CN110343288A - It is a kind of using aqueous two-phase lotion as the porous calcium alginate microsphere of template, preparation method and applications - Google Patents
It is a kind of using aqueous two-phase lotion as the porous calcium alginate microsphere of template, preparation method and applications Download PDFInfo
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- CN110343288A CN110343288A CN201910654949.6A CN201910654949A CN110343288A CN 110343288 A CN110343288 A CN 110343288A CN 201910654949 A CN201910654949 A CN 201910654949A CN 110343288 A CN110343288 A CN 110343288A
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- 239000006210 lotion Substances 0.000 title claims abstract description 89
- 239000004005 microsphere Substances 0.000 title claims abstract description 76
- 239000000648 calcium alginate Substances 0.000 title claims abstract description 67
- 235000010410 calcium alginate Nutrition 0.000 title claims abstract description 67
- 229960002681 calcium alginate Drugs 0.000 title claims abstract description 67
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000002245 particle Substances 0.000 claims abstract description 20
- 239000001110 calcium chloride Substances 0.000 claims abstract description 17
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 17
- 239000000243 solution Substances 0.000 claims description 142
- 229920001223 polyethylene glycol Polymers 0.000 claims description 38
- 239000007788 liquid Substances 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000007664 blowing Methods 0.000 claims description 7
- 238000005485 electric heating Methods 0.000 claims description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 229940098773 bovine serum albumin Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000004945 emulsification Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 238000012604 3D cell culture Methods 0.000 claims description 3
- 229920001503 Glucan Polymers 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000017 hydrogel Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000011148 porous material Substances 0.000 abstract description 16
- 239000000839 emulsion Substances 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 9
- 102000004169 proteins and genes Human genes 0.000 abstract description 6
- 108090000623 proteins and genes Proteins 0.000 abstract description 6
- 230000002687 intercalation Effects 0.000 abstract 1
- 238000009830 intercalation Methods 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 82
- 238000001000 micrograph Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004140 cleaning Methods 0.000 description 8
- 239000006071 cream Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 5
- 230000001804 emulsifying effect Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 239000004816 latex Substances 0.000 description 4
- 229920000126 latex Polymers 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 206010050017 Lung cancer metastatic Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000005501 phase interface Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000575 polymersome Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/28—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
- C08J9/286—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum the liquid phase being a solvent for the monomers but not for the resulting macromolecular composition, i.e. macroporous or macroreticular polymers
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0062—General methods for three-dimensional culture
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/04—Alginic acid; Derivatives thereof
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- C12N2513/00—3D culture
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- C12N2533/00—Supports or coatings for cell culture, characterised by material
- C12N2533/70—Polysaccharides
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Abstract
The invention discloses a kind of using aqueous two-phase lotion as the porous calcium alginate microsphere of template, preparation method and applications, comprising the following steps: mPEG-BSA particle preparation, the preparation of PEG-Dex aqueous two-phase, PEG-CaCl2Solution is prepared, the preparation of porous calcium alginate microsphere；The porous calcium alginate microsphere that the present invention is prepared avoids the residual of oily phase in porous structure forming process, improves the biocompatibility of porous microsphere；Emulsion intercalation method, the pore size of porous microsphere easier to control are improved using protein high molecular particle；It is with a wide range of applications in biomedicine field.
Description
Technical field
The present invention relates to a kind of preparation methods of porous microsphere, and in particular to a kind of using aqueous two-phase lotion as the porous of template
Calcium alginate microsphere, preparation method and applications.
Background technique
Porous microsphere is a kind of new material with special internal structure, because it can with pore size and internal structure
The features such as regulation, low-density, high-specific surface area and be widely used in medicament slow release (Kim I, Byeon H J, Kim T H,
et al. Doxorubicin-loaded highly porous large PLGA microparticles as a
sustained- release inhalation system for the treatment of metastatic lung
Cancer [J] Biomaterials, 2012,33 (22): 5574-5583.), 3D cell culture (Kankala R K,
Zhao J, Liu C, et al. Highly porous microcarriers for minimally invasive in
Situ skeletal muscle cell delivery [J] Small, 2019,1901397.), tissue engineering bracket
(Cheng D, Cao X, Gao H, et al. Superficially porous poly (lactic-co-glycolic
acid)/calcium carbonate microsphere developed by spontaneous pore-forming
Method for bone repair [J] RSC Advances, 2013,3 (19): 6871-6878.) etc. various fields.
Emulsion template method is a kind of novel method for preparing porous microsphere developed in recent years.Lotion is mutual by two kinds
Immiscible liquid under external force, the body of formation being dispersed in droplets by a kind of liquid in another liquid
System.It is typically prepared porous microsphere and is all made of oil-in-water (O/W) lotion, by the way that moulding material (such as alginic acid, shell are added in foreign minister
Glycan and high-molecular copolymer etc.) it forms the internal drop for being enclosed with numerous lotions and utilizes gel cross-linkage induction volume rapid
It shrinks and the small oil droplet inside extrusion, to form porous structure (Marco C, Jan G, Andrea B, et al.
Electric field assisted microfluidic platform for generation of tailorable
porous microbeads as cell carriers for tissue engineering[J]. Advanced
Function Material, 2018,28 (20): 1800847.).It can control by adjusting internal emulsion size and density
The aperture in the porous microsphere hole of formation and the density (preparation research of the porous calcium alginate gel bead of Zhang Fengju emulsion template method
[D] University Of Tianjin, 2003).
When the extruding force deficiency that gel is generated by outside stimulus crosslinking, small oil droplet can not be all discharged, porous microsphere
In have the residual of oily phase, reduce the biocompatibility of porous microsphere, limit the application in biomedicine field.Aqueous two-phase cream
Liquid, also referred to as water-in-water emulsion are by the aqueous solution or a kind of high molecular polymer of two kinds of immiscible high molecular polymers
Aqueous solution and a kind of salting liquid are mixed in a certain proportion to be formed.Due to being free of any organic reagent, have biocompatibility high, green
The advantages that color, environmental protection, it is widely used in biomedicine field (Ma Q M, Song Y, Baier G, et al. Osmo-
solidification of all-aqueous emulsion with enhanced preservation of protein
Activity [J] Journal of Materials Chemistry B, 2016,4 (7): 1213-1218.).Using double
Aqueous phase emulsion, which prepares porous microsphere for template, huge potentiality.But since aqueous two-phase lotion is with extremely low surface
Power and biggish interfacial thickness can not allow Small molecular surfactant across entire phase interface (Buzza D M A,
Fletcher P D I, Georgiou T K, et al. Water-in-water emulsions based on
incompatible polymers and stabilized by triblock copolymers-templated
Polymersomes [J] Langmuir, 2013,29 (48): 14804-14814.).Therefore, aqueous two-phase lotion is unlike oil
Aqueous emulsion can be stablized with surfactant, cause lotion size inhomogenous, greatly constrain aqueous two-phase lotion items and answer
With the process of research.Preparing porous microsphere using aqueous two-phase lotion for template is a challenge.
Summary of the invention
The present invention provides a kind of utilization protein high molecular particle mPEG-BSA for prior art problem, improves lotion
Stability using aqueous two-phase lotion as the porous calcium alginate microsphere of template, preparation method and applications.
The technical solution adopted by the present invention is that:
It is a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, comprising the following steps:
Step 1: being in mass ratio that 1:1 is added to pH by bovine serum albumin(BSA) BSA and methoxy poly (ethylene glycol)-acetaldehyde mPEG-CHO
In=5 aqueous solution, after sufficiently dissolving fully reacting, drying obtains mPEG-BSA particle；
Step 2: being that 16% polyethylene glycol PEG solution and glucan Dex solution sufficiently mix in equal volume by mass percent concentration
It closes, takes phase solution for C solution after standing split-phase；
Step 3: alginic acid Alg, the PEG- that configuration Alg mass percent concentration is 2wt% being added in the C solution that step 2 is obtained
Alg solution is solution D；
Step 4: calcium chloride CaCl being added in the C solution that step 2 is obtained2, configure CaCl2Mass percent concentration is 10wt%
PEG-CaCl2Solution is E solution；
Step 5: being that 16% PEG solution and Dex solution are sufficiently mixed to be added after split-phase in equal volume and walk by mass percent concentration
Rapid 1 obtained mPEG-BSA particle forms the solution that mPEG-BSA mass percent concentration is 0.5wt%, and A cream is obtained after emulsification
Liquid；
Step 6: the solution D that step 3 obtains is mixed with the A lotion that step 5 obtains by setting ratio, after being sufficiently mixed uniformly
To B lotion；
Step 7: B lotion being instilled in E solution with every 3~5 seconds speed of drop, porous calcium alginate microsphere needed for being formed.
Further, it is sealed against after BSA and mPEG-CHO dissolution in the step 1, reacts 48h at room temperature,
Then dry in 37 DEG C of electric heating constant-temperature blowing drying box, required mPEG-BSA particle can be obtained in drying.
Further, the PEG molecular weight is 8kDa, and Dex molecular weight is 500kDa.
Further, turbula shaker is used to obtain A cream with 2800~12000rpm/min emulsification 15s in the step 5
Liquid.
Further, B lotion is added dropwise at 3~5cm of distance E liquid level of solution using syringe in the step 7.
A kind of porous calcium alginate microsphere, the porous calcium alginate microsphere surface are calcium alginate hydrogel, and inside is
The good porous structure of connectivity, pore size are 20~80 μm, and microspherulite diameter is 2~3mm.
A kind of application of porous calcium alginate microsphere, the porous calcium alginate microsphere carry in medicine preparation as drug
Body.
A kind of application of porous calcium alginate microsphere, the porous calcium alginate microsphere are used for 3D cell culture.
The beneficial effects of the present invention are:
(1) the aqueous two-phase cream that the present invention is formed using two kinds of immiscible macromolecule glucan Dex and polyethylene glycol PEG solution
Liquid avoids the residual of oily phase in porous structure forming process, improves the biocompatibility of porous microsphere.
(2) present invention improves the steady of lotion using the protein high molecular particle mPEG-BSA for stablizing aqueous two-phase lotion
It is qualitative, the pore size of porous microsphere easier to control.
(3) present invention prepares a kind of full water ring by instillation using the particle stabilized aqueous two-phase lotion of protein high molecular
The controllable porous calcium alginate microsphere of porous structure, improves biocompatibility under border.
Detailed description of the invention
Fig. 1 is preparation flow schematic diagram of the present invention.
Fig. 2 is the shape appearance figure for the porous calcium alginate microsphere that the embodiment of the present invention 1 is prepared, and wherein a is top view, b
For side view, c is overall picture micrograph, and d is partial enlarged view.
Fig. 3 is the SEM figure for the porous calcium alginate microsphere that the embodiment of the present invention 1 is prepared, and the part that wherein b is a is put
Big figure.
Fig. 4 is the figure in the embodiment of the present invention 1, and wherein a is the micrograph for the lotion that step 5 obtains, and b is that step 6 obtains
Lotion micrograph, the porous calcium alginate microsphere that c is SEM figure, d be c partial enlarged view；
Fig. 5 is the figure in the embodiment of the present invention 2, and a is the micrograph for the lotion that step 5 obtains, and b is the lotion that step 6 obtains
Micrograph, the SEM figure for the porous calcium alginate microsphere that c is, d is the partial enlarged view of c.
Fig. 6 is the figure in the embodiment of the present invention 3, and a is the micrograph for the lotion that step 5 obtains, and b is the cream that step 6 obtains
The micrograph of liquid, the SEM figure for the porous calcium alginate microsphere that c is, d is the partial enlarged view of c.
Fig. 7 is the figure in the embodiment of the present invention 4, and a is the micrograph for the lotion that step 5 obtains, and b is the cream that step 6 obtains
The micrograph of liquid, the SEM figure for the porous calcium alginate microsphere that c is, d is the partial enlarged view of c.
Fig. 8 is difference in the embodiment of the present invention into the pore size frequency distribution of the porous calcium alginate microsphere of newborn frequency
Figure.
Fig. 9 is that aqueous two-phase lotion and the porous calcium alginate of PEG-Alg solution different volumes ratio are micro- in the embodiment of the present invention
The pore size frequency distribution of ball.
Specific embodiment
The present invention will be further described in the following with reference to the drawings and specific embodiments.
As shown in Figure 1, a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template including following
Step:
Step 1: bovine serum albumin(BSA) (BSA) and methoxy poly (ethylene glycol)-acetaldehyde (mPEG-CHO) are added in mass ratio for 1:1
Into the aqueous solution of pH=5, the mass concentration for sufficiently dissolving BSA and mPEG-CHO in mixed solution is 10wt%；It will react molten
Liquid sealing, after reacting 48h at room temperature, reaction solution is placed in 37 DEG C of electric heating constant-temperature blowing drying box and is dried, and is dried
Products therefrom is mPEG-BSA particle after dry.
Step 2: preparing molecular weight 8kDa, the PEG solution that mass percent concentration is 16% is denoted as solution A, preparation molecular weight
500kDa, the Dex solution that mass percent concentration is 16%, are denoted as B solution；Isometric solution A and B solution is measured to rotate
After being sufficiently mixed on incubator, split-phase after standing 6 hours, upper phase is that PEG is rich in phase, and lower phase is that Dex is rich in phase, is mutually remembered in extraction
For C solution.
Step 3: Alg, the PEG- that configuration Alg mass percent concentration is 2wt% will be added in C solution that step 2 obtains
Alg solution is solution D；
Step 4: CaCl will be added in C solution that step 2 obtains2, configure CaCl2Mass percent concentration is the PEG- of 10wt%
CaCl2Solution is E solution；
Step 5: measuring isometric mass percent concentration is that 16% PEG solution and Dex solution fill on rotary incubator
After dividing mixing to stand 6 hours split-phases, mPEG-BSA particle is added and forms mPEG-BSA mass percent concentration as the molten of 0.5wt%
Liquid；Then dispersed phase is obtained as Dex after emulsifying 15s using turbula shaker with 12000rpm/min, and continuous phase is the Dex/ of PEG
PEG lotion is denoted as A lotion.
Step 6: by mass mixings such as the solution D that step 3 obtains and the A lotions that step 5 obtains, after being sufficiently mixed uniformly
It is Dex to dispersed phase, continuous phase is the Dex/PEG-Alg lotion of PEG-Alg, is denoted as B lotion.
Step 7: drawing B lotion with commercially available 10mL syringe, put on the syringe needle that internal diameter is 0.8mm, will inject
Device is maintained to be received at 3~5cm of liquid level away from E solution, hanging vertical.By pushing injector push-rod by B lotion with every drop 3~5
The speed of second instills in E solution, and it is 20~40 μm that pore size is formed after 15~30min, and diameter is the porous sea of 2~3mm
Calcium alginate microballoon.
Embodiment 1
It is a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, comprising the following steps:
Step 1: it is in mass ratio that 1:1 is added in the aqueous solution of pH=5 by BSA and mPEG-CHO, stirring dissolves it sufficiently,
The mass concentration of BSA and mPEG-CHO is 10wt% in solution.Reaction solution is sealed, it, will be anti-after reacting 48h at room temperature
It answers solution to be placed in 37 DEG C of electric heating constant-temperature blowing drying box to be dried, products therefrom is mPEG-BSA particle after drying.
Step 2: preparing molecular weight 8kDa, the PEG solution that mass percent concentration is 16wt% is denoted as solution A, preparation molecule
It measures 500kDa, the Dex solution that mass percent concentration is 16wt%, is denoted as B solution；Isometric solution A and B solution is measured to exist
After being sufficiently mixed on rotary incubator, split-phase after standing 6 hours, upper phase is that PEG is rich in phase, and lower phase is that Dex is rich in phase, in extraction
Mutually it is denoted as C solution.
Step 3: Alg, the PEG- that configuration Alg mass percent concentration is 2wt% will be added in C solution that step 2 obtains
Alg solution is solution D；
Step 4: CaCl will be added in C solution that step 2 obtains2, configure CaCl2Mass percent concentration is the PEG- of 10wt%
CaCl2Solution is E solution；
Step 5: measuring PEG solution and Dex solution that isometric mass percent concentration is 16wt% on rotary incubator
It is sufficiently mixed after standing 6 hours split-phases, it is 0.5wt%'s that mPEG-BSA particle, which is added, and forms mPEG-BSA mass percent concentration
Solution；Then dispersed phase is obtained as Dex after emulsifying 15s using turbula shaker with 12000rpm/min, and continuous phase is PEG's
Dex/PEG lotion is denoted as A lotion.
Step 6: the quality such as A lotion that the solution D that step 3 obtains is obtained with step 5 slowly uniformly being mixed, are sufficiently mixed
It is Dex that dispersed phase is obtained after uniformly, and continuous phase is the Dex/PEG-Alg lotion of PEG-Alg, is denoted as B lotion.
Step 7: drawing B lotion with commercially available 10mL syringe, put on the syringe needle that internal diameter is 0.8mm, will inject
Device is maintained to be received at 3~5cm of liquid level away from E solution, hanging vertical.By pushing injector push-rod by B lotion with every drop 3~5
The speed of second instills in E solution, and it is 20~40 μm that pore size is formed after 15~30min, and diameter is the porous sea of 2~3mm
Calcium alginate microballoon.
Obtained porous calcium alginate microsphere is as shown in Figure 2；Its microscopy results as shown in figures 2 a and 2b, Cong Tuzhong
It can be seen that microballoon monodispersity is good, particle diameter distribution is uniform, partial size is 2~3mm.
The porous calcium alginate microsphere being prepared with deionized water cleaning step 7 repeatedly to remove interior phase Dex, then will
The microballoon water removal that cleaning is completed is put into the test tube of 15mL, is put into freezing later with liquid nitrogen frozen and with the sealing of porose preservative film
In drier, it is freeze-dried.
SEM, SEM figure and partial enlarged view are carried out to the porous calcium alginate microsphere obtained after freeze-drying, such as Fig. 3 a
With shown in 3b.It can be seen that porous calcium alginate microsphere surface texture.
As shown in fig. 4 a, the micrograph of lotion B is as shown in Figure 4 b for the micrograph of latex A.
SEM is carried out to the porous calcium alginate microsphere obtained after freeze-drying, as shown in Fig. 4 c and 4d, it can be seen that in it
Portion's structure.
Embodiment 2
It is a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, comprising the following steps:
Step 1: it is in mass ratio that 1:1 is added in the aqueous solution of pH=5 by BSA and mPEG-CHO, stirring dissolves it sufficiently,
The mass concentration of BSA and mPEG-CHO is 10wt% in mixed solution.Reaction solution is sealed, after reacting 48h at room temperature,
Reaction solution is placed in 37 DEG C of electric heating constant-temperature blowing drying box and is dried, products therefrom is mPEG-BSA after drying
Grain.
Step 2: preparing molecular weight 8kDa, the PEG solution that mass percent concentration is 16wt% is denoted as solution A, preparation molecule
It measures 500kDa, the Dex solution that mass percent concentration is 16wt%, is denoted as B solution；Isometric solution A and B solution is measured to exist
After being sufficiently mixed on rotary incubator, split-phase after standing 6 hours, upper phase is that PEG is rich in phase, and lower phase is that Dex is rich in phase, in extraction
Mutually it is denoted as C solution.
Step 3: Alg, the PEG- that configuration Alg mass percent concentration is 2wt% will be added in C solution that step 2 obtains
Alg solution is solution D；
Step 4: CaCl will be added in C solution that step 2 obtains2, configure CaCl2Mass percent concentration is the PEG- of 10wt%
CaCl2Solution is E solution；
Step 5: measuring PEG solution and Dex solution that isometric mass percent concentration is 16wt% on rotary incubator
It is sufficiently mixed after standing 6 hours split-phases, it is 0.5wt%'s that mPEG-BSA particle, which is added, and forms mPEG-BSA mass percent concentration
Solution；Then dispersed phase is obtained as Dex after emulsifying 15s using turbula shaker with 2800rpm/min, and continuous phase is PEG's
Dex/PEG lotion is denoted as A lotion.
Step 6: the quality such as A lotion that the solution D that step 3 obtains is obtained with step 5 slowly uniformly being mixed, are sufficiently mixed
It is Dex that dispersed phase is obtained after uniformly, and continuous phase is the Dex/PEG-Alg lotion of PEG-Alg, is denoted as B lotion.
Step 7: drawing B lotion with commercially available 10mL syringe, put on the syringe needle that internal diameter is 0.8mm, will inject
Device is maintained to be received at 3~5cm of liquid level away from E solution, hanging vertical.By pushing injector push-rod by B lotion with every drop 3~5
The speed of second instills in E solution, and it is 20~40 μm that pore size is formed after 15~30min, and diameter is the porous sea of 2~3mm
Calcium alginate microballoon.
The porous calcium alginate microsphere being prepared with deionized water cleaning step 7 repeatedly to remove interior phase Dex, then will
The microballoon water removal that cleaning is completed is put into the test tube of 15mL, is put into freezing later with liquid nitrogen frozen and with the sealing of porose preservative film
In drier, it is freeze-dried.
The micrograph of latex A is as shown in Figure 5 a, and the micrograph of lotion B is as shown in Figure 5 b.
SEM is carried out to the porous calcium alginate microsphere obtained after freeze-drying, as shown in figures 5 c and 5d, it can be seen that in it
Portion's structure.
Embodiment 3
It is a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, comprising the following steps:
Step 1: it is in mass ratio that 1:1 is added in the aqueous solution of pH=5 by BSA and mPEG-CHO, stirring dissolves it sufficiently,
The mass concentration of BSA and mPEG-CHO is 10wt% in mixed solution.Reaction solution is sealed, after reacting 48h at room temperature,
Reaction solution is placed in 37 DEG C of electric heating constant-temperature blowing drying box and is dried, products therefrom is mPEG-BSA after drying
Grain.
Step 2: preparing molecular weight 8kDa, the PEG solution that mass percent concentration is 16wt% is denoted as solution A, preparation molecule
It measures 500kDa, the Dex solution that mass percent concentration is 16wt%, is denoted as B solution；Isometric solution A and B solution is measured to exist
After being sufficiently mixed on rotary incubator, split-phase after standing 6 hours, upper phase is that PEG is rich in phase, and lower phase is that Dex is rich in phase, in extraction
Mutually it is denoted as C solution.
Step 3: Alg, the PEG- that configuration Alg mass percent concentration is 2wt% will be added in C solution that step 2 obtains
Alg solution is solution D；
Step 4: CaCl will be added in C solution that step 2 obtains2, configure CaCl2Mass percent concentration is the PEG- of 10wt%
CaCl2Solution is E solution；
Step 5: measuring PEG solution and Dex solution that isometric mass percent concentration is 16wt% on rotary incubator
It is sufficiently mixed after standing 6 hours split-phases, it is 0.5wt%'s that mPEG-BSA particle, which is added, and forms mPEG-BSA mass percent concentration
Solution；Then dispersed phase is obtained as Dex after emulsifying 15s using turbula shaker with 2800rpm/min, and continuous phase is PEG's
Dex/PEG lotion is denoted as A lotion.
Step 6: the solution D that step 3 obtains slowly uniformly being mixed in equal volume with the A lotion that step 5 obtains, is sufficiently mixed
It is Dex that dispersed phase is obtained after uniformly, and continuous phase is the Dex/PEG-Alg lotion of PEG-Alg, is denoted as B lotion.
Step 7: drawing B lotion with commercially available 10mL syringe, put on the syringe needle that internal diameter is 0.8mm, will inject
Device is maintained to be received at 3~5cm of liquid level away from E solution, hanging vertical.By pushing injector push-rod by B lotion with every drop 3~5
The speed of second instills in E solution, and it is 20~50 μm that pore size is formed after 15~30min, and diameter is the porous sea of 2~3mm
Calcium alginate microballoon.
The porous calcium alginate microsphere being prepared with deionized water cleaning step 7 repeatedly to remove interior phase Dex, then will
The microballoon water removal that cleaning is completed is put into the test tube of 15mL, is put into freezing later with liquid nitrogen frozen and with the sealing of porose preservative film
In drier, it is freeze-dried.
The micrograph of latex A is as shown in Figure 6 a, and the micrograph of lotion B is as shown in Figure 6 b.
SEM is carried out to the porous calcium alginate microsphere obtained after freeze-drying, as described relative to figs. 6c and 6d, it can be seen that in it
Portion's structure.
Embodiment 4
It is a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, comprising the following steps:
Step 1: it is in mass ratio that 1:1 is added in the aqueous solution of pH=5 by BSA and mPEG-CHO, stirring dissolves it sufficiently,
The mass concentration of BSA and mPEG-CHO is 10wt% in mixed solution.Reaction solution is sealed, after reacting 48h at room temperature,
Reaction solution is placed in 37 DEG C of electric heating constant-temperature blowing drying box and is dried, products therefrom is mPEG-BSA after drying
Grain.
Step 2: preparing molecular weight 8kDa, the PEG solution that mass percent concentration is 16wt% is denoted as solution A, preparation molecule
It measures 500kDa, the Dex solution that mass percent concentration is 16wt%, is denoted as B solution；Isometric solution A and B solution is measured to exist
After being sufficiently mixed on rotary incubator, split-phase after standing 6 hours, upper phase is that PEG is rich in phase, and lower phase is that Dex is rich in phase, in extraction
Mutually it is denoted as C solution.
Step 3: Alg, the PEG- that configuration Alg mass percent concentration is 2wt% will be added in C solution that step 2 obtains
Alg solution is solution D；
Step 4: CaCl will be added in C solution that step 2 obtains2, configure CaCl2Mass percent concentration is the PEG- of 10wt%
CaCl2Solution is E solution；
Step 5: measuring PEG solution and Dex solution that isometric mass percent concentration is 16wt% on rotary incubator
It is sufficiently mixed after standing 6 hours split-phases, it is 0.5wt%'s that mPEG-BSA particle, which is added, and forms mPEG-BSA mass percent concentration
Solution；Then dispersed phase is obtained as Dex after emulsifying 15s using turbula shaker with 2800rpm/min, and continuous phase is PEG's
Dex/PEG lotion is denoted as A lotion.
Step 6: the solution D that step 3 obtains and the A lotion that step 5 obtains slowly uniformly are mixed in the ratio that volume is 1:2
It closes, it is Dex that dispersed phase is obtained after being sufficiently mixed uniformly, and continuous phase is the Dex/PEG-Alg lotion of PEG-Alg, is denoted as B lotion.
Step 7: drawing B lotion with commercially available 10mL syringe, put on the syringe needle that internal diameter is 0.8mm, will inject
Device is maintained to be received at 3~5cm of liquid level away from E solution, hanging vertical.By pushing injector push-rod by B lotion with every drop 3~5
The speed of second instills in E solution, and it is 20~70 μm that pore size is formed after 15~30min, and diameter is the porous sea of 2~3mm
Calcium alginate microballoon.
The porous calcium alginate microsphere being prepared with deionized water cleaning step 7 repeatedly to remove interior phase Dex, then will
The microballoon water removal that cleaning is completed is put into the test tube of 15mL, is put into freezing later with liquid nitrogen frozen and with the sealing of porose preservative film
In drier, it is freeze-dried.
The micrograph of latex A is as shown in Figure 7a, and the micrograph of lotion B is as shown in Figure 7b.
SEM is carried out to the porous calcium alginate microsphere obtained after freeze-drying, as shown in figures 7 c and 7d, it can be seen that in it
Portion's structure.
The porous calcium alginate microsphere that embodiment 1 is prepared carries out SEM, observes its internal structure, randomly selects 100
A hole measures and records.The porous calcium alginate microsphere that embodiment 2 is prepared carries out SEM, observes its internal structure,
100 holes are randomly selected to be recorded；Record data, which are carried out statistics, can be obtained shown in Fig. 8, and difference is at the porous of newborn frequency
The pore size frequency distribution of calcium alginate microsphere.
The porous calcium alginate microsphere that embodiment 3 is prepared carries out SEM, observes its internal structure, randomly selects 100
A hole measures and records.The porous calcium alginate microsphere that embodiment 4 is prepared carries out SEM, observes its internal structure,
100 holes are randomly selected to be recorded；Record data, which are carried out statistics, can be obtained shown in Fig. 9, aqueous two-phase lotion and PEG-Al；
The pore size frequency distribution of the porous calcium alginate microsphere of g solution different volumes ratio.
The present invention prepares porous structure under a kind of full water environment using the particle stabilized aqueous two-phase lotion of protein high molecular
Controllable porous calcium alginate microsphere.The biocompatibility of the porous microsphere is high, pore size is controllable；By changing aqueous two-phase cream
Liquid controls aqueous two-phase lotion at newborn frequency or aqueous two-phase lotion and the volume ratio of polyethylene glycol-alginic acid (PEG-Alg) solution
Size, to control the pore size of porous microsphere；It is formed using two kinds of incompatible macromolecule Dex and PEG solution double
Aqueous phase emulsion improves the biocompatibility of porous microsphere；Using protein high molecular particle, so that lotion is more stable, it is easier to
Control the pore size of porous microsphere.
Claims (8)
1. a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template, which is characterized in that including following
Step:
Step 1: being in mass ratio that 1:1 is added to pH by bovine serum albumin(BSA) BSA and methoxy poly (ethylene glycol)-acetaldehyde mPEG-CHO
In=5 aqueous solution, after sufficiently dissolving fully reacting, drying obtains mPEG-BSA particle；
Step 2: by mass percent concentration be 16% polyethylene glycol PEG solution and glucan Dex solution it is abundant in equal volume
Mixing takes phase solution for C solution after standing split-phase；
Step 3: alginic acid Alg being added in the C solution that step 2 is obtained, configuration Alg mass percent concentration is 2wt%'s
PEG-Alg solution is solution D；
Step 4: calcium chloride CaCl being added in the C solution that step 2 is obtained2, configure CaCl2Mass percent concentration is 10wt%
PEG-CaCl2Solution is E solution；
Step 5: by mass percent concentration be 16% PEG solution and Dex solution be sufficiently mixed split-phase in equal volume after be added
The mPEG-BSA particle that step 1 obtains forms the solution that mPEG-BSA mass percent concentration is 0.5wt%, obtains A after emulsification
Lotion；
Step 6: the solution D that step 3 obtains is mixed with the A lotion that step 5 obtains by setting ratio, after being sufficiently mixed uniformly
To B lotion；
Step 7: B lotion being instilled in E solution with every 3~5 seconds speed of drop, porous calcium alginate microsphere needed for being formed.
2. it is according to claim 1 a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template,
It is characterized in that, being sealed against after bovine serum albumin(BSA) and methoxy poly (ethylene glycol)-acetaldehyde dissolution in the step 1, in room temperature
Under the conditions of react 48h, then dry in 37 DEG C of electric heating constant-temperature blowing drying box, drying can be obtained required mPEG-BSA
Grain.
3. it is according to claim 1 a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template,
It is characterized in that, the PEG molecular weight is 8kDa, Dex molecular weight is 500kDa.
4. it is according to claim 1 a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template,
It is characterized in that, turbula shaker is used to obtain A lotion with 2800~12000rpm/min emulsification 15s in the step 5.
5. it is according to claim 1 a kind of using aqueous two-phase lotion as the preparation method of the porous calcium alginate microsphere of template,
It is characterized in that, B lotion is added dropwise at 3~5cm of distance E liquid level of solution using syringe in the step 7.
6. a kind of porous calcium alginate microsphere obtained such as any one of Claims 1 to 5 with preparation method, which is characterized in that institute
Stating porous calcium alginate microsphere surface is calcium alginate hydrogel, and inside is the good porous structure of connectivity, microspherulite diameter 2
~3mm.
7. a kind of application of the porous calcium alginate microsphere obtained such as any one of Claims 1 to 5 with preparation method, feature exist
In the porous calcium alginate microsphere is used as pharmaceutical carrier in medicine preparation.
8. a kind of application of the porous calcium alginate microsphere obtained such as any one of Claims 1 to 5 with preparation method, feature exist
In the porous calcium alginate microsphere is used for 3D cell culture.
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| CN113634208A (en) * | 2021-08-20 | 2021-11-12 | 西南交通大学 | Method for preparing porous calcium alginate microspheres by using microfluidic double-aqueous-phase emulsion as template |
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