CN1816360A - 多孔基质 - Google Patents
多孔基质 Download PDFInfo
- Publication number
- CN1816360A CN1816360A CNA2004800077597A CN200480007759A CN1816360A CN 1816360 A CN1816360 A CN 1816360A CN A2004800077597 A CNA2004800077597 A CN A2004800077597A CN 200480007759 A CN200480007759 A CN 200480007759A CN 1816360 A CN1816360 A CN 1816360A
- Authority
- CN
- China
- Prior art keywords
- cell
- mutually
- poly
- substrate
- technology
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000011159 matrix material Substances 0.000 title claims abstract description 14
- 230000012010 growth Effects 0.000 claims abstract description 13
- 239000003102 growth factor Substances 0.000 claims abstract description 3
- 210000004027 cell Anatomy 0.000 claims description 68
- 229920000642 polymer Polymers 0.000 claims description 43
- 239000000758 substrate Substances 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 31
- 239000012071 phase Substances 0.000 claims description 25
- 238000005516 engineering process Methods 0.000 claims description 24
- 230000008520 organization Effects 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- -1 diketene acetal Chemical class 0.000 claims description 12
- 239000011859 microparticle Substances 0.000 claims description 11
- 108010049003 Fibrinogen Proteins 0.000 claims description 9
- 102000008946 Fibrinogen Human genes 0.000 claims description 9
- 229920001577 copolymer Polymers 0.000 claims description 9
- 229940012952 fibrinogen Drugs 0.000 claims description 9
- 210000000130 stem cell Anatomy 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 210000000988 bone and bone Anatomy 0.000 claims description 7
- 229940088598 enzyme Drugs 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 235000015097 nutrients Nutrition 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 5
- 102000013275 Somatomedins Human genes 0.000 claims description 5
- 235000001014 amino acid Nutrition 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 229920000728 polyester Polymers 0.000 claims description 5
- 101710155857 C-C motif chemokine 2 Proteins 0.000 claims description 4
- 102000000018 Chemokine CCL2 Human genes 0.000 claims description 4
- 229920002101 Chitin Polymers 0.000 claims description 4
- 102000001253 Protein Kinase Human genes 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- ZSTLPJLUQNQBDQ-UHFFFAOYSA-N azanylidyne(dihydroxy)-$l^{5}-phosphane Chemical compound OP(O)#N ZSTLPJLUQNQBDQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 210000001612 chondrocyte Anatomy 0.000 claims description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 4
- 108060006633 protein kinase Proteins 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 3
- 210000000845 cartilage Anatomy 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 230000005070 ripening Effects 0.000 claims description 3
- 230000008467 tissue growth Effects 0.000 claims description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical class 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 2
- 102100023995 Beta-nerve growth factor Human genes 0.000 claims description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 claims description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 102000004127 Cytokines Human genes 0.000 claims description 2
- 108090000695 Cytokines Proteins 0.000 claims description 2
- 102000016942 Elastin Human genes 0.000 claims description 2
- 108010014258 Elastin Proteins 0.000 claims description 2
- 102000009123 Fibrin Human genes 0.000 claims description 2
- 108010073385 Fibrin Proteins 0.000 claims description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 claims description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 2
- 102000016359 Fibronectins Human genes 0.000 claims description 2
- 108010067306 Fibronectins Proteins 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 2
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 claims description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 102000015696 Interleukins Human genes 0.000 claims description 2
- 108010063738 Interleukins Proteins 0.000 claims description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims description 2
- 102000015636 Oligopeptides Human genes 0.000 claims description 2
- 108010038807 Oligopeptides Proteins 0.000 claims description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 2
- 229920002732 Polyanhydride Polymers 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229920001710 Polyorthoester Polymers 0.000 claims description 2
- 229920000388 Polyphosphate Polymers 0.000 claims description 2
- 229920011250 Polypropylene Block Copolymer Polymers 0.000 claims description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 claims description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 210000001789 adipocyte Anatomy 0.000 claims description 2
- 210000002821 alveolar epithelial cell Anatomy 0.000 claims description 2
- 210000001691 amnion Anatomy 0.000 claims description 2
- 102000023732 binding proteins Human genes 0.000 claims description 2
- 108091008324 binding proteins Proteins 0.000 claims description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 claims description 2
- 230000002308 calcification Effects 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 210000001136 chorion Anatomy 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 239000000084 colloidal system Substances 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- 229960003638 dopamine Drugs 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 229920002549 elastin Polymers 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 210000003725 endotheliocyte Anatomy 0.000 claims description 2
- 210000000981 epithelium Anatomy 0.000 claims description 2
- 229940011871 estrogen Drugs 0.000 claims description 2
- 239000000262 estrogen Substances 0.000 claims description 2
- 230000001605 fetal effect Effects 0.000 claims description 2
- 229950003499 fibrin Drugs 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 230000036541 health Effects 0.000 claims description 2
- 229920000669 heparin Polymers 0.000 claims description 2
- 229960002897 heparin Drugs 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 230000002107 myocardial effect Effects 0.000 claims description 2
- 229920005615 natural polymer Polymers 0.000 claims description 2
- 229940053128 nerve growth factor Drugs 0.000 claims description 2
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 210000002826 placenta Anatomy 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 claims description 2
- 229920000070 poly-3-hydroxybutyrate Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 239000001205 polyphosphate Substances 0.000 claims description 2
- 235000011176 polyphosphates Nutrition 0.000 claims description 2
- 229920001299 polypropylene fumarate Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 235000018102 proteins Nutrition 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 239000003229 sclerosing agent Substances 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 239000007790 solid phase Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229960003604 testosterone Drugs 0.000 claims description 2
- 210000004962 mammalian cell Anatomy 0.000 claims 1
- YOURXVGYNVXQKT-UHFFFAOYSA-N oxacycloundecane-2,11-dione Chemical compound O=C1CCCCCCCCC(=O)O1 YOURXVGYNVXQKT-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 238000003780 insertion Methods 0.000 abstract description 2
- 230000037431 insertion Effects 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 239000002407 tissue scaffold Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- 150000003839 salts Chemical class 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 19
- 239000008187 granular material Substances 0.000 description 18
- 239000007788 liquid Substances 0.000 description 16
- 239000002609 medium Substances 0.000 description 13
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 11
- 239000004531 microgranule Substances 0.000 description 11
- 108090000190 Thrombin Proteins 0.000 description 10
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 10
- 229960004072 thrombin Drugs 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 8
- 238000009331 sowing Methods 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 210000004207 dermis Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 210000002950 fibroblast Anatomy 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 239000000017 hydrogel Substances 0.000 description 5
- 239000004570 mortar (masonry) Substances 0.000 description 5
- 230000003068 static effect Effects 0.000 description 5
- 238000013019 agitation Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 230000009477 glass transition Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000000465 moulding Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 208000034189 Sclerosis Diseases 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000000919 ceramic Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 3
- 230000001815 facial effect Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 3
- 238000005325 percolation Methods 0.000 description 3
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000007598 dipping method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
- 238000013012 foaming technology Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000003701 histiocyte Anatomy 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002955 secretory cell Anatomy 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000005245 sintering Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000004017 vitrification Methods 0.000 description 2
- VPVXHAANQNHFSF-UHFFFAOYSA-N 1,4-dioxan-2-one Chemical compound O=C1COCCO1 VPVXHAANQNHFSF-UHFFFAOYSA-N 0.000 description 1
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- VDHWOHDSOHPGPC-UHFFFAOYSA-N 3,3-dihydroxyoxepan-2-one Chemical compound OC1(O)CCCCOC1=O VDHWOHDSOHPGPC-UHFFFAOYSA-N 0.000 description 1
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 239000005057 Hexamethylene diisocyanate Substances 0.000 description 1
- 101001073409 Homo sapiens Retrotransposon-derived protein PEG10 Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100035844 Retrotransposon-derived protein PEG10 Human genes 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 229940067597 azelate Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003989 dielectric material Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 230000035616 enchondral ossification Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229940081104 fibrinogen / thrombin Drugs 0.000 description 1
- 230000001723 fibrinogenic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000002241 glass-ceramic Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 125000001288 lysyl group Chemical group 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001432 poly(L-lactide) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- A61L2300/254—Enzymes, proenzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/43—Hormones, e.g. dexamethasone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Botany (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
Abstract
本发明描述了一种适合用作组织支架的多孔基质。所述基质在插入到靶组织部位处或其内之前进行成型，或经危害最小的侵入式方法进行注射。基质可与靶组织细胞一起播种或用来支撑局部内源性组织的生长。基质可含有生长因子或其它药物可接受的部分例如抗生素。
Description
本发明涉及一种多孔基质。更具体地说，本发明涉及预计用于动物体并在靶组织部位原位形成的多孔基质。
许多专利申请描述了凝胶或溶胶特别是水凝胶用作组织支架的用途。例如，WO00/23054描述了聚乙烯醇微球在血管阻塞或栓塞中的用途。WO 99/15211和WO00/64977描述了水凝胶作为组织支架的用途。水凝胶被植入病人体内，以便支撑组织的生长或修复。
水凝胶用作组织支架的难题在于，尽管凝胶自身可以适当填充其所插入的洞，但是它们的扩散性差，并且供给组织的药物、营养物或其它因子同样不能通过凝胶进行适当扩散。此问题在凝胶与活细胞一起播种(seed)的情形中尤为严重，这是因为营养物的较差扩散性导致细胞死亡过早，从而无法进行治疗。有关凝胶支架的另一个问题是，用于稳定或固化凝胶(尤其是原位)的交联法，能够损坏截留细胞。
基于水溶性聚合物的支架在本领域内也是公知的，例如WO 99/25391描述了聚(交酯-共-乙交酯)(PLGA)用作组织尤其是骨组织再生的聚合物支架。对聚合物进行处理，以便形成多孔结构。与水凝胶一样，这些水溶性聚合物被植入病人体内，以便支撑组织生长或修复。
然而，这些水溶性聚合物的缺陷是，它们仅能填充具有开放形状的洞，并且材料的成型方法也待优选。此外，在支架与细胞一起播种的情形中，播种没有效果(仅有少数孔被细胞填充)，或者是细胞在播种过程中被结构损坏，而周围的组织细胞也可被植入过程损坏。
WO 99/11196描述了微粒基质作为组织支架的用途，这些颗粒具有用于稳定颗粒结构的内部交联性。
同样，PCT/GB02/02813描述了一种以药物的形式在体内用于靶组织内或靶组织上的微粒材料的开放多孔基质，所述基质包括彼此交联以便在二者之间限定出孔的颗粒。
本发明提供了一种多孔基质的生产工艺，所述工艺包括如下步骤：
-使第一相成为流体状态，
-将第二相引入第一相，
-使第一相和第二相混合，以确保第二相通过第一相实现所需的分布，以及
-使第一相固化或改变状态，而第二相就在其中。
有益的是，此工艺使基质在插入靶细织内或靶组织上之前成型或部分成型。
此处所用的术语“流体”是指任何流动的物质，并因此包括能够流动并顺应容器外形的液体、气体和固体(例如粉状、粒状或谷粒形式、或塑料固体)。
此处所用的术语“固化”是指相变为固态或半固态。
第一相可以是载体相，其中这个相承载或包含第二相的材料，或者可以是包被第二相材料的包被相。优选的是，第一相不是液态或完全液化态的，但却是流动的，足以混合、承载或包被第二相。例如，第一相可以流动但有些粘稠并包被第二相的微粒材料。或者是，第一相和第二相可以是微粒或粉末形式并混合在一起。在这种情形下，还期望第一相有些软或粘稠或同样能够包被第二相的任何微粒材料。
优选的是，在一个参数例如温度、pH、交联、硬化或胶凝剂的引入、光线的存在/缺乏、紫外熟化改变时或者在厌氧条件下，第一相从流态转变为固态或半固态。最优选的是，第一相由于温度、pH的改变或交联、硬化或胶凝剂的引入而发生变形。在采用温度的情形中，优选的是，温度足以使相工作但却不破坏周围的组织。烧结步骤的预先使用可应用到任一相中。第二相优选是固相，但也可采用液相，尤其是在液体是微粒材料的乳液或悬浮液时。在多孔基质用作组织支架基质的情形中，第二相任选地包含用于形成新组织的细胞。
然而，本发明人已经发现，基质在无需引入细胞的前提下也可用作组织支架。当组织支架(没有细胞)置于所需部位处或部位上时，局部的内源性细胞就在导致现存组织发生新的生长的支架内或围绕该支架生长。此效果由于支架现存的适当生长因子的存在而得以增强。这样的情形特别有用，因为新的组织与引入非内源性组织相比，几乎没有排斥的机会或其它免疫反应。因此，用免疫抑制剂治疗病人的需要减少了，与此有关的问题也减少了。此外，此技术对于已经免疫妥协的病人(例如癌症病人、非常年青的人、年长的人、孕妇或患有艾滋病或乙肝的人)是有用的。
据此，本发明还提供了一种组织支架基质，这种基质包括第一相和包含在第一相之内的第二相。优选的是，组织支架基质按照上述方法来制备。
本发明中所用的第一相和第二相可以用具有不同的固化或硬化特性的相似材料来制备。例如，第一相和第二相可以用具有不同的胶凝pHs或不同熔融温度或玻璃化点的相似聚合物来制备。
通常，本发明的一个或两个相包括一种或多种聚合物。可用于本发明的合成聚合物的实例包括：聚(α-羟基酸)特别是聚乳酸或聚乙醇酸、聚交酯聚乙交酯共聚物、聚交酯聚乙二醇(PEG)共聚物；其它的聚酯，包括聚(ε-己内酯)、聚(3-羟丁酸酯)、聚(s-己酸)、聚(p-二噁酮(dioxanone))和聚(丙烯富马酸酯)；聚(原酸酯)，包括多羟基/双烯酮乙缩醛(polyol/diketene acetals)加成聚合物(如Heller ACSSymposium Series 567，292-305，1994所述)；聚酐，包括聚(癸二酸酐)(PSA)、聚(羧基双羧苯氧基苯氧基己烷)(PCPP)、聚[双(对-羧苯氧基)甲烷](PCPM)以及SA、CPP和CPM的共聚物(如Tamada and Langer in Journal of Biomaterials SciencePolymer Edition，3，315-353，1992和Domb in Chapter 8 of the Handbook ofBiodegradable Polymers，ed.Domb A.J.and Wiseman R.M.，Harwood AcademicPublishers所述)；聚(氨基酸)；聚(假氨基酸)(包括James andKohn at pages 389-403of Controlled Drug Delivery Challenges and Strategies，American Chemical Society，Washington DC所述的那些)；聚磷腈，包括：聚[(二氯)磷腈]、聚[(有机)磷腈]聚合物的衍生物(如Schacht in Biotechnology and Bioengineering，52，102-108，1996所述)；聚磷酸酯；聚乙二醇聚丙烯嵌段共聚物(例如以PluronicsTM为商品名所出售的)。
也可以采用天然聚合物，例如丝绸、弹性蛋白、壳质、脱乙酰的甲壳质(chitosan)、纤维蛋白、纤维蛋白原、聚糖(包括胶质)、和藻酸酯、胶原质、聚(氨基酸)、肽、多肽或蛋白质。
也可以采用由这些聚合物的单体制备的共聚物，诸如可以将这些聚合物随机掺和或者将它们混合或组合。
聚合物可以用各种方法进行交联，这些方法包括诸如：丙烯酸酯聚合物的UV交联、硫醇盐或丙烯酸酯聚合物的Michael加成反应、经由乙烯基砜交联的硫醇盐聚合物、经由琥珀酸酯或乙烯基砜的交联、经由肼的交联、热诱导的冻结、酶交联(例如凝血酶与纤维蛋白原的加成)、经由盐或离子(特别是Ca2+离子)加成的交联、经由异氰酸酯(诸如1，6-己二异氰酸酯)的交联。
在一个优选实施例中，采用聚(乳-共-聚乙醇)酸(PLGA)的聚酯。这些聚合物是由FDA批准用于胃肠外施用的。因为PLGA在初始阶段经由非酶水解而发生降解，所以由体外数据能够预测体内降解速率。PLGA降解为乳酸和乙醇酸，这些都是在体内天然发现的物质。
然而，聚酯可具有为一些实施例选择的聚合物系统。当聚酯材料断裂成分子量为约5000道尔顿时，材料就可以被细胞(包括巨噬细胞)摄取，因此一些感染与这些聚合物的断裂有关。
可以合成与氨基酸的共聚物，例如乙醇酸与甘氨酸，或乳酸与赖氨酸(Barrera等人的(1993)J Am Chem Soc 115，11010-11011和Cook等人的(1997)J Biomed MatRes 35，513-523)。这些可用于固定其它分子，诸如经由赖氨酰s-氨基部分。这些聚合物利用共价键，可用来将肽附着到表面上。例如，利用1，1’-羰基-二咪唑(CDI，Aldrich)作为交联剂，可以将肽附着到聚(乳酸-共-赖氨酸)上。
通过操纵乳酸和乙醇酸的摩尔比以及共聚物的分子量，能够获得不同的降解图形。聚-L-交酯在体外具有数月至数年的降解时间。这样长的降解时间是由于聚合物的高结晶度保护其避免被水渗透。聚乙交酯具有一至数月的降解时间，而聚-D，L-交酯是非晶形的，并具有一至数月的降解时间。D、L、PLGA在体外具有数周至数月的降解时间。当乙醇酸的比例增大时，降解速率就增大。S-己酸的均聚物在2-3年的植入周期中仍然能够保持完整无缺。
优选的是，至少其中一个相还包括增塑剂，所述增塑剂的例子包括聚乙二醇(PEG)、聚丙二醇、这些聚合物的聚己内酯低分子量低聚物或常规增塑剂，例如专用于日用塑料材料的那些增塑剂，包括(但不限于)己二酸酯、磷酸酯、邻苯二甲酸酯、sabacates、壬二酸酯和柠檬酸酯。也可采用与用来形成第一和第二相的聚合物(例如聚交酯、交酯-共-乙交酯)相同的增塑剂。
第二相通常包括播种或形成组织支架所必需的组织细胞。这些细胞可播种到包括、包含或承载在第二相内部的微粒材料内。
在本发明的组织支架中可采用任何动物细胞。可使用的细胞的实例包括(但不限于)骨、骨先祖细胞(诸如来自于骨)、软骨、肌肉、肝、肾、皮肤、内皮细胞、肠或肠内细胞，或专门的细胞例如心血管细胞、心肌细胞、肺细胞或其它呼吸细胞、胎盘、羊膜、绒毛膜或胎儿细胞、干细胞、软骨细胞或来自身体其它部分的重编细胞诸如重编为软骨细胞的脂肪细胞。
在使用干细胞的情形中，它们优选是非胚胎干细胞，例如来自成人骨髓或角膜的那些干细胞或者其它内源性干细胞，优选取自于待治疗的病人的干细胞。
本发明人在实验中已经注意到，骨先祖细胞在某些条件下在体外环境中除了骨之外，还将产生软骨，因此容易使软骨骨化，从而允许骨-软骨界面进行组织建造。
可用于包含或引入细胞的第二相的颗粒，是待审专利申请PCT/GB02/02813中所述的类型。
在微粒材料用于第二相的情形中，优选的是，颗粒是多孔的。优选，颗粒的空隙率至少为10％，更优选在40％以上，理想的甚至有70-97％那么高。便利的工作范围在50-95％之间。在任何情形下，优选的是，颗粒的孔径至少足以将细胞容纳在其内。细胞在基质植入时或者在这之前加入到基质中，或者之后加入(在从内源性细胞原位募集的情形中)。
通常，颗粒是微粒；尽管采用大细胞，但颗粒也可以在mm的范围内。
颗粒可以利用超临界流体来产生。
理想的是，粒径在10-80μm直径的量级上。这意味着，粒径通常在50μm-1mm直径的量级上，或者优选在250-500μm的量级上。正如所看到的，所有粒径都是孔径的函数。也就是说，基质的最终应用将决定基质的尺寸、粒径和孔径。例如，在基质不承载细胞的情形中，孔径变得没有什么临界，只要仍然能够通过基质发生扩散即可。此外，松弛的包装使孔径增大，从而使营养物或其它物质的传送更佳，反之亦然。然而，孔径不总是细胞大小的函数，因为大孔可与微小细胞一起播种。这些颗粒的使用具有如下优点：确保整个基质保持足以使细胞生长并因此容纳生长组织的空隙率。优选的是，颗粒至少在其外表面上是粗糙的，因此孔还可在封闭的包装颗粒之间形成。此外，颗粒的粗糙表面能够改善细胞对颗粒的粘附性。
基质可包括利用诸如另一聚合物相或无机相的附加相。包括在每个附加相中的无机材料的实例包括生物玻璃、陶瓷、羟磷灰石、玻璃、玻璃陶瓷及复合材料。将可用于促进组织生长和发育的因子加入到其中一个相或两个相中，或者用来包被颗粒。此外，将不同的因子加入到每个相中或者加入到这个或每个包被液中。经常加入的因子包括(但不限于)上皮生长因子、血小板衍生生长因子、碱性成纤维生长因子、血管内皮生长因子、胰岛素样生长因子、神经生长因子、肝细胞生长因子、转化生长因子和骨形成蛋白、细胞因子，包括干扰素、白细胞介素、单核细胞趋化蛋白-1(MCP-1)、雌激素、睾丸激素、激酶、化学激酶、葡萄糖或其它糖、氨基酸、石灰化因子、多巴胺、富胺寡肽例如在诸如纤连蛋白和层粘连蛋白之类的粘合蛋白中发现的肝素结合域、其它胺类三苯氧胺、顺式铂、肽和某些类毒素。此外，药物、激素、酶、营养物或其它治疗剂或因子或它们的混合物可加入到其中一个相或两相中。再者，可以将不同的药物、激素、酶、抗生素、营养物或其它治疗剂或因子或它们的混合物加入到每个相中。
然而，如上所述，本发明人已经发现，基质在无需引入细胞的前提下可用作组织支架。当组织支架(没有细胞)置于需要定位的部位内或部位处时，就募集或激励内源性细胞，以便在支架上、支架中或围绕支架生长。此效果由于在支架中存在一种或多种上述生长因子而得以加强。
按照本发明方法形成的组织可在体内用作植入组织，或在体外用作组织培养物。例如，组织在体内可用来代替被除去的患病、损坏或不起作用的组织，或者在体外用作组织培养物。有益的是，本发明可产生或生成三维培养组织，这种组织例如在药物扩散或摄取的研究中或者在分泌细胞的使用中可用作研究工具，其中分泌细胞为了发生分泌经常要求细胞呈三维分布。
在基质用于组织的情形中，优选在固化之前将其引入组织。
在一个优选实施例中，在组织于体内使用的情形中，优选的是，第一相在或接近动物体温时，或者在或接近适当组织的pH时转变为固态或半固态。或者是，硬化剂可用来加速固化。在任何情况下，优选的是，使第一相固化所必需的条件对于包含在其内的任何细胞都没有害。
本发明还提供了一种如上所述的组织支架基质的形成药盒。
在本发明的一个优选实施例中，第一相包括一种聚合物，这种聚合物具有低玻璃化点(Tg)或熔点，诸如在45℃之下，优选在40℃之下，理想的是在37℃或之下，第二相包括一种聚合物，这种聚合物具有较高的玻璃化点或熔点，诸如＞55℃。第一相在45℃之上、优选在40℃之上、理想的是在37℃之上进行加热，以便使聚合物粘稠或完全液化，然后将第二相引入到第一相中并进行混合。使混合物冷却。当细胞存在于基质中时，这些细胞可以在引入到第一相之前或者更优选的是在基质固化之前加入到第二相中。任一相还可包括生长因子或其它药物活性化合物，以便在使用时达到控释的效果。
除了颗粒本身固有的空隙率之外，多孔结构还由这个或每个相的颗粒之间的缝隙形成，或者通过第一相的不完全液化而形成。
在第二个实施例中，基质优选通过胶凝而形成。在该实施例中，第一相包括随温度发生胶凝(例如琼脂糖)或随pH发生胶凝(例如丙烯酰亚胺)或随着硬化或胶凝剂的加入而发生胶凝(例如将凝血酶加入到纤维蛋白原中以产生纤维凝胶)的材料。第一相进入流态或液态，然后与非胶凝的、优选是固态的第二相进行混合。使混合物冷却或胶凝。细胞可以在与第一相混合之前或混合之后但是在凝胶发生完全胶凝之前加入到第二相中。
现在参照下面实例来描述本发明的实施例，这些实施例如附图1-3所示，其中：
图1表示出利用刃天青(Resazurin)还原测定法测定的、在温度交联的15％PEG1000/PLGA作用下的细胞生长状况。数值表示减去无细胞的对照值(n＝3，±SD)之后的来自还原反应产物的相对荧光单位；
图2表示出利用刃天青还原测定法测定的、在酶交联的多孔PDLLA片作用下的细胞生长状况。数值表示减去无细胞的对照值(n＝3，±SD)之后的来自还原反应产物的相对荧光单位；
图3表示出利用刃天青还原测定法测定的、在与人真皮纤维原细胞一起播种的酶交联PDLLA微粒作用下的细胞生长状况。数值表示减去无细胞的对照值(n＝3，±SD)之后的来自还原反应产物的相对荧光单位。
例1
经由温度触发的固化的交联
在此例中，第一相包括聚(乙二醇)/聚(DL-交酯)掺和颗粒(10wt％聚乙二醇)，第二相包括用常规的微粒沥滤法制造的多孔聚(DL-交酯)颗粒。将这两种组分混合到一起(20∶80至80∶20的比例范围)，然后加热到60℃，从而产生展性材料，这种材料由外科医生成型并施加到缺陷部位。在该例中，第一相在处理温度(聚合物的玻璃化温度之上)不完全液化，但变成“粘稠的”半固体。在另一个实例中，(不同聚合物掺和组合物)第一相在40-60℃(聚合物熔化转变点之上)可完全液化。随后第二相的多孔颗粒与仍然为液态的第一相混合到一起。材料然后由外科医生成型并施加到缺陷部位。
例1A
温度触发的固化
聚合物掺和组合物、它们的玻璃化转变温度(用示差扫描量热法测定的)以及交联温度的其它实例如下表所示。
| 材料 | 玻化温度(℃) | 交联温度(℃) |
| PDLLA15％PEG3400/PDLLA20％Poly(caprolactone diol530)/PDLLA15％PEG400/PDLLA20％PEG1000/PDLLA10％DL-Lactide/PDLLAPLGA15％PEG1000/PLGA | 482323158464316 | 75-80℃55-65℃50-55℃45℃37-40℃65-70℃70℃37-40℃ |
例1b
温度触发的具有细胞播种的交联
通过在置于电热板上的陶瓷瓦上加热组分(1.70g的PLGA，0.3g的PEG1000)并物理混合熔融状态的组分，来制造熔融掺合物。将材料冷却、从瓦上拿下，并且在液氮中冷却之后立即进行切割和研磨。研磨的掺合物在使用之前储存在真空干燥器内。用示差扫描量热法测定玻璃化转变温度，而温度取自转变区域的中点。PLGA的玻璃化转变温度在43℃测定，而掺合物的玻璃化转变温度在16℃测定。
在与人真皮纤维原细胞(和无细胞的对照物)一起播种的支架(三份重复样品)上测定静态培养物中的细胞生长。研磨的掺和材料(80mgs的15％PEG1000/5050DL研磨掺合物)在37℃于6mm的PDMS模具中预先烧结15分钟。然后将细胞悬浮液加入到材料(100μl完全介质中的5×105人真皮纤维原细胞(@p8，50岁的老年供体/面式活检))中，并用刮勺按压材料，然后在37℃再烧结1小时。然后将支架从PDMS模具中拿出并置于完全培养介质中。通过用100μl的完全介质取代细胞悬浮液，来制备无细胞的对照物。支架在完全介质中培养17天(静态培养物)，而全介质每3-4天改变一次。
用刃天青还原测定法测定细胞的生长和增殖(图1)，并且每3-4天读取一次数值。将支架从培养物中取出，在PBS中洗涤并在无血清的介质中于1ml的10μg/ml刃天青溶液中放置1小时。然后将溶液等分(3×150μl)到96孔板内，在具有350nm激发频率和590nm发射频率的板式读数器上读取荧光强度。
例2
通过胶凝固化
在此例中，第一相是由在25℃之上经历液体-凝胶转变的Pluronics F127溶液(在缓冲液或介质中为20wt％)组成的。第二相包括用常规的微粒沥滤法制造的多孔聚(DL-交酯)颗粒。将这两种组分混合到一起(以可能的大范围比例，诸如100μls的第一相和100mgs的第二相)，并在室温之下保持为液体。然后使组分经注射运送到缺陷部位，在该部位材料在达到37℃之后发生胶凝。
例3
通过胶凝固化
在此例中，第一相是由在加入凝血酶之后胶凝的纤维蛋白原溶液(例如在缓冲液或介质中为30-200mg/ml)组成的。第二相包括用常规的微粒沥滤法制造的多孔聚(DL-交酯)颗粒。将这两种组分混合到一起(以可能的大范围比例，诸如100μls的第一相和100mgs的第二相)，并在准备注射的注射器内保持为液体。然后在注射到缺陷部位之后与凝血酶溶液混合(用双筒注射器)(产生最终的凝血酶浓度为诸如1-1000单位/ml)，从而导致第一相发生交联和胶凝。
例3a
细胞填充的多孔PDLLA片(1-2mm的大片)的交联
通过溶剂浇注和微粒沥滤、用80％重量分数的盐产生多孔PDLLA片。使45wt％PDLLA的DCM溶液(2ml中含有900mgs)与3.6g的盐粒(在研磨和筛过之后为63-106μm的尺寸分数，平均尺寸＝88±27μm)混合。然后将含有盐的聚合物溶液倾注到陶瓷瓦上，并放置过夜以使溶剂蒸发。将聚合物盐组合物从瓦上拿下并人工切成1-2mm大小的片。通过在水中浸渍并搅拌过夜，而将盐从片中沥滤出来。
在与人真皮纤维原细胞(和无细胞的对照物)一起播种的支架(三份重复样品)上测定静态培养物中的细胞生长。多孔PDLLA片(2×120mgs)经轻微搅拌在血清(2mls)中包被1小时。通过将120mgs血清包被的PDLLA放置到1ml的细胞悬浮液中并轻微搅拌1小时，而完成细胞播种(在血清的介质中为1.2×106c/ml，人真皮纤维原细胞@p8，50岁的老年供体/面式活检)。将无细胞的对照物在无血清的介质中放置1小时。细胞固定之后，将片在无Ca2+的HBSS中进行洗涤。将纤维蛋白原+凝血酶溶液(160μl的100mgml纤维蛋白原和10U/ml的凝血酶)加入到片中并与之混合，除去过量的液体，然后使片交联15分钟。将支架在完全介质(添加有胎牛血清的DMEM)中培养17天(静态培养物)，而全介质每3-4天改变一次。
用刃天青还原测定法测定细胞的生长和增殖(图2)，并且每3-4天读取一次数值。将支架从培养物中取出，在PBS中洗涤并在无血清的介质中于1ml的10μg/ml刃天青溶液中放置1小时。然后将溶液等分(3×150μl)到96孔板内，在具有350nm激发频率和590nm发射频率的板式读数器上读取荧光强度。
例3b
细胞填充的多孔PDLLA片(250-500μm的小片)的交联
通过溶剂浇注和微粒沥滤、用90％重量分数的盐产生多孔PDLLA片。使45wt％PDLLA的DCM溶液(2ml中含有900mgs)与8.1g的研磨盐粒(在乳钵和臼中研磨之后没有过筛)混合。然后将含有盐的聚合物溶液放置到陶瓷瓦上，并放置过夜以使溶剂蒸发。将聚合物盐组合物从瓦上拿下并用乳杯和臼研磨。通过在水中浸渍并搅拌过夜，而将盐从片中沥滤出来。盐沥滤之后将多孔片过筛，并保留250-500μm的分数。
多孔PDLLA片(40mgs)经轻微搅拌而用血清进行包被。然后将片在PBS中进行洗涤。通过将多孔片在无血清的介质中于1ml的细胞悬浮液(9×105个细胞/ml)中放置并轻微搅拌1小时，而将人真皮纤维原细胞(来自成人供体@通道15)播种到多孔片上。
细胞固定之后，将纤维蛋白原+凝血酶溶液(160μl的100mgml纤维蛋白原和5U/ml的凝血酶)加入到片中并与之混合，除去过量的液体，然后使片交联30分钟。
将支架上的细胞代谢和生长测定72小时。然后将支架从培养物中取出，在PBS中洗涤并在无血清的介质中于1ml的10μg/ml刃天青溶液中放置1小时。然后将溶液等分(3×150μl)到96孔板内，在具有350nm激发频率和590nm发射频率的板式读数器上读取荧光强度。在24与72小时之间，来自支架的RFU值从296RFU增大到569RFU(在减去背景之后)。
例3c
PDLLA微粒与细胞的交联
将4g的PDLLA溶解到20ml的二氯甲烷中，从而生成20wt％的溶液。将聚(乙烯醇)(88％水解的)溶解到蒸馏水中，从而给出通过0.45μm过滤器进行过滤的0.05wt％溶液。用均化器以6,000rpm的速度将PVA溶液分散15分钟，然后将PDLLA/dcm溶液注入分散的PVA溶液中。混合物在搅拌过夜以使DCM蒸发之前再均化5分钟。然后，微粒在冻干之前在离心机中用蒸馏水洗涤3次。用亮场显微镜和图像分析法测定微粒直径在20μm(±10μm)。
将人真皮纤维原细胞(来自于50岁的老年供体/面式活检，在通道8)重新悬浮到少量的全介质(50μl中有5×105c细胞)中。使该细胞悬浮液与100μl的纤维蛋白原/凝血酶溶液(HBSS中含有150mg/ml的纤维蛋白原和15U/ml的凝血酶)混合，然后将此溶液加入到200mgs的微粒中并混合。将所生成的糊放到6mm的PDMS立方体成型模具中并在37℃放置40分钟，以使交联完成。通过用50μl的完全介质取代细胞悬浮液，来制备无细胞的对照物。将支架在完全介质中培养17天(静态培养物)，而全介质每3-4天改变一次。
用刃天青还原测定法测定细胞的生长和增殖(图2)，并且每3-4天读取一次数值。将支架从培养物中取出，在PBS中洗涤并在无血清的介质中于1ml的10μg/ml刃天青溶液中放置1小时。然后将溶液等分(3×150μl)到96孔板内，在具有350nm激发频率和590nm发射频率的板式读数器上读取荧光强度。
例4
多孔颗粒
在此例中，用常规的盐沥滤技术产生大孔颗粒(≥500μm)。用乳钵和臼对盐进行研磨，然后过筛，从而将尺寸合适的部分保留下来。理想的是，盐粒的大小为50-100μm。然后在熔融相或适当的溶剂中，使盐粒与聚(DL-交酯)混合。盐的填充在50与90wt％之间。然后，通过研磨和切割，将整块的盐/聚合物组合物固体(在冷却或溶剂提取之后)处理成大的颗粒。随后，通过在水中搅拌至少24小时，而将盐从组合物中沥滤出来。
在另一个实例中，利用诸如超临界CO2、通过常规的气体发泡技术，可以处理盐/聚合物组合物。在另一个实例中，利用诸如超临界CO2、通过常规的气体发泡技术，可以制造多孔聚合物片。
Claims (30)
1、一种多孔基质的生产工艺，所述工艺包括如下步骤：
—使第一相成为流体状态，
—将第二相引入第一相，
—使第一相和第二相混合，以确保第二相通过第一相实现所需的分布，以及
—使第一相固化，而第二相就在第一相内。
2、根据权利要求1所述的工艺，其特征在于，第一相是粘稠的。
3、根据权利要求1或2所述的工艺，其特征在于，第一相包被第二相。
4、根据权利要求1-3任一项所述的工艺，其特征在于，在一个参数改变时，第一相从流态转变为固态或半固态。
5、根据权利要求4所述的工艺，其特征在于，所述参数是温度、pH、硬化剂的引入、光线的存在/缺乏、紫外熟化、红外熟化，或者在厌氧条件下。
6、根据前述任一项权利要求所述的工艺，其特征在于，第二相是固相。
7、根据权利要求1-5任一项所述的工艺，其特征在于，第二相是液相。
8、根据权利要求7所述的工艺，其特征在于，所述液相是微粒材料的乳液或悬浮液。
9、根据权利要求8所述的工艺，其特征在于，所述微粒材料是多孔的。
10、根据权利要求8或9所述的工艺，其特征在于，所述微粒材料是多孔的，所述颗粒的空隙率在10-97％之间。
11、根据前述任一项权利要求所述的工艺，其特征在于，将细胞加入到一个相中。
12、根据权利要求11所述的工艺，其特征在于，将所述细胞加入到第二相中。
13、根据前述任一项权利要求所述的工艺，其特征在于，第一和第二相是具有不同固化特性的相似材料。
14、根据前述任一项权利要求所述的工艺，其特征在于，所述相包括聚合物。
15、根据权利要求14所述的工艺，其特征在于，所述聚合物选自：聚(α-羟基酸)、聚乳酸或聚乙醇酸、聚交酯聚乙交酯共聚物、聚交酯聚乙二醇(PEG)共聚物、聚酯、聚(ε-己内酯)、聚(3-羟丁酸酯)、聚(s-己酸)、聚(对-二噁酮)、聚(丙烯富马酸酯)、聚(原酸酯)、多羟基/双烯酮乙缩醛(polyol/diketene acetals)加成聚合物、聚酐、聚(癸二酸酐)(PSA)、聚(羧基双羧苯氧基苯氧基己烷)(PCPP)、聚[双(对-羧苯氧基)甲烷](PCPM)、SA、CPP和CPM的共聚物、聚(氨基酸)、聚(假氨基酸)、聚磷腈、聚[(二氯)磷腈]、聚[(有机)磷腈]聚合物的衍生物、聚磷酸酯；聚乙二醇聚丙烯嵌段共聚物、天然聚合物、丝绸、弹性蛋白、壳质、脱乙酰的甲壳质(chitosan)、纤维蛋白、纤维蛋白原、聚糖(包括胶质)、藻酸酯、胶原质、聚(氨基酸)、肽、多肽或蛋白质、由这些聚合物的单体制备的共聚物、这些聚合物的随机掺和物或者它们的混合物或组合物。
16、根据权利要求14或15所述的工艺，其特征在于，所述聚合物是能够生物降解的。
17、根据权利要求14-16任一项所述的工艺，其特征在于，所述聚合物是交联的。
18、根据前述任一项权利要求所述的工艺，其特征在于，将增塑剂加入到其中一相或两相中。
19、一种组织支架基质，所述基质包括第一、载体相和包含在第一相之内的第二、悬浮相，所述基质还包括细胞。
20、一种根据前述任一权利要求所述的工艺制备的组织支架基质。
21、根据权利要求19或20所述的组织支架基质，其特征在于，第二相包括细胞。
22、根据权利要求19-21任一项所述的组织支架基质，其特征在于，将细胞播种到包含或承载在第二相内的微粒材料中。
23、根据权利要求19-22任一项所述的组织支架基质，其特征在于，所述细胞是动物细胞。
24、根据权利要求19-23任一项所述的组织支架基质，其特征在于，所述细胞是哺乳动物细胞。
25、根据权利要求19-24任一项所述的组织支架基质，其特征在于，所述细胞是人细胞。
26、根据权利要求23-25任一项所述的组织支架基质，其特征在于，所述细胞是骨、骨先祖细胞、心血管细胞、内皮细胞、心肌细胞、肺细胞或其它呼吸细胞、肠或肠内细胞、软骨、肌肉、肝、肾、皮肤、或专门的细胞例如胎盘、羊膜、绒毛膜或胎儿细胞、干细胞、软骨细胞、或来自身体其它部分的重编细胞诸如重编为软骨细胞的脂肪细胞。
27、根据权利要求19-26任一项所述的基质，其特征在于，所述基质还包括可用于促进组织生长和发育的因子。
28、根据权利要求19-27任一项所述的基质，其特征在于，所述基质还包括上皮生长因子、血小板衍生生长因子、碱性成纤维生长因子、血管内皮生长因子、胰岛素样生长因子、神经生长因子、肝细胞生长因子、转化生长因子和骨形成蛋白、细胞因子，包括干扰素、白细胞介素、单核细胞趋化蛋白-1(MCP-1)、雌激素、睾丸激素、激酶、化学激酶、葡萄糖或其它糖、氨基酸、石灰化因子、多巴胺、富胺寡肽例如在诸如纤连蛋白和层粘连蛋白之类的粘合蛋白中发现的肝素结合域、其它胺类三苯氧胺、顺式铂、肽和某些类毒素。
29、根据权利要求19-28任一项所述的基质，其特征在于，所述基质在两相中还包括药物、激素、酶、抗生素、营养物或其它治疗剂或因子或它们的混合物。
30、根据权利要求19-27任一项所述的基质，其特征在于，所述基质的每个相包括不同的药物、激素、酶、抗生素、营养物或其它治疗剂或因子或它们的混合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0307011.7 | 2003-03-27 | ||
| GBGB0307011.7A GB0307011D0 (en) | 2003-03-27 | 2003-03-27 | Porous matrix |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1816360A true CN1816360A (zh) | 2006-08-09 |
| CN100566763C CN100566763C (zh) | 2009-12-09 |
Family
ID=9955594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800077597A Expired - Fee Related CN100566763C (zh) | 2003-03-27 | 2004-03-29 | 组织支架以及该组织支架的生产工艺 |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US10232087B2 (zh) |
| EP (1) | EP1605984B1 (zh) |
| JP (1) | JP4818905B2 (zh) |
| CN (1) | CN100566763C (zh) |
| AT (1) | ATE525100T1 (zh) |
| AU (1) | AU2004224547B2 (zh) |
| CA (1) | CA2520398C (zh) |
| ES (1) | ES2373955T3 (zh) |
| GB (2) | GB0307011D0 (zh) |
| HK (1) | HK1086205A1 (zh) |
| WO (1) | WO2004084968A1 (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271723A (zh) * | 2009-01-12 | 2011-12-07 | 哈达斯特医疗研究服务和开发有限公司 | 组织再生膜 |
| CN109141693A (zh) * | 2018-06-25 | 2019-01-04 | 厦门大学 | 一种柔性压力传感器及其制备方法 |
| CN110585486A (zh) * | 2019-08-28 | 2019-12-20 | 湖南光琇医院有限公司 | 羊膜复合材料及其制备方法和应用 |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0307011D0 (en) * | 2003-03-27 | 2003-04-30 | Regentec Ltd | Porous matrix |
| GB0329654D0 (en) | 2003-12-23 | 2004-01-28 | Smith & Nephew | Tunable segmented polyacetal |
| US8012210B2 (en) | 2004-01-16 | 2011-09-06 | Warsaw Orthopedic, Inc. | Implant frames for use with settable materials and related methods of use |
| AU2007207429A1 (en) | 2006-01-19 | 2007-07-26 | Warsaw Orthopedic, Inc. | Injectable and moldable bone substitute materials |
| AU2007207495A1 (en) | 2006-01-19 | 2007-07-26 | Warsaw Orthopedic, Inc. | Porous osteoimplant |
| CA2669114C (en) | 2006-11-13 | 2014-12-16 | The University Of Sydney | Use of tropoelastin for repair or restoration of tissue |
| EP2120745B1 (en) | 2006-11-30 | 2010-12-29 | Smith & Nephew, Inc. | Fiber reinforced composite material |
| WO2008067655A1 (en) * | 2006-12-05 | 2008-06-12 | Q6 Biomaterials Inc. | Biocompatible hydrogel-based scaffolds |
| GB0701896D0 (en) | 2007-02-01 | 2007-03-14 | Regentec Ltd | Composition |
| EP2142353A1 (en) | 2007-04-18 | 2010-01-13 | Smith & Nephew PLC | Expansion moulding of shape memory polymers |
| WO2008131197A1 (en) | 2007-04-19 | 2008-10-30 | Smith & Nephew, Inc. | Multi-modal shape memory polymers |
| AU2008243035B2 (en) | 2007-04-19 | 2013-09-12 | Smith & Nephew, Inc. | Graft fixation |
| WO2009081408A2 (en) * | 2007-12-26 | 2009-07-02 | Metamorefix | Pulverized fibrin clots and pharmaceutical compositions containing them |
| GB0903810D0 (en) | 2009-03-05 | 2009-04-22 | Regentec Ltd | Delivery system |
| US9352003B1 (en) | 2010-05-14 | 2016-05-31 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
| US10130736B1 (en) | 2010-05-14 | 2018-11-20 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
| US8883210B1 (en) | 2010-05-14 | 2014-11-11 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
| WO2012111000A1 (en) * | 2011-02-14 | 2012-08-23 | Technion Research And Development Foundation Ltd | Tissue engineering construct comprising fibrin |
| CN102266590B (zh) * | 2011-07-15 | 2013-10-09 | 陕西师范大学 | 壳聚糖/羟基磷灰石三维多孔支架材料的制备方法 |
| US10369248B2 (en) * | 2014-07-29 | 2019-08-06 | The United States Of America As Represented By The Secretary Of The Army | Porous polymer composites |
| CN117398350A (zh) | 2014-12-15 | 2024-01-16 | 约翰霍普金斯大学 | 舒尼替尼制剂及其在治疗青光眼中的使用方法 |
| US9238090B1 (en) | 2014-12-24 | 2016-01-19 | Fettech, Llc | Tissue-based compositions |
| EP3297694A1 (en) | 2015-05-21 | 2018-03-28 | Musculoskeletal Transplant Foundation | Modified demineralized cortical bone fibers |
| BR112018009644A2 (pt) | 2015-11-12 | 2018-11-06 | Graybug Vision Inc | micropartículas agregantes sólidas modificadas na superfície, material injetável, processo para preparação de micropartículas agregantes sólidas modificadas na superfície, método para tratamento de um distúrbio ocular, e, uso de micropartículas agregantes sólidas modificadas na superfície |
| CA3018629A1 (en) | 2016-03-24 | 2017-09-28 | Locate Therapeutics Limited | Scaffolding material, methods and uses |
| GB201702475D0 (en) * | 2017-02-15 | 2017-03-29 | Locate Therapeutics Ltd | Tissue scaffold and scaffold composition |
| JP7217022B2 (ja) | 2017-03-23 | 2023-02-02 | グレイバグ ビジョン インコーポレイテッド | 眼障害の治療のための薬物及び組成物 |
| WO2018191274A1 (en) * | 2017-04-11 | 2018-10-18 | University Of Florida Research Foundation | Systems and methods for in-situ, bottom-up tissue generation |
| EP3621654A4 (en) | 2017-05-10 | 2021-02-17 | Graybug Vision, Inc. | PROLONGED-RELEASE MICROPARTICLES AND SUSPENSIONS OF THESE INTENDED FOR MEDICAL THERAPY |
| GB201710414D0 (en) | 2017-06-29 | 2017-08-16 | Univ Nottingham | Chemotherapy |
| GB202106973D0 (en) | 2021-05-14 | 2021-06-30 | Locate Bio Ltd | Osteoconductive implant material with BMP-2 delivery |
Family Cites Families (95)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB215832A (en) | 1923-02-14 | 1924-05-14 | James Ernest Johnson | Improvements in and relating to means for deaerating water and particularly feed water for steam boilers |
| US4997443A (en) * | 1985-08-26 | 1991-03-05 | Hana Biologics, Inc. | Transplantable artificial tissue and process |
| US5843156A (en) * | 1988-08-24 | 1998-12-01 | Endoluminal Therapeutics, Inc. | Local polymeric gel cellular therapy |
| US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
| US5702716A (en) | 1988-10-03 | 1997-12-30 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
| US5725491A (en) | 1988-10-03 | 1998-03-10 | Atrix Laboratories, Inc. | Method of forming a biodegradable film dressing on tissue |
| US5632727A (en) | 1988-10-03 | 1997-05-27 | Atrix Laboratories, Inc. | Biodegradable film dressing and method for its formation |
| JP2694372B2 (ja) * | 1988-12-12 | 1997-12-24 | ウロプラスティ，インコーポレイテッド | 微小移植物質 |
| US5487897A (en) | 1989-07-24 | 1996-01-30 | Atrix Laboratories, Inc. | Biodegradable implant precursor |
| US5324519A (en) | 1989-07-24 | 1994-06-28 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
| US5077049A (en) | 1989-07-24 | 1991-12-31 | Vipont Pharmaceutical, Inc. | Biodegradable system for regenerating the periodontium |
| US5286495A (en) * | 1992-05-11 | 1994-02-15 | University Of Florida | Process for microencapsulating cells |
| US5344701A (en) * | 1992-06-09 | 1994-09-06 | Minnesota Mining And Manufacturing Company | Porous supports having azlactone-functional surfaces |
| GB9304500D0 (en) * | 1993-03-05 | 1993-04-21 | Glaxo Spa | Heterocyclic compounds |
| EP2025353A2 (en) | 1993-04-30 | 2009-02-18 | Massachusetts Institute of Technology | Injectable polysaccharide-cell compositions |
| US5709854A (en) | 1993-04-30 | 1998-01-20 | Massachusetts Institute Of Technology | Tissue formation by injecting a cell-polymeric solution that gels in vivo |
| US5502092A (en) * | 1994-02-18 | 1996-03-26 | Minnesota Mining And Manufacturing Company | Biocompatible porous matrix of bioabsorbable material |
| WO1996010374A1 (en) | 1994-10-03 | 1996-04-11 | Otogen Corporation | Differentially biodegradable biomedical implants |
| US5612052A (en) * | 1995-04-13 | 1997-03-18 | Poly-Med, Inc. | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
| US6132463A (en) | 1995-05-19 | 2000-10-17 | Etex Corporation | Cell seeding of ceramic compositions |
| US6541037B1 (en) | 1995-05-19 | 2003-04-01 | Etex Corporation | Delivery vehicle |
| US6117456A (en) | 1995-05-19 | 2000-09-12 | Etex Corporation | Methods and products related to the physical conversion of reactive amorphous calcium phosphate |
| US8333996B2 (en) | 1995-05-19 | 2012-12-18 | Etex Corporation | Calcium phosphate delivery vehicle and adjuvant |
| US5676976A (en) | 1995-05-19 | 1997-10-14 | Etex Corporation | Synthesis of reactive amorphous calcium phosphates |
| US20020136696A1 (en) | 1995-05-19 | 2002-09-26 | Dosuk D. Lee | Orthopedic and dental ceramic implants |
| US6287341B1 (en) | 1995-05-19 | 2001-09-11 | Etex Corporation | Orthopedic and dental ceramic implants |
| US6027742A (en) | 1995-05-19 | 2000-02-22 | Etex Corporation | Bioresorbable ceramic composites |
| US5677284A (en) | 1995-06-06 | 1997-10-14 | Regen Biologics, Inc. | Charged collagen particle-based delivery matrix |
| US6129761A (en) | 1995-06-07 | 2000-10-10 | Reprogenesis, Inc. | Injectable hydrogel compositions |
| US5776193A (en) * | 1995-10-16 | 1998-07-07 | Orquest, Inc. | Bone grafting matrix |
| US5842477A (en) | 1996-02-21 | 1998-12-01 | Advanced Tissue Sciences, Inc. | Method for repairing cartilage |
| US6953594B2 (en) | 1996-10-10 | 2005-10-11 | Etex Corporation | Method of preparing a poorly crystalline calcium phosphate and methods of its use |
| ATE381314T1 (de) | 1996-10-16 | 2008-01-15 | Etex Corp | Biokeramische zusammensetzung |
| DK0936929T3 (da) | 1996-10-16 | 2004-11-08 | Etex Corp | Fremgangsmåde til fremstilling af svag krystallinsk calciumphosphat samt fremgangsmåder til dens anvendelse |
| US5866155A (en) * | 1996-11-20 | 1999-02-02 | Allegheny Health, Education And Research Foundation | Methods for using microsphere polymers in bone replacement matrices and composition produced thereby |
| GB9704749D0 (en) * | 1997-03-07 | 1997-04-23 | Univ London | Tissue Implant |
| US6224893B1 (en) | 1997-04-11 | 2001-05-01 | Massachusetts Institute Of Technology | Semi-interpenetrating or interpenetrating polymer networks for drug delivery and tissue engineering |
| AU8681098A (en) | 1997-08-01 | 1999-03-08 | Massachusetts Institute Of Technology | Three-dimensional polymer matrices |
| WO1999011196A1 (en) | 1997-09-04 | 1999-03-11 | Point Biomedical Corporation | Injectable tissue reconstruction material |
| US20020164374A1 (en) | 1997-10-29 | 2002-11-07 | John Jackson | Polymeric systems for drug delivery and uses thereof |
| CA2221195A1 (en) * | 1997-11-14 | 1999-05-14 | Chantal E. Holy | Biodegradable polymer matrix |
| US6143293A (en) | 1998-03-26 | 2000-11-07 | Carnegie Mellon | Assembled scaffolds for three dimensional cell culturing and tissue generation |
| US6841617B2 (en) * | 2000-09-28 | 2005-01-11 | Battelle Memorial Institute | Thermogelling biodegradable aqueous polymer solution |
| WO2000007639A1 (en) | 1998-08-07 | 2000-02-17 | Tissue Engineering, Inc. | Bone precursor compositions |
| US6818018B1 (en) * | 1998-08-14 | 2004-11-16 | Incept Llc | In situ polymerizable hydrogels |
| US7022522B2 (en) * | 1998-11-13 | 2006-04-04 | Limin Guan | Macroporous polymer scaffold containing calcium phosphate particles |
| GB9826701D0 (en) | 1998-12-05 | 1999-01-27 | Univ Newcastle | Microcellular polymers as cell growth media and novel polymers |
| US6376742B1 (en) | 1999-02-17 | 2002-04-23 | Richard J. Zdrahala | In vivo tissue engineering with biodegradable polymers |
| WO2000064977A1 (en) * | 1999-04-26 | 2000-11-02 | California Institute Of Technology | In situ forming hydrogels |
| US6333029B1 (en) * | 1999-06-30 | 2001-12-25 | Ethicon, Inc. | Porous tissue scaffoldings for the repair of regeneration of tissue |
| JP4433430B2 (ja) * | 1999-08-06 | 2010-03-17 | 株式会社クラレ | 医療用高分子ゲルおよびその製造方法 |
| DE19956503A1 (de) | 1999-11-24 | 2001-06-21 | Universitaetsklinikum Freiburg | Spritzbares Knochenersatzmaterial |
| GB9927850D0 (en) | 1999-11-26 | 2000-01-26 | Univ Nottingham | Microporous polymer matrices |
| JP4907824B2 (ja) | 2000-01-05 | 2012-04-04 | ノバルティス アーゲー | ヒドロゲル |
| GB2363115A (en) * | 2000-06-10 | 2001-12-12 | Secr Defence | Porous or polycrystalline silicon orthopaedic implants |
| US20020076443A1 (en) | 2000-06-19 | 2002-06-20 | Stanley Stein | Multiple phase cross-linked compositions and uses thereof |
| GB0015430D0 (en) | 2000-06-24 | 2000-08-16 | Victrex Mfg Ltd | Bio-compatible polymeric materials |
| US8366787B2 (en) | 2000-08-04 | 2013-02-05 | Depuy Products, Inc. | Hybrid biologic-synthetic bioabsorbable scaffolds |
| US6638312B2 (en) | 2000-08-04 | 2003-10-28 | Depuy Orthopaedics, Inc. | Reinforced small intestinal submucosa (SIS) |
| CN1156253C (zh) | 2000-08-17 | 2004-07-07 | 中国科学院化学研究所 | 周围神经修复用组织工程诱导支架 |
| US6521258B1 (en) * | 2000-09-08 | 2003-02-18 | Ferro Corporation | Polymer matrices prepared by supercritical fluid processing techniques |
| GB2370777B (en) | 2001-01-06 | 2002-12-31 | Roozbeh Shirandami | Biodegradable tissue scafold and bone template |
| US6675118B2 (en) | 2001-03-19 | 2004-01-06 | Hewlett-Packard Development Company, L.P. | System and method of determining the noise sensitivity characterization for an unknown circuit |
| JP2002325831A (ja) | 2001-05-02 | 2002-11-12 | Asahi Optical Co Ltd | 生体用充填材、および生体用充填材の製造方法 |
| US6444222B1 (en) * | 2001-05-08 | 2002-09-03 | Verigen Transplantation Services International Ag | Reinforced matrices |
| US20020183858A1 (en) * | 2001-06-05 | 2002-12-05 | Contiliano Joseph H. | Attachment of absorbable tissue scaffolds to scaffold fixation devices |
| JP2004535245A (ja) | 2001-07-16 | 2004-11-25 | デピュイ・プロダクツ・インコーポレイテッド | 多孔質細胞外基質支持骨格材料および方法 |
| WO2003007879A2 (en) | 2001-07-16 | 2003-01-30 | Depuy Products, Inc. | Cartilage repair and regeneration scaffold and method |
| US20030032961A1 (en) | 2001-07-16 | 2003-02-13 | Pelo Mark Joseph | Devices from naturally occurring biologically derived materials |
| US7819918B2 (en) | 2001-07-16 | 2010-10-26 | Depuy Products, Inc. | Implantable tissue repair device |
| AU2002354911B2 (en) | 2001-07-16 | 2007-08-30 | Depuy Products, Inc. | Meniscus regeneration device and method |
| EP1416880B1 (en) | 2001-07-16 | 2011-03-02 | DePuy Products, Inc. | Cartilage repair apparatus |
| EP1416879A4 (en) | 2001-07-16 | 2007-04-25 | Depuy Products Inc | UNITARY SURGICAL DEVICE AND METHOD |
| US8025896B2 (en) | 2001-07-16 | 2011-09-27 | Depuy Products, Inc. | Porous extracellular matrix scaffold and method |
| AU2002320517B2 (en) | 2001-07-16 | 2008-03-13 | Depuy Products, Inc. | Hybrid biologic-synthetic bioabsorable scaffolds |
| US7201917B2 (en) | 2001-07-16 | 2007-04-10 | Depuy Products, Inc. | Porous delivery scaffold and method |
| JP2005515802A (ja) | 2001-07-16 | 2005-06-02 | デピュイ・プロダクツ・インコーポレイテッド | 混成生物／合成品型多孔質細胞外基質支持骨格 |
| JP2003024272A (ja) | 2001-07-18 | 2003-01-28 | Olympus Optical Co Ltd | 信号処理装置 |
| US20050063959A1 (en) * | 2001-07-27 | 2005-03-24 | Toshimasa Uemura | Method of regenerating bone/chondral tissues by transferring transcriptional factor gene |
| GB0121985D0 (en) | 2001-09-11 | 2001-10-31 | Isis Innovation | Tissue engineering scaffolds |
| WO2003024316A2 (en) | 2001-09-21 | 2003-03-27 | Stryker Corporation | Pore-forming agents for orthopedic cements |
| US20030059460A1 (en) * | 2001-09-27 | 2003-03-27 | Yasuhiko Tabata | Hybrid material for regeneration of living body tissue |
| HUP0402135A3 (en) | 2001-11-30 | 2008-04-28 | Pfizer | Controlled release implant forming polymeric compositions of bone growth promoting compounds and process for their preparation |
| GB0129008D0 (en) | 2001-12-04 | 2002-01-23 | Univ London | Method for forming matrices of hardened material |
| WO2003053216A2 (en) | 2001-12-06 | 2003-07-03 | University Of Washington | Biodegradable, porous structures useful for growing living tissue, and methods of manufacture |
| US7166133B2 (en) * | 2002-06-13 | 2007-01-23 | Kensey Nash Corporation | Devices and methods for treating defects in the tissue of a living being |
| GB0215832D0 (en) | 2002-07-09 | 2002-08-14 | Akay Galip | Preparation of composite high internal phase emulsion polymerised microporous polymers and their applications |
| US20040166169A1 (en) | 2002-07-15 | 2004-08-26 | Prasanna Malaviya | Porous extracellular matrix scaffold and method |
| AU2002950340A0 (en) | 2002-07-23 | 2002-09-12 | Commonwealth Scientific And Industrial Research Organisation | Biodegradable polyurethane/urea compositions |
| EP1433489A1 (en) | 2002-12-23 | 2004-06-30 | Degradable Solutions AG | Biodegradable porous bone implant with a barrier membrane sealed thereto |
| US8676853B2 (en) * | 2003-02-27 | 2014-03-18 | Hewlett-Packard Development Company, L.P. | System and method for software reuse |
| GB0307011D0 (en) * | 2003-03-27 | 2003-04-30 | Regentec Ltd | Porous matrix |
| US20040234571A1 (en) | 2003-05-22 | 2004-11-25 | Jang Bor Z. | Direct injection of nano fibers and nano fiber composites for biomedical applications |
| US7767221B2 (en) | 2004-03-05 | 2010-08-03 | The Trustees Of Columbia University In The City Of New York | Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone |
| GB0502493D0 (en) | 2005-02-07 | 2005-03-16 | Orthogem Ltd | Bone cement |
-
2003
- 2003-03-27 GB GBGB0307011.7A patent/GB0307011D0/en not_active Ceased
-
2004
- 2004-03-29 ES ES04724075T patent/ES2373955T3/es not_active Expired - Lifetime
- 2004-03-29 JP JP2006506072A patent/JP4818905B2/ja not_active Expired - Fee Related
- 2004-03-29 US US10/550,151 patent/US10232087B2/en active Active
- 2004-03-29 GB GB0518898A patent/GB2415142B/en not_active Expired - Fee Related
- 2004-03-29 AU AU2004224547A patent/AU2004224547B2/en not_active Ceased
- 2004-03-29 AT AT04724075T patent/ATE525100T1/de not_active IP Right Cessation
- 2004-03-29 CA CA2520398A patent/CA2520398C/en not_active Expired - Fee Related
- 2004-03-29 CN CNB2004800077597A patent/CN100566763C/zh not_active Expired - Fee Related
- 2004-03-29 EP EP04724075A patent/EP1605984B1/en not_active Expired - Lifetime
- 2004-03-29 WO PCT/GB2004/001419 patent/WO2004084968A1/en active Application Filing
-
2006
- 2006-06-01 HK HK06106327A patent/HK1086205A1/xx not_active IP Right Cessation
-
2008
- 2008-05-08 US US12/117,683 patent/US9486558B2/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102271723A (zh) * | 2009-01-12 | 2011-12-07 | 哈达斯特医疗研究服务和开发有限公司 | 组织再生膜 |
| CN102271723B (zh) * | 2009-01-12 | 2015-03-04 | 哈达斯特医疗研究服务和开发有限公司 | 组织再生膜 |
| CN109141693A (zh) * | 2018-06-25 | 2019-01-04 | 厦门大学 | 一种柔性压力传感器及其制备方法 |
| CN110585486A (zh) * | 2019-08-28 | 2019-12-20 | 湖南光琇医院有限公司 | 羊膜复合材料及其制备方法和应用 |
| CN110585486B (zh) * | 2019-08-28 | 2021-11-30 | 湖南光琇医院有限公司 | 羊膜复合材料及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2373955T3 (es) | 2012-02-10 |
| HK1086205A1 (en) | 2006-09-15 |
| US10232087B2 (en) | 2019-03-19 |
| ATE525100T1 (de) | 2011-10-15 |
| GB0307011D0 (en) | 2003-04-30 |
| GB2415142B (en) | 2008-03-05 |
| GB2415142A (en) | 2005-12-21 |
| JP2006521144A (ja) | 2006-09-21 |
| EP1605984B1 (en) | 2011-09-21 |
| US9486558B2 (en) | 2016-11-08 |
| US20080241248A1 (en) | 2008-10-02 |
| CA2520398C (en) | 2013-03-05 |
| CN100566763C (zh) | 2009-12-09 |
| AU2004224547B2 (en) | 2009-12-10 |
| JP4818905B2 (ja) | 2011-11-16 |
| US20060263335A1 (en) | 2006-11-23 |
| WO2004084968A1 (en) | 2004-10-07 |
| EP1605984A1 (en) | 2005-12-21 |
| GB0518898D0 (en) | 2005-10-26 |
| AU2004224547A1 (en) | 2004-10-07 |
| CA2520398A1 (en) | 2004-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100566763C (zh) | 组织支架以及该组织支架的生产工艺 | |
| Yao et al. | Three dimensional electrospun PCL/PLA blend nanofibrous scaffolds with significantly improved stem cells osteogenic differentiation and cranial bone formation | |
| AU2011311904B2 (en) | Injectable, pore-forming hydrogels for materials-based cell therapies | |
| CA2456286C (en) | Porous matrix comprising cross-linked particles | |
| CN1568903A (zh) | 接种哺乳动物细胞的复合支架 | |
| US20020022883A1 (en) | Tissue engineering composite | |
| CN102421415A (zh) | 具有支架的输送系统 | |
| US20080206308A1 (en) | Hydrogel Porogents for Fabricating Biodegradable Scaffolds | |
| US20130295081A1 (en) | Polyurethane Composite for Wound Healing and Methods Thereof | |
| CN105658251A (zh) | 组合物和递送系统 | |
| CN1653112A (zh) | 带有内部分布的沉积物的聚合物复合物 | |
| US20120183622A1 (en) | Encapsulated cells and composites thereof | |
| WO2011075183A1 (en) | Injectable/in situ forming tissue polyurethane composites and methods thereof | |
| CN102921038A (zh) | 制备具有形状记忆功能的多孔支架的方法 | |
| JP2022068212A (ja) | 足場材料、方法および使用 | |
| Bhatt et al. | Polymeric scaffolds for antitumor immune cell priming | |
| CN117159802B (zh) | 一种响应性水凝胶及其制备方法和应用 | |
| Vibhute et al. | CELL DELIVERY SYSTEMS FOR PERIODONTAL REGENERATION. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: POSITIONING THERAPY LTD. Free format text: FORMER NAME: REGENTEC LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: British Nottingham Patentee after: LOCATE THERAPEUTICS Ltd. Address before: British Nottingham Patentee before: Regentec Ltd. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: England Patentee after: Lecott Biology Co.,Ltd. Address before: England Patentee before: LOCATE THERAPEUTICS Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20091209 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |