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    Chitosan core matrix containing cells encapsulated in a thermoplastic semipermeable membrane
    1.
    发明授权
    Chitosan core matrix containing cells encapsulated in a thermoplastic semipermeable membrane 失效
    壳聚糖核心基质含有包封在热塑性半透膜中的细胞

    公开(公告)号：US6140089A

    公开(公告)日：2000-10-31

    申请号：US251004

    申请日：1999-02-16

    Applicant: Patrick Aebischer ,  Beth A. Zielinski

    Inventor： Patrick Aebischer ,  Beth A. Zielinski

    IPC: A61K35/12 ,  A61L27/20 ,  A61L27/38 ,  C12N5/077 ,  C12N5/0793 ,  C12N11/10 ,  C12N11/04 ,  C12N5/00

    CPC classification number: C12N5/0012 ,  A61L27/20 ,  A61L27/38 ,  A61L27/3804 ,  C12N5/0618 ,  C12N5/0619 ,  A61K2035/128 ,  A61K35/12

    Abstract: Encapsulated viable cells for implanting are prepared having cells dispersed in a particulate, essentially non cross-linked chitosan core matrix that is enclosed within a semipermeable membrane. The cells are entrapped between chitosan particles of the core matrix and there is essentially no interfacial cross-linking between the core matrix and the membrane. The core matrix provides a physical support for the cells such that the cells are evenly dispersed throughout the core matrix so as to allow their maintenance, growth, proliferation and differentiation. The encapsulated cells may be prepared by mixing viable cells with a solution of chitosan, encapsulating the resultant mixture in a thermoplastic semipermeable membrane, and causing the chitosan to precipitate such as by changing the pH to form the core matrix. Alternatively, the chitosan in solution is precipitated to form the core matrix containing cells, and the core matrix is encapsulated in a semipermeable membrane. Cells encapsulated include neurosecretory cell lines, .beta.-cell-derived cells lines, fibroblasts, myocytes and glial cells.

    Abstract translation: 制备用于植入的包封的活细胞，其具有分散在颗粒状基本上非交联壳聚糖核心基质中的细胞，其被包封在半透膜内。 细胞被截留在核心基质的壳聚糖颗粒之间，并且核心基质和膜之间基本上没有界面交联。 核心基质为细胞提供物理支持，使得细胞均匀地分散在整个核心基质中，以便使其维持，生长，增殖和分化。 包封的细胞可以通过将活细胞与壳聚糖溶液混合，将所得混合物包封在热塑性半透膜中并使壳聚糖沉淀，例如通过改变pH以形成核心基质来制备。 或者，将溶液中的壳聚糖沉淀以形成含核心基质的细胞，并将核心基质包封在半透膜中。 包封的细胞包括神经分泌细胞系，β-细胞来源的细胞系，成纤维细胞，肌细胞和神经胶质细胞。

    Pharmaceutical microencapsulation
    2.
    发明授权
    Pharmaceutical microencapsulation 失效
    药物微胶囊化

    公开(公告)号：US6080412A

    公开(公告)日：2000-06-27

    申请号：US162590

    申请日：1998-09-29

    Applicant: Olivier Jordan ,  Patrick Aebischer ,  Jean-Francois Clemence

    Inventor： Olivier Jordan ,  Patrick Aebischer ,  Jean-Francois Clemence

    IPC: A61K9/50 ,  A61K35/12 ,  A61L27/00 ,  A61L27/38 ,  C12N5/071 ,  C12N11/04 ,  C07K1/00

    CPC classification number: A61L27/3804 ,  A61K9/5026 ,  A61K9/5089 ,  C12N11/04 ,  C12N5/0677 ,  A61K2035/128

    Abstract: A method of producing a microencapsulated pharmaceutical formulation is disclosed comprising causing a dye to be attached to the surface of pharmaceutical particles or particle clusters and applying a source of radiant energy to the dye in the presence of a liquid polymeric or polymerisable material so as to cause the material to cross-link, producing a conformal layer of cross-linked polymer on the particulate surfaces. Preferably, the polymer provides an immuno-protective layer around the particles, while allowing therapeutic components to exit the microcapsules. Microencapsulated pharmaceutical formulations and their medical use are also disclosed, especially for the treatment of diabetes by encapsulating insulin secreting cells.

    Abstract translation: 公开了一种生产微胶囊化药物制剂的方法，其包括使染料附着在药物颗粒或颗粒簇的表面上，并在液体聚合或可聚合材料的存在下将辐射能源施加到染料上，从而引起 交联的材料，在颗粒表面上产生交联聚合物的共形层。 优选地，聚合物在颗粒周围提供免疫保护层，同时允许治疗成分离开微胶囊。 还公开了微囊化药物制剂及其医疗用途，特别是用于通过包封胰岛素分泌细胞治疗糖尿病。

    Particulate non cross-linked chitosan core matrices for encapsulated cells
    3.
    发明授权
    Particulate non cross-linked chitosan core matrices for encapsulated cells 失效
    用于封装细胞的颗粒非交联壳聚糖核心基质

    公开(公告)号：US5871985A

    公开(公告)日：1999-02-16

    申请号：US294149

    申请日：1994-08-22

    Applicant: Patrick Aebischer ,  Beth A. Zielinski

    Inventor： Patrick Aebischer ,  Beth A. Zielinski

    IPC: A61K35/12 ,  A61L27/20 ,  A61L27/38 ,  C12N5/077 ,  C12N5/0793 ,  C12N11/10 ,  C12N11/04 ,  C12N5/00

    CPC classification number: C12N5/0012 ,  A61L27/20 ,  A61L27/38 ,  A61L27/3804 ,  C12N5/0618 ,  C12N5/0619 ,  A61K2035/128 ,  A61K35/12

    Abstract: Vehicles containing cells for implanting in the tissue of an individual are prepared having cells dispersed in a particulate, essentially non cross-linked chitosan core matrix that is enclosed within a semipermeable membrane. The cells are entrapped between chitosan particles of the core matrix and there is essentially no interfacial cross-linking between the core matrix and the membrane. The core matrix provides a physical support for viable cells within the vehicle such that the cells are evenly dispersed throughout the core matrix so as to allow their maintenance, growth, proliferation and differentiation. The vehicle can be prepared by mixing viable cells with a solution of chitosan, encapsulating the resultant mixture in a semipermeable membrane and causing the chitosan to precipitate such as by changing the pH to form the core matrix. Alternatively, the chitosan is precipitated to form the core matrix containing cells and then the core matrix is encapsulated in a semipermeable membrane. Cells within the core matrix may be neurosecretory cell lines, .beta.-cell-derived cells lines, fibroblasts, myocytes and glial cells.

    Abstract translation: 制备含有用于植入个体组织的细胞的载体，其具有分散在颗粒状基本上非交联壳聚糖核心基质中的细胞，所述壳聚糖核心基质被包封在半透膜内。 细胞被截留在核心基质的壳聚糖颗粒之间，并且核心基质和膜之间基本上没有界面交联。 核心基质为载体内的活细胞提供物理支持，使得细胞均匀分散在整个核心基质中，以使其维持，生长，增殖和分化。 载体可以通过将活细胞与壳聚糖溶液混合来制备，将所得混合物包封在半透膜中并使壳聚糖沉淀，例如通过改变pH以形成核心基质。 或者，将壳聚糖沉淀形成含核心基质的细胞，然后将核心基质包封在半透膜中。 核心基质内的细胞可以是神经分泌细胞系，β-细胞来源的细胞系，成纤维细胞，肌细胞和神经胶质细胞。

    Controlling proliferation of cells before and after encapsulation in a bioartificial organ by gene transformation
    5.
    发明授权
    Controlling proliferation of cells before and after encapsulation in a bioartificial organ by gene transformation 失效
    通过基因转化控制生物人工器官中包封前后细胞的增殖

    公开(公告)号：US5843431A

    公开(公告)日：1998-12-01

    申请号：US432698

    申请日：1995-05-09

    Applicant: Malcolm Schinstine ,  Molly S. Shoichet ,  Frank T. Gentile ,  Joseph P. Hammang ,  Laura M. Holland ,  Brian M. Cain ,  Edward J. Doherty ,  Shelley R. Winn ,  Patrick Aebischer

    Inventor： Malcolm Schinstine ,  Molly S. Shoichet ,  Frank T. Gentile ,  Joseph P. Hammang ,  Laura M. Holland ,  Brian M. Cain ,  Edward J. Doherty ,  Shelley R. Winn ,  Patrick Aebischer

    IPC: A01K67/027 ,  A61K48/00 ,  A61L27/00 ,  A61L27/18 ,  A61L27/22 ,  A61L27/38 ,  C07K14/82 ,  C12N5/00 ,  C12N5/10 ,  C12N15/09 ,  C12N15/12 ,  C12N11/00 ,  C12N11/10

    CPC classification number: A61L27/3839 ,  A61L27/18 ,  A61L27/227 ,  C07K14/82 ,  C12N5/0012 ,  C12N5/0068 ,  A61K48/00 ,  C12N2510/00 ,  C12N2510/04 ,  C12N2533/30 ,  C12N2533/54 ,  C12N2533/74

    Abstract: Methods and compositions are provided for controlling cell distribution within an implantable bioartificial organ by exposing the cells to a treatment that inhibits cell proliferation, promotes cell differentiation, or affects cell attachment to a growth surface within the bioartificial organ. Such treatments include (1) genetically manipulating cells, (2) exposing the cells to a proliferation-inhibiting compound or a differentiation-inducing compound or removing the cells from exposure to a proliferation-stimulating compound or a differentiation-inhibiting compound; exposing the cells to irradiation, and (3) modifying a growth surface of the bioartificial organ with extracellular matrix molecules, molecules affecting cell proliferation or adhesion, or an inert scaffold, or a combination thereof. These treatments may be used in combination. Cells can be transformed with a proliferation-promoting gene such as the oncogene, SV40, linked to a regulatable promoter such as the Mx1 promoter, the promotor is activated in vitro to express the gene to result in cell proliferation, and the promotor is inactivated before or after insertion of the cells in the bioartificial organ to inhibit expression of the gene to reduce or stop cell proliferation in vivo. The promoter can be reactivated in vivo to again express the gene to result in further cell proliferation. The gene may be a proliferation-suppressing gene such as p53 gene or RB gene, or a differentiation-inducing gene such as high mobility group chromosomal protein 14. Inhibiting gene expression in vitro causes cell proliferation, and inducing gene expression reduces or stops cell proliferation in vivo.

    Abstract translation: 提供了用于通过将细胞暴露于抑制细胞增殖，促进细胞分化或影响细胞附着于生物人造器官内的生长表面的处理来控制可植入的生物人造器官内的细胞分布的方法和组合物。 这样的处理包括（1）遗传操纵细胞，（2）将细胞暴露于增殖抑制化合物或分化诱导化合物，或除去细胞暴露于增殖刺激化合物或分化抑制化合物; 将细胞暴露于照射下，和（3）用细胞外基质分子，影响细胞增殖或粘附的分子，或惰性支架或其组合修饰生物人造器官的生长表面。 这些处理可以组合使用。 可以用增殖促进基因转化细胞，例如与可调节启动子如Mx1启动子连接的癌基因SV40，启动子在体外被激活以表达基因以导致细胞增殖，并且启动子在 或在细胞插入生物人造器官中以抑制基因表达以减少或停止体内细胞增殖。 启动子可以在体内再活化以再次表达基因以导致进一步的细胞增殖。 该基因可以是增殖抑制基因如p53基因或RB基因，或分化诱导基因如高迁移率组染色体蛋白14.体外抑制基因表达引起细胞增殖，诱导基因表达降低或停止细胞增殖 体内。

    Implantable delivery system for biological factors
    8.
    发明授权
    Implantable delivery system for biological factors 失效
    生物因子植入式输送系统

    公开(公告)号：US5011472A

    公开(公告)日：1991-04-30

    申请号：US240939

    申请日：1988-10-06

    Applicant: Patrick Aebischer ,  Pierre M. Galletti ,  George Panol ,  Luigi Miracoli

    Inventor： Patrick Aebischer ,  Pierre M. Galletti ,  George Panol ,  Luigi Miracoli

    IPC: A61F2/02 ,  A61M5/142

    CPC classification number: A61M5/14276 ,  A61F2/022 ,  A61M2205/3523

    Abstract: Devices and methods are disclosed to provide hybrid, modular systems for the constitutive delivery of appropriate dosages of active factor to a subject and, in some instances, to specific anatomical regions of the subject. The systems include a cell reservoir containing living cells capable of secreting an active agent, which is preferably adapted for implantation within the body of the subject and further includes at least one semipermeable membrane, whereby the transplanted cells can be nourished by nutrients transported across the membrane while at the same time protected from immunological, bacterial, and viral assault. The systems further include a pumping means, which can be implantable or extracorporeal, for drawing a body fluid from the subject into the cell reservoir and for actively transporting the secreted biological factors from the cell reservoir to a selected region of the subject.

    Abstract translation: 公开了装置和方法以提供混合模块化系统，用于将主动因子的合适剂量的组成型递送给受试者，并且在某些情况下提供给对象的特定解剖区域。 该系统包括含有能够分泌活性剂的活细胞的细胞储库，其优选适于植入受试者的身体内并且还包括至少一种半透膜，由此可以通过跨膜运送的营养物滋养移植的细胞 同时保护免受免疫，细菌和病毒攻击。 所述系统还包括可植入或体外的抽吸装置，用于将体液从受试者吸入细胞储存器中并用于将分泌的生物因子从细胞储存器积极输送到受试者的选定区域。

    Bioartificial extracellular matrix containing hydrogel matrix derivatized with cell adhesive peptide fragment
    10.
    发明授权
    Bioartificial extracellular matrix containing hydrogel matrix derivatized with cell adhesive peptide fragment 有权
    生物人造细胞外基质含有细胞粘附肽片段衍生的水凝胶基质

    公开(公告)号：US6156572A

    公开(公告)日：2000-12-05

    申请号：US160654

    申请日：1998-09-25

    Applicant: Ravi Bellamkonda ,  John P. Ranieri ,  Patrick Aebischer

    Inventor： Ravi Bellamkonda ,  John P. Ranieri ,  Patrick Aebischer

    IPC: A61L27/00 ,  A61K38/00 ,  A61L27/20 ,  A61L27/22 ,  A61L27/38 ,  A61L27/52 ,  A61L31/00 ,  A61L31/04 ,  C07K7/06 ,  C07K7/08 ,  C07K14/78 ,  C12N5/00 ,  C07K17/02 ,  C07K17/10 ,  C12N11/10

    CPC classification number: A61L27/3839 ,  A61L27/20 ,  A61L27/227 ,  A61L27/52 ,  A61L31/005 ,  A61L31/047 ,  C07K14/78 ,  A61K38/00 ,  A61L2430/32 ,  Y10S530/812 ,  Y10S530/813

    Abstract: A bioartificial extracellular matrix for use in tissue regeneration or replacement is provided by derivatizing a three-dimensional hydrogel matrix with a cell adhesive extracellular matrix protein or cell adhesive peptide fragment of the protein. Preferably, derivatizing is by covalent immobilization of a cell adhesive peptide fragment having the amino acid sequence, ArgGlyAsp, TyrIleGlySerArg or IleLysValAlaVal. Cartilage or tendon can be regenerated by implanting a matrix containing an adhesive peptide fragment that favors chondrocyte invasion. The matrix can be pre-seeded with cells, and tissue can be reconstituted in vitro and then implanted. A cell-seeded matrix can be encapsulated in a semi-permeable membrane to form a bioartificial organ. An agarose hydrogel matrix having an agarose concentration of 0.5-1.25% (w/v) and an average pore radius between 120 nm and 290 nm is preferred. A nerve guidance channel for use in regenerating severed nerve is prepared containing a tubular semi-permeable membrane having openings adapted to receive ends of a severed nerve, and an inner lumen containing the hydrogel matrix having a bound cell adhesive peptide fragment through which the nerve can regenerate.

    Abstract translation: 通过用蛋白质的细胞粘附细胞外基质蛋白或细胞粘附肽片段衍生三维水凝胶基质来提供用于组织再生或替代的生物人造细胞外基质。 优选地，衍生化是通过共价固定具有氨基酸序列ArgGlyAsp，TyrIleGlySerArg或IleLysValAlaVal的细胞粘附性肽片段。 可以通过植入含有有利于软骨细胞侵入的粘合肽片段的基质来再生软骨或肌腱。 基质可以用细胞预种子，组织可以在体外重建然后植入。 细胞接种的基质可以包封在半透膜中以形成生物人造器官。 具有琼脂糖浓度为0.5-1.25％（w / v）且平均孔半径在120nm与290nm之间的琼脂糖水凝胶基质是优选的。 制备用于再生切断的神经的神经引导通道，其包含具有适于接收切断的神经的端部的开口的管状半透膜，以及含有具有结合的细胞粘附肽片段的水凝胶基质的内腔，神经可穿过该片段 再生。

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