylamide, hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan and Ammonium persulfate. is 160-190:10-40:5-10.
Above-mentioned phosphate buffer is that sodium hydrogen phosphate and sodium dihydrogen phosphate are prepared in the ratio of mole proportioning 1:2.
Hydroxyethyl methylacrylate-polycaprolactone of the present invention-g-α-(1 → 6)-D-glucosan (wherein, R is hydrogen or hydroxyethyl methylacrylate-polycaprolactone, m=93-123, n=3) synthetic route:
Biodegradable hydrogel with temperature sensitivity of the present invention not only has the temperature sensitivity feature but also has biodegradation character, and preparation method is simple, resulting hydrogel good biocompatibility is suitable for the application in organizational project or medicine sustained release as external medicine sustained release or tissue engineering bracket material; Also can be used for wrapping up the application of stem cell at myocardial infarction treatment.
Description of drawings
Fig. 1 is glucosan g-polycaprolactone synthetic product nuclear-magnetism figure of the present invention;
Fig. 2 is the gelation process sketch map of hydrogel of the present invention;
Fig. 3 is the rheological property figure of hydrogel of the present invention;
Fig. 4 is the inside shape appearance figure of hydrogel of the present invention;
Fig. 5 is for reaching external degradation figure in the water gel of the present invention;
Fig. 6 controls outward for water gel of the present invention and discharges BSA figure;
Fig. 7 is the cytotoxicity experiment of hydrogel of the present invention figure as a result;
Fig. 8 is the tissue slice figure under the hydrogel injection skin of the present invention;
Routine blood test and the hepatic and renal function indicatrix of the rat of Fig. 9 after for hydrogel of the present invention injection;
Figure 10 injects the function effect behind Left Ventricular Remodeling and the myocardial infarction for hydrogel of the present invention.
The specific embodiment
Embodiment 1:(1) preparation of hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan: a: the hydroxyethyl methylacrylate (HEMA) that will wait mol ratio and ε-caprolactone (CL) are in nitrogen atmosphere, with the stannous octoate is catalyst, 110 degrees centigrade were reacted 3 hours, and wherein mol ratio is a hydroxyethyl methylacrylate: ε-caprolactone: stannous octoate=1:1:0.01.Post reaction mixture is dissolved in oxolane, precipitates in cold water then, and this precipitate is dissolved in ethyl acetate, spends the night with dried over mgso, and concentrating under reduced pressure obtains hydroxyethyl methylacrylate-polycaprolactone (PCL-HEMA) then.B: the product hydroxyethyl methylacrylate-polycaprolactone and the carbonyl dimidazoles (CDI) that obtain are dissolved in oxolane with mol ratio 1:1, reaction is 24 hours in nitrogen atmosphere, by rotary evaporation to hydroxyethyl methylacrylate-polycaprolactone-imidazoles (HEMA-PCL-CL).C: above-mentioned product hydroxyethyl methylacrylate-polycaprolactone-imidazoles and α-(1 → 6)-D-glucosan (Dextran) mol ratio with 20:1 is dissolved in the dimethyl sulfoxine (DMSO), add with hydroxyethyl methylacrylate-polycaprolactone-imidazoles equimolar right-dimethylamino naphthyridine (DMAP), reaction is 4 days under the room temperature, the mixture that obtains precipitates in the isopropyl alcohol of 20 times of amounts, use washed with isopropyl alcohol then three times, vacuum drying obtains hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan (Dex-PCL-HEMA), its nuclear-magnetism figure as shown in Figure 1, by Fig. 1 C as can be seen, the two keys of hydroxyethyl methylacrylate appear at a peak, illustrate that the present invention has made hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan.
(2) N-N-isopropylacrylamide and hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan are dissolved in sodium hydrogen phosphate and sodium dihydrogen phosphate mole proportioning 1:2 phosphate buffer (pH7.4) the phosphate buffer phosphate buffer, the N that adds Ammonium persulfate. and catalytic amount then, N, N ', N '-tetramethylethylenediamine reacts under the room temperature and obtained hydrogel in 12-24 hours; The hydrogel that obtains is at room temperature dialysed with phosphate buffer, obtain Biodegradable hydrogel with temperature sensitivity; Wherein, the weight average molecular weight of α-(1 → 6)-D-glucosan is 15000-25000, the weight average molecular weight of hydroxyethyl methylacrylate-polycaprolactone is 500-3200, and the grafting degree of hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan is that per hundred glucosan unit have three polycaprolactone molecules to replace the hydroxyl of α-(1 → 6)-D-glucosan.
Embodiment 2: water gel is controlled outward and is discharged bovine serum albumin (BSA)
20 milligrams bovine serum albumins (number-average molecular weight is 67000) are dissolved in 1000 milligrams the phosphate buffer solution of DN2 hydrogel, wherein the content of hydrogel is 8%.Then, the phosphate buffer solution of this hydrogel is fully mixed with bovine serum albumin, place 50 milliliters centrifuge tube to spend the night, make the solution of hydrogel become the hydrogel of viscosity in 37 ℃ water-bath.20 milliliters of phosphate buffer solutions that are warming up to 37 ℃ in advance join in the DN2 hydrogel that has wrapped up bovine serum albumin at leisure.At the time point of setting, each phosphate buffer solution that takes out 4 milliliters from 20 milliliters delivery system adds fresh phosphate buffer solution simultaneously and makes its constancy of volume.With the concentration of ultraviolet spectrometer detection BSA wherein, the uv absorption wavelength is 280 nanometers, thereby calculates the BSA content that discharges from hydrogel.The cumulative release amount %=M of BSA
t/ M
0) * 100, wherein M
tBe the total BSA quality that discharges during for t the time, M
0It is the quality that the quality of 20 milligrams of BSA beginning to drop into is not wrapping to the BSA in the hydrogel during with parcel.In this experiment, the parcel efficient of BSA is 98%.Gelinite is controlled outward and is discharged the BSA curve as shown in Figure 6, discharges the soonest in preceding 5 hours, and the BSA of DN1, DN2, DN3, DN4 cumulative release is respectively 39%, 30%, 23%, 17%.Because the degraded of first day crosslinked ester bond is very fast, the speed that hydrophilic BSA is diffused in the buffer solution is also very fast, but at ensuing seven days, discharges progression and be almost zero level.
Embodiment 3: hydrogel carries mesenchymal stem cells MSCs and myocardial cell is injected in the rat body, relatively the differentiation of mesenchymal stem cells MSCs under varying environment and the difference of function and myocardial cell differentiation.
After rat is bought seven days, it is divided into four groups at random: 1. myocardial infarction group (8), 2. injection water gel group (8), 3. injection groups of cells (8), 4. injection cell and hydrogel group (11).All injections are all passed through No. 29 needle injection to the interior layer segment of cardiac muscle, and the volume of every group of injection is 200 microlitres.Inject 200 microlitre DMEM/F12 culture medium to myocardium internal layer for first group; Inject 200 microliters of water gels for second group; Inject the 200 microlitres 1*10 that suspended for the 3rd group
7The DMEM/F12 culture medium of individual mesenchymal stem cells MSCs; Inject the 1*10 that suspended for the 4th group
7Individual bone marrow monokaryon sarcoplast.According to being detection time 30 days, excessive pentobarbital sodium is put to death rat, get the left ventricle embedding then after frozen section carry out pathological analysis.Ultrasoundcardiogram: detect and injected the myoblastic left ventricular ejection mark of bone marrow monokaryon.The infarcted region cambium is observed in histological examination: HE dyeing, and the infarction wall thickness is measured in Masson ' Trichrome dyeing, calculates infarct size (infarcted region area/gross area).As can be known, behind the injection water gel, the blood circulation and the myocardial infarction of cardiac muscle have all obtained obvious improvement from harmony in the exterior figure.
The injection of subordinate list 1. hydrogels is to the function effect behind Left Ventricular Remodeling and the myocardial infarction.
Hydrogel of the present invention is as shown in figure 10 injected the function effect behind Left Ventricular Remodeling and the myocardial infarction: wherein, the LVEF left ventricular ejection fraction, the terminal diastole diameter of LVEDD left ventricle, the terminal contracted diameter of LVESD left ventricle, the terminal systolic pressure of LVSP left ventricle, the terminal diastolic pressure of LVEDP left ventricle, the first derivative of dp/dt pressure, infarct size myocardial infarction size, p＜0.005 expression has statistically-significant difference.
The character of Biodegradable hydrogel with temperature sensitivity of the present invention and experiment:
What last table was represented is the hydrogel for preparing under four kinds of different conditions of mixture ratios, wherein Dex-PCL-HEMA refers to hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan, NIPAAm refers to the N-N-isopropylacrylamide, APS refers to Ammonium persulfate., TEMED refers to N, N, N ', N '-tetramethylethylenediamine.
1. hydrogel colloidal sol and gel reversibility change
Hydrogel colloidal sol and gel reversibility as shown in Figure 2, along with the rising of temperature, hydrogel solution becomes gel in 1min; Reduce temperature, gel also becomes colloidal sol very soon.By the gelation process of the hydrogel solution of variable concentrations as can be known: concentration is high more, and gelation is fast more.When being raised to 37 ℃, when higher than its LCST (33.2 ℃), the hydrophilic/hydrophobic balance of PNIPAAm chain changes, and the PNIPAAm chain dewaters, and as shown in Figure 2, it is opaque that hydrogel solution becomes.But be noted that when being warmed up to 37 ℃, hydrogel only loses a spot of water, it still contains a large amount of moisture after the gelation.Fig. 2 shows that temperature is on LCST, and hydrogel forms a more stable gel rubber system, and this continues aspect the release good application is arranged at medicine and protein parcel.
Fig. 3 illustrates that hydrogel of the present invention is that 29-32 degrees centigrade of generations change mutually in temperature, and colloidal sol-gel conversion just takes place, and the intensity of hydrogel reaches maximum and stable in the time of 37 degrees centigrade, is suitable for injection in the body and as tissue engineering material.Gel 1, gel 2, gel 3 gels 4 are exactly respectively DN1, DN2, DN3, DN4.
2. inner pattern
As shown in Figure 4: the average pore size of hydrogel is dwindled along with the increase of the content of cross-linking agent, and the DN1 average pore size is 8 microns, reduces gradually then, and the average pore size of DN2, DN3, DN4 is respectively 6,4,2 microns, and the DN4 bore dia is 1/4 of DN1.Relation between the content of cross-linking agent and the hydrogel bore dia: crosslink density increases with the increase of the content component of cross-linking agent.This is because the crosslinked group of cross-linking agent is to be positioned at multiple glucose unit on the glucosan main chain.
3. reach external degradation in the body
As can be seen from Figure 5A: in the time of 37 ℃, than very fast, first day degradation rate is 2.8%-10.9% (DN1 increases gradually to DN4) to hydrogel in first three day degraded, and degradation rate obviously slows down after 3 days, between the 4-16 day, the degradation rate of DN1, DN2, DN3, four kinds of hydrogels of DN4 increases successively.First three day, dextran chain is cushioned solution and surrounds, ester bond generation hydrolysis between glucosan and the PCL-HEMA.In the time of 37 ℃, the hydrophilic and PNIPAAm hydrophobic of dextran chain, along with more and more glycosidic bonds fractures diffuse into buffer solution, gel is hydrophobic more and more, and therefore, water is difficult to be diffused in the hydrogel network.DN1, the DN2 that Fig. 4 shows, DN3, DN4 are after 16 days, and its weight reaches a steady statue, basically no longer degraded.
Roughly infer the degraded of hydrogel with the subcutaneous hydrogel maximum transverse diameter of subcutaneous injection group, represent (Fig. 5 B) with transverse diameter-time graph, we are similar to external degradation as can be seen, degraded in preceding 5 days is very fast, degraded later on slows down gradually, and the more external height of its final degradation rate can reach about 87%.
4. water gel is controlled outward and is discharged bovine serum albumin (BSA)
Gelinite is controlled outward and is discharged the BSA curve as shown in Figure 6, discharges the soonest in preceding 5 hours, and the BSA of DN1, DN2, DN3, DN4 cumulative release is respectively 39%, 30%, 23%, 17%.Because the degraded of first day crosslinked ester bond is very fast, the speed that hydrophilic BSA is diffused in the buffer solution is also very fast, but at ensuing seven days, discharges progression and be almost zero level.This be because, along with the degraded of crosslinked ester bond, hydrophilic dextran chain begins to be diffused among the PBS, hydrogel slowly becomes hydrophobicity.And at 37 ℃, the PNIPAAm structure of subsiding can be wrapped in remaining BSA in a large number, thereby postpones the release of BSA.When having only the DN degradation rate to tend towards stability, BSA burst size ability and time are linear.Degraded finishes, and release also finishes.Hence one can see that, and the release behavior of BSA medicine mainly is that the degraded by the cross-linking agent of DN hydrogel decides, rather than diffusion mechanism.
5. the cytotoxicity of hydrogel
Fig. 7 as can be seen, by the comparison of light absorption value and matched group, the hydrogel cell growth does not have obvious influence.
6. biocompatibility in the body
All rat lower limb exercise abilities do not have decline in the process of the test, the subcutaneous injection group has 1 the local skin necrosis to occur, be coated with to put on the skin after 4 days with erythromycin ointment and take a turn for the better, all the other rat parts not show are swollen, downright bad, frozen section after one week (Fig. 8, subcutaneous injection and the reaction of intramuscular injection rat local inflammation are slight; Hydrogel is injected and is respectively organized the blood leukocytes analysis after a week and do not have obvious significant difference.
The rat diet amount does not have significant change in the process of the test, no significant difference statistically between each group of hepatic and renal function index alanine aminotransferase, aspartate transaminase, creatinine, blood urea nitrogen, we have observed blood sugar concentration between three groups, hemocyte number there are no significant difference.(see figure 9)
Claims (6)
1. Biodegradable hydrogel with temperature sensitivity is made by purgation: (1) with mol ratio be the hydroxyethyl methylacrylate of 1:1-1:10 and ε-caprolactone in nitrogen atmosphere, be catalyst with the stannous octoate, 100-120 ℃ of reactions 3-12 hours; Post reaction mixture is dissolved in the oxolane, precipitation, and precipitate is dissolved in ethyl acetate, uses dried over mgso, and concentrating under reduced pressure obtains hydroxyethyl methylacrylate-polycaprolactone then; Hydroxyethyl methylacrylate-the polycaprolactone and the carbonyl dimidazoles that obtain are dissolved in oxolane with mol ratio 1:1-1:2, in nitrogen atmosphere, reacted 16-24 hours, obtain hydroxyethyl methylacrylate-polycaprolactone-imidazoles by rotary evaporation; With above-mentioned product hydroxyethyl methylacrylate-polycaprolactone-imidazoles and weight average molecular weight is that α-(1 → 6)-D-glucosan of 15000-25000 is dissolved in the dimethyl sulfoxine with the mol ratio of 20:1-30:1, add with hydroxyethyl methylacrylate-polycaprolactone-imidazoles equimolar right-dimethylamino naphthyridine, reacted 3-4 days under the room temperature, the mixture that obtains precipitates in isopropyl alcohol, use washed with isopropyl alcohol then, vacuum drying obtains hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan; (2) N-N-isopropylacrylamide and hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan is dissolved in the phosphate buffer of pH=7.4, the N that adds Ammonium persulfate. and catalytic amount then, N, N ', N '-tetramethylethylenediamine reacts under the room temperature and obtained hydrogel in 12-24 hours; The hydrogel that obtains is at room temperature dialysed with phosphate buffer, obtain Biodegradable hydrogel with temperature sensitivity.
2. the preparation method of the described Biodegradable hydrogel with temperature sensitivity of claim 1, it is characterized in that: (1) is that the hydroxyethyl methylacrylate of 1:1-1:10 and ε-caprolactone are in nitrogen atmosphere with mol ratio, with the stannous octoate is catalyst, and 100-120 ℃ were reacted 3-12 hours; Post reaction mixture is dissolved in the oxolane, precipitation, and precipitate is dissolved in ethyl acetate, uses dried over mgso, and concentrating under reduced pressure obtains hydroxyethyl methylacrylate-polycaprolactone then; Hydroxyethyl methylacrylate-the polycaprolactone and the carbonyl dimidazoles that obtain are dissolved in oxolane with mol ratio 1:1-1:2, in nitrogen atmosphere, reacted 16-24 hours, obtain hydroxyethyl methylacrylate-polycaprolactone-imidazoles by rotary evaporation; With above-mentioned product hydroxyethyl methylacrylate-polycaprolactone-imidazoles and weight average molecular weight is that α-(1 → 6)-D-glucosan of 15000-25000 is dissolved in the dimethyl sulfoxine with the mol ratio of 20:1-30:1, add with hydroxyethyl methylacrylate-polycaprolactone-imidazoles equimolar right-dimethylamino naphthyridine, reacted 3-4 days under the room temperature, the mixture that obtains precipitates in isopropyl alcohol, use washed with isopropyl alcohol then, vacuum drying obtains hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan; (2) N-N-isopropylacrylamide and hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan is dissolved in the phosphate buffer of pH=7.4, the N that adds Ammonium persulfate. and catalytic amount then, N, N ', N '-tetramethylethylenediamine reacts under the room temperature and obtained hydrogel in 12-24 hours; The hydrogel that obtains is at room temperature dialysed with phosphate buffer, obtain Biodegradable hydrogel with temperature sensitivity.
3. preparation method according to claim 2 is characterized in that: the consumption mass ratio of N-N-isopropylacrylamide, hydroxyethyl methylacrylate-polycaprolactone-g-α-(1 → 6)-D-glucosan and Ammonium persulfate. is 160-190:10-40:5-10.
4. according to claim 2 or 3 described preparation methoies, it is characterized in that: phosphate buffer is that sodium hydrogen phosphate and sodium dihydrogen phosphate are prepared in the ratio of mole proportioning 1:2.
5. the described Biodegradable hydrogel with temperature sensitivity of claim 1 is as the application of external medicine sustained release or tissue engineering bracket material.
6. the application of the described Biodegradable hydrogel with temperature sensitivity of claim 1 in the parcel stem cell of preparation treatment myocardial infarction.
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| CN1284811C (en) * | 2004-06-18 | 2006-11-15 | 武汉大学 | Biodegradable temperature-sensitive hydrogel and method for preparing same |
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