CN103418023B - Multilayer composite hemostatic material and preparation method thereof - Google Patents
Multilayer composite hemostatic material and preparation method thereof Download PDFInfo
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Abstract
The invention provides a multilayer composite hemostatic material, which is characterized in that the material is formed by compounding a PLGA hollow nano fiber layer, a gelatin hollow nano fiber layer, a chitosan hollow nano fiber layer and an alginate nano fiber layer through mould pressing at the periphery. The multilayer composite hemostatic material has the advantages that the defects that the fiber hemostatic material prepared through electrostatic spinning is thinner and softer are overcome, the thickness of the material is increased, the compression hemostasis effect is improved, the defects that the traditional hemostatic material has a single variety, is narrow in application range, and cannot be applied to various complex bleeding situations are overcome, and the application range is widened. In addition, the multilayer composite hemostatic material provided by the invention takes the material shape with the soft middle part and hard periphery, easy to take for use, and can be applied in an operation more conveniently.
Description
Technical field
The present invention relates to a kind of MULTILAYER COMPOSITE hemostatic material and preparation method thereof, belong to pharmaceuticals field.
background technology
In operation and the wound phenomenon of conventionally bleeding profusely, conventional processing method has Manual press, burns, stitching etc., but can effectively not control the leakage of blood.Traditional hemorrhage, as taking gelatin protoplasm as basic powder, sponge and fabric etc., for the formation of natural thrombosis provides grid, but easily stimulates the endogenous hemostasis cascade reaction of patient, thereby easily causes forming thromboembolism and local inflammatory response.Therefore need a kind of be applicable to various operations and field traumatism treatment have outstanding haemostatic effect can bio-absorbable hemostatic material replace traditional hemostatic material, especially in the operations such as operation on heart, operation on vertebra and liver transplantation or ablation of tumors, neurosurgery, it is particularly important that the anthemorrhagic speed of hemostatic material and haemostatic effect seem.
At present, existing multiple patents and lot of documents have been reported the development of novel hemostatic material, and kind and the technology of preparing of the material of developing are also varied.In these patents and document, have a large amount of similarities, as the selection of hemostatic material nothing more than common several hemostatic materials as sodium carboxymethyl cellulose class material (ZL201210563634.9 sodium alginate and sodium carboxymethyl cellulose blended fiber and preparation and application thereof; 201110328419.6 medical wet combine dressing and manufacture methods thereof), gelatin class material (ZL200910092911.0 multi-purpose gelatin fiber and preparation method thereof; Tissue engineering comea fibrous scaffold and preparation method that mono-kind of ZL200910217762.6 degraded is controlled), chitosan class material (the local and inner hemorrhage using of ZL201010185135.1; ZL201020688022.9 chitosan fiber medical dressings; ZL201110044474.2 Chitosan first aid hemostatic material), alginates material (ZL201110081468.4 spinning solution and manufacture raw doctor's fiber process; The preparation method of ZL200810100981.1 pure sodium alginate sodium rice fiber film material), and the material of these compounds even compound or blending of mutually combining, this material mainly adopts the method preparations such as wet spinning, lyophilization, electrostatic spinning.
Wherein electrospinning process is a kind of method of simple, convenient, cheap production nano-fiber film material, and prepared fibre diameter can be received to hundreds of and between micron, regulate arbitrarily, changes in tens nanometers.This nanofiber has larger specific surface area with respect to traditional fabric, thereby has more outstanding absorption property.But electrostatic spinning is prepared the critical defect of material, can only obtain very thin fiber film material, this ultra-thin membrane material very light weight, the hemostatic material making is in use very easily curling, and because it is ultra-thin, cannot form effective Compressive Hemostasis, limit its practical application in clinical medicine.
summary of the invention
The object of the present invention is to provide a kind of MULTILAYER COMPOSITE hemostatic material with outstanding haemostatic effect and preparation method thereof.
MULTILAYER COMPOSITE hemostatic material of the present invention, is characterized in that, it is composited through mold pressing in surrounding by PLGA hollow Nano fiber in use layer, gelatin hollow Nano fiber in use layer, chitosan hollow nanofiber layer and alginate nano fibrous layer.
In addition, also can be as required at the hemostasis of filling between layers class medicine, anti-infection drug, the pain relieving class medicine of MULTILAYER COMPOSITE hemostatic material of the present invention or promote the tissue repair factor.The thickness of MULTILAYER COMPOSITE hemostatic material of the present invention can be adjustable arbitrarily according to actual needs, generally between 0.3-3cm.
Method for the preparation of above-mentioned MULTILAYER COMPOSITE hemostatic material of the present invention, is characterized in that, comprises the steps:
(1) coaxial spin processes is prepared PLGA hollow Nano fiber in use net
With chloroform, DMF, the mixed liquor of THF or DMF and THF is solvent, compound concentration is the PLGA spinning solution of 0.5-1.5g/ml, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-2.0ml/h, stratum nucleare solution flow rate is 0.2-1.0ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-20kV, collecting distance is 5-15cm, acquisition time is 8-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, afterwards with cyclohexane extraction or carbon tetrachloride extraction oil ingredient wherein, last vacuum drying, obtain pure PLGA hollow Nano fiber in use net,
(2) coaxial spin processes is prepared gelatin hollow Nano fiber in use net
Taking formic acid or water as solvent, compound concentration is the gelatin spinning solution of 15-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-1.0ml/h, stratum nucleare solution flow rate is 0.2-0.5ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, the ambient temperature of spinning duration is controlled at more than 40 DEG C, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure gelatin hollow Nano fiber in use net,
(3) coaxial spin processes is prepared chitosan hollow nanometer fiber net
Taking spirit acid or trifluoroethanol as solvent, compound concentration is the chitosan spinning solution of 5-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 10-40 μ l/h, stratum nucleare solution flow rate is 5-20 μ l/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure chitosan hollow nanometer fiber net,
(4) method of electrostatic spinning is prepared alginate nano fleece
Can adopt patent and literature method preparation, specifically can be referring to the preparation method of Chinese patent ZL200810100981.1 pure sodium alginate nano fiber membrane material and document Biomacromolecules2008,9,1362-1365.Concrete steps are: by alginate and glycerol by weight volume ratio 2-4g/ml mix, then in mixed liquor, add aqueous solvent, wherein the volume ratio of water and glycerol is 0.5-1:1, stirs, static bubble removing, obtain spinning solution, spinning solution flow velocity is 50-200 μ l/h, and solution flow rate is accurately controlled by syringe pump, and spinning voltage regulates between 10-40kV, spinning head and receptor spacing are 5-15cm, and receptor is immersed in by CaCl
2in the coagulating bath of aqueous solution and dehydrated alcohol composition, acquisition time is 36-72 hour, and collected web thickness is adjustable continuously between hundreds of micron to 2 millimeter, by obtained fleece vacuum drying, obtains alginate nano fleece;
(5) through the compound layers of material of mold pressing
Get the each fleece preparing, it is superimposed, and fill between the layers as required hemostasis class medicine, anti-infection drug, pain relieving class medicine or promote after the tissue repair factor, adopt hollow shape mould, it is pressed into hard, the middle soft shape of surrounding of given size, then use cutter cutting, wherein molding pressure is 100-400N/cm
2(changing along with the thickness of sample), each fibroreticulate number of plies is 1 layer or multilamellar;
(6) disinfect
With gamma-radiation to the composite disinfection obtaining after, just obtain MULTILAYER COMPOSITE hemostatic material.
In at least in any one of the coaxial spinning shell solution of step (1)-(3), also preferably further add the CNT of single wall or many walls, to play toughness reinforcing and antibacterial effect.In step (5), the interpolation of various medicines can adopt electrostatic atomization technology.
MULTILAYER COMPOSITE hemostatic material of the present invention has overcome the prepared softer shortcoming of fiber hemostatic material compare Bao ﹑ of electrostatic spinning, improve material thickness, improve Compressive Hemostasis, and improve traditional hemostatic material kind Dan mono-﹑ narrow application range, cannot tackle the shortcoming of Various Complex bleeding, expanded its range of application.In addition, the hard material shape of soft surrounding in the middle of MULTILAYER COMPOSITE hemostatic material of the present invention forms and has, within easy reach can use more easily in operation.
Brief description of the drawings
Fig. 1 is the schematic diagram of showing MULTILAYER COMPOSITE hemostatic material mode of appearance of the present invention.
Fig. 2 is the schematic diagram of showing MULTILAYER COMPOSITE hemostatic material cross-section structure of the present invention.
Fig. 3 is the SEM figure of the gelatin hollow Nano fiber in use net materials prepared of embodiment 1.
Fig. 4 is PLGA hollow Nano fiber in use net materials prepared by embodiment 1, and wherein (a) is photo in kind, (b) with the SEM figure that (c) is respectively positive and section.
Fig. 5 is the SEM figure of the chitosan hollow nanofiber net materials prepared of embodiment 1.
Detailed description of the invention
MULTILAYER COMPOSITE hemostatic material of the present invention, is characterized in that, it is composited through mold pressing in surrounding by PLGA hollow Nano fiber in use layer, gelatin hollow Nano fiber in use layer, chitosan hollow nanofiber layer and alginate nano fibrous layer., MULTILAYER COMPOSITE hemostatic material of the present invention is a kind of middle layering forming by mould pressing technology and the not stratified stereochemical structure of surrounding.
Fig. 1 is the schematic diagram of showing MULTILAYER COMPOSITE hemostatic material mode of appearance of the present invention, and Fig. 2 is the schematic diagram of showing MULTILAYER COMPOSITE hemostatic material cross-section structure of the present invention.As Fig. 1, shown in 2, it is the part of surrounding through mold pressing that MULTILAYER COMPOSITE hemostatic material of the present invention has huttriall A() and the i.e. middle part without mold pressing of the soft B(of portion), layer 1-4 represents respectively each layer of MULTILAYER COMPOSITE hemostatic material of the present invention, it is PLGA hollow Nano fiber in use layer, gelatin hollow Nano fiber in use layer, chitosan hollow nanofiber layer and alginate nano fibrous layer, each layer put in order is not particularly limited, can adjust arbitrarily as required, but preferably press gelatin, alginate, chitosan, the order of PLGA is arranged each layer, this is because gelatin fiber, alginate fiber has extremely strong hygroscopicity, can be adsorbed on wound surface in moment, form gel state, be conducive to the quick-acting haemostatic powder of wound, and the network structure of chitin fiber and PLGA fiber (especially PLGA fiber) has special support effect to wound, can reduce the secondary of wound tears and wound adhesion.
MULTILAYER COMPOSITE hemostatic material of the present invention has above-mentioned 4 layers of structure at least, can, according to the required mechanical property of practical application and required haemostatic effect, adjust each fibrolaminar number of plies and ratio.
In addition, as shown in Figure 2, also can be as required in the hemostasis of filling between layers class medicine, anti-infection drug, pain relieving class medicine or the promotion tissue repair factor of MULTILAYER COMPOSITE hemostatic material of the present invention, MULTILAYER COMPOSITE hemostatic material of the present invention also can further contain medicine layer 5.As hemostasis class medicine, can enumerate Ba Quting, card network sulphur, kind peaceful, etamsylate, Aminomethylbenzoic Acid etc.; As described anti-infection drug, can enumerate gentamycin, lincomycin, erythromycin etc.; As pain relieving class medicine, can enumerate lidocaine hydrochloride etc.In addition, the thickness of MULTILAYER COMPOSITE hemostatic material of the present invention can be adjustable arbitrarily according to actual needs, generally between 0.3-3cm.
Method for the preparation of above-mentioned MULTILAYER COMPOSITE hemostatic material of the present invention, is characterized in that, comprises the steps:
(1) coaxial spin processes is prepared PLGA hollow Nano fiber in use net
With chloroform, DMF, the mixed liquor of THF or DMF and THF is solvent, compound concentration is the PLGA spinning solution of 0.5-1.5g/ml, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-2.0ml/h, stratum nucleare solution flow rate is 0.2-1.0ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-20kV, collecting distance is 5-15cm, acquisition time is 8-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, afterwards with cyclohexane extraction or carbon tetrachloride extraction oil ingredient wherein, last vacuum drying, obtain pure PLGA hollow Nano fiber in use net,
(2) coaxial spin processes is prepared gelatin hollow Nano fiber in use net
Taking formic acid or water as solvent, compound concentration is the gelatin spinning solution of 15-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-1.0ml/h, stratum nucleare solution flow rate is 0.2-0.5ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, the ambient temperature of spinning duration is controlled at more than 40 DEG C, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure gelatin hollow Nano fiber in use net,
(3) coaxial spin processes is prepared chitosan hollow nanometer fiber net
Taking spirit acid or trifluoroethanol as solvent, compound concentration is the chitosan spinning solution of 5-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 10-40 μ l/h, stratum nucleare solution flow rate is 5-20 μ l/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge (for example 30,000 revs/min) centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure chitosan hollow nanometer fiber net,
(4) method of electrostatic spinning is prepared alginate nano fleece
Can adopt patent and literature method preparation, specifically can be referring to the preparation method of Chinese patent ZL200810100981.1 pure sodium alginate nano fiber membrane material and document Biomacromolecules2008,9,1362-1365.Concrete steps are: by alginate and glycerol by weight volume ratio 2-4g/ml mix, then in mixed liquor, add aqueous solvent, wherein the volume ratio of water and glycerol is 0.5-1:1, stirs, static bubble removing, obtain spinning solution, spinning solution flow velocity is 50-200 μ l/h, and solution flow rate is accurately controlled by syringe pump, and spinning voltage regulates between 10-40kV, spinning head and receptor spacing are 5-15cm, and receptor is immersed in by CaCl
2in the coagulating bath of aqueous solution and dehydrated alcohol composition, acquisition time is 36-72 hour, and collected web thickness is adjustable continuously between hundreds of micron to 2 millimeter, by obtained fleece vacuum drying, obtains alginate nano fleece;
(5) through the compound layers of material of mold pressing
Get the each fleece preparing, it is superimposed, and fill between the layers as required hemostasis class medicine, anti-infection drug, pain relieving class medicine or promote after the tissue repair factor, adopt hollow shape mould, it is pressed into hard, the middle soft shape of surrounding of given size, then use cutter cutting, wherein molding pressure is 100-400N/cm
2(changing along with the thickness of sample), each fibroreticulate number of plies is 1 layer or multilamellar;
(6) disinfect
With gamma-radiation to the composite disinfection obtaining after, just obtain MULTILAYER COMPOSITE hemostatic material.
In at least in any one of the coaxial spinning shell solution of step (1)-(3), also preferably further add the CNT of single wall or many walls, to play toughness reinforcing and antibacterial effect.In step (5), the interpolation of various medicines can adopt electrostatic atomization technology.
MULTILAYER COMPOSITE hemostatic material of the present invention has following beneficial effect:
(1) combine with multilamellar mould pressing technology, overcome prepared fiber hemostatic material thinner (thickness <1mm) shortcoming that ﹑ is softer of electrostatic spinning, improved material thickness, improved Compressive Hemostasis.
(2) between each layer, add as required the various medicines of different cultivars, various dose, improve traditional hemostatic material kind Dan mono-﹑ narrow application range, cannot tackle the shortcoming of Various Complex bleeding, expand its range of application, reduced anaphylaxis and rejection in corrective surgery process.
(3) by mold pressing processing, form and there is the hard material shape of middle soft surrounding, within easy reach can use more easily in operation.
(4) PLGA fiber has good mechanical property, can absorb moisture and form after gel at gelatin fiber, chitin fiber and alginate fiber, in dressing, still keep original fibrillar meshwork structure, maintain moist environment, and make the gel film that forms can be long-term placement of wound site and not fragile.When wound enters into granulation growth stage, PLGA fiber can be used as skeleton, for granulation growth provides space and nutrition switched environment.At the last stage of wound healing, i.e. epithelization regeneration period, the network structure of PLGA fiber is very beneficial for epithelial tissue growth and climbs attachedly, promotes wound healing.The wound oozing out for severe, utilizes the network structure of PLGA fiber, and the wound that need to support some has special-effect, can also reduce the secondary of wound and tear.
(5) the especially use of hollow Nano fiber in use of nanofiber, has increased the specific surface area of fiber, has improved absorption property and the drug loading amount of hemostatic material.
(6) all adopt degradable biomedical material, can automatically degrade after surgery, and can prevent the adhesion between tissue, accelerate wound repair.
Embodiment
Further illustrate the present invention below by embodiment.But the present invention is not subject to the restriction of this embodiment, before and after meeting the present invention, in the scope of aim, can do suitable variation, these include in technical scope of the present invention.
One, the preparation of MULTILAYER COMPOSITE hemostatic material
The preparation of embodiment 1(1 sample)
(1) preparation of gelatin hollow Nano fiber in use net materials
Spinning experiment adopts coaxial spinning syringe needle, and its specification is that inner syringe needle internal diameter is 0.3mm, and outside syringe needle internal diameter is 1.2mm.Taking gelatin as raw material, formic acid is solvent, at normal temperatures, gelatin is dissolved in formic acid, and agitating solution homogeneous transparent, wherein the mass fraction of gelatin is 20%, the shell solution that this solution is coaxial spinning.Stratum nucleare solution adopts Oleum sesami.Above-mentioned solution left standstill is removed to bubble as spinning solution, inject syringe, shell solution flow rate is 0.6ml/h, and stratum nucleare solution flow rate is 0.3ml/h, and solution flow rate is accurately controlled by syringe pump.At 22kV voltage, under the condition that spinning head and receptor (aluminum film) spacing is 12cm, carry out electrostatic spinning, acquisition time is 48 hours, and the ambient temperature of spinning duration is controlled at more than 40 DEG C, and the thickness of collected doughnut net materials is about 2 millimeters.First the doughnut net materials of collection is put into the high speed centrifuge centrifugation de-oiling of 30,000 revs/min, extracted oil ingredient wherein afterwards with cyclohexane extraction, last vacuum drying 8h, obtains pure gelatin hollow Nano fiber in use net materials.
(2) preparation of sodium alginate nano fiber net materials
Taking sodium alginate as raw material, modifier is glycerol, at normal temperatures sodium alginate is scattered in glycerol, wherein sodium alginate and glycerol by weight volume ratio be 4g/ml, then in mixed liquor, add water, wherein the volume ratio of water and glycerol is 1:1, stirs, static bubble removing, obtains spinning solution.Be 22kV at voltage, flow velocity is 92 μ l/h, and spinning head and receptor (copper mesh) spacing is 10cm, and receptor is immersed in coagulating bath, and (coagulating bath is the CaCl by mass percentage concentration 6%
2the mixed liquor of aqueous solution and the dehydrated alcohol composition that mass percent is 80% in mixed liquor) in, carry out electrostatic spinning, acquisition time is 48 hours, the thickness of collected web material is about 1 millimeter.By the material vacuum drying 8h obtaining, obtain sodium alginate nano fiber net materials.
(3) preparation of PLGA hollow Nano fiber in use net materials
Spinning experiment adopts coaxial spinning syringe needle, and its specification is that inner syringe needle internal diameter is 0.3mm, and outside syringe needle internal diameter is 1.2mm.With PLGA(50:50, M
w=120,000) be raw material, taking the mixed liquor of DMF and THF as solvent (volume ratio of DMF and THF is as 1:1), at normal temperatures PLGA is dissolved in the mixed liquor of DMF and THF, being mixed with PLGA concentration is 1.0g/ml, stir, and standing, gas removal bubble, obtain spinning solution, the shell solution that this solution is coaxial spinning.Stratum nucleare solution adopts Oleum sesami.Above-mentioned solution is injected to syringe, and solution flow rate is accurately controlled by syringe pump, and shell solution flow rate is 1.0ml/h, and stratum nucleare solution flow rate is 0.6ml/h.Spinning voltage is 15kV, and spinning head and receptor (aluminum film) spacing is 15cm, and acquisition time is 48 hours, and the thickness of collected doughnut net materials is about 1.5 millimeters.First the material obtaining is put into the high speed centrifuge centrifugation de-oiling of 30,000 revs/min, extracted oil ingredient wherein afterwards with cyclohexane extraction, last vacuum drying 8h, obtains pure PLGA hollow Nano fiber in use net materials.
(4) preparation of chitosan hollow nanofiber net materials
With chitosan (molecular weight 106,000g/mol) be raw material, taking spirit acid (quality of acetic acid mark as 90% aqueous solution) as solvent, at normal temperatures chitosan is dissolved in spirit acid, be mixed with mass fraction and be 6% chitosan solution, stir, standing, gas removal bubble under room temperature, the shell solution that this solution is coaxial spinning.Stratum nucleare solution adopts Oleum sesami.Solution flow rate is accurately controlled by syringe pump, and shell solution flow rate is 20 μ l/h, and stratum nucleare solution flow rate is 10 μ l/h.Spinning voltage 30kV, spinning head and receptor (aluminum film) spacing is 10cm, and acquisition time is 48 hours, and the thickness of collected doughnut net materials is about 1.5 millimeters.First material is put into the high speed centrifuge centrifugation de-oiling of 30,000 revs/min, extracted oil ingredient wherein afterwards with cyclohexane extraction, last vacuum drying 8h, obtains pure chitosan hollow nanofiber net materials.
(5) mold pressing of composite
The above-mentioned web material preparing is respectively got to portion, by each stacked being added together, adopt hollow shape mould (external diameter 1.0cm × 1.0cm, internal diameter 0.6cm × 0.6cm), at 180N/cm by the order of gelatin, alginate, chitosan, PLGA
2under pressure, suppress after 3 minutes on tablet machine, take off, by the unnecessary part of cutter cutting, form hard, the middle soft shape of surrounding, wherein soft portion is 0.6cm × 0.6cm, and huttriall is in soft portion surrounding, and every side width is 0.2cm.Soft portion thickness after compacting is about 7mm, and huttriall thickness is about 4mm.
(6) disinfect
With after gamma-radiation disinfection, obtain sample No. 1.
The preparation of embodiment 2(2 sample)
(1) preparation of gelatin hollow Nano fiber in use net materials
In the preparation of spinning solution, the mass fraction of gelatin solution is made as to 16%; When coaxial spinning, shell solution flow rate is made as to 0.5ml/h, stratum nucleare solution flow rate is made as 0.2ml/h, and spinning voltage is made as 15kV, and acquisition time is made as 36 hours, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(2) preparation of sodium alginate nano fiber net materials
In the preparation of spinning solution, the w/v of sodium alginate and glycerol is made as to 3g/ml, the volume ratio of water and glycerol is made as 0.5:1; When electrostatic spinning, voltage is made as 28kV, and flow velocity is made as 100 μ l/h, and spinning head and receptor spacing are made as 12cm, and coagulating bath is the CaCl by mass percent concentration 10%
2the mixed liquor of aqueous solution and the dehydrated alcohol composition that mass percent is 80% in mixed liquor, other are with embodiment 1.The thickness of collected web material is about 1 millimeter.
(3) preparation of PLGA hollow Nano fiber in use net materials
In the preparation of spinning solution, the concentration of PLGA solution is made as 0.5g/ml; When coaxial spinning, shell solution flow rate is made as 0.6ml/h, and stratum nucleare solution flow rate is made as 0.3ml/h, and spinning voltage is made as 10kV, and other are with embodiment 1.The thickness of collected web material is about 1 millimeter.
(4) preparation of chitosan hollow nanofiber net materials
It is 7% chitosan solution that shell solution preparation becomes mass fraction, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(5) mold pressing of composite nano materials
The pressure of mold pressing is made as 100N/cm
2, being pressed into soft portion thickness and being about 6mm, huttriall thickness is about 4mm, and other are with embodiment 1.
(6) disinfect
With embodiment 1.
The preparation of embodiment 3(3 sample)
(1) preparation of gelatin hollow Nano fiber in use net materials
In the preparation of spinning solution, the mass fraction of gelatin solution is made as to 18%; When coaxial spinning, shell solution flow rate is made as to 0.5ml/h, stratum nucleare solution flow rate is made as 0.2ml/h, and spinning voltage is made as 20kV, and other are with embodiment 1.The thickness of collected web material is about 2 millimeters.
(2) preparation of sodium alginate nano fiber net materials
In the preparation of spinning solution, the volume ratio of water and glycerol is made as to 0.5:1; When electrostatic spinning, voltage is made as 28kV, and flow velocity is made as 100 μ l/h, and coagulating bath is the CaCl by mass percent concentration 10%
2the mixed liquor of aqueous solution and the dehydrated alcohol composition that mass percent is 80% in mixed liquor, other are with embodiment 1.The thickness of collected web material is about 1.2 millimeters.
(3) preparation of PLGA hollow Nano fiber in use net materials
In the preparation of spinning solution, the concentration of PLGA solution is made as 1.5g/ml, and the volume ratio of DMF and THF is made as 3:1; When coaxial spinning, shell solution flow rate is made as 1.2ml/h, and stratum nucleare solution flow rate is made as 0.5ml/h, and spinning voltage is made as 10kV, and other are with embodiment 1.The thickness of collected web material is about 2 millimeters.
(4) preparation of chitosan hollow nanofiber net materials
It is 7.5% chitosan solution that shell solution preparation becomes mass fraction, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(5) mold pressing of composite
The pressure of mold pressing is made as 150N/cm
2, being pressed into soft portion thickness and being about 7mm, huttriall thickness is about 4.5mm, and other are with embodiment 1.
(6) disinfect
With embodiment 1.
The preparation of embodiment 4(4 sample)
(1) preparation of gelatin hollow Nano fiber in use net materials
In the preparation of spinning solution, the mass fraction of gelatin solution is made as to 16%; When coaxial spinning, shell solution flow rate is made as to 0.5ml/h, stratum nucleare solution flow rate is made as 0.2ml/h, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(2) preparation of sodium alginate nano fiber net materials
In the preparation of spinning solution, the volume ratio of water and glycerol is made as to 0.5:1; When electrostatic spinning, voltage is made as 28kV, and flow velocity is made as 100 μ l/h, and coagulating bath is the CaCl by mass percent concentration 10%
2the mixed liquor of aqueous solution and the dehydrated alcohol composition that mass percent is 80% in mixed liquor, other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(3) preparation of PLGA hollow Nano fiber in use net materials
When coaxial spinning, stratum nucleare solution flow rate is made as 0.5ml/h, and spinning voltage is made as 10kV, and other are with embodiment 1.The thickness of collected web material is about 2 millimeters.
(4) preparation of chitosan hollow nanofiber net materials
It is 6.5% chitosan solution that shell solution preparation becomes mass fraction, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(5) mold pressing of composite
The pressure of mold pressing is made as 150N/cm
2, being pressed into soft portion thickness and being about 7mm, huttriall thickness is about 4.5mm, and other are with embodiment 1.
(6) disinfect
With embodiment 1.
The preparation of embodiment 5(5 sample)
(1) preparation of gelatin hollow Nano fiber in use net materials
In the preparation of spinning solution, the mass fraction of gelatin solution is made as to 14%; When coaxial spinning, shell solution flow rate is made as to 0.5ml/h, stratum nucleare solution flow rate is made as 0.2ml/h, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(2) preparation of sodium alginate nano fiber net materials
In the preparation of spinning solution, the w/v of sodium alginate and glycerol is made as to 3g/ml, other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(3) preparation of PLGA hollow Nano fiber in use net materials
When coaxial spinning, stratum nucleare solution flow rate is made as 0.5ml/h, and other are with embodiment 1.The thickness of collected web material is about 2 millimeters.
(4) preparation of chitosan hollow nanofiber net materials
It is 7% chitosan solution that shell solution preparation becomes mass fraction, and other are with embodiment 1.The thickness of collected web material is about 1.5 millimeters.
(5) mold pressing of composite
Mould external diameter is 8cm × 8cm, and internal diameter is 6cm × 6cm, and the every side in huttriall is 1cm, and the pressure of mold pressing is made as 150N/cm
2, being pressed into soft portion thickness and being about 7mm, huttriall thickness is about 4.5mm, and other are with embodiment 1.
(6) disinfect
With embodiment 1.
Two, mice hemostasis trial
Test with Kunming kind white mice: SPF level, body weight 18-22g, purchased from Dalian Medical Univ's Experimental Animal Center (animal credit number: SCXK (the Liao Dynasty) 2002-0002).
MULTILAYER COMPOSITE hemostatic material is the 1-5 sample of preparing in above-described embodiment; Safe thin silk fabric absorbable styptic gauze and common gauze are provided by the attached Second Academy of Dalian Medical Univ.
24 of mices, male and female half and half, are divided into 4 groups at random, 6 every group, are respectively: MULTILAYER COMPOSITE hemostatic material group (1-5 sample sets), safe thin silk fabric absorbable styptic gauze group (positive controls), common gauze group and blank group.With after 2% pentobarbital sodium (0.002mL/g) intraperitoneal injection of anesthesia, cut off mousetail 1cm with sharp operating scissors, and start timing, each experimental group covers respectively respective material or gauze (1cm × 1cm bilayer) on wound, and oppress a little with forefinger, material or gauze and wound are close to, until stopped bleeding records bleeding stopping period.Blank group is not added a cover any hemostasis and is applied material or medicine, and same method records bleeding stopping period.
Adopt SPSS10.0 statistical software to carry out date processing, result represents with x ± s, compares group difference and checks with t, and P<0.05 is that difference has statistical significance.Experimental result is as shown in table 1.
Experimental result: five kinds of novel multi-layer compound hemostatic materials all can obviously shorten the bleeding time, 1, No. 2 material haemostatic effects are significantly better than positive controls, all, significantly better than common gauze group, prove that MULTILAYER COMPOSITE hemostatic material of the present invention has excellent anastalsis.
The impact (n=6) of the each group of table 1 material on docking mice haemostatic effect
Note: with the comparison of blank group,
*p<0.05,
*p<0.01; With the comparison of common gauze group, #p<0.05, ##p<0.01; With positive controls comparison, △ p<0.05.
Claims (5)
1. a MULTILAYER COMPOSITE hemostatic material, is characterized in that, it is composited through mold pressing in surrounding by PLGA hollow Nano fiber in use layer, gelatin hollow Nano fiber in use layer, chitosan hollow nanofiber layer and alginate nano fibrous layer.
2. MULTILAYER COMPOSITE hemostatic material according to claim 1, is characterized in that, is filled with between the layers hemostasis class medicine, anti-infection drug, pain relieving class medicine or promotes the tissue repair factor.
3. MULTILAYER COMPOSITE hemostatic material according to claim 1, is characterized in that, the thickness of described MULTILAYER COMPOSITE hemostatic material is 0.3-3cm.
4. for the preparation of a method for MULTILAYER COMPOSITE hemostatic material described in any one in claim 1-3, it is characterized in that, comprise the steps:
(1) coaxial spin processes is prepared PLGA hollow Nano fiber in use net
With chloroform, DMF, the mixed liquor of THF or DMF and THF is solvent, compound concentration is the PLGA spinning solution of 0.5-1.5g/ml, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-2.0ml/h, stratum nucleare solution flow rate is 0.2-1.0ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-20kV, collecting distance is 5-15cm, acquisition time is 8-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge centrifugation de-oiling, afterwards with cyclohexane extraction or carbon tetrachloride extraction oil ingredient wherein, last vacuum drying, obtain pure PLGA hollow Nano fiber in use net,
(2) coaxial spin processes is prepared gelatin hollow Nano fiber in use net
Taking formic acid or water as solvent, compound concentration is the gelatin spinning solution of 15-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 0.5-1.0ml/h, stratum nucleare solution flow rate is 0.2-0.5ml/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, the ambient temperature of spinning duration is controlled at more than 40 DEG C, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure gelatin hollow Nano fiber in use net,
(3) coaxial spin processes is prepared chitosan hollow nanometer fiber net
Taking spirit acid or trifluoroethanol as solvent, compound concentration is the chitosan spinning solution of 5-30wt%, this solution is shell solution, stratum nucleare solution adopts Oleum sesami, mineral oil, dimethicone or blending edible oil, shell solution flow rate is 10-40 μ l/h, stratum nucleare solution flow rate is 5-20 μ l/h, solution flow rate is accurately controlled by syringe pump, spinning voltage regulates between 10-30kV, collecting distance is 5-15cm, acquisition time is 4-72 hour, collected web thickness is adjustable continuously between hundreds of micron to 3 millimeter, first the fleece of collection is put into high speed centrifuge centrifugation de-oiling, extract oil ingredient wherein with cyclohexane extraction afterwards, last vacuum drying, obtain pure chitosan hollow nanometer fiber net,
(4) method of electrostatic spinning is prepared alginate nano fleece
By alginate and glycerol by weight volume ratio 2-4g/ml mix, then in mixed liquor, add aqueous solvent, wherein the volume ratio of water and glycerol is 0.5-1:1, stirs, static bubble removing, obtain spinning solution, spinning solution flow velocity is 50-200 μ l/h, and solution flow rate is accurately controlled by syringe pump, and spinning voltage regulates between 10-40kV, spinning head and receptor spacing are 5-15cm, and receptor is immersed in by CaCl
2in the coagulating bath of aqueous solution and dehydrated alcohol composition, acquisition time is 36-72 hour, and collected web thickness is adjustable continuously between hundreds of micron to 2 millimeter, by obtained fleece vacuum drying, obtains alginate nano fleece;
(5) through the compound layers of material of mold pressing
Get the each fleece preparing, it is superimposed, and fill between the layers as required hemostasis class medicine, anti-infection drug, pain relieving class medicine or promote after the tissue repair factor, adopt hollow shape mould, it is pressed into hard, the middle soft shape of surrounding of given size, then use cutter cutting, wherein molding pressure is 100-400N/cm
2, each fibroreticulate number of plies is 1 layer or multilamellar;
(6) disinfect
With gamma-radiation to the composite disinfection obtaining after, just obtain MULTILAYER COMPOSITE hemostatic material.
5. preparation method according to claim 4, is characterized in that, at least in any one of the coaxial spinning shell solution of step (1)-(3), is also further added with the CNT of single wall or many walls.
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| GB2461019B (en) * | 2008-04-25 | 2013-06-05 | Medtrade Products Ltd | Haemostatic material |
| CN101496795B (en) * | 2009-03-03 | 2011-07-20 | 沈阳师范大学 | Technique for preparing biodegradable composite controlled release membrane of medicament |
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