CN108159491A - A kind of Cardiac Stem Cells seed and carrying method - Google Patents
A kind of Cardiac Stem Cells seed and carrying method Download PDFInfo
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- CN108159491A CN108159491A CN201810000543.1A CN201810000543A CN108159491A CN 108159491 A CN108159491 A CN 108159491A CN 201810000543 A CN201810000543 A CN 201810000543A CN 108159491 A CN108159491 A CN 108159491A
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
- A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3895—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/58—Materials at least partially resorbable by the body
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- A61L2400/00—Materials characterised by their function or physical properties
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
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Abstract
The invention belongs to biotechnologys and biomedical engineering field, and in particular to and a kind of Cardiac Stem Cells seed makes and implantation methods, it is characterized in that：This method is by being planted in seed cell on the biodegradable stent with three-dimensional structure, then in directional planting to infarcted myocardial tissue, seed cell used is the stem cell that can be divided into cardiac muscle cell, and the timbering material is degradable high polymer material or biogenic material.The skeleton of induction Cardiac Stem Cells development is made by the physics such as femtosecond laser, melt-out spinning method, improve the biotic environment of the induction differentiation of Cardiac Stem Cells by methods such as anchoring growth factors, planted by approach such as surgery, puncture or interventions and Cardiac Stem Cells seed is gradually planted to deep layer to central area, from surface layer along infarcted region periphery.The present invention improves the survival rate and targeting of seed cell, promotes directed differentiation, improves the effect of reparation, has preferable application prospect in organizational project.
Description
Technical field：
The invention belongs to high molecular materials and biomedical engineering field, and in particular to a kind of Cardiac Stem Cells seed and plantation side
Method.
Background technology：
Acute myocardial infarction AMI（Acute myocardial infarction, AMI）It is that coronary artery is acute, duration ischemic lacks
Myocardial necrosis caused by oxygen.This disease is most common in America and Europe, and there are about 1,500,000 human hairs life myocardial infarctions every year in the U.S..China is in recent years
Being in apparent ascendant trend, it is newly sent to few 500,000 every year, now suffers from least 2,000,000.Principle of reatment is to save dying cardiac muscle, is reduced
Infarct size, cardioprotection function.Although current therapy (thrombolysis, interventional procedure, bridging) can make the coronal of some patientss
Artery realizes revascularization, improves the quality of life of patient, but still has quite a few patient finally death due to heart failure.
Therefore, the regulatory mechanism in AMI generations, evolution is explored, seeks the new therapy targets of AMI and measure with very important
Theory significance and practical urgency.In recent years find with regeneration potential Cardiac Stem Cells (cardiac stemcells,
CSCs), the brand-new gate of a fan is opened for cardiovascular regenerative medicine research.
In recent years, stem cells technology is quickly grown, it has also become the main force in cardiac regeneration field, a large amount of clinical tests are first
Step proves its validity.Clinical myocardinal stem cell transplantation mainly has 2 kinds of modes：1st kind is to carry out the heart under surgical operation direct-view
Intramuscular injection, the most animals experiment and clinical practice occurred at present all employs this mode, wherein in ischemia margin zone
Injection have confirmed with it is definite the effect of.2nd kind is that stem cell injection is carried out in coronary artery by conduit, this is conducive to
Treated for specific infarcted region, there is multinomial clinical practice to report at present, majority report all confirm its feasibility and
Validity.The method wound is small, but positions poor.
The Chinese invention patent of Patent No. CN103860597A discloses a kind of stem cell for treating ischemic cardiomyopathy
Preparation and preparation method thereof, for preparation by mescenchymal stem cell, Cardiac Stem Cells and blood vessel endothelium stem cell composition, solvent is patient
Platelet-rich plasm lysate.This method merely provides the composition of Cardiac Stem Cells preparation, do not refer to carrier and
Implantation methods.
Chen Xiao it is bright et al.《Chinese Tissue Engineering Study》On delivered it is entitled " stem cell transplantation acute myocardial infarction AMI close
And the changes of cardiac function of heart failure patient " document, observe single autologous peripheral blood stem cell transplantation Acute myocardial obstruct
The after death clinical efficacy in patients with heart failure, application carry out follow-up in 2 years with coronary angiography injection injection infarct-related artery.
Now, stem-cell therapy is there are still many difficulties, be first how to make more to treat cell survival and go back to the nest to
In cardiac muscle.There are the death in first week for the treatment of researches show that about 90% transplanted cells, and the cell major part quilt transplanted
Cycle is taken away and can not work.Built directly in cardiac muscle by the biomaterial of injectable one suitable for stem cell survival with
The three-dimensional microenvironment of differentiation is increasingly becoming an important research direction.Be improved cell survival rate and integrated degree are exerted
Power all concentrates on development and provides the good growing environment of cell and the novel concept of biocompatible stent that can function it
Material.
The present invention improves depositing for seed cell using the biodegradable stent with three-dimensional structure as the carrier of seed cell
Motility rate, the attachment proteins contained in carrier promote sticking, sprawling for seed cell, and the growth factor (danshensu) contained can promote
Seed cell is directly planted to cardiac muscular tissue, improves targeting and directed differentiation rate by the differentiation of seed cell and proliferation,
Improve the effect repaired.
Invention content
The purpose of the present invention is to provide a kind of Cardiac Stem Cells seed and implantation methods, are used to implement the above-mentioned mesh of the present invention
Technical solution it is as follows：
Attachment proteins or growth factor are dissolved in degradation material, after curing or extrusion molding, cut into the small of definite shape
Type carrier, utilizes numerically-controlled machine tool（CNC）, ultrasonic spraying, the physical technologies such as laser engraving, on degradable high polymer material
The inducement structures such as three-dimensional slot, hole, hole are formed, the three-dimensional pore space structure biodegradable stent of sterilizing is put into seed cell liquid and is induced
Culture, regularly replaces culture solution, and induction Cardiac Stem Cells are made along the skeleton of design in the microenvironment of Induction of committed differentiation
Cardiac Stem Cells seed.Cardiac Stem Cells seed can be planted in the heart by the method that surgery, percutaneous puncture or blood vessel are intervened
Flesh infarct location, plantation method can gradually be induced by the primary or repeatedly gradually centre plantation around infarct
Cardiac muscular tissue is survived, restores myocardial function.In the above-mentioned technical solutions, seed cell select stem cell, embryonic stem cell, can
The multipotential stem cell and cardiac progenitor cell of induction.
In the above-mentioned technical solutions, attachment proteins select RGD series peptides, collagen, fibronectin, polypeptide chain.
In the above-mentioned technical solutions, growth factor selects transforming growth factor, fibroblast growth factor, hepatic cell growth
The factor, Basic Fibroblast Growth Factor.
In the above-mentioned technical solutions, degradation material selects gelatin, chitosan, hyaluronic acid, sodium alginate, polylactic acid
(PLA), poly lactic-co-glycolic acid (PLGA), polylactic acid caprolactone copolymer (PCLA), polyethylene glycol hydrogel.
In the above-mentioned technical solutions, the biodegradable stent shape is tubulose, sheet or bulk.
In the above-mentioned technical solutions, the directional planting system is the tube being tapered, diameter range 0.1mm-
5mm, front end is soft, conductive.
In the above-mentioned technical solutions, three-dimensional 5 μm -1000 μm of hole structure size.
In the above-mentioned technical solutions, plantation method can be by primary or repeatedly from edge to center, from surface layer to depth
Layer plantation, gradually induction survive cardiac muscular tissue, restore myocardial function.
Technical solution of the present invention can realize following advantageous effect:
1st, the stent that uses of the present invention is for degradable high polymer material, with high swelling property, permeability and with tissue phase
Like the features such as.
2nd, attachment proteins are creatively introduced into stent by the present invention, and discovery can promote sticking, spreading for seed cell
Exhibition.
3rd, the present invention uses computer digital control machine tool（CNC）Or laser forms three-dimensional pore space structure on the hydrogel,
The structure not only increases the content of seed cell, may additionally facilitate differentiation and the proliferation of cell, pore space structure shadow of different shapes
Ring the form of cell.
4th, the directional planting system that the present invention uses is conductive, can detect after connection instrument and contacts cardiac muscular tissue
It is electroactive.
5th, the present invention survives cardiac muscular tissue using from edge to center, from surface layer to the implantation methods of deep layer, gradually induction,
Restore myocardial function.
Description of the drawings
Fig. 1 shows the structure of rack surface prepared by the embodiment of the present invention 1.
The structure diagram of hydrogel prepared by Fig. 2 embodiments 2.
The structure diagram of hydrogel prepared by Fig. 3 embodiments 3.
Fig. 4 directional planting conduit schematic diagrames.
Fig. 5 planting patterns schematic diagrames.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But these embodiments are only exemplary, and do not form any restrictions to the scope of the present invention.People in the art
Member it should be understood that without departing from the spirit and scope of the invention can to the details of technical solution of the present invention and form into
Row modifications or substitutions, but these modifications and replacement are each fallen in protection scope of the present invention.
Embodiment 1
(1) attachment proteins RGD series peptides and fibroblast growth factor are dissolved in hyaluronic acid gel, mass fraction is
0.05%, curing molding；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.5mm × 0.5mm × 0.5mm, after glass bottle packaging
Irradiation sterilization；
(3) 5ml stem cell liquid is moved into the hydrogel after sterilizing, be placed in 37 DEG C, 5% CO2Static training in incubator
It supports, Fiber differentiation 14 days, a culture solution is replaced every three days, by the hydrogel direct injection containing stem cell to the downright bad heart
Muscular tissue edge.
Rack surface surface texture:
As shown in figure, rack surface is planar structure.
Stem cell morphology after Fiber differentiation:
About 82% cell length-width ratio is between 1-4.
Embodiment 2
(1) attachment proteins RGD series peptides and fibroblast growth factor are dissolved in hyaluronic acid gel, mass fraction is
0.05%, curing molding；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.5mm × 0.5mm × 0.5mm, using laser in hydrogel
Upper formation groove structure uses irradiation sterilization after glass bottle packaging hydrogel；
(3) 5ml stem cell liquid is moved into the hydrogel after sterilizing, be placed in 37 DEG C, 5% CO2Static training in incubator
It supports, Fiber differentiation 14 days, a culture solution is replaced every three days, by the hydrogel direct injection containing stem cell to the downright bad heart
Muscular tissue edge.
Rack surface surface texture:
As shown in Figure 2, rack surface is groove structure.
Stem cell morphology after Fiber differentiation:
About 80% cell length-width ratio is between 4-30.
Embodiment 3
(1) attachment proteins RGD series peptides and fibroblast growth factor are dissolved in hyaluronic acid gel, mass fraction is
0.05%, curing molding；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.5mm × 0.5mm × 0.5mm, using laser in hydrogel
Upper formation hexgonal structure uses irradiation sterilization after glass bottle packaging hydrogel；
(3) 5ml stem cell liquid is moved into the hydrogel after sterilizing, be placed in 37 DEG C, 5% CO2Static training in incubator
It supports, Fiber differentiation 14 days, a culture solution is replaced every three days, by the hydrogel direct injection containing stem cell to the downright bad heart
Muscular tissue edge.
Rack surface surface texture:
Such as figure three shows, rack surface is circular configuration.
Stem cell morphology after Fiber differentiation:
Most cells are circle.
Embodiment 4
(1) attachment proteins fibronectin and hepatocyte growth factor are dissolved in Sodium Alginate Hydrogel Films, mass fraction is
0.08%, curing molding；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.3mm × 0.3mm × 0.5mm, using laser in hydrogel
It is upper to form recessed linear structure, use irradiation sterilization after glass bottle packaging hydrogel；
(3) 5ml cardiac progenitor cell liquid is moved into the hydrogel after sterilizing, be placed in 37 DEG C, static training in 5% CO2 incubators
It supports, Fiber differentiation 14 days, a culture solution is replaced every three days, by the hydrogel direct injection containing cardiac progenitor cell to the downright bad heart
Muscular tissue edge.
Rack surface surface texture:
Rack surface is recessed linear structure.
Stem cell morphology after Fiber differentiation:
About 80% cell length-width ratio is between 4-30.
Embodiment 5
(1) attachment proteins fibronectin and hepatocyte growth factor are dissolved in hydrogel, mass fraction 0.1% is solidified into
Type；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.3mm × 0.3mm × 0.5mm, using laser in hydrogel
It is upper to form recessed linear structure, use irradiation sterilization after glass bottle packaging hydrogel；
(3) the derivable multipotential stem cells of 5ml are moved into the hydrogel after sterilizing, be placed in 37 DEG C, in 5% CO2 incubators
Static culture, Fiber differentiation 14 days replace a culture solution every three days, and the hydrogel containing derivable multipotential stem cell is straight
It connects and is injected to necrotic myocardium organization edge.
Hydrogel surface structure:
Hydrogel is recessed linear structure.
Stem cell morphology after Fiber differentiation:
About 85% cell length-width ratio is between 4-30.
Embodiment 6
(1) attachment proteins fibronectin and collagen are dissolved in polyethylene glycol hydrogel hydrogel, mass fraction 1%, Gu
Chemical conversion type；
(2) hydrogel after molding is cut into the fritter hydrogel of 0.3mm × 0.3mm × 0.5mm, using laser in hydrogel
It is upper to form recessed linear structure, use irradiation sterilization after glass bottle packaging hydrogel；
(3) 5ml embryonic stem cells are moved into the hydrogel after sterilizing, are placed in 37 DEG C, static culture in 5% CO2 incubators,
Fiber differentiation 14 days replaces a culture solution, by the hydrogel direct injection containing embryonic stem cell to necrotic myocardium every three days
Organization edge.
Hydrogel surface structure:
Hydrogel is recessed linear structure.
Stem cell morphology after Fiber differentiation:
About 85% cell length-width ratio is between 4-30.
Embodiment 7
(1) it is tube by polylactic acid caprolactone copolymer (PCLA) extrusion molding, a diameter of 100 μm, wall thickness is 10 μm, is used
Femtosecond laser cutting on the outer wall of pipe, groove width are 10 μm, and pipe is soaked into the attachment proteins fibre that mass fraction is 1% connects
In the aqueous solution of albumen and collagen, impregnate 3 hours；
(2) pipe is used into the short tube for being laser-cut into 0.3mm long；
(3) 5ml embryonic stem cells are moved into the short tube after sterilizing, be placed in 37 DEG C, static culture in 5% CO2 incubators, lure
Culture 14 days is led, a culture solution is replaced every three days, by the hydrogel direct injection containing embryonic stem cell to necrotic myocardium group
In selvedge edge.
Tube surface structure:
Tube surface is groove structure.
Stem cell morphology after Fiber differentiation:
About 87% cell length-width ratio is between 4-30.
Embodiment 8
(1) it is tube by polylactic acid caprolactone copolymer (PCLA) extrusion molding, a diameter of 100 μm, wall thickness is 10 μm, is used
Femtosecond laser cutting on the inner wall of pipe, groove width are 10 μm, and pipe is soaked into the attachment proteins fibre that mass fraction is 1% connects
In the aqueous solution of albumen and collagen, impregnate 3 hours；
(2) pipe is used into the short tube for being laser-cut into 0.3mm long；
(3) 5ml embryonic stem cells are moved into the short tube after sterilizing, be placed in 37 DEG C, static culture in 5% CO2 incubators, lure
Culture 14 days is led, a culture solution is replaced every three days, by the hydrogel direct injection containing embryonic stem cell to necrotic myocardium group
In selvedge edge.
Tube surface structure:
Tube surface is groove structure.
Stem cell morphology after Fiber differentiation:
About 86% cell length-width ratio is between 4-30.
Embodiment 9
(1) it is tube by polylactic acid caprolactone copolymer (PCLA) extrusion molding, a diameter of 100 μm, wall thickness is 10 μm, is used
Femtosecond laser cutting on the inner wall of pipe, groove width are 10 μm；
(2) pipe is used into the short tube for being laser-cut into 0.3mm long；
(3) 5ml embryonic stem cells are moved into the short tube after sterilizing, be placed in 37 DEG C, static culture in 5% CO2 incubators, lure
Culture 14 days is led, a culture solution is replaced every three days, by the hydrogel direct injection containing embryonic stem cell to necrotic myocardium group
In selvedge edge.
Tube surface structure:
Tube surface is groove structure.
Stem cell morphology after Fiber differentiation:
About 28% cell length-width ratio is between 4-30.
Claims (10)
1. a kind of Cardiac Stem Cells seed makes and implantation methods, it is characterised in that：This method is by Cardiac Stem Cells with three
It ties up and Cardiac Stem Cells seed is formed on the degradable skeleton of design, orientation is planted to infarcted myocardial tissue with having levels：
Preparation method is as follows:Attachment proteins or growth factor are dissolved in degradation material, after curing or extrusion molding, cutting
Into the small container of definite shape, numerically-controlled machine tool is utilized（CNC）, ultrasonic spraying, the physical technologies such as laser engraving, can drop
It solves and the inducement structures such as three-dimensional slot, hole, hole is formed on high molecular material, the three-dimensional pore space structure biodegradable stent of sterilizing is put into kind
Fiber differentiation in careful cytosol regularly replaces culture solution, and induction Cardiac Stem Cells are along the skeleton of design in Induction of committed differentiation
Microenvironment in Cardiac Stem Cells seed is made.
2. Cardiac Stem Cells seed can be planted in myocardial infarction portion by the method that surgery, percutaneous puncture or blood vessel are intervened
Position, plantation method can survive cardiac muscle by primary or the repeatedly gradually centre plantation around infarct, gradually induction
Tissue restores myocardial function.
3. according to claim 1, which is characterized in that the seed cell is stem cell, embryonic stem cell, be can induce
Multipotential stem cell and cardiac progenitor cell etc. can be divided into one or more of stem cell of cardiac muscle cell.
4. according to claim 1, which is characterized in that the attachment proteins are RGD series peptides, collagen, fibronectin,
The mixing of one or more of polypeptide chain, mass fraction are 0.01% -20%.
5. according to claim 1, which is characterized in that the growth factor is transforming growth factor, fibroblastic growth
The mixing of one or more of the factor, hepatocyte growth factor, Basic Fibroblast Growth Factor, mass fraction for 0.01 ‰-
20‰。
6. according to claim 1, which is characterized in that degradation material for gelatin, chitosan, hyaluronic acid, sodium alginate,
Polylactic acid (PLA), poly lactic-co-glycolic acid (PLGA), polylactic acid caprolactone copolymer (PCLA), polyethylene glycol hydrogel, glue
The mixing of one or more of the degradable high polymer materials such as original, plant fiber or biogenic material.
7. according to claim 1, which is characterized in that the biodegradable stent shape is tubulose, sheet or bulk.
8. according to claim 1, which is characterized in that the directional planting system is the tube being tapered, diameter model
0.1mm-5mm is enclosed, front end is soft, conductive, facilitates electrocardioscopy necrotic zone.
9. according to claim 1, which is characterized in that 5 μm -1000 μm of the three-dimensional hole structure size range.
10. according to claim 1, which is characterized in that the plantation method can by it is primary or repeatedly from edge to
Center is planted from surface layer to deep layer, and gradually induction survives cardiac muscular tissue, restores myocardial function.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109876185A (en) * | 2019-03-18 | 2019-06-14 | 张海军 | A kind of bracket and preparation method thereof that directional induction is neural stem cell differentiating |
| CN111214703A (en) * | 2018-11-25 | 2020-06-02 | 中国科学院大连化学物理研究所 | iPS-derived myocardial cell composite patch and preparation and application thereof |
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| US20080226726A1 (en) * | 2004-03-24 | 2008-09-18 | Jaconi Marisa E E | 3D-Cardiac Tissue Engineering For the Cell Therapy of Heart Failure |
| US20080299169A1 (en) * | 2005-08-12 | 2008-12-04 | Diane Hoffman-Kim | Topographical Templating of Polymeric Materials Using Cellular Morphology |
| WO2012077891A1 (en) * | 2010-12-08 | 2012-06-14 | 이화여자대학교 산학협력단 | Patch for regenerating damaged tissue and configured with a fibrous porous 3d support |
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| US20080226726A1 (en) * | 2004-03-24 | 2008-09-18 | Jaconi Marisa E E | 3D-Cardiac Tissue Engineering For the Cell Therapy of Heart Failure |
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| CN111214703A (en) * | 2018-11-25 | 2020-06-02 | 中国科学院大连化学物理研究所 | iPS-derived myocardial cell composite patch and preparation and application thereof |
| CN109876185A (en) * | 2019-03-18 | 2019-06-14 | 张海军 | A kind of bracket and preparation method thereof that directional induction is neural stem cell differentiating |
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