CN108624581A - A kind of microballoon and brainpower insufflation system of mescenchymal stem cell materials for binding biological - Google Patents
A kind of microballoon and brainpower insufflation system of mescenchymal stem cell materials for binding biological Download PDFInfo
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- CN108624581A CN108624581A CN201810462716.1A CN201810462716A CN108624581A CN 108624581 A CN108624581 A CN 108624581A CN 201810462716 A CN201810462716 A CN 201810462716A CN 108624581 A CN108624581 A CN 108624581A
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- microballoon
- sodium alginate
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- protein ingredient
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- 239000000463 material Substances 0.000 title claims abstract description 58
- 210000000130 stem cell Anatomy 0.000 title claims abstract description 44
- 230000036624 brainpower Effects 0.000 title claims abstract description 10
- 239000000661 sodium alginate Substances 0.000 claims abstract description 56
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 56
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 54
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000004615 ingredient Substances 0.000 claims abstract description 32
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 31
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- 238000006243 chemical reaction Methods 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 20
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- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
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- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 3
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/14—Enzymes or microbial cells immobilised on or in an inorganic carrier
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M35/00—Devices for applying media, e.g. remedies, on the human body
-
- 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
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/10—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a carbohydrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2210/00—Anatomical parts of the body
- A61M2210/04—Skin
Abstract
The invention discloses a kind of microballoon of mescenchymal stem cell materials for binding biological and brainpower insufflation systems, select sodium alginate as carrier organism material first, and partial oxidation processing is carried out to sodium alginate, pass through the immobilized protein ingredient with free amino of hydrazone bond, wherein, it is added to lithium hydroxide during immobilized, the fixed efficiency that salicylide ingredient effectively increases material to protein ingredient；Then C N singly-bounds are obtained with sodium borohydride reduction hydrazone bond；The effect of cell 3D cultivates microballoon, is effectively increased the survival rate after stem cell transplantation, improves stem-cell therapy skin wound is finally mixed with the material of immobilized protein ingredient and stem cell；Due to the fragility of cell class product, easily destroyed during the transplantation process by loss, therefore the sprinkling drug delivery system to match with the microballoon is additionally provided in this case, make microballoon precise and high efficiency is sprayed to affected part, avoids unnecessary loss and waste.
Description
Technical field
The present invention relates to biological medicine industries, specially by medical device technology and medical biotechnology collaborative innovation, needle
What to large skin defect, this frequently-occurring disease for seriously affecting quality of life was treated segments market, and provides a kind of mesenchyma
The microballoon and brainpower insufflation system of stem cell materials for binding biological.
Background technology
The healing of wound is the different phases such as a complicated dynamic process, including inflammation, hyperplasia and remodeling and phase mutual respect
It is folded.The harm of the defect of skin of larger area：First, protopathy or defect area is excessive that wound is caused to be difficult to heal and then cause
The complication such as secondary infection, second is that the factors such as chronic inflammation can cause epithelium to convert (epitheLiaL- to mesenchyma
MesenchymaL transition) (Li et aL., 2016), there is local fibrosis and generate scar, influences apparent appearance
And normal function.Therefore, ideal therapeutic scheme should take into account accelerating wound healing and reduce the generation of the complication such as scar.But so far
Until, there has been no the real artificial skin product appearances for restoring skin texture and Reconstruction of The Function.Existing product often will appear blood flow
Cycle establishes bad, resistance to mechanical pressure and friction force difference, is difficult to be integrated into local microenvironment, easily forms scar and immunological rejection etc.
Many disadvantages.Stem cell is a kind of cell with self duplication ability and multi-lineage potential, human body multiple tissues and
Organ has all been isolated to different types of stem cell.It is dry at present with deep and technology the progress of stem-cell research
Cell becomes the most promising direction of skin repair treatment.Stem cell can not only substitute the thin of tissue damage loss in situ
Born of the same parents can more secrete cytokine profiles and adjust local microenvironment, and antagonism wound scar is formed.
Mescenchymal stem cell (mesenchymaL stem ceLLs, MSC) is the ideal chose of current cellular transplantation therapy.
For more other cell types, mescenchymal stem cell has the advantages that incomparable：(1) its amplification in vitro ability is strong, is easy to obtain
Next step transplantation treatment is carried out enough to the stem cell of number；(2) there is the ability across differentiation of germinal layers, be that current known energy provides
The optimum cell source that skin multilayered structure is naturally repaired；(3) have immunoloregulation function, the inflammatory that wound location can be reduced anti-
It answers, meanwhile, low immunogenicity makes it possible heteroplastic transplantation；(4) have the function of powerful paracrine, can secrete various kinds of cell because
Son and growth factor promote repair process.Animal experiments show that MSC local transplantations dramatically speed up the healing rate of skin wound,
And significantly fight wound fibrosis and scar and formed, show huge potential applicability in clinical practice (Akram et aL., 2013).It is early
In 2005, Ichioka just reported an example application Mesenchymal Stem Cells in Treatment an example chronic leg ulcer case, is transplanting
Two weeks surface of a wound start to show reparation sign afterwards, and the granulation tissue (Ichioka et aL., 2005) of health occur.2008
Yoshikawa is combined 20 patients for suffering from chronic lower limb wound of artificial skin (PeLnac) and Mesenchymal Stem Cells in Treatment,
16 patient's wounds show all healed (Yoshikawa et aL., 2008).Such stem cell relevant clinical experiment is in the whole world
Carry out nearly 6000, much all achieves the effect of other therapies are unable to reach.
But survival rate is low after the common problem of cell replacement therapy is cell differentiation efficiency and transplants, major influence factors
Have：1) from external 2D condition of culture to the change of internal 3D tissue microenvironments and structural constituent；2) graft is immunized in body
Repulsion and inflammatory reaction；3) it interacts between cell shortage and cell or extracellular matrix in external two-dimentional incubation；4) it receives
Obtain enzymic digestion or the mechanical damage etc. in cell processes.3 D stereo culture and developing into for biomaterial solve in cell therapy
These problems provide new powerful.Compared with traditional two dimensional surface cultivating system, dimensional culture can be utmostly
Simulated in vivo environment, increase gap junctional intercellular communications, and can realize that cell culture condition is controllable, improve differentiation efficiency.Pass through
After grafting or fixed extracellular matrix components or other protein moleculars can then be effectively increased stem cell transplantation on biomaterial
Survival rate.This project prepares corresponding cell according to skin wound feature Precise spraying, exploitation novel intelligent biomaterial
3D cultivates microballoon, forms " bullet " to match with sprinkling system, improves differentiation and the survival efficiency of transplanting stem cell, improves dry
The effect of cell therapy skin wound.Due to the fragility of cell class product and the complexity of stem cell extraction process and high-leveled and difficult
Degree, stem cell it is expensive, and according to the otherness of individual physique and age, the active stem cell population that can be obtained has
Limit, therefore, the sprinkling drug delivery system to match with stem cell is very necessary.
Invention content
For the shortcomings of the prior art, the purpose of the present invention is to provide a kind of combinations of mescenchymal stem cell
The microballoon and brainpower insufflation system of biomaterial are not only prepared for 3D stem cells culture microballoon, but also provide for the microballoon
The brainpower insufflation system of spraying, to improve differentiation and the survival efficiency of transplanting stem cell, enhancing stem-cell therapy skin wound
Curative effect.
The present invention provides a kind of microballoons of mescenchymal stem cell materials for binding biological, and the preparation process of the microballoon is such as
Under：
1) mescenchymal stem cell for preparing clinic rank preserves for use；
2) the sodium alginate material of partial oxidation is prepared；
3) protein ingredient, the sodium alginate material being modified are grafted or cured on the sodium alginate material；
4) the sodium alginate material being modified and the cell suspension of the mescenchymal stem cell are mixed, this is mixed
Liquid is closed to instill in calcium chloride solution by three-dimensional microballoon generating means；
5) after sodium alginate material and calcium chloride it is full cross-linked after, detach calcium chloride solution, be used in combination culture solution cleaning to get
To the microballoon of the mescenchymal stem cell materials for binding biological.
Preferably, the sodium alginate material of the partial oxidation described in step 2) is to use sodium periodate oxidation system
Standby, operating process is as follows：
S1,0.25moL/L sodium periodate solutions are prepared with deionized water, is protected from light and stores for future use；
S2, the sodium alginate soln for being 1% with deionized water compound concentration, and the appropriate sodium periodate solution is added,
It is placed in and is protected from light concussion reaction on ice 1-1.1 hours；
S3, proper amount of glycol is added into system for terminating oxidation reaction, suitable chlorination is added after 20-30 minutes
Sodium Alginate Hydrogel Films are precipitated in sodium and absolute ethyl alcohol；
S4, the Sodium Alginate Hydrogel Films are dissolved in deionized water, are placed in 72 hours in bag filter and are done to dialysing
Only；Wherein, water is changed daily 3-5 times；
S5, the sodium alginate soln in bag filter is poured into container, freeze-drying is to get to the alginic acid of partial oxidation
Sodium material.
Preferably, the operating process for being grafted described in step 3) or curing protein ingredient is as follows：
S1, the solution that the sodium alginate material of the partial oxidation is configured to 20g/L with deionized water, and 1- is added
1.5mL/L acetic acid, 0.06-0.08mmoL/L salicylides or its derivative, are protected from light oscillating reactions 2 hours at 4 DEG C；
S2, it is added into previous solu and waits being grafted in right amount or cured protein ingredient, be protected from light concussion reaction 2-2.5 hours,
The sodium alginate of the protein ingredient and partial oxidation is set to be grafted or cure by hydrazone bond；0.2-0.25mmoL/L boron is then added
Sodium hydride concussion reaction 1-1.5 hours at normal temperatures；
S3,3 times of volumes of deionized water are added into solution, and are placed in 48-72 hours in bag filter at 4 DEG C and are done to dialysing
Only, it is grafted or is cured the sodium alginate material of protein ingredient, freeze-drying preserves.
Preferably, the sodium alginate material of the grafting or solidification protein ingredient is made into deionized water when in use
0.22 μm of filter filtration sterilization is used in combination in 3% aqueous solution.
Preferably, the protein ingredient has free amino, selected from polypeptides such as extracellular matrix, epidermal growth factor
Or antibody class protein ingredient.
Preferably, the microballoon of the mescenchymal stem cell materials for binding biological of preparation is put into cell culture fluid
CO2It is cultivated in incubator.
The present invention also provides a kind of brainpower insufflation systems of mescenchymal stem cell materials for binding biological, including：
Transportation system is made of peristaltic pump and magnetic rotor, for the sterile conveying microballoon；
System is injected, is made of voltage Micropump, nozzle and spray gun, for the fixed or hand-held sprinkling microballoon；
Monitoring system is made of traffic monitoring and monitoring temperature；
By master control borad, power supply and structure composition is made, for controlling entire sprinkling system in support system.
Preferably, the traffic monitoring is realized by flow sensor and circuit board；Wherein, the circuit board has number
Mould is converted and analog-digital conversion function.
Preferably, the monitoring temperature is realized by temperature sensor, heating unit, refrigeration unit and circuit board；Its
In, the heating unit selects resistance wire, the refrigeration unit that semiconductor cooler, the circuit board is selected to have digital-to-analogue conversion
And analog-digital conversion function.
The beneficial effects of the invention are as follows：The microballoon and intelligence of involved mescenchymal stem cell materials for binding biological in the present invention
Energy sprinkling system, selects sodium alginate to carry out partial oxidation processing as carrier organism material, and to it first；Then pass through hydrazone
The protein ingredient of the free amino of the immobilized band of key, wherein by carrying out specially treated, i.e. partial oxidation, addition hydrogen-oxygen to sodium alginate
Change lithium as basic catalyst, using salicylide or derivatives thereof with confactor, effectively increases material to amino-containing egg
The fixed efficiency of Bai Chengfen；Then C-N singly-bounds are obtained with sodium borohydride reduction hydrazone bond, the immobilized of protein ingredient is made more to stablize length
Long；Cell 3D is finally mixed with the material of immobilized protein ingredient and stem cell and cultivates microballoon, it can maximum analogue body
Interior environment increases gap junctional intercellular communications, keeps cell culture condition controllable, improve differentiation efficiency, is effectively increased stem cell shifting
The effect of survival rate after plant, raising stem-cell therapy skin wound.Due to the fragility of cell class product, during the transplantation process
It is easily destroyed by loss, therefore additionally provides the sprinkling drug delivery system to match with the microballoon in this case, this system is dry to combine
The microballoon of cell is used as " bullet ", and precise and high efficiency is sprayed to affected part, avoids unnecessary loss and waste.
Description of the drawings
Fig. 1 is sodium alginate grafting materials or cures the process schematic of protein ingredient；Wherein, grey ellipse be albumen at
Point；
Fig. 2 is the schematic diagram of the microballoon sprinkling system of mescenchymal stem cell materials for binding biological.
Specific implementation mode
Present invention will be described in further detail below with reference to the accompanying drawings, to enable those skilled in the art with reference to specification text
Word can be implemented according to this.
It should be appreciated that such as " having ", "comprising" and " comprising " term used herein are not discharged one or more
The presence or addition of a other elements or combinations thereof.
It is further illustrated the present invention below by way of specific embodiment.But the detail of embodiment is only used for explaining this hair
It is bright, it should not be construed as limited overall technical solution.
Step 1: preparing clinical rank fat stem cell, its function is identified in vitro and completes Quality Control；
Wherein, all operations and agents useful for same are with reference to cGMP guides and China《Stem cell General Requirement》Regulation, and
It is completed in high-cleanness grade cell workshop according to the design of GMP standards, adipose tissue-derived enters in surgery or liposuction
The inspection of various files and appearance label is first carried out before workplace；Adipose tissue, removal fascia are washed in Biohazard Safety Equipment simultaneously
It shreds, uses clostridiopetidase A-NB6 to digest 30 minutes later, centrifuged after suspension and abandon supernatant, 300 mesh filter screens filter after precipitation is resuspended, and count
8 × 10 are pressed afterwards4A/cm2Inoculum density be inoculated with into culture bottle.Culture solution is the autologous patient that inactivation treatment is added in DMEM and crosses
Serum or medicinal rank fetal calf serum；After cell reaches 85-90% continuitys, carries out TrypLE and pass on and carry out according to demand
Passage or Cell Cryopreservation again.
Fat stem cell production Quality Control is to ensure the safety of stem cell medicine as far as possible, avoid pollution, immune response
With other side reactions etc., in cell cultivation process, the additive of animal origin is avoided as far as possible, it is necessary if it can not avoid
Use the clinical use or pharmaceutical grades preparation for meeting GMP standards.All quality inspection steps form standardization flow (standard
Operating practice, SOP) and place on record.Before culture, in and transplanting before choose appropriate index respectively, do micro- life
Object, communicable disease, cell state, karyotyping and stem cell surface marker analysis.
Step 2: preparing srnart biomaterials；Following methods can be passed through in this case：(1) on hydrogel material
Grafting or the fixed polypeptides such as extracellular matrix components or epidermal growth factor or antibody class protein ingredient, are created for transplanted cells
Better local microenvironment, sodium alginate generates aldehyde radical by sodium metaperiodate partial oxidation, and polypeptide or antibody class protein ingredient contain
There are free amino, aldehyde radical that schiff base reaction can occur with amino and be grafted, it later can be further by sodium borohydride reduction
On ankyrin ingredient to sodium alginate material, protein ingredient is grafted on dimensional culture micro-sphere material accordingly；(2) preparing can
Degradation sodium alginate micro ball, the sodium alginate of partial oxidation is prepared using sodium periodate oxidation, is passed through and is adjusted degree of oxidation control
Micro-sphere structure processed from degrading, reduces the damage in migration process in vivo, improves transplanting efficiency；(3) layer-by-layer is micro-
Encapsulated transplanted cells prepare Sodium Alginate-Polylysine-Sodium Alginate (APA) or sodium alginate-according to electrostatic absorption principle
Chitin-sodium alginate (ACA) micro-capsule prevents inflammatory macromolecular from attacking in micro-capsule and moves while allowing small molecule nutriment to penetrate
Cell is planted, the immune response high-incidence season for avoiding allograft reaction is assisted while promoting Cell survival.
According to actual conditions, the method in the application selection occupation mode (1) first prepares the sodium alginate material of partial oxidation
Material, then protein ingredient, the sodium alginate material being modified are grafted or cured on the sodium alginate material.
Specifically, preparing the sodium alginate material of partial oxidation：Electronic balance weighs 0.2675g sodium metaperiodates, and 5mL is added
Deionized water, be configured to 0.25M sodium periodate solutions be placed in aluminium foil cladding 10mL centrifuge tubes in be protected from light storage, it is spare；Take three
Branch 50mL centrifuge tubes are simultaneously numbered, and weigh the seaweed that 0.5g sodium alginates are added in 50mL deionized waters obtained a concentration of 1% respectively
Acid sodium aqueous solution；The 0.25M high iodine of 1000 μ L, 500 μ L, 250 μ L are separately added into three centrifuge tubes that number is respectively abc
Acid sodium aqueous solution is protected from light concussion reaction 1 hour on ice, and 200 μ L ethylene glycol use is separately added into 1 hour backward three centrifuge tube
In termination oxidation reaction；0.15g sodium chloride is added into each centrifuge tube again after twenty minutes, then is added in equal volume into each centrifuge tube
Absolute ethyl alcohol so that the sodium alginate of partial oxidation is precipitated, a little deionized water dissolving is added, be placed in bag filter thoroughly
Analysis 72 hours, changes water 3 to 5 times daily；Wait for that hydrogel dialysis is clean, by the sodium alginate aqueous solution of the partial oxidation in bag filter
It in packing to 50mL centrifuge tubes, puts to -80 degrees Celsius of refrigerators, after complete freezing, obtains three kinds of different seaweed of degree of oxidation
Material is lyophilized with freeze-drying instrument for sour sodium material.
Sodium alginate can be with the free amino shape of protein ingredient by will produce aldehyde radical, aldehyde radical after sodium metaperiodate partial oxidation
At hydrazone bond, later by sodium borohydride reduction at stable C-N singly-bounds, such protein ingredient can stablize grafting and be fixed on material table
Face both ensure that cell factor was lasting in this way without adding cell factor in the medium again in cell cultivation process
Stimulus signal, and it can be extended using activity, while having saved experimental cost.It is grafted on the sodium alginate material of partial oxidation
Or the specific method of solidification protein ingredient is：
S1, the sodium alginate material for the partial oxidation that viscosity is 17mPa.S is configured to the molten of 20g/L with deionized water
Liquid, and 1.2mL/L acetic acid, 0.06mmoL/L salicylides is added, oscillating reactions is protected from light at 4 DEG C 2 hours；
S2,6g/L growth factors are added into previous solu as protein ingredient, are protected from light concussion reaction 2 hours, make described
The sodium alginate of growth factor and partial oxidation is grafted or is cured by hydrazone bond；0.2mmoL/L sodium borohydrides are then added normal
The lower concussion reaction of temperature 1.2 hours；
S3,3 times of volumes of deionized water are added into solution, and are placed in bag filter 50 hours at 4 DEG C, be grafted or
Cure the sodium alginate material of growth factor, freeze-drying preserves.
Step 3: preparing mescenchymal stem cell-sodium alginate three-dimensional microballoon, sodium alginate can join shape with bivalent cation glue
At hydrogel；The sodium alginate material of the graft growth factor is made into deionized water to 3% aqueous solution, 0.22 μm of filtering is used in combination
Mixed with the cell suspension of mescenchymal stem cell after device filtration sterilization, by control 3D microballoon generating means voltage swing and
Liquid level, makes to be mixed with the sodium alginate soln of cell and is slowly dropped into CaCl with certain rate2In solution, wait for sodium alginate with
CaCl2After abundant glue connection, by CaCl2Solution detaches, and culture solution is used in combination to clean, and three-dimensional spongiocyte microballoon can be used for next step
Transplantation experiments.Wherein, the operating procedure of 3D microballoons generating means is as follows：
(1) suitable fixture is selected in injection parameters column drop-down table to be adapted to the syringe of different size, 1mL,
2.5mL, 5mL are optional；
(2) oneself demand selection automatic sterilizing pattern or manual sterilization mode (point are combined according to operation interface on sterilization column
The switch that ultraviolet lamp is carried out by ultraviolet lamp touch button controls sterilizing time)；
(3) it after sterilization mode selection, by mating draw point, piping connection and is fixed on instrument；
(4) suspension that biomaterial and cell are drawn with suitable disposable syringe, fixture is fixed on by syringe
On, and connect liquid line；
(5) CaCl will be filled2The culture dish of solution is placed on the support plate of front door and closes the door；
(6) it chooses touch screen left motor motion module and controls vertical motor movement, adjustment draw point end is closed to away from liquid level
Suitable distance；
(7) high voltage power supply push button is pressed, high-pressure modular is opened；
(8) suitable high voltage parameter is keyed on voltage parameter column；
(9) liquor capacity that dimensional culture is carried out needed for being keyed on volume parameters column, must be less than or equal to the total range of syringe
And syringe soakage；
(10) movement velocity of high-accuracy horizontal step motor is keyed on speed parameter column.
(11) it presses horizontal motor and promotes arrow button, arrow lamp is bright, and three dimensional culture system is started to work；
(12) microballoon forming operation terminates back pullout (BPO) and carefully sucks solution in culture dish, and physiological saline is used in combination to clean 3 times,
Finally addition cell culture fluid is put into CO2It is cultivated in incubator.
The present embodiment additionally provides a kind of intelligent delivery system of the microballoon for mescenchymal stem cell materials for binding biological,
Including：
Transportation system is made of peristaltic pump and magnetic rotor, for the sterile conveying microballoon；
System is injected, is made of voltage Micropump, nozzle and spray gun, for the fixed or hand-held sprinkling microballoon；
Monitoring system is made of traffic monitoring and monitoring temperature；Traffic monitoring is realized by flow sensor and circuit board；
Wherein, the circuit board has digital-to-analogue conversion and analog-digital conversion function；The monitoring temperature is single by temperature sensor, heating
Member, refrigeration unit and circuit board are realized；Wherein, the heating unit selects resistance wire, the refrigeration unit to select semiconductor system
Cooler, the circuit board have digital-to-analogue conversion and analog-digital conversion function；
By master control borad, power supply and structure composition is made, for controlling entire sprinkling system in support system.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With.It can be applied to various suitable the field of the invention completely.It for those skilled in the art, can be easily
Realize other modification.Therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and embodiment shown here.
Claims (9)
1. a kind of microballoon of mescenchymal stem cell materials for binding biological, which is characterized in that the preparation process of the microballoon is as follows：
1) mescenchymal stem cell for preparing clinic rank preserves for use；
2) the sodium alginate material of partial oxidation is prepared；
3) protein ingredient, the sodium alginate material being modified are grafted or cured on the sodium alginate material；
4) the sodium alginate material being modified and the cell suspension of the mescenchymal stem cell are mixed, by the mixed liquor
It is instilled in calcium chloride solution by three-dimensional microballoon generating means；
5) after sodium alginate material and calcium chloride are full cross-linked, calcium chloride solution is detached, is used in combination culture solution cleaning to get to institute
State the microballoon of mescenchymal stem cell materials for binding biological.
2. microballoon according to claim 1, which is characterized in that the sodium alginate material of the partial oxidation described in step 2)
It is to be prepared using sodium periodate oxidation, operating process is as follows：
S1,0.25moL/L sodium periodate solutions are prepared with deionized water, is protected from light and stores for future use；
S2, the sodium alginate soln for being 1% with deionized water compound concentration, and the appropriate sodium periodate solution is added, it is placed in
It is protected from light concussion reaction on ice 1-1.1 hours；
S3, proper amount of glycol is added into system for terminating oxidation reaction, added after 20-30 minute suitable sodium chloride with
Sodium Alginate Hydrogel Films are precipitated in absolute ethyl alcohol；
S4, the Sodium Alginate Hydrogel Films are dissolved in deionized water, are placed in 72 hours in bag filter and extremely dialyse totally；Its
In, water is changed daily 3-5 times；
S5, the sodium alginate soln in bag filter is poured into container, freeze-drying is to get to the sodium alginate material of partial oxidation
Material.
3. microballoon according to claim 1, which is characterized in that the operation of protein ingredient is grafted or cured described in step 3)
Process is as follows：
S1, the solution that the sodium alginate material of the partial oxidation is configured to 20g/L with deionized water, and 1-1.5mL/ is added
L acetic acid, 0.06-0.08mmoL/L salicylides or its derivative, are protected from light oscillating reactions 2 hours at 4 DEG C；
S2, it is added into previous solu and waits being grafted in right amount or cured protein ingredient, be protected from light concussion reaction 2-2.5 hours, make institute
The sodium alginate for stating protein ingredient and partial oxidation is grafted or is cured by hydrazone bond；0.2-0.25mmoL/L hydroborations are then added
Sodium concussion reaction 1-1.5 hours at normal temperatures；
S3,3 times of volumes of deionized water are added into solution, and are placed in 48-72 hours in bag filter and are extremely dialysed totally at 4 DEG C,
It is grafted or is cured the sodium alginate material of protein ingredient, freeze-drying preserves.
4. microballoon according to claim 3, which is characterized in that the sodium alginate material of the grafting or solidification protein ingredient
3% aqueous solution is made into deionized water when in use, 0.22 μm of filter filtration sterilization is used in combination.
5. microballoon according to claim 1, which is characterized in that the protein ingredient has free amino, is selected from cell
Epimatrix, epidermal growth factor.
6. microballoon according to claim 1, which is characterized in that the mescenchymal stem cell materials for binding biological of preparation
Microballoon is put into CO in cell culture fluid2It is cultivated in incubator.
7. a kind of brainpower insufflation system of mescenchymal stem cell materials for binding biological, which is characterized in that including：
Transportation system is made of peristaltic pump and magnetic rotor, for the sterile conveying microballoon；
System is injected, is made of voltage Micropump, nozzle and spray gun, for the fixed or hand-held sprinkling microballoon；
Monitoring system is made of traffic monitoring and monitoring temperature；
By master control borad, power supply and structure composition is made, for controlling entire sprinkling system in support system.
8. brainpower insufflation system according to claim 7, which is characterized in that the traffic monitoring by flow sensor and
Circuit board is realized；Wherein, the circuit board has digital-to-analogue conversion and analog-digital conversion function.
9. brainpower insufflation system according to claim 7, which is characterized in that the monitoring temperature by temperature sensor,
Heating unit, refrigeration unit and circuit board are realized；Wherein, the heating unit selects resistance wire, the refrigeration unit to select half
Conductor refrigerator, the circuit board have digital-to-analogue conversion and analog-digital conversion function.
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