CN1169494C - Composite structural cell scaffold for tissue engineering and its preparation method and application - Google Patents
Composite structural cell scaffold for tissue engineering and its preparation method and application Download PDFInfo
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- CN1169494C CN1169494C CNB011183160A CN01118316A CN1169494C CN 1169494 C CN1169494 C CN 1169494C CN B011183160 A CNB011183160 A CN B011183160A CN 01118316 A CN01118316 A CN 01118316A CN 1169494 C CN1169494 C CN 1169494C
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- lactic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
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- 239000000463 material Substances 0.000 claims abstract description 90
- 210000001519 tissue Anatomy 0.000 claims abstract description 34
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- 210000000988 bone and bone Anatomy 0.000 claims abstract description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 229960000448 lactic acid Drugs 0.000 claims description 36
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- 239000004310 lactic acid Substances 0.000 claims description 23
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- 239000000203 mixture Substances 0.000 claims description 20
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 8
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](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]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 7
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
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- 229920001436 collagen Polymers 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
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- 238000010612 desalination reaction Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
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- 210000003238 esophagus Anatomy 0.000 claims description 3
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims 4
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- 229920002732 Polyanhydride Polymers 0.000 claims 2
- 229920001710 Polyorthoester Polymers 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 2
- 229920002521 macromolecule Polymers 0.000 claims 2
- 239000002745 poly(ortho ester) Substances 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
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- Materials For Medical Uses (AREA)
Abstract
The present invention discloses a cell bracket with a composite structure for tissue engineering, which has the following structure: (1) the cell bracket is composed of a structure 1 and a structure 2, wherein the structure 1 and the structure 2 are directly connected, and holes of the structure 1 and the structure 2 are mutually communicated, or (2) the cell bracket is composed of the structure 1, the structure 2, and a compact layer which is arranged between the structure 1 and the structure 2 and is formed from a material 3, wherein the holes of the structure 1 and the structure 2 are not mutually communicated. The present invention also discloses a preparation method of the cell bracket. The present invention can be used as the cell bracket for the engineering of various cell tissues of skins, blood vessels, bones/cartilages, esophagi, tracheae, etc., and can be used for the restoration and the construction of the tissues and organs of skins, blood vessels, patellae, esophagi, tracheae, etc.
Description
The core of organizational project is the complex that makes up by cell and biomaterial be combined into.In the organizational project, that histiocyte depends on is prepared by biomaterial, have on the identical shaped support with the tissue or the organ of required reparation, formerly, make it finally to reach reconstruction tissue or organ, restore funcitons purpose through behind the cultured and amplified in vitro, implant the intravital sick position of decreasing again.Therefore, the cytoskeleton that cell, biomaterial constituted, and the formation of tissue and organ and regeneration are three big key elements of organizational project.The three-dimensional porous cytoskeleton of organizational project not only plays a part decision cambium, organ shape size, the more important thing is to cell proliferation plays provides nutrition, carries out gas exchange, gets rid of refuse, for cell proliferation, procreation provide the important function in place, so the cytoskeleton of organizational project must satisfy certain requirement:
Because cytoskeleton plays a part to be the cell proliferation environment construction in organizational project, therefore it must be along with breeding and the growth and fade away of cell on support, thereby give cell with the space, the tissue of final generation is had with support identical shape and size with organ.Cytoskeleton not only must have good affinity of pair cell and specific three-dimensional configuration structure thus, and cell can be grown and breed thereon; Simultaneously must have biological degradability, guarantee can degrade automatically, become micromolecule by macromole in the environment sub-mount material of physiology and body, and finally by organism metabolism or absorption.For the influence that the growth and breeding that guarantees cell is not existed by support, also require cytoskeletal degradation speed to be complementary and growth and breeding that its catabolite can pair cell produce adverse influence with the growth rate of cell.
Require to consider that cytoskeleton also must be able to tolerate the operation of sterilization, guarantee can keep original shape and structure in sterilization, cell culture and operation technique from clinical practice; And have certain pliability, can sew up mutually and can fit, can stand operation technique and mechanical property not broken, that body tissue is not caused mechanical damage with body tissue with body tissue.Therefore the cytoskeleton as organizational project must satisfy performance requirements such as biocompatibility, cellular affinity, biological degradability, sterilizability, and mechanical property and morphosis simultaneously.
Because the cell of different tissues and organ is not only different on shape and size, and is also very not identical on orientation when cell is grown and the density of texture, cytoskeleton must have and the histiocyte cultivated requires corresponding to three-dimensional configuration structure.In addition, owing to must cultivate two kinds of cells simultaneously as the organizational project of various kinds of cell such as skin tissue engineering, intravascular tissue engineering, joint tissue engineering, esophageal tissue engineering, tracheal tissue's engineering on cytoskeleton, cytoskeleton must satisfy the requirement of these two kinds of sizes and the identical or different cell of growth and breeding speed simultaneously.Therefore according to the difference of tissue and the different of organ and two kinds of cell categories being cultivated, cytoskeleton must satisfy the requirement of these two kinds of cell growth and breedings simultaneously on mechanical property, degradation speed and three-dimensional configuration structure, promptly according to concrete organizational project object, being with identical or different material, preparation between the hole of identical or different three-dimensional configuration structure and two kinds of structures is to communicate mutually or obstructed cell scaffold with composite structure adapts therewith mutually.
Yet, cytoskeleton of today all is prepared by commaterial, the cytoskeleton that is single three-dimensional configuration structure, for example by the natural macromolecular material chitin, chitosan, alginate, collagen protein, glucosan, hyaluronic acid, the cytoskeleton that gelatin and agar are prepared, by natural inorganic material hydroxyapatite, the cytoskeleton that calcium phosphate and coral reef are prepared, and by the synthesized polymer material aliphatic polyester, poly-anhydride, poly phosphazene, cytoskeleton (king's body state etc. of poe and polyethers preparation, China's orthopaedic trauma magazine, 2000,16 (6): 328-330.); King's body state etc., Chinese invention patent 99105984.0); King's body state etc., Chinese invention patent ZL92113100.3; King's body state etc., Chinese invention patent 98102212.X).Though the mechanical property that such cytoskeleton is had nothing in common with each other, degradation speed and three-dimensional configuration structure, go for the requirement of different tissues engineerings such as bone, cartilage, but because their mechanical property, degradation speed and three-dimensional configuration structure are all very single, therefore only be applicable to cytoskeleton, and can not be applicable to cytoskeleton as the various kinds of cell organizational project as the single cell organizational project.
The object of the present invention is to provide a kind of cell scaffold with composite structure that is applicable to as the various kinds of cell tissue engineering cell scaffold.
Another object of the present invention is to provide a kind of method for making that is applicable to as the cell scaffold with composite structure of various kinds of cell tissue engineering cell scaffold.
The present invention also aims to provide a kind of purposes that is applicable to as the cell scaffold with composite structure of various kinds of cell tissue engineering cell scaffold.
The present invention proposes a kind of cell scaffold with composite structure that is applicable to as the various kinds of cell tissue engineering cell scaffold, its structure is as follows:
(1) be made up of structure 1 and structure 2 two parts, structure 1 and structure 2 are directly joined, the hole of structure 1 and structure 2 communicates mutually; Or
(2) one deck that is reached between the two by structure 1 and structure 2 is made up of the compacted zone that material 3 is constituted, and makes the hole of structure 1 and structure 2 not connected;
The material 1 that wherein constitutes structure 1 can be the degradation speed same material identical with mechanical property with the material 2 that constitutes structure 2, also can be the degradation speed two kind materials different with mechanical property; Structure 1 can be the three-dimensional configuration structure (aperture, porosity and pore morphology structure) that is identical with structure 2, also can be different three-dimensional configuration structures, wherein a kind of aperture of structure can be in 5 nanometers～600 micrometer ranges, porosity in 30～95% scopes, the aperture of another kind of structure also can be in 5 nanometers～600 micrometer ranges, porosity in 30～95% scopes, and two thickness of structure are all in 0.2～10mm scope; Two kinds of structures can be identical open bore structures, also can be different open bore structures.The dense layer thickness that is made of material 3 is in 0.05～1.0mm scope.Structure 1, structure 2 and material 3 can be made of same material among the present invention, also can be made of different materials.The degradation speed of three kinds of materials is all 3 days to 3 years scope;
Structure 1 employed material 1 of the present invention and structure 2 employed materials 2 can be respectively by natural macromolecular material chitin, chitosan, alginate, collagen protein, glucosan, hyaluronic acid, gelatin and agar, or natural inorganic material hydroxyapatite, calcium phosphate and coral reef, or a kind of or blend between them in synthesized polymer material aliphatic polyester, poly-anhydride, poly phosphazene, poe and the polyethers, also can all form by synthesized polymer material.Wherein in the synthesized polymer material based on aliphatic polyester, poly (l-lactic acid) (PLLA) is wherein arranged, poly-DL-lactic acid (PDLLA), copolymerization (L-lactic acid/DL-lactic acid) (PLLA-co-PDLLA), polyglycolic acid (PGA), copolymerization (lactic acid/glycolic) bipolymer (PLGA), copolymerization (lactic acid/caprolactone) bipolymer (PLC), polycaprolactone (PCL), copolymerization (glycolic/lactic acid/caprolactone) terpolymer (PLGC), polycaprolactone/polyether block copolymer (PCE), polycaprolactone/polyethers/polylactic acid terpolymer (PCEL), polylactic acid/polyether bipolymer (PLE), and a kind of or blend between them in other polyhydroxy acid (PHA).
Described material 3 can be the natural macromolecular material chitin, chitosan, alginate, collagen protein, glucosan, hyaluronic acid, gelatin and agar, or the poly (l-lactic acid) in the synthesized polymer material aliphatic polyester (PLLA), poly-DL-lactic acid (PDLLA), copolymerization (L-lactic acid/DL-lactic acid) (PLLA-co-PDLLA), polyglycolic acid (PGA), copolymerization (lactic acid/glycolic) bipolymer (PLGA), copolymerization (lactic acid/caprolactone) bipolymer (PLC), polycaprolactone (PCL), copolymerization (glycolic/lactic acid/caprolactone) terpolymer (PLGC), polycaprolactone/polyether block copolymer (PCE), polycaprolactone/polyethers/polylactic acid terpolymer (PCEL), polylactic acid/polyether bipolymer (PLE), and a kind of or blend between them in other polyhydroxy acid (PHA).
That the prepared cell scaffold with composite structure of the present invention can be is bar-shaped, tabular, membranaceous, tubulose or specific shape.
The three-dimensional configuration structure of structure 1 or structure 2 can be the structure of natural inorganic material among the present invention, also can be by common freeze-drying, solution casting method, thermoplastic shaping method, compression molding method, control evaporation, laser ablation method, spraying freezing, mechanical processing method, fibrage method (D.W.Hatmacher etc., Biomaterials, 2000,21:2529-2543) one or both methods in make.
Can adopt common Method for bonding, fusion process or pressing method to engage among the present invention between structure 1, structure 2 and the material 3.
The concrete grammar that adopts solution casting method to prepare cell scaffold with composite structure of the present invention is: material 1 and material 2 each 1～50 part of solvent that are dissolved in separately; described solvent is dichloromethane, dichloroethanes, chloroform, oxolane, dioxane or distilled water, diluted acid, dilute alkaline soln; after being made into 1～20% solution; respectively with the ratio of 0.5g/1.0g～1.0g/20.0g with 5～300 purpose salt grain mix homogeneously, water respectively again and cast from the mould.Solvent flashing vacuum drying 12～72 hours again after 5～72 hours, then resulting 2 of salt material 1 and the materials of containing immersed desalination in the deionized water, changed one time water in per 1～10 hour, in cleaning mixture, detect till the residual ion less than salt, the material 1 that has taken off salt and material 2 porous supports air drying 5～72 hours, are made material 1 and material 2 porous supports.When one or both of material 1 and material 2 are the natural inorganic material, can carry out above processing and directly use.
Bonding material 1 and material 2 porous supports with the solution of 0.5～10% material 3, vacuum drying is 12～72 hours again, obtaining material 1 and material 2 average pore sizes is that 5 nanometers～600 micrometer ranges, porosity are in 30～95% scopes, material 1 and material 2 thickness are in 0.2～10mm scope, the thickness of material 3 at thickness in 0.05～1.0mm scope, by material 1, material 2 and 3 three layers of cell scaffold with composite structure of forming of material.
A face of above-mentioned material that has taken off salt 1 that makes and material 2 porous supports is coated with directly to engage immediately behind the cosolvent of minute quantity, described cosolvent is dichloromethane, dichloroethanes, chloroform, oxolane, dioxane or distilled water, diluted acid, dilute alkaline soln, and vacuum drying is 12～72 hours again; Or face of material 1 and material 2 porous supports and temperature are pressing immediately again after 55～200 ℃ hot plate contacts; Or material 1 and material 2 porous supports pressurizeed 12～72 hours face to face, then obtain only by material 1 and the material 2 two-layer cell scaffold with composite structure of forming.
Be suitable for cytoskeleton with the prepared cell scaffold with composite structure of the present invention, be used to carry out the reparation and the structure of tissues such as skin, blood vessel, patella, esophagus, trachea and organ as various kinds of cell organizational projects such as skin, blood vessel, bone/cartilage, esophagus, tracheas.
Fig. 1 is a cell scaffold with composite structure for tissue engineering structural representation of the present invention.
1 is that structure 1,2 is that structure 2,3 is a material 3.
Below in conjunction with embodiment the present invention is done further detailed description.
Embodiment 1
Copolymerization (lactic acid/glycolic) (70/30) (PLGA730) after each 5 parts of (molecular weight 50,000) and poly-DL-lactic acid (PDLLA) (molecular weight 40,000) are dissolved in the dichloromethane; respectively with the ratio of 1.0g/1.0g and 1.0g/10.0g with 40-60 purpose salt grain mix homogeneously, water respectively again and cast from the mould.Solvent flashing 24 hours and vacuum drying 24 hours immerse desalination in the deionized water to resulting saliferous PLGA/NaCl and PDLLA/NaCl piece then, change water one time in per 4 hours, detect less than till the chloride ion in cleaning mixture.The PLGA that has taken off salt and PDLLA porous support air drying after 24 hours the PLGA dichloromethane with 5% bonding, vacuum drying is 48 hours again, obtaining PDLLA layer average pore size and be 200 microns, porosity is 90%, PLGA layer average pore size is that 30 microns, porosity are 80%, the PLGA/PDLLA cell scaffold with composite structure that two-layer hole is not connected.
Embodiment 2
Copolymerization (lactic acid/glycolic) (85/15) (PLGA8515) (molecular weight 60,000) each 5 parts be dissolved in the dichloromethane back with the ratio of 1.0g/10.0g respectively with 20-40 order and 120 purpose salt grain mix homogeneously; water respectively and cast from the mould back solvent flashing 24 hours and vacuum drying 24 hours; then resulting two kinds of saliferous PLGA/NaCl pieces are immersed desalination in the deionized water; changed water one time in per 4 hours, and in cleaning mixture, detected less than till the chloride ion.Bonding after 24 hours the PLGA porous support that has taken off salt with the dichloromethane solution that contains 1%PLGA8515 at air drying, vacuum drying is 48 hours again, obtains average pore size and is respectively the logical PLGA cell scaffold with composite structure of the mutual structure in hole that 200 microns and 500 microns, porosity all are about 90%, two interlayers.
Embodiment 3
5 parts of copolymerization (lactic acid/caprolactone) (90/10) bipolymers (PLC910) (molecular weight～50,000) be dissolved in the dichloromethane back with the ratio of 1.0g/10.0g with 60-80 purpose salt grain mix homogeneously; the same method is watered and is cast from the mould back solvent flashing and slough salinity, obtains average pore size and is 200 microns, porosity and be about 90% PLC910 support.Get natural inorganic material hydroxyapatite again, after being cut into the sheet of 2 millimeters thick, coated one deck covers rapidly on the above-mentioned PLC910 support after containing 5% PLC910 dichloromethane solution, behind the vacuum drying 48 hours, obtain the not connected hydroxyapatite/PLC cell scaffold with composite structure in hole of two interlayers.
Embodiment 4
With embodiment 3 methods; but adopting 5 parts of copolymerization (glycolic/lactic acid/caprolactone) terpolymers (PLGC) is material; the back is watered after with 60-80 purpose salt grain mix homogeneously with the ratio of 1.0g/10.0g again and is cast from the mould back solvent flashing and slough salinity in being dissolved in dichloromethane, obtains average pore size and is 180 microns, porosity and be about 90% PLGC support.It is bonding with the chitosan stent that by the prepared aperture of freeze-drying is 80 microns that reuse contains 5% PLA dichloromethane solution, and vacuum drying obtained the not connected chitosan/PLGC cell scaffold with composite structure in hole of two interlayers after 48 hours.
Embodiment 5
With embodiment 3 methods; but adopting 5 parts of polycaprolactone/polyethers/polylactic acid terpolymer (PCEL) is material; the back casts from the mould back solvent flashing and sloughs salinity with watering behind the 120 purpose salt grain mix homogeneously again with the ratio of 1.0g/5.0g in being dissolved in dichloromethane, obtains average pore size and is 80 microns, porosity and be about 85% PCEL support.It is bonding with the alginate support that by the prepared aperture of freeze-drying is 80 microns that reuse contains 1% PLA dichloromethane solution, behind the vacuum drying 48 hours, obtain chitosan/PLGC cell scaffold with composite structure that two-layer aperture is identical, the mutual again structure in the hole of two interlayers leads to.
Embodiment 6
To be used for skin tissue engineering by embodiment 1 resulting PLGA/PDLLA cell scaffold with composite structure, the PLGA holder part that its mesopore is little is used for the epidermis cell cultivation, the big PDLLA holder part in hole is used for fibroblastic cultivation, the result shows that two parts cell does not contact mutually, all growth and breeding is good, and the collagen stroma secretion is arranged.
Embodiment 7
To be used for the patella reparation by embodiment 3 resulting hydroxyapatite/PLC cell scaffold with composite structure, wherein the hydroxyapatite holder part is used for the osteocyte cultivation, the PLC holder part is used for articular cartilage and cultivates, the result shows two-part cell, and all growth and breeding is good, and the collagen stroma secretion is arranged.
Reference examples 1:
Will be bonding with 1% PLGA dichloromethane by embodiment 1 prepared PLGA that has taken off salt and PDLLA porous support, vacuum drying is 48 hours again, obtaining PDLLA layer average pore size and be 200 microns, porosity is 90%, PLGA layer average pore size is that 30 microns, porosity are the sensible mutually PLGA/PDLLA cell scaffold with composite structure in hole of 80%, two interlayer.Be used for skin tissue engineering then, the PLGA holder part that its mesopore is little is used for the epidermis cell cultivation, the big PDLLA holder part in hole is used for fibroblastic cultivation, the result shows: because the hole of double-layer structure is penetrating mutually, make the growth of epidermis cell be subjected to the inhibition of fibroblastic growth, the growth procreation is undesired.
Reference examples 2:
Copolymerization (lactic acid/glycolic) (70/30) (PLGA730) after each 5 parts of (molecular weight 50,000) and polylactic acid (PLLA) (molecular weight 40,000) are dissolved in the dichloromethane; all with the ratio of 1.0g/10.0g with 40-60 purpose salt grain mix homogeneously, water respectively again and cast from the mould.Solvent flashing 24 hours and vacuum drying 24 hours immerse desalination in the deionized water to resulting saliferous PLGA/NaCl and PLLA/NaCl piece then, change water one time in per 4 hours, detect less than till the chloride ion in cleaning mixture.The PLGA that has taken off salt and PLLA porous support air drying after 24 hours the PLGA dichloromethane with 5% bonding, vacuum drying is 48 hours again, obtains PLLA layer and PLGA layer average pore size and all be 200 microns, porosity and be 90% cell scaffold with composite structure.This cell scaffold with composite structure is used for skin tissue engineering, wherein the PLGA holder part is used for the epidermis cell cultivation, the PLLA holder part is used for fibroblastic cultivation, the result shows: the fibroblastic growth of PLLA holder part is good, and the epidermis cell of PLGA layer then is that cell is few, growth is poor.This is because two kinds of cells of fibroblast and epidermis cell are different to the requirement of aperture pore structure, and 200 microns cytoskeleton aperture fibroblast is proper, and is that the aperture is too big for epidermis cell, therefore makes the cell can't adherent and normal growth.
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