CN104136602A - Adhesive cell tissue gels - Google Patents
Adhesive cell tissue gels Download PDFInfo
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- CN104136602A CN104136602A CN201180073036.7A CN201180073036A CN104136602A CN 104136602 A CN104136602 A CN 104136602A CN 201180073036 A CN201180073036 A CN 201180073036A CN 104136602 A CN104136602 A CN 104136602A
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Abstract
Described herein is a cell tissue gel cross-linked with a cross-linking agent, and a quenching agent bound to a reactive group of the cross-linking agent.
Description
[prior art]
Cell tissue sizing agent has application miscellaneous because of its adhesion characteristic, and mostly traditional sizing agent is to use linking agent for making material.But linking agent is toxic to organism., in the time of the use of cell tissue sizing agent, must be reduced the toxicity of linking agent.
[summary of the invention]
The present invention is based on unexpected a discovery, and cell tissue gluing can, by producing crosslinkedly with a linking agent, and comprise that a resistance stops agent, can be in conjunction with the functional group that this linking agent showed, improve its boundary intensity and reduction toxicity.
Therefore, the invention is characterized in the one or more substrate molecules of a kind of cell tissue sizing agent Bao Kuo ︰ (matrix molecule), itself and a linking agent (cross-linkingagent) produce crosslinked, and one resistance stop agent (quenching agent), it is bonded to a functional group of described linking agent.
Above-mentioned one or more substrate molecules are to be selected from by collagen protein (collagen), hyaluronic acid (hyaluronan), gelatin (gelatin), fiber connects albumen (fibronectin), elastin (elastin), tenascin (tenascin), basement membrane element (laminin), vitronectin (vitronectin), Suleparoid (heparan sulfate), chrondroitin (chondroitin), chondroitin sulfate (chondroitin sulfate), keratin (keratan), keratan sulfate (keratan sulfate), dermatan sulfate (dermatansulfate), carrageenin (carrageenan), heparin (heparin), chitin (chitin), spherical chitosan (chitosan), alginates (alginate), agar-agar (agarose), agar (agar), Mierocrystalline cellulose (cellulose), methylcellulose gum (methyl cellulose), the group that carboxymethyl cellulose (carboxyl methyl cellulose) and glycogen (glycogen) form, but not as limit.In one embodiment, described substrate molecule comprises collagen protein, any one in hyaluronic acid and gelatin.
Linking agent (cross-linking agent) has two or more functional response's bases conventionally, and this functional group can be identical or not identical.Above-mentioned linking agent is to be selected to contain epoxide (epoxide), dialdehyde-based (dialdehyde), N-hydroxy-succinamide (N-hydroxysuccinimide ester), carbon imide (carbodiimide), gardenin (genipin), riboflavin (riboflavin), flavonoid (flavonoid), 6-dimaleoyl imino caproic acid active ester (6-maleimidohexanoic acid activeester), succinimide suberate (disuccinimidyl suberate), sulfosuccinimide base-4-(N-maleimide methyl) group that forms of hexanaphthene-1-carboxylic acid tert-butyl ester (sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate) and two (thiosuccimide base) suberate (bis (sulfosuccinimidyl) suberate), but not as limit.It is to be selected to contain the group that diamines (diamine), few amine (oligoamine), polyamines (polyamine), dicarboxylic acid (dicarboxylic acid), few carboxylic acid (oligo-carboxylic acid), poly carboxylic acid (polycarboxylic acid), multi-thioalcohol compound (polysulfhydryl compound), polyol (polyhydroxycompound) and the compound containing isodigeranyl base (heterobifunctional) form that described resistance stops agent, but not as limit.
In one embodiment, described linking agent is that to stop agent be poly-L-Lysine (poly-L-lysine) for gardenin and described resistance.The molecular-weight average of wherein said polylysine is greater than 20kDa, best, is greater than 99kDa or is greater than 212kDa.In another embodiment, described linking agent is ethylene glycol diglycidylether (ethylene glycol diglycidyl ether), and it is water that described resistance stops agent.In another embodiment, described linking agent is ethylene glycol diglycidylether, and it is polylysine (poly-lysine) or r-polyglutamic acid (r-polyglutamic acid) that described resistance stops agent.
Cell of the present invention is knitted sizing agent and is further contained a nutritive substance (for example, cell culture medium), biologically active agent, and/or cell (for example, stem cell).Described biologically active agent can be a somatomedin, be selected from by Urogastron (epidermal growthfactor, EGF), fiber mother cell growth factor (fibroblast growth factor, FGF), vascular endothelial growth factor (vascular endothelial growth factor, VEGF), Connective Tissue Growth Factor (connective tissue growth factor, CTGF), Thr6 PDGF BB (platelet-derived growth factor, PDGF), insulin-like growth factor (insulin-like growth factor, IGF), nerve growth factor (nerve growth factor, NGF), pHGF (hepatocyte growthfactor, HGF), group's stimulating factor (colony-stimulating factor, CSF), STEM CELL FACTOR (stem cell factor, SCF), keratinocyte growth factor (keratinocyte growth factor, KGF), white cell somatomedin (granulocytecolony-stimulating factor, GCSF), scavenger cell group stimulating factor (granulocyte macrophage colony-stimulating factor), the derivative neural factor (the glial derived neurotrophic factor that nourishes of neuroglia, GDNF), hair shape neurotrophic factor (ciliary neurotrophic factor), endotheliocyte monocytic activity polypeptide (endothelial-monocyte activating polypeptide), the neutral ball active polypeptide of epidermis (epithelial neutrophil activating peptide), erythropoietin (erythropoietin), bone plastotype albumen (bone morphogeneticprotein), the brain derived neural factor (brain-derived neurotrophicfactor) of nourishing, conversion growth factor-β (transforming growth factor beta), the group that mammary gland performance chemokine (BRAK) and tumour necrosis factor (tumor necrosis factor) form.
The present invention also provides a kind of cell (for example stem cell) of implanting to provide a kind of cell implant (cell implant) in method of individuality Bao Kuo ︰ (i), and described cell implant comprises cell tissue sizing agent as above and a cell source; And (ii) described implant is implanted in to this individuality.Further within the scope of the invention, be to utilize cell tissue sizing agent in the implant unit of manufacturing cell transmission use.
The present invention, in following description, further describes with regard to the details of multiple embodiment, is can show and know its inventive features and advantage.
[embodiment]
The invention provides a kind of bio-compatibility small cell that can be used for Growth of Cells and organize sizing agent.Comprise one or above substrate molecule (seeing below), itself and a linking agent produce crosslinked, and a resistance stops agent, and it is bonded to a functional group of described linking agent.Cell tissue gel of the present invention further comprises a nutritive substance (for example, cell culture medium), biologically active agent, and/or cell (for example, stem cell).
substrate molecule
Substrate molecule (for example, macromolecular compound) help cell to remain on an implant site, it is an extracellular molecules in extracellular matrix, in this reference person for example: collagen protein, hyaluronic acid, gelatin, fiber connects albumen, elastin, tenascin, basement membrane element, vitronectin, polypeptide, Suleparoid, chrondroitin, chondroitin sulfate, keratan sulfate, keratan sulfate, dermatan sulfate, carrageenin, heparin, chitin, deacetylchitosan, alginate, agarose, agar, methylcellulose gum, methylcellulose gum, carboxymethyl cellulose, glycogen or derivatives thereof, but be not limited to this.In addition, substrate molecule can also be scleroproein, Fibrinogen, zymoplasm, and polyglutamic acid, synthetic polymer (for example, acrylate, poly(lactic acid), polyglycolic acid, or poly-(lactic acid-altogether-oxyacetic acid), best, the high molecular weight material that is applied to the substrate molecule of organizing gel using in the present invention, to improve the viscosity of gel.
Any naturally occurring collagen protein or its its sense variant (functionalvariants), all can be used for preparing tissue glue of the present invention.At present, at least found the collagen protein of 28 kinds of different genes species.Collagen protein can be simply from being rich in collagen protein tissue (as skin, tendon, ligament and osseous tissue) of the mankind or animal separate, purifying out.Separation and purification collagen protein method has been well-known in this field.(can be with reference to for example ︰ United States Patent (USP) 5,512,291, No. 20040138695 communiques of U.S. Patent Application Publication, Methodsin Enzymology, vol.82, pp.33-64,1982, The Preparation ofHighly Purified Insoluble Collagen, Oneson, I., et al, Am.Leather Chemists Assoc., Vol.LXV, pp.440-450,1970, United States Patent (USP) 6,090,996).Collagen protein also can use recombinant technology preparation, as described at AdvancedTissue Sciences (La Jolla, Calif.), or buys (as Fibrogen from different suppliers; South San Francisco, Calif.).Below an embodiment: ox musculus flexor profundus tendon, except washing with water after degrease and manadesma, freezes, and is cut into 0.5 millimeter of (mm) thin slice with food slicer.First the tendon water of 50 milliliters (mL) of cutting into slices in right amount is at room temperature extracted to 24 hours.Abandon water-soluble portion, the tendon of then cutting into slices and acidic solution (as 0.2N hydrochloric acid) are at suitable temperature (as room temperature) one section of reasonable time of lower extraction (as 12 hours to 24 hours).Hydrochloric acid soln abandons rear water and washes away the acid solution remaining on tendon.The tendon rinsing uses basic solution (as 0.75M sodium hydroxide) to extract one section of reasonable time (as 12 hours to 24 hours) in suitable temperature (as room temperature).Removal of alkaline solution afterwards, uses acidic solution (as 0.1N hydrochloric acid) to neutralize section tendon until pH value is 4 to 7 (as pH5), then reuses water and washes away the alkali lye that remains in tendon.Afterwards tendon is used alcohols (as Virahol) to carry out one section of time enough of degreasing (as 16 hours) in room temperature.Extract is poured out and is used alcohols (as Virahol), in room temperature, tendon is done to further extraction for some time (as 12 hours to 24 hours), form the solution containing collagen protein, the solution of collagen protein is dry in clean exhausting cabinet.Therefore the collagen protein powder forming can leach in acidic solution (as 0.5M or 0.25M acetic acid), reacts one section of reasonable time under the existence that contains proteolytic ferment (as trypsinase or stomach en-) in 4 DEG C.Carry out filtering mixt with the stainless steel mesh screen of 100 orders, and can use 5% salt solution to make soluble collagen Shen Dian, the collagen protein that Shen Dian goes out can dissolve with above-mentioned acidic solution again, and the solution therefore forming can filter with 100 order stainless steel mesh screens, to remove insoluble microparticle.Then this glue protein solution is dialysed and is removed the acid in solution in pure water.
The hyaluronic acid that the present invention chatted is made a general reference naturally occurring anionic, the poly-candy (glycosaminoglycan) of osamine of non-sulfuric acid, comprise the multiple disaccharide unit of N-acetyl-glucosamine (N-acetylglucosamine) and D-glucuronic acid (D-glucuronic acid), and its derivative.Hyaluronic acid can be separated from natural goods, as the vitreum of cryptomere suis, cockscomb, cartilage, synovial joint fluid, umbilical cord, skin histology and eyes, by such as Guillermo Lago et al.Carbohydrate Polymers62 (4): 321-326,2005 and Ichika Amagai et al.Fisheries Science75 (3): 805-810, the art methods described in 2009.Or, can be to the supplier of business, for example Genzyme Corporation, Lifecore Biomedical, LLC and HyaluronContract Manufacturing buy.Natural hyaluronic derived prods includes but not limited to following hyaluronic acid ester (hyaluronan esters), adipic dihydrazide-modification hyaluronic acid (adipic dihydrazide-modified hyaluronan), hyaluronic acid acid amides product (hyaluronan amide products), cross-linked-hyaluronic acid (crosslinkedhyaluronic acid), the heavy metal salt of half fat succinic acid (hemiesters of succinic acid) or hyaluronic acid, part or full-creamization hyaluronic acid, sulfuration hyaluronic acid (sulphated hyaluronic acid), N-sulfuration hyaluronic acid (N-sulphatedhyaluronic acid) and amine or diamine modified hyaluronic acid.Derivatives of hyaluronic acids also can obtain by above functional group's chemically modified, wherein this functional group include, but are not limited to carboxylic acid group (carboxylic acid group), hydroxyl (hydroxyl group), reducing end group (reducing end group) and N-ethanoyl (N-acetyl group) wherein carboxylic acid group's modification reaction can modify by the catalysis of carbon imide (carbodiimide) and bishydrazide (bishydrazide) or esterification (esterification); The wherein modification reaction of hydroxyl, include but not limited to sulfation (sulfation), esterification, isourea coupling (isourea coupling), cyanogen bromide-activated (cyanogen bromide activation) and periodate oxidation (periodate oxidation); Reducing end group can be by reduction amination (reductive amination) to modify reducing end group.Hyaluronic acid also can be linked to phospholipid, dyestuff (as fluorophor or chromophoric group) and in order to prepare the reagent of nucleophilicity matrix.The derivative of natural hyaluronic acid also can be by using linking agent, molecule lactonize (internal esterification), photo-crosslinking (photocross-linking) or surface plasma processing (surface plasma treatment) and obtain, wherein the linking agent of use comprises, but be not limited to di-epoxide (bisepoxide), divinyl sulfone (divinylsulfone), dual-carbodiimide (biscarbodiimide), the difunctionality base bridging agent that molecule is less, formaldehyde (formaldehyde), NSC 87419 (cyclohexylisocyanide), from amino acid ethyl ester (lysine ethyl ester), anionic metal, hydrazides (hydrazide) or above-mentioned combination.
Shown transparency the at present hyaluronic acid (being greater than 5kDa) of matter acid, particularly high molecular, can effectively promote blood vessel newly to become, and then promote wound healing.The temporary transient application case 61/390,789 of for example U.S., the molecular weight of hyaluronic acid is 50kDa to 5,000kDa (as 70kDa to 1,500kDa, 200kDa to 1,500kDa, 500kDa to 1,500kDa or 700kDa to 1,500kDa).
Further, be to show the stem cell improvement that shows survival rate, contain collagen protein and hyaluronic acid in 0.01-100(collagen protein when it is grown in one): 1(hyaluronic acid) the cell tissue sizing agent of weight ratio.Referring to No. 12/974535 communique of United States Patent (USP).Making cell tissue sizing agent described in the invention, the concentration of hyaluronic acid can be every milliliter 0.001 to 100mg/mL (as: 0.01 to 1mg/mL); The concentration of collagen protein can be 0.001 to 100mg/mL.Preferably, the concentration of collagen protein is 0.1 to 100mg/mL, and the concentration of hyaluronic acid is 0.01-35mg/mL.Better, the concentration of collagen protein is 3-75mg/mL (as 6mg/mL or 9mg/mL), the concentration of hyaluronic acid is 0.2-20mg/mL.
linking agent
Linking agent must react with target molecule and be crosslinked together with target molecule, and this linking agent comprises at least two functional response's bases that can react with the functional group of target molecule conventionally, table 1 has been enumerated functional response's base and functional group, and linking agent and functional group are known by prior art.
Linking agent used herein can comprise, but be not limited to imines ester (imidoester), epoxide (epoxide) [as: ethylene glycol bisthioglycolate glycidyl ethers (ethylene glycol diglycidyl ether)], glutaraldehyde (glutaraldehyde), N-maloyl imines ester (N-hydroxysuccinimide ester) [as: 2, 3-dibromo propionyl N-maloyl imines ester (2, 3-dibromopropionyl-N-hydroxysuccinimide ester), sulfonic group-N-maloyl imines ester (sulfo-N-hydroxysuccinimideester) and Chlorambucil N-maloyl imines ester (chlorambucil-N-hydroxysuccinimideester)], carbon imide (carbodiimide) [as: 1-ethyl-3-[3-dimethylamino] carbon imide (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride)], gardenin (genipin), maleimide (maleimide), repeatedly nitrogen (azide), halo acetyl (haloacetyl), pyridine disulphide (pyridyl disulfide), hydrazides (hydrazide), flavine (riboflavin), Vitamin P complex (bioflavonoid), core flavonoid (flavonoid) and derivative thereof [as: pycnogenols (proanthocyanidin), catechin (catechin), l-Epicatechol (epicatechin), epigallocatechin (epigallo catechin), L-Epicatechin gallate (epicatechin gallate), nutgall catechin gallic acid (epigallocatechin gallate), Quercetin (quercetin), phenyl styryl ketone element (chalcones), apigenin (apigenin), luteoiin, a polymethoxylatedfiavone, quercitoi, kaempferol (kaempferol), ampelopsin (myricetin), anthocyanidin (anthocyanin), resveritrol, an isoflavanoid, daidzein (daidzein), genestiein, Nobiletin (nobiletin), orange peel (tangeretin) and tannic acid (tannic acid)], 6-(dimaleoyl imino) caproic acid active ester (6-maleimidohexanoic acid active ester), two amber imines acyl suberic acid carbamyl phosphates (disuccinimidyl suberate), double amber imide suberate [bis (sulfosuccinimidyl) suberate], azide (azide), two ethylene imines (diazirine), 4-(N-maleimide methyl) hexanaphthene-1-carboxylic acid sulfonic group succinimide ester [sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate] and derivative thereof.This linking agent can be also that a sodium polyacrylate comprises multiple identical or different functional response's base, as polyepoxides (polyepoxy compound) and poly-(alcohol acid) (poly (hydroxy acid)).
Table 1. reactive group and and target functional group
resistance stops agent
To stop agent be reagent react with linking agent reactive group in this reference person in resistance, after target molecule and linking agent are cross-linked, hinder stop agent can with do not react with the linking agent reactive group of target functional response radical reaction.By " exhausting " unreacted reactive group, resistance stops agent and can reduce wholly or in part the toxicity of linking agent.It can be a compound that resistance stops agent, comprises amine (amine), sulfydryl (sulfhydryl), carbonyl (carbonyl), ethylene glycol (glycol), carboxyl (carboxyl), azide (azide) or photo-crosslinking group (photo-crosslinking group).In other words, resistance stop agent comprise a sense base system can with functional response's radical reaction of this linking agent.In one embodiment, when linking agent is to contain the group reacting with amido, resistance stops agent including but not limited to diamine (diamines), and few amine (oligoamines) and polyamine (polyamines) are as poly-lysine (polylysine) and poly glutamy acid (polyglutamine).In another embodiment, when linking agent is to contain and the group of carboxyl reaction, resistance stops agent and comprises di-carboxylic acid, few carboxylic acid or poly carboxylic acid as polyglutamate (polyglutamate or polyglutamate acid).The resistance of other embodiment stop agent comprise can for the sulfydryl reactive group that suppresses containing polysulfhydryl compound, and can be used for the hydroxyl reaction base that suppresses containing polyhydric compound.
nutritive substance
Nutritive substance is the essential source of nutrition of Growth of Cells in this reference person, and it is Amino acid, VITAMIN, mineral substance, carbon source (as glucose), lipid acid or above-mentioned mixture.In one embodiment, described nutritive substance is cell culture medium, and it includes but not limited to minimum necessary substratum (Minimum Essential Medium, MEM), basis is according to lattice substratum (BasalMedium Eagle, BME), Du Shi improvement Ying Geer substratum (Dulbecco's ModifiedEagle's medium, DMEM), nutrition mixed culture medium (Ham's Nutrient MixturesF-10 or F-12), substratum 199 (Medium199), the micro-park of Luo Si institute substratum (Roswell Park Memorial Institute medium, RPMI medium), peace Mu Shi substratum (Ames'Medium), BGJb Medium (Fitton-JacksonModification), Ke Like substratum (Click's Medium), CMRL-1066Medium, take snow substratum (Fischer's Medium), Glasgow MEM (GlasgowMinimum Essential Medium), Iscove's Modified Dulbecco's Medium, L-15Medium, McCoy's5A Modified Medium, NCTC Medium, Swim'sS-77Medium, Waymouth Medium or William's Medium E.
biologically active agent
Any reagent (as won peptide, winning peptide, few candy, polysaccharide or small molecules more), can promote cell survival ability, and promoting hyperplasia ability or Cell differentiation inducing activity all can provide the present invention's cell tissue sizing agent to use.In one embodiment, described biochemical activity molecule is somatomedin, it comprises Urogastron (epidermal growth factor, EGF), fiber mother cell growth factor (fibroblast growth factor, FGF), vascular endothelial growth factor (vascular endothelial growth factor, VEGF), Connective Tissue Growth Factor (connective tissue growth factor, CTGF), Thr6 PDGF BB (platelet-derived growth factor, PDGF), insulin-like growth factor (insulin-like growth factor, IGF), nerve growth factor (nerve growthfactor, NGF), pHGF (hepatocyte growth factor, HGF), group's stimulating factor (colony-stimulating factor, CSF), STEM CELL FACTOR (stemcell factor, SCF), hydroxy-tryptamine (serotonin) and vWF ELISA (vonWillebrand factor), transforming growth factor (transforming growthfactor), keratinocyte growth factor (keratinocyte growth factor, KGF), white cell somatomedin (granulocyte colony-stimulating factor, GCSF), scavenger cell group stimulating factor (granulocyte macrophagecolony-stimulating factor), granulocyte/macrophage colony stimulating factor (granulocyte/macrophage colony stimulating factor), the derivative neural factor (the glial derived neurotrophic factor that nourishes of neuroglia, GDNF), hair shape neurotrophic factor (ciliary neurotrophic factor), endotheliocyte monocytic activity polypeptide (endothelial-monocyte activating polypeptide), the neutral ball active polypeptide of epidermis (epithelial neutrophil activating peptide), erythropoietin (erythropoietin), plastotype albumen (bone morphogenetic protein), the brain derived neural factor (brain-derived neurotrophic factor) of nourishing of bone.In another embodiment, this biochemical activity molecule is a cytokine/chemical chemotactic hormone (cytokines/chemokine), it includes but not limited to IL-2, thymus gland performance chemistry element (the breast-expressed chemokine that becomes, BRAK), kidney shows the composition of chemical chemotactic hormone (kidney-expressed chemokine, CXCL14) or above-mentioned substance.This biochemical activity molecule is a cell differentiation factor, as: synthetic reflunomide (dexamethasone), Sodium.alpha.-ketopropionate (sodium pyruvate), vitamins C phosphoric acid salt (ascorbic acid-2-phosphate), retinoic acid (retinoic acid), proline (proline), Regular Insulin (insulin), transferrin (transferrin), selenous acid (selenous acid), linolic acid (linoleic acid), bovine serum albumin (bovineSerum Albumin), conversion growth factor-β 3 (transforming growth factorbeta3, TGF-3).In another embodiment, this differentiation factor is the compound (be illustrated in United States Patent (USP) 5,908, hold within 784 communiques disclose) that can promote the Chondrogenesis of mesenchymal stem cell, bone new life is [as dexamethasone (dexamethasone), vitamins C (ascorbicacid), β-phospho-glycerol (β-glycerol phosphate)], steatogenesis is [as Regular Insulin (insulin), isobutyl methylxanthine (isobutylmethylxanthine), dexamethasone (dexamethasone), draw a U.S.A and spill pungent (indomethacin)], Myocardium Differentiation is [as activin A (activin A), bone morphogenetic protein-4 (bone morphogeneticprotein-4, BMP-4)], endothelial cell differentiation is [as endotheliocyte (EBM-2), dexamethasone (dexamethasone) and vascular endothelial growth factor (VEGF)], smooth muscle cell differentiation [as Thr6 PDGF BB (PDGF)], nerve-inducing is [as basic fibroblast growth factor (basic fibroblast growth factor, bFGF), Urogastron (EGF), B27supplement, dimethyl sulfoxide (DMSO) (DMSO), butylhydroxy methoxy benzene (butylatedhydroxyanisole), coleus element (forskolin), valproic acid (valproic acid), Repone K, K252a and N2supplement] and entoderm spectrum be that differentiation (endodermallineage differentiation) is [as dexamethasone, pHGF (HGF) and fiber mother cell growth factor-4 (FGF-4)].In better embodiment, biochemical activity molecule is herbal medicine or the effective constituent of herbal medicine.
the embedded preparation of organizing sizing agent of cell
The preparation of organizing sizing agent described herein, can impel mixture formative tissue sizing agent by above-mentioned materials is mixed and is maintained at suitable condition with specific weight ratio.And the embedded sizing agent of organizing of preparation one cell, cell source can mix with the constituent of sizing agent before sizing agent forms.Cell source can be the stem cell being obtained by mammal (as: ox, pig, mouse, horse, dog, cat, sheep, monkey and people).In one embodiment, described stem cell, it includes but not limited to embryonic stem cell (placenta-derived stem cells), bone marrow stem cell (bone marrow-derived stem cells), stroma cell (stromal cells) [as adipose stromal cells (dipose-derived stromal cells)], mesenchymal stem cell (mesenchymal stem cells), tissue-derived cell (tissue progenitor cells), initiating cell (blast cells) or fibrocyte (fibroblasts)
Aforementioned cell tissue sizing agent is combined the cell implant that formed and can be implanted into the position of human body with cell source, to carry out tissue repair and other therapeutic purpose.
Those skilled in the art can, according to description above, utilize the present invention to greatest extent.System proposes an embodiment, is only illustrative explanation, and the rest part of limit publicity content not.All reference of quoting herein are all incorporated to herein by reference.
embodiment: the cell tissue glue that contains poly-L-Lysine linking agent
glutinous agent
(A) materials and methods
The resistance of this place use stops agent and comprises spermine (spermine), fish amine (protamine), 1-6 hexanediamine (1,6-hexanediamine), and polylysine is the molecular weight of different groups.The molecular-weight average of polylysine is respectively 3.4kDa, 20kDa, 99kDa, 212kDa and 225kDa.
The polylysine of equivalent is mixed in phosphate buffered saline buffer with the gelatin of 300mg/mL, to form polylysine-gelatin solution, the gardenin solution that is 20mg/mL by equal-volume and concentration again mixes to form cell tissue sizing agent with above-mentioned polyamine-gelatin solution, then [its size is 10x30x0.7 to 0.9 cubic millimeter of (mm to be added to pigskin sample
3)] corium side.Two pigskin samples are relative with corium face, and centre is cell tissue sizing agent (10x10mm
2), the counterweight of 50 grammes per square metres is placed on to the top 30 minutes of two pigskin samples, and be system (LloydInstruments Ltd. with LRX testing of materials, England), under the pulling force with 10 centimetres of (mm/min) speed of per minute, separate two pigskin samples and organize with test cell the link strength of sizing agent.
The cell tissue sizing agent of 10 μ L is added to the culture dish central authorities of 24 porose discs, then plant into 2x10
4the fibroblast of individual cells/well (cell/well), and be incubated under 5% carbonic acid gas (COx), 37 DEG C of environment and go through 38 hours.The cell quantity of survival quantitatively, is carried out the measurement of toxicity evaluation by blood counting chamber.
By RheoStress RS150 (Haake, Germany) can measure the rheological property that contains and do not contain the cell tissue sizing agent of polylysine, and real time record elastic storage modulus (elastic storagemodulus, G') and temperature of reaction are that 1 handkerchief (Pa) and frequency are the data under the concussion test condition of 1 hertz (Hz) in fixing shearing stress (fixed shearstress).
(B) link strength test
Result shows the link strength that can promote cell tissue sizing agent during higher than 20kDa when the molecular weight of polylysine, selecting molecular weight is that the polylysine of 212kDa makes further research, and the link strength of the cell tissue sizing agent that contains polylysine can strengthen along with the rising of polylysine concentration, until polylysine concentration is up to 46.8mN.What the cell tissue sizing agent of making for use 17.5mN polylysine and the sizing agent that does not use polylysine carried out studies show that, the maximum value of the link strength of the cell tissue sizing agent that contains polylysine is greater than the cell tissue sizing agent that does not use polylysine.
The no matter concentration of gardenin, along with the rising of polylysine content, the link strength of cell tissue sizing agent will rise; In addition, strength of connection also strengthens along with the raising of gardenin concentration.
(C) toxicity evaluation
Toxicity without the cell tissue sizing agent of polylysine improves along with the rising of gardenin concentration.Add the effect that poisons of minimizing gardenin that polylysine can show.In the time using the gardenin of 7.5mg/mL and the polylysine of 46.8mN, do not observe the cytotoxic effect (cytotoxic effect) showing.
(D) rheological property (rheological properties)
In order further to understand the impact of the physics and chemistry character of polylysine on sizing agent, the numerical value of elastic storage modulus (G ') (the elasticstorage modulus) is measured by monitoring in real time.Through fixing shearing stress (fixed shear stress) (1Pa) and the vibration test of frequency (1Hz), test-results demonstration, the numerical value of elastic storage modulus (G ') is along with cell tissue sizing agent increases from liquid formation.The numerical value of elastic storage modulus (G ') improves along with polylysine joins in cell tissue sizing agent and showing.The numerical value of elastic storage modulus is detected in the variation of differential responses temperature, and carries out at 50 DEG C when reaction, and the reaction times shows while being 90 minutes that the numerical value of elastic storage modulus has rising sharply.This phase transition phenomenon shows that polylysine has participated in the crosslinking reaction of cell tissue sizing agent, and has increased the elastic storage modulus of cell tissue sizing agent.While not adding polylysine, do not observe phase transition phenomenon.
[other embodiments]
All features open in specification sheets can be combined by any form.In specification sheets, disclosed each feature can be used to identically, and alternative features equivalent or similar object is replaced.Therefore, except as otherwise noted, otherwise the equivalence that each open feature is only general series or an embodiment of similar characteristics.
From description above, those skilled in the art can easily determine essential feature of the present invention, and do not depart from spirit and scope of the invention and set out and carry out various changes, make it be applicable to different purposes and condition.Therefore, other embodiment also in the claims.
Claims (21)
1. a cell tissue sizing agent, is characterized in that wrapping and draws together ︰
One or more substrate molecules (matrix molecule), itself and linking agent (cross-linking agent) produce crosslinked; And
Resistance stops agent (quenching agent), functional group's bonding of itself and described linking agent.
2. cell tissue sizing agent as claimed in claim 1, it is characterized in that described linking agent is to be selected to contain epoxide (epoxide), dialdehyde-based (dialdehyde), N-hydroxy-succinamide (N-hydroxysuccinimide ester), carbon imide (carbodiimide), gardenin (genipin), riboflavin (riboflavin), flavonoid (flavonoid), 6-dimaleoyl imino caproic acid active ester (6-maleimidohexanoic acid active ester), succinimide suberate (disuccinimidyl suberate), sulfosuccinimide base-4-(N-maleimide methyl) one or more in hexanaphthene-1-carboxylic acid tert-butyl ester (sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate) and two (thiosuccimide base) suberate (bis (sulfosuccinimidyl) suberate).
3. cell tissue sizing agent as claimed in claim 1, it is to be selected from by containing one or more in diamines (diamine), few amine (oligoamine), polyamines (polyamine), dicarboxylic acid (dicarboxylic acid), few carboxylic acid (oligo-carboxylicacid), poly carboxylic acid (polycarboxylic acid), multi-thioalcohol compound (polysulfhydryl compound) and polyol (polyhydroxy compound) that wherein said resistance stops agent.
4. cell tissue sizing agent as claimed in claim 1, wherein said linking agent is gardenin, it is poly-L-Lysine (poly-L-lysine) that described resistance stops agent.
5. cell tissue sizing agent as claimed in claim 4, the molecular-weight average of wherein said polylysine is greater than 20kDa.
6. cell tissue sizing agent as claimed in claim 5, the molecular-weight average of wherein said polylysine is more than or equal to 99kDa.
7. cell tissue sizing agent as claimed in claim 5, the molecular-weight average of wherein said polylysine is more than or equal to 212kDa.
8. cell tissue sizing agent as claimed in claim 1, wherein said linking agent is ethylene glycol diglycidylether (ethylene glycoldiglycidyl ether), it is water that described resistance stops agent.
9. cell tissue sizing agent as claimed in claim 1, wherein said linking agent is ethylene glycol diglycidylether, it is polylysine (poly-lysine) or r-polyglutamic acid (r-polyglutamicacid) that described resistance stops agent.
10. cell tissue sizing agent as claimed in claim 1, wherein said substrate molecule is to be selected from by collagen protein (collagen), hyaluronic acid (hyaluronan), gelatin (gelatin), fiber connects albumen (fibronectin), elastin (elastin), tenascin (tenacin), basement membrane element (laminin), vitronectin (vitronectin), Suleparoid (heparan sulfate), chrondroitin (chondroitin), chondroitin sulfate (chondroitinsulfate), keratin (keratan), keratan sulfate (keratansulfate), dermatan sulfate (dermatan sulfate), carrageenin (carrageenan), heparin (heparin), chitin (chitin), spherical chitosan (chitosan), alginates (alginate), agar-agar (agarose), agar (agar), Mierocrystalline cellulose (cellulose), methylcellulose gum (methyl cellulose), one or more in carboxymethyl cellulose (carboxyl methyl cellulose) or glycogen (glycogen).
11. cell tissue sizing agents as claimed in claim 10, wherein said substrate molecule is to be selected from the group being made up of collagen protein, hyaluronic acid and gelatin.
12. cell tissue sizing agents as claimed in claim 11, wherein said substrate molecule is collagen protein and hyaluronic acid.
13. cell tissue sizing agents as claimed in claim 4, wherein said substrate molecule comprises gelatin.
14. cell tissue sizing agents as claimed in claim 8, wherein said substrate molecule comprises collagen protein.
15. cell tissue sizing agents as claimed in claim 9, wherein said substrate molecule comprises gelatin.
16. cell tissue sizing agents as claimed in claim 1, it also comprises nutritive substance and biologically active agent (bioactive agent).
17. cell tissue sizing agents as claimed in claim 16, wherein said nutritive substance is cell culture medium.
18. cell tissue sizing agents as claimed in claim 16, wherein said biologically active agent is somatomedin, be selected from by Urogastron (epidermal growth factor, EGF), fiber mother cell growth factor (fibroblast growth factor, FGF), vascular endothelial growth factor (vascular endothelial growth factor, VEGF), Connective Tissue Growth Factor (connective tissue growth factor, CTGF), Thr6 PDGF BB (platelet-derivedgrowth factor, PDGF), insulin-like growth factor (insulin-like growth factor, IGF), nerve growth factor (nerve growth factor, NGF), pHGF (hepatocyte growth factor, HGF), group's stimulating factor (colony-stimulating factor, CSF), STEM CELL FACTOR (stem cell factor, SCF), keratinocyte growth factor (keratinocyte growth factor, KGF), white cell somatomedin (granulocyte colony-stimulating factor, GCSF), scavenger cell group stimulating factor (granulocyte macrophagecolony-stimulating factor), the derivative neural factor (the glial derived neurotrophic factor that nourishes of neuroglia, GDNF), hair shape neurotrophic factor (ciliary neurotrophic factor), endotheliocyte monocytic activity polypeptide (endothelial-monocyteactivating polypeptide), the neutral ball active polypeptide of epidermis (epithelial neutrophil activating peptide), erythropoietin (erythropoietin), bone plastotype albumen (bonemorphogenetic protein), the brain derived neural factor (brain-derived neurotrophic factor) of nourishing, conversion growth factor-β (transforming growth factor beta), one or more in mammary gland performance chemokine (BRAK) or tumour necrosis factor (tumor necrosisfactor).
19. cell tissue sizing agents as claimed in claim 16, it further comprises stem cell source.
20. cell tissue sizing agents as claimed in claim 12, wherein said collagen protein and hyaluronic weight ratio are 0.01-100:1.
Implant stem cell in the method for an individuality for 21. 1 kinds, bag is drawn together ︰
Cell implant (cell implant) is provided, and described cell implant includes cell tissue sizing agent as claimed in claim 1 and a stem cell source; And described implant is implanted in to this individuality.
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| PCT/US2011/041629 WO2012177257A1 (en) | 2011-06-23 | 2011-06-23 | Adhesive cell tissue gels |
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| WO2012177257A1 (en) | 2012-12-27 |
| JP6120225B2 (en) | 2017-04-26 |
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