A SUPERABSORBENT POLYMER HYDROGEL XEROGEL SPONGE AND PREPARATION METHOD AND APPLICATION THEREOF

Abstract

The patent provides a superabsorbent polymer hydrogel xerogel sponge and a preparation method and an application thereof. The sponge is a three-dimensional network porous sponge with chitosan as its skeleton, superabsorbent polymer as its branched chain, and macromolecule or polymer with flexible structure as its cross-linking agent. The sponge can be prepared by a one-pot method. The product has porous structure, having the characteristic of superabsorbent and maintaining integrity and certain mechanical strength after water absorption. The material can be used in the emergency hemostasis of large arteriovenous hemorrhage. The effect is better than that of the existing materials in the market. The superabsorbent hydrogel xerogel sponge provided by the invention has the advantages of simple preparation process, low cost. The product has outstanding hemostatic effect, good safety, with no heat production and no residue, and has significant medical value and industrial potential.

Claims

1-9. (canceled)

10. A superabsorbent polymer hydrogel xerogel sponge, wherein it is a three-dimensional network porous sponge with chitosan as its skeleton, superabsorbent polymer as its branched chain, and macromolecule or polymer with flexible structure as its cross-linking agent; wherein the superabsorbent polymer is sodium polyacrylate, polyacrylamide, polymethyl methacrylate and/or polyvinyl alcohol, and the cross-linking agent is one or more of NN-dimethyl acrylamide, methacrylic anhydride-terminated polyethylene glycol, acrylic anhydride-terminated polyethylene glycol, maleic anhydride-terminated polyethylene glycol, itaconic anhydride-terminated polyethylene glycol, formaldehyde and glutaraldehyde.

11. The superabsorbent polymer hydrogel xerogel sponge according to claim 10, wherein the chitosan is one or more of a methacrylic anhydride-terminated chitosan which is modified with methacrylic anhydride, an acrylic anhydride-terminated chitosan which is modified with acrylic anhydride, a maleic anhydride-terminated chitosan which is modified with maleic anhydride and an itaconic anhydride-terminated chitosan which is modified with itaconic anhydride.

12. The superabsorbent polymer hydrogel xerogel sponge according to claim 10, wherein the polyethylene glycol is selected from PEG-400, PEG-600, PEG-1500, PEG-4000, PEG-6000 and PEG-20000.

13. The superabsorbent polymer hydrogel xerogel sponge according to claim 10, wherein the chitosan accounts for 110% of the total mass of the sponge; the superabsorbent polymer accounts for 8598% of the total mass of the sponge; the cross-linking agent accounts for 0.55% of the total mass of the sponge.

14. The superabsorbent polymer hydrogel xerogel sponge according to claim 10, wherein the sponge further includes plasticizer, emulsifier and/or antioxidant.

15. The superabsorbent polymer hydrogel xerogel sponge according to claim 14, wherein the plasticizer is selected from propylene glycol, glycerin, sorbitol, span, tween, polyethylene glycol and/or sodium fatty acid.

16. The superabsorbent polymer hydrogel xerogel sponge according to claim 14, wherein the emulsifier is selected from span, tween or SDS solution.

17. A preparation method of a superabsorbent polymer hydrogel xerogel sponge, wherein the method comprises: mixing chitosan, superabsorbent polymer monomer, cross-linking agent, ammonium persulfate and pore-forming agent, and then obtaining porous sponge through free radical polymerization reaction; wherein, the superabsorbent polymer monomer is sodium acrylate, acrylamide, methyl methacrylate and/or vinyl alcohol; the cross-linking agent is one or more of NN-dimethyl acrylamide, methacrylic anhydride-terminated polyethylene glycol, acrylic anhydride-terminated polyethylene glycol, maleic anhydride-terminated polyethylene glycol, itaconic anhydride-terminated polyethylene glycol, formaldehyde and glutaraldehyde; the pore-forming agent is Na.sub.2CO.sub.3 or NaHCO.sub.3; the mass ratio of the chitosan, the superabsorbent polymer monomer, the cross-linking agent, the ammonium persulfate and the pore-forming agent is 1:(100300):(0.55):(0.55):(1020).

18. The preparation method according to claim 17, wherein the chitosan is one or more of a methacrylic anhydride-terminated chitosan which is modified with methacrylic anhydride, an acrylic anhydride-terminated chitosan which is modified with acrylic anhydride, a maleic anhydride-terminated chitosan which is modified with maleic anhydride and an itaconic anhydride-terminated chitosan which is modified with itaconic anhydride.

19. The preparation method according to claim 17, wherein the polyethylene glycol is selected from PEG-400, PEG-600, PEG-1500, PEG-4000, PEG-6000 and PEG-20000.

20. The preparation method according to claim 17, wherein it comprises the following steps: adding the cross-linking agent and the chitosan solution with a concentration of 1%-30% (g/ml) into the superabsorbent polymer monomer aqueous solution with a concentration of (70-99) v % at room temperature, stirring, and then adding the ammonium persulfate, after stirring, adding the pore-forming agent with a concentration of 1%-20% (g/ml), stirring and reacting at 50100 C. for 30-60 minutes to obtain porous sponge.

21. A superabsorbent polymer hydrogel xerogel sponge, wherein the sponge is prepared by using the methods of claim 17.

22. An application of the superabsorbent polymer hydrogel xerogel sponge according to claim 10 as a hemostatic sponge.

23. The application of claim 22, wherein the hemostatic sponge is used in emergency hemostasis, packing hemostasis, and wound plugging.

24. The superabsorbent polymer hydrogel xerogel sponge according to claim 11, wherein the chitosan accounts for 110% of the total mass of the sponge; the superabsorbent polymer accounts for 8598% of the total mass of the sponge; the cross-linking agent accounts for 0.55% of the total mass of the sponge.

25. The superabsorbent polymer hydrogel xerogel sponge according to claim 12, wherein the chitosan accounts for 110% of the total mass of the sponge; the superabsorbent polymer accounts for 8598% of the total mass of the sponge; the cross-linking agent accounts for 0.55% of the total mass of the sponge.

26. The superabsorbent polymer hydrogel xerogel sponge according to claim 11, wherein the sponge further includes plasticizer, emulsifier and/or antioxidant.

27. The superabsorbent polymer hydrogel xerogel sponge according to claim 12, wherein the sponge further includes plasticizer, emulsifier and/or antioxidant.

28. The preparation method according to claim 18, wherein it comprises the following steps: adding the cross-linking agent and the chitosan solution with a concentration of 1%-30% (g/ml) into the superabsorbent polymer monomer aqueous solution with a concentration of (70-99) v % at room temperature, stirring, and then adding the ammonium persulfate, after stirring, adding the pore-forming agent with a concentration of 1%-20% (g/ml), stirring and reacting at 50100 C. for 30-60 minutes to obtain porous sponge.

29. The preparation method according to claim 19, wherein it comprises the following steps: adding the cross-linking agent and the chitosan solution with a concentration of 1%-30% (g/ml) into the superabsorbent polymer monomer aqueous solution with a concentration of (70-99) v % at room temperature, stirring, and then adding the ammonium persulfate, after stirring, adding the pore-forming agent with a concentration of 1%-20% (g/ml), stirring and reacting at 50100 C. for 30-60 minutes to obtain porous sponge.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 illustrates the structure of a superabsorbent polymer hydrogel xerogel sponge.

[0033] FIG. 2 illustrates the water absorbency of the superabsorbent polymer hydrogel xerogel sponge.

[0034] FIG. 3 illustrates the hemostatic effect of femoral artery in rabbits.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The invention is further illustrated with reference to specific embodiments as follows. It should be noted that the embodiments herein are used only to illustrate the invention but not to limit the scope of the invention.

Embodiment 1 Preparation of Sample 1 of the Superabsorbent Polymer Hydrogel Xerogel Sponge

[0036] A polyethylene glycol (PEG) modified by methacrylic anhydride (MAA) as cross-linking agent and a sodium polyacrylate as water-absorbing polymer are reacted with MAA-terminated chitosan (MAACTS) to prepare sodium polyacrylate modified chitosan. The flow chart of the synthesis process is as follows:

##STR00001## ##STR00002##

[0037] Step 1: To 100 ml of chitosan (CTS) solution with a mass/volume fraction (g/ml) of 3%, 3 ml of methacrylic anhydride (MAA) was added. The mixture was mechanically stirred for 60 min at a speed of 1200 r/min to give methacrylic anhydride-terminated chitosan (MAACTS).

[0038] Step 2: To 50 ml of chloroform, 1 g of PEG-6000 was added. The mixture was magnetically stirred for 3 h, then 1 ml of methacrylic anhydride was added and magnetically stirred for 6 h, and thenvolatilized to remove chloroform to give PEG-6000 terminated with methacrylic acid white powder.

[0039] Step 3: To 300 ml of deionized water in a salt ice bath, 100 g of NaOH was added, the solution was mechanically stirred. When the temperature of the NaOH solution was droped to 0 C., 200 ml of acrylic acid (AA) solution was added while the solution temperature was controlled within 80 C. Then the solution temperature drops to room temperature, the solution obtained in Step 1 and the white powder obtained in Step 2 were added, and the mixture was mechanically stirred for 4 h.

[0040] Step 4: To the mixture obtained in Step 3, 6 g of ammonium persulfate was added, the mixture was mechanically stirred for 30 min, then 100 ml of 10% NaHCO.sub.3 was added with mechanically stirring to give white emulsion. The emulsion was added into a teflon grinding tool for reacting for 120 min at 80 C. to give white porous sponge.

[0041] Step 5: The sponge obtained in Step 4 was sequentially washed in 60%, 70% and 80% ethanol solutions for 4 times, and then volatilized to remove the ethanol to give white elastic sponge. The sponge was packaged, cut, and irradiated by cobalt 60 for sterilization.

Embodiment 2 Preparation of Sample 2 of the Superabsorbent Polymer Hydrogel Xerogel Sponge

[0042] Step 1: To 100 ml of chitosan solution with a mass/volume fraction (g/ml) of 3%, 3 ml of methacrylic anhydride was added. The mixture was mechanically stirred for 60 min at a speed of 1200 r/min to give methacrylic anhydride-terminated chitosan.

[0043] Step 2: To 50 ml of chloroform, 1 g of PEG-20000 was added. The mixture was magnetically stirred for 3 h, then 1 g of maleic anhydride was added and magnetically stirred for 6 h. Then the solution was added dropwise into excess ether to obtain white powder. The powder was dried under vacuum for 36 h. The dried white powder was purified in a co-precipitation system of chloroform/ether for 4 times, and thendried under vacuum for 36 h to give PEG-20000 terminated with maleic anhydride white powder.

[0044] Step 3: To 150 ml of deionized water in a salt ice bath, 50 g of NaOH was added, the solution was mechanically stirred. When the temperature of the NaOH solution drops to 0 C., 100 ml of acrylic acid solution was added while the solution temperature was controlled within 80 C. Then the solution temperature drops to room temperature, 50 g of acrylamide, the solution obtained in Step 1 and the white powder obtained in Step 2 was added, and the mixture was mechanically stirred for 4 h.

[0045] Step 4: To the mixture obtained in Step 3, 6 g of ammonium persulfate was added, the mixture was mechanically stirred for 30 min, then 100 ml of 10% NaHCO.sub.3 was added with mechanically stirring to give white emulsion. The emulsion was added into a teflon grinding tool for reacting for 120 min at 80 C. The product was sequentially washed in 60%, 70% and 80% ethanol solutions for four times, then volatilized to remove the ethanol to give white porous sponge. The sponge was packaged, cut, and irradiated by cobalt 60 for sterilization.

Embodiment 3 Preparation of Sample 3 of the Superabsorbent Polymer Hydrogel Xerogel Sponge

[0046] Step 1: To 100 ml of chitosan solution with a mass/volume fraction (g/ml) of 3%, 3 ml of methacrylic anhydride was added. The mixture was mechanically stirred for 60 min at a speed of 1200 r/min to give methacrylic anhydride-terminated chitosan.

[0047] Step 2: To 50 ml of chloroform, 1 g of PEG-20000 was added. The mixture was magnetically stirred for 3 h, then 1 g of itaconic anhydride was added and magnetically stirred for 6 h. The solution was added dropwise into excess ether to obtain white powder. The powder was dried under vacuum for 36 h. The dried white powder was purified in a co-precipitation system of chloroform/ether for 4 times, and then dried under vacuum for 36 h to give PEG-20000 terminated with itaconic anhydride white powder.

[0048] Step 3: To 150 ml of deionized water in a salt ice bath, 50 g of NaOH was added, the mixture was mechanically stirred. When the temperature of the NaOH solution was droped to 0 C., 100 ml of acrylic acid solution was added while the solution temperature was controlled within 80 C. Then the solution temperature drops to room temperature, 50 g of acrylamide, 50 ml of methyl methacrylate solution, the solution obtained in Step 1 and the white powder obtained in Step 2 was added, and the mixture was mechanically stirred for 4 h.

[0049] Step 4: To the mixture of Step 3, 6 g of ammonium persulfate, the mixture was mechanically stirred for 30 min, then 100 ml of 10% NaHCO.sub.3 was added with mechanically stirring to give white emulsion. The emulsion was added into a teflon grinding tool for reacting for 120 min at 80 C. to give white porous sponge.

[0050] Step 5: The sponge obtained in Step 4 was sequentially washed in 60%, 70% and 80% ethanol solutions for four times, and then volatilized to remove ethanol to give white porous sponge. The sponge was packaged, cut, and irradiated by cobalt 60 for sterilization.

Embodiment 4 Preparation of Sample 4 of the Superabsorbent Polymer Hydrogel Xerogel Sponge

[0051] Step 1: To 100 ml of chitosan solution with a mass/volume fraction (g/ml) of 3%, 3 ml of methacrylic anhydride was added. The mixture is mechanically stirred for 60 min at a speed of 1200 r/min to give methacrylic anhydride-terminated chitosan.

[0052] Step 2: To 50 ml of chloroform, 1 g of PEG-6000 was added. The mixture was magnetically stirred for 3 h, then 1 ml of methacrylic anhydride was added and magnetically stirred for 6 h, and then volatilized to remove chloroform to give PEG-6000 terminated with methacrylic acid white powder.

[0053] Step 3: To 150 ml of deionized water in a salt ice bath, 50 g of NaOH was added, the solution was mechanically stirred. When the temperature of the NaOH solution was droped to 0 C., 100 ml of acrylic acid solution was added while the solution temperature was controlled within 80 C. Then the solution temperature drops to room temperature, 50 g of acrylamide, 50 ml of polyvinyl alcohol solution, 50 ml of methyl methacrylate solution, the solution obtained in Step 1 and the white powder obtained in Step 2 was added, and the mixture was mechanically stirred for 4 h.

[0054] Step 4: To the mixture obtained in Step 3, 6 g of ammonium persulfate was added, the mixture was mechanically stirred for 30 min, then 100 ml of 10% NaHCO.sub.3 was added with mechanically stirring to give white emulsion. The emulsion was added into a teflon grinding tool for reacting for 120 min at 80 C. to give white porous sponge.

[0055] Step 5: The sponge obtained in Step 4 was sequentially washed in 60%, 70% and 80% ethanol solutions for four times, and then volatilized to remove ethanol to give white porous sponge. The sponge was packaged, cut, and irradiated by cobalt 60 for sterilization.

Embodiment 5 Physical and Structural Characteristics

[0056] The emergency hemostatic sponge material obtained in the embodiments 1-4 has a porous sponge-like structure (FIG. 2A), with a porosity of 40%-80%, a pore size of 100 um-2 mm, and extensive communication between the pores. Blood was rapidly drawn into the porous structure and concentrated once the sponge contacting with blood. After water absorption, the pore wall was thicken and gelled, the lumen was narrow down, and the viscoelasticity of the wall was increased, thereby buffering the blood flow. Moreover, the blood was high concentrated, rapidly forming and starting clotting, the formed blood clots would become more firmer through continuous water absorption, thereby a quick and effective hemostasis effect was achieved.

[0057] The samples of the superabsorbent polymer hydrogel xerogel sponge prepared by the embodiments 1-4 were observed for their general structures before and after contacting with blood, and the microstructures were examined with a scanning electron microscope. Represented by the Sample 1 as shown in FIG. 1, the samples are soft porous sponges with elastic, flexible and odorless features (FIG. 1 A). An interconnected porous structure is displayed under an electron microscope (FIG. 1B). Upon contacting with blood (FIG. 1C), the pore wall rapidly absorbs water and expands, making the channels narrow down until closed (FIG. 1D), and blood coagulate for rapid concentration (FIG. 1E).

Embodiment 6 Water-Absorbing Characteristic

[0058] Water-absorbing is an important characteristic in the invention. 0.100 g of a sample was accurately weighed and placed in a nylon fabric bag, which was then immersed in distilled water (pH=7.0, and the temperature of 25 C.) for naturally absorbing water and swelling at room temperature. The swelling sample was weighed after absorbing water on the surface of the fabric bag at 10 seconds, 20 seconds, 30 seconds, 45 seconds, 1 minute, 2 minutes, 4 minutes and 8 minutes, 16 minutes and 32 minutes respectively. The water absorption rate at each time point was calculated, so as to draw the relation curve between water absorption rate and time.

[0059] The formula for calculating the water absorption rate Q is that: Q=(m2m1)/m1, wherein, Q is the water (brine) absorption rate, g/g; ml is the mass of the sample before imbibing, g; m2 is the mass of the sample after imbibing, g.

[0060] Results as shown in FIG. 2 shows that the samples 1-4 exhibit similar water absorption, reach maximum water absorption rate of about 165 times and maximum brine absorption rate of about 72 times within 3 minutes.

Embodiment 7 In-Vitro Clotting Ability

[0061] The emergency hemostatic sponge prepared in Embodiment 1 was used for in vitro coagulation test. Collagen hemostatic fiber (Avitene) was used as a control group to be compared with the material provided by the invention. Blood samples were collected from healthy donors (n=3). The experimental process and results as follows:

[0062] Effect Analysis of In-Vitro Coagulation Test is that:

[0063] The in-vitro clotting ability of the emergency hemostatic sponge was detected by a hemate elastometer (TEG) (as shown in Table 1). The experimental results show that compared with the negative control group, R-time and K-time of the samples in each group are significantly decreased (p<0.05), while Angle deg and MA values are significantly increased; compared with the positive control group, no significant difference is provided in R-time, K-time, Angle deg and MA (p>0.05). These indicate that the experimental materials in each group have the same strength as the collagen fiber (Avitene) as the control group to initiate the endogenous coagulation mechanism of blood.

TABLE-US-00001 TABLE 1 TEG Analysis Materials R.sup.c(min) K.sup.d (min) Angle deg.sup.e MA (mm).sup.f Negative 7.63 0.45 3.80 0.22 51.47 1.52 52.20 2.41 control group.sup.a Positive control 3.41 0.24 2.63 0.33 57.33 0.71 54.51 2.41 group.sup.b Sample 1 3.56 0.25 2.23 0.28 60.50 0.65 59.70 1.45 Sample 2 3.35 0.32 2.22 0.19 59.46 0.48 58.37 2.26 Sample 3 3.64 0.54 2.43 0.22 58.47 0.57 57.64 2.19 Sample 4 3.55 0.19 2.59 0.31 56.78 0.39 59.34 1.98 .sup.aNo hemostatic material is added to the negative control group, and blood is naturally coagulated. .sup.bThe positive control group is collagen sponge (Avitene), a strong trigger for endogenous coagulation. .sup.cR: the time that activating thrombin should be used, namely, the time that blood clots just occurred in blood. .sup.dK: the time required to form a stable clot. .sup.eAngle deg: measuring the rate of fibrin netting, thereby the rate of clot formation is evaluated. .sup.fMA: the strength of the fibrin blood clot.

Embodiment 8 Hemostasis Test of Femoral Artery of Rabbits

[0064] Healthy male rabbits, weighing 2.5-3.1 kg, are anesthetized with 1% of pentobarbital sodium in the marginal ear vein. The groin skin of right hind leg was shaved, the skin and subcutaneous tissue were cut, the femoral artery 2 cm from the groin was separated, and then punctured through the wall of the contralateral blood vessel with a 16 G needle. Then the arterial clamp was released for naturally bleeding for 5 seconds. Using gauze to wipe off the blood, and then immediately stop bleeding. Common gauze of 32 layers was used as a negative control, and QuikClot Combat Gauze (Z-Medica, U.S., Army Equipment Force) was used as a positive control. Each group comprises 10 animals. Local pressure was applied for 1 minute to observe whether the bleeding was stopped. The material was carefully removed after five minutes if no bleeding, and then observed whether bleeding. The results are shown in Table 2.

[0065] In the course of hemostasis, no effective hemostasis was shown in the negative control group, and all animals died. In QuikClot Combat Gauze group, 7 animals still had different degrees of bleeding after removing pressure, only 3 animals showed no bleeding yet all bled again after 5 minutes of material removal. The water-absorbent polymer hydrogel xerogel sponge of the four formulas provided by the invention achieved hemostatic effect in the hemostasis of rabbit femoral artery in all cases (FIG. 3). All animals in the experimental groups had no bleeding within 5 minutes after removing pressure. The hemostatic sponge closely adhered to the wound tissue once removed from the wound surface, showing excellent wound closure. After the removal, the wound surface was clean, no secondary bleeding, and no blood clot residue. The bleeding loss of animals was far less than that of the control group (p<0.01).

TABLE-US-00002 TABLE 2 Hemostasis of Femoral Artery in Rabbits Performance Number of Successful Secondary Blood loss Materials animals Press-time hemostasis.sup.d bleeding.sup.e (g) Control 10 1 0/10 NA NA 1.sup.a Control 10 1 5/10 3/10 4.67 0.31 2.sup.b Control 10 1 7/10 2/10 0.39 0.57 2.sup.c Sample 1 10 1 10/10 0/10 2.35 0.21 Sample 2 10 1 10/10 0/10 3.24 0.35 Sample 3 10 1 10/10 0/10 2.69 0.19 Sample 4 10 1 10/10 0/10 2.89 0.36 .sup.aControl 1 is 32 layers of plain gauze .sup.bControl 2 is QuikClot Combat Gauze .sup.cControl 3 is Celox .sup.dNo bleeding after removal of pressure is considered as successful hemostasis .sup.eNo bleeding after the removal of pressure yet bleeding within the next 5 minutes is considered secondary bleeding.