CN104804199A - Biomedical composite hydrogel, and preparation method and applications thereof - Google Patents
Biomedical composite hydrogel, and preparation method and applications thereof Download PDFInfo
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- CN104804199A CN104804199A CN201510038004.3A CN201510038004A CN104804199A CN 104804199 A CN104804199 A CN 104804199A CN 201510038004 A CN201510038004 A CN 201510038004A CN 104804199 A CN104804199 A CN 104804199A
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Abstract
The invention discloses a biomedical composite hydrogel. The biomedical composite hydrogel comprises following raw materials: hyaluronic acid, sodium alginate, 1,4-butanediol diglycidyl ether cross-linking agent, and sodium hydroxide solvent; mass ratio of hyaluronic acid to sodium alginate is 64-1:1-4; and concentration of 1,4-butanediol diglycidyl ether cross-linking agent ranges from 0.1 to 2%. Present application range of biodegradable biomedical gel is widened, the novel biomedical composite hydrogel can be applied to the field of cosmetic raw material or auxiliary material, tissue filling material, drug carrier or drug ingredient, wound or skin auxiliary material, tissue engineering scaffold material, anti-adhesion isolation material, and materials used for beautifying, wrinkle removing, and moisture retention. mechanical properties of the biomedical composite hydrogel is improved greatly without influencing gel biocompatibility and degradation properties; and biosecurity and degradability of the using amount of the crosslinking agent are ensured in single crosslinked membrane preparation.
Description
Technical field
The present invention relates to a kind of bio-medical composite aquogel, the invention still further relates to a kind of preparation method of bio-medical composite aquogel, the invention still further relates to a kind of application of bio-medical composite aquogel, belong to medical article field.
Background technology
Hydrogel is a kind of tridimensional network material formed by high molecular crosslink, because it contains a large amount of moisture content and quality is soft and be similar to bio-tissue, biomedicine is a kind of desirable material.The current research about composite aquogel and progress thereof mainly concentrate on nondegradable synthesized polymer material, the gel that mechanical property is very excellent can be obtained, break through conventional gel and be limited by the poor predicament of physical strength, but the non-biodegradable of synthesized gel rubber also there is very large restriction to its application at biomedical sector.Medically conventional hydrogel mostly is acrylamide series products, but this series products has monomer residue more, removes residual monomer very difficult, because this series products is substantially not biodegradable, therefore can only be used for long-time packing material.
Consider the requirement of regenerative medicine field to biomaterial degradability, in recent years, utilize degradation material to prepare the hydrogel with biocompatibility and become one of study hotspot, but prepared gel generally has poor mechanical property, resistance to compression, tension and anti-fatigue performance are poor, cause in use dressing easy fracture or frangible, the slight pressure that body kinematics brings can not be born, make in rehabilitation course, to need frequent more change dressings, can inconvenience be produced in the application, and certain negative impact is also produced to the healing of wound.More can not meet some special applications, as having the tissue regeneration of mechanical strength.
Hyaluronic acid (Hyaluronic acid, be called for short HA, the HA of commercial form mainly sells with the form of hyaluronate sodium, is the natural straight chain polymer polysaccharide (glycosaminoglycan that dissacharide units forms by NAG-D-Glucose aldehydic acid; GAG), the molecular weight of HA can up to 1-2000,000Da, there is good visco-elasticity, be distributed widely in the places such as the extracellular matrix of mammalian connective tissue, cockscomb and streptococcic folder film, there is good moisture retention, viscoelasticity, oilness, medicament slow release, suppression Inflammatory response and promote the functions such as wound healing.HA is the one of mucopolysaccharide, close interaction is had with cell surface, in the growth that bone develops, grow and play several functions in process of reconstruction, and in a lot of biological procedures, also having very important effect, as cell migration, propagation, organization formation, wound healing, vascularization and orga-nogenesis etc.Because HA is without kind and organspecific, demonstrating excellent body biocompatibility when implanting, is one of a kind of desirable bio-medical raw material.Natural HA is easily by the enzyme liberating in when injected organism tissue, and retention time is very short in vivo for it.Be 1 day according to the document HA transformation period in skin, be 1-1.5 hour in eyes, and be 1-3 week in cartilage, the transformation period in glass metal is 70 days.
Sodium alginate (Sodium Alginate, be called for short SA) the random block linear copolymer that is made up of α-L-guluronic acid (being denoted as G) and its steric isomer beta-D-mannuronic acid (being denoted as M) 2 kinds of monomers, by the mucopolysaccharide that Isosorbide-5-Nitrae-glycosidic link is formed by connecting.SA extracts from natural brown alga, there is good biocompatibility, biodegradability, moisture absorption become the advantage such as colloidality, high oxygen permeability, it is a kind of natural phant trauma repair material, implant and flap coverage time and body have no adverse reaction, and can treat or defective tissue in alternative body, Promotive union.
The HA gel be cross-linked by various method reported at present can extend its absorption in vivo, is mainly used in drainer for plastic surgery, mainly plays moisture-keeping function after injection.In the various cross-linking method reported and corresponding linking agent, with 1,4-butanediol diglycidyl ether (1,4-butanediol diglycidyl ether, referred to as BDDE) gel that obtains for linking agent approves the most at present in biological safety and degradation property, applies also extensive.But under the prerequisite keeping degradability and biocompatibility, HA gel ubiquity mechanical strength is poor, can not carry out the shortcomings such as effective sustained release to bioactive molecules.
Same, it is reported that the Wound dressing made of SA intercepting bacterium, virus except having during application, providing the functions such as the microenvironment being beneficial to healing, the more important thing is the Na in the human body penetrating fluid that wound infiltrates for wound
+with Ca
2+there is permutoid reaction, and Ca
2+be discharged into wound surface can play induced platelet activation, produce hemostasis somatomedin and the effect such as hemostasis and healing acceleration, obtain good market response.Due in SA gelation process without the need to adding other toxic cross-linking agents, therefore SA base gel application can not discharge hazardous and noxious substances in pharmaceutical carrier or tissue engineering bracket material, has been used as tissue engineering bracket material at present and has been expelled in animal and human's body.But the gel mechanics poor-performing that SA is formed, cannot be stressed, therefore can not be used for regenerating tendon or load-bearing district bone or the complex tissue such as cartilage or tooth, and the tissue that other biological mechanical property requirements is higher.
As can be seen here, independent sodium alginate and hyaluronic acid have very large use value and result of use, but also all there is a series of shortcoming and defect, how to be used for the Regeneration and Repair material of the high tissue of tendon equal strength, also the repair materials that need bear the surface of a wound or wound inside and outside certain stress solid can be used for, or heavy burden bone, cartilage regeneration, be those skilled in the art endeavour always study problem.
Summary of the invention
The object of the invention is to for deficiency of the prior art, a kind of bio-medical composite aquogel and preparation method and application thereof are provided, do not affect on the basis of gel biological compatibility and degradation property, there is the HA-SA plural gel of excellent mechanical intensity.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of bio-medical composite aquogel, its innovative point is: comprise following material composition: hyaluronate sodium, sodium alginate, BDO glycidyl ether crosslinking agent and sodium hydroxide solvent; Both mass ratioes of described hyaluronic acid and sodium alginate are 64 ~ 1:1 ~ 4; Described BDO glycidyl ether crosslinking agent volume concentration range is 0.1% ~ 2%.
Further, both mass ratioes of described hyaluronate sodium and sodium alginate are 32 ~ 1:1 ~ 2.
Further, both mass ratioes of described hyaluronate sodium and sodium alginate are 16 ~ 1:1.
Further, described BDO glycidyl ether crosslinking agent volume concentration range is 0.3% ~ 1.8%.
Further, described BDO glycidyl ether crosslinking agent volume concentration range is 0.4 ~ 1.2%.
Further, the concentration of polymer solution scope of described sodium hydroxide solvent is: 0.1% ~ 5%.
Another object of the present invention is to provide a kind of preparation method of bio-medical composite aquogel, and its innovative point is: specifically comprise the following steps:
(1) accurately take the hyaluronate sodium of proportional quantity, set to 0 in the sodium hydroxide solution of .1% ~ 5%, until dissolve completely, make hyaluronic mass concentration be 1%-8%;
(2) add the sodium alginate of proportional quantity in hyaluronic acid solution, both mass ratioes making hyaluronate sodium and sodium alginate are 64 ~ 1:1 ~ 4, (namely ensureing to make sodium alginate mass concentration be 0.015625% ~ 32%), Keep agitation is until thoroughly mix formation mixing solutions;
(3) in mixing solutions, add the BDO glycidyl ether crosslinking agent of proportional quantity, make BDO glycidyl ether crosslinking agent volume concentration range be 0.1% ~ 2%;
(4) mixing solutions in step (3) is placed in 40 ~ 60 DEG C and makes its Homogeneous phase mixing 3 ~ 8h, then mixed solution drying at room temperature 2 ~ 5d, treat that moisture evaporation rate is 85 ~ 95%, obtain hyaluronic acid-sodium alginate transparent membrane;
(5), after residual alkali lye being removed in diaphragm cleaning, being placed on mass concentration is 0.2% ~ 12%CaCl
2soak 8 ~ 32 hours in solution, obtain hyaluronic acid-sodium alginate plural gel;
(6) diaphragm cleans repeatedly with under phosphate buffered saline buffer and deionized water room temperature successively, and the linking agent of reaction is not participated in removing, obtains final hyaluronic acid-sodium alginate gel.
Further, described CaCl
2mass concentration scope is 0.4% ~ 10%.
Further, CaCl
2mass concentration scope is 0.6% ~ 8%.
A further object of the invention is to provide a kind of bio-medical composite aquogel, is mainly used in the field such as daily use chemicals raw material or auxiliary material, tissue bulking material, pharmaceutical carrier or drug formulations, the surface of a wound or skin auxiliary material, tissue engineering rack material, anti isolated material, beauty treatment, smoothing wrinkle, material which can retain moisture.
The theoretical basis of preparation method of the present invention: HA and SA is before crosslinking reaction starts, primary prerequisite is by the abundant dissolving of HA, SA and thoroughly mix, thus ensure that its macromolecular chain is mutually wound around with the unordered but form of complexity in whipping process, the first step is by BDDE being cross-linked HA, make to form the first layer tridimensional network between HA molecular chain, diaphragm can not be dissolved in water but form the good gel of water-absorbent, but mechanical property poor (all can be proved by the comparative example 1 and 3 in embodiment).Second step passes through Ca
2+sA in the first layer network structure is cross-linked, make to form second layer network structure between SA macromole, and second layer structure penetrates in the first layer structure, thus form a kind of penetrating type double cross connection gel network structure.Beneficial effect of the present invention is as follows:
(1) a kind of bio-medical composite aquogel of the present invention, with the effective constituent hyaluronic acid in hyaluronate sodium and sodium alginate for main raw material(s), form product hyaluronic acid-sodium alginate plural gel, not only there is degradability, also there is the characteristic of high strength, merged degradability and high strength performance cleverly, end-use is wide, is worth high.
(2) a kind of bio-medical composite aquogel of the present invention, break through the application category that biodegradable bio-medical gel is current, as a kind of novel bio-medical composite aquogel, Application Areas comprises daily use chemicals raw material or auxiliary material, tissue bulking material, pharmaceutical carrier or drug formulations, the surface of a wound or skin auxiliary material, tissue engineering rack material, anti isolated material, beauty treatment, smoothing wrinkle and material which can retain moisture etc.
(3) preparation method of a kind of bio-medical composite aquogel of the present invention, adopt penetrating type double cross connection preparation principle, on the basis not affecting gel biological compatibility and degradation property, the HA-SA plural gel with excellent mechanical intensity can be prepared, the Regeneration and Repair material of the high tissue of tendon equal strength can be used for, also can be used for the repair materials that need bear the surface of a wound or wound inside and outside certain stress solid, or heavy burden bone, cartilage regeneration.This technology utilizes BDDE and Ca
2+two kinds of different mechanism of crosslinkings, method is simple, without any toxicity, and can accurately control HA, SA degree of crosslinking separately and outstanding gel mechanical property.
(4) preparation method of a kind of bio-medical composite aquogel of the present invention, on the basis not affecting gel biological compatibility and degradation property, enhances the mechanical property of plural gel greatly; Above dosage of crosslinking agent, has proved biological safety and degradability all when preparing single cross connection diaphragm.Before crosslinking reaction occurs, HA and SA molecular chain is wound around in the solution each other mutually, is similar to " coil ", and after crosslinking reaction, molecular chain is fixed together by linking agent, forms a kind of inierpeneirating network structure; There is no the combination of chemical bond in two network component between differing molecular chain, all remain its respective performance, so the performance between two components can obtain complementation.Therefore, these two kinds of networks penetrate mutually and interact, and performance can produce special synergy, thus the intensity of hydrogel is improved.
Accompanying drawing explanation
Fig. 1 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 1.
Fig. 2 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 2.
Fig. 3 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 3.
Fig. 4 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 4.
Fig. 5 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 5.
Fig. 6 is gel Elongation test collection of illustrative plates in the specific embodiment of the invention 6.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is elaborated.
Hyaluronic acid (Hyaluronic acid is called for short HA) in following examples is the natural straight chain polymer polysaccharide (glycosaminoglycan that dissacharide units forms by NAG-D-Glucose aldehydic acid; GAG), the HA of commercial form mainly sells with the form of hyaluronate sodium, and namely the HA in following examples refers to hyaluronate sodium.
Embodiment 1
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 56 μ lBDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9 mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
When gel to be cut into the specification of 5cm × 3cm × 0.3cm by the plural gel of the present embodiment for detecting mechanical property.When for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Embodiment 2
Accurately take 0.4g HA, be placed in 0.56% sodium hydroxide solution of 9ml, until dissolve completely, in above-mentioned HA solution, add SA, make the concentration of SA be 2.1%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 72 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
As for detecting mechanical property gel being cut into the specification of 5cm × 3cm × 0.3cm.As for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Embodiment 3
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of HA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 28 μ l BDDE(linking agent final volume concentration is 0.4%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
As for detecting mechanical property gel being cut into the specification of 5cm × 3cm × 0.3cm.As for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Embodiment 4
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 84 μ l BDDE(linking agent final volume concentration is 1.2%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
As for detecting mechanical property gel being cut into the specification of 5cm × 3cm × 0.3cm.As for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Embodiment 5
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 56 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 1% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
As for detecting mechanical property gel being cut into the specification of 5cm × 3cm × 0.3cm.As for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Embodiment 6
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 56 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its mixing 4h that stirs, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 5% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
As for detecting mechanical property gel being cut into the specification of 5cm × 3cm × 0.3cm.As for cell and experiment in vivo, then should be placed in high pressure steam sterilization (120 DEG C, 20 min) and use afterwards.
Comparative example 1
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, and in mixing solutions, add 56 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h.Then mixed solution is placed in 3% CaCl
2soak 24 hours in solution, final gel-free is formed.
Comparative example 2
Accurately take 0.4g HA, be placed in 1% sodium hydroxide solution of 5ml, until dissolve completely.In HA solution, add 40 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak after 24 hours in solution, use phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final gel for subsequent use.
Comparative example 3
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.In above-mentioned HA solution, add SA, make the concentration of SA be 1.3%(mass percent), Keep agitation is until thoroughly mix, solution is placed in 40 DEG C and makes its Homogeneous phase mixing 4h, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.After residual alkali lye is removed in diaphragm cleaning, be placed on 3% CaCl
2soak 24 hours in solution, obtain HA-SA plural gel.Diaphragm uses phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH successively
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
Comparative example 4
Accurately take 0.4g HA, be placed in 0.71% sodium hydroxide solution of 7ml, until dissolve completely.SA is added in above-mentioned HA solution, the concentration of SA is made to be 1.3%(mass percent), Keep agitation is until thoroughly mix, in mixing solutions, add 56 μ l BDDE(linking agent final volume concentration is 0.8%), solution is placed in 40 DEG C and makes its mixing 4h that stirs, then mixed solution drying at room temperature 3d, treat that moisture evaporation rate is 90%, obtain HA-SA transparent membrane.Diaphragm is used successively phosphate buffered saline buffer (PBS: sodium-chlor (NaCl) 9mg/ml, potassium primary phosphate (KH
2pO
4) 0.03mg/ml, Sodium phosphate dibasic (Na
2hPO
4× 2H
2o) 0.14mg/ml, pH=7) and deionized water room temperature under repeatedly clean, to remove the linking agent not participating in reaction, obtain final HA-SA gel for subsequent use.
After the experiment of above embodiment and comparative example, the mechanical property tests data of preparation-obtained plural gel under drawing differential responses condition, shown in table 1 specific as follows, 2:
Table 1
| HA and SA mass ratio | BDDE concentration | CaCl 2Concentration | Plastic film mulch time of drying | Tension strain/% | Tensile stress/KPa | Remarks | |
| Embodiment 1 | 4:1 | 0.8% | 3% | 3d | 301.6% | 5.80 | |
| Embodiment 2 | 2:1 | 0.8% | 3% | 3d | 195.3% | 5.79 | |
| Embodiment 3 | 4:1 | 0.4% | 3% | 3d | 226.4% | 3.52 | |
| Embodiment 4 | 4:1 | 1.2% | 3% | 3d | 177.3% | 6.60 | |
| Embodiment 5 | 4:1 | 0.8% | 1% | 3d | 239.4% | 3.58 | |
| Embodiment 6 | 4:1 | 0.8% | 5% | 3d | 256.5% | 6.86 | |
| Comparative example 1 | 4:1 | 0.8% | 3% | / | / | / | Gel-free produces |
| Comparative example 2 | Participate in without SA | 0.8% | 3% | 3d | 123.4% | 1.23 | |
| Comparative example 3 | 4:1 | / | 3% | 3d | / | / | Gel-free produces |
| Comparative example 4 | 4:1 | 0.8% | / | 3d | 150% | 2.5 |
Table 2
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Ultimate load value (N) | 0.61 | 0.70 | 0.42 | 0.50 | 0.38 | 0.72 |
| Maximum tension displacement (mm) | 69.92 | 36.42 | 44.83 | 26.92 | 51.04 | 55.79 |
| Tension strain (%) | 301.6% | 195.3% | 226.4% | 177.3% | 239.4% | 256.5% |
As can be seen from table 1,2 data: the relative usage relation of the mechanical property of plural gel and two kinds of raw materials is very large.When the mass ratio of HA and SA is reduced to 2:1 from 4:1, gel tension strain declines, and be down to 195.3% from 301.6%, tensile stress is almost constant, can find out the consumption suitably reducing SA, can improve gel mechanical property; BDDE concentration also can affect plural gel mechanical property, when BDDE concentration is increased to 0.8% from 0.4%, gel tension strain is increased to 301.6% from 226.4%, tensile stress is increased to 5.80KPa from 3.52KPa, and when BDDE concentration is increased to 1.2% from 0.8%, gel tension strain declines, 177.3% is down to from 301.6%, tensile stress raises, and is increased to 6.6KPa, illustrates that the increase of BDDE linking agent makes gel fragility also increase from 5.8KPa.CaCl
2concentration and plural gel mechanical property have certain relation, along with CaCl
2concentration is increased to 3% from 1% and is increased to 5% again, and plural gel tension strain is increased to 301.6% from 239.4% and is reduced to 256.5% again, and tensile stress is increased to 5.80KPa from 3.58KPa is increased to 6.86KPa again, and the effect of embodiment 1 is best.
Gel detection is tested:
1, the mechanics of HA-SA gel detects
Before detecting for mechanical stretch (Instron5548, Instron, USA), gel sample is cut into 5 × 3 × 0.3cm
3specification, gel two sections, with in the fixing process of fixture, guarantees that gel does not stress, undeformed, guarantees that, before stretching experiment starts, gel is in the most original state.Under whole drawing process is in room temperature condition, rate of extension is 25mm/min, as shown in figs. 1 to 6: the gel Elongation test collection of illustrative plates in embodiment 1 ~ 6.
Macroscopic result shows: finally prepare and be cut into 5 × 3 × 0.3cm
3the HA-SA plural gel of specification, gel water white transparency, and water content is high, tensile property is good, not easily broken; 5 × 3 × 0.3cm
3the carrying out that the HA-SA plural gel of specification is fixed on instrument before stretching and after stretching by fixture contrasts, and shows the tensile property of this plural gel excellence.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (10)
1. a bio-medical composite aquogel, is characterized in that: comprise following material composition: hyaluronate sodium, sodium alginate, BDO glycidyl ether crosslinking agent and sodium hydroxide solvent; Both mass ratioes of described hyaluronate sodium and sodium alginate are 64 ~ 1:1 ~ 4; Described BDO glycidyl ether crosslinking agent volume concentration range is 0.1% ~ 2%.
2. bio-medical composite aquogel according to claim 1, is characterized in that: both mass ratioes of described hyaluronate sodium and sodium alginate are 32 ~ 1:1 ~ 2.
3. bio-medical composite aquogel according to claim 1, is characterized in that: both mass ratioes of described hyaluronate sodium and sodium alginate are 16 ~ 1:1.
4. bio-medical composite aquogel according to claim 1, is characterized in that: described BDO glycidyl ether crosslinking agent volume concentration range is 0.3% ~ 1.8%.
5. bio-medical composite aquogel according to claim 1, is characterized in that: described BDO glycidyl ether crosslinking agent volume concentration range is 0.4 ~ 1.2%.
6. bio-medical composite aquogel according to claim 1, is characterized in that: the mass concentration scope of described sodium hydroxide solution is 0.1% ~ 5%.
7. a preparation method for bio-medical composite aquogel according to claim 1, is characterized in that: specifically comprise the following steps:
Accurately take the hyaluronate sodium of proportional quantity, set to 0 in the sodium hydroxide solution of .1% ~ 5%, until dissolve completely, make hyaluronic mass concentration be 1%-8%;
In hyaluronic acid solution, add the sodium alginate of proportional quantity, both mass ratioes making hyaluronate sodium and sodium alginate are 64 ~ 1:1 ~ 4, and Keep agitation is until thoroughly mix formation mixing solutions;
In mixing solutions, add the BDO glycidyl ether crosslinking agent of proportional quantity, make BDO glycidyl ether crosslinking agent volume concentration range be 0.1% ~ 2%;
Mixing solutions in step (3) is placed in 40 ~ 60 DEG C and makes its Homogeneous phase mixing 3 ~ 8h, then mixed solution drying at room temperature 2 ~ 5d, treat that moisture evaporation rate is 85 ~ 95%, obtain hyaluronic acid-sodium alginate transparent membrane;
After residual alkali lye is removed in diaphragm cleaning, being placed on mass concentration is 0.2% ~ 12%CaCl
2soak 8 ~ 32 hours in solution, obtain hyaluronic acid-sodium alginate plural gel;
Diaphragm cleans repeatedly with under phosphate buffered saline buffer and deionized water room temperature successively, and the linking agent of reaction is not participated in removing, obtains final hyaluronic acid-sodium alginate gel.
8. the preparation method of bio-medical composite aquogel according to claim 7, is characterized in that: described CaCl
2mass concentration scope is 0.4% ~ 10%.
9. the preparation method of bio-medical composite aquogel according to claim 8, is characterized in that: described CaCl
2mass concentration scope is 0.6% ~ 8%.
10. a bio-medical composite aquogel according to claim 1, is mainly used in daily use chemicals raw material or auxiliary material, tissue bulking material, pharmaceutical carrier or drug formulations, the surface of a wound or skin auxiliary material, tissue engineering rack material, anti isolated material, beauty treatment, smoothing wrinkle, material which can retain moisture field.
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