CN102413820A - 包囊的肝细胞组合物 - Google Patents
包囊的肝细胞组合物 Download PDFInfo
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- CN102413820A CN102413820A CN2010800188449A CN201080018844A CN102413820A CN 102413820 A CN102413820 A CN 102413820A CN 2010800188449 A CN2010800188449 A CN 2010800188449A CN 201080018844 A CN201080018844 A CN 201080018844A CN 102413820 A CN102413820 A CN 102413820A
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- hepatocyte
- microcapsule
- liver
- erythropoietin
- cell
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Abstract
一种微胶囊，其包含胶囊壳，所述胶囊壳包囊有与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞悬液。
Description
本发明涉及包含肝细胞(liver cell)和促红细胞生成素的微胶囊，制备所述微胶囊的方法，和包括对患者应用所述微胶囊的治疗患者的方法。
尽管健康受治疗者的肝脏能通过修复或替代损伤或患病组织而自行再生，不幸的是，一旦一定量的肝细胞已经死亡或已经因疾病或损伤严重受损，整个器官就可能衰竭。这样的衰竭(它可以是急性的或慢性的衰竭)可导致疾病和死亡。肝病的治疗包括常规的方式，诸如药物给药。尽管如此，移植肝脏或其部分也是本领域的现有技术。此外，在患者中移植肝细胞群为公众熟知，诸如在例如WO 2004/009766 A2中所述的。尽管如此，在用于治疗急性或慢性肝病的疗法设计中递送肝细胞至具有相应需要的患者仍然是主要挑战，根据所移植的肝细胞在靶组织中的活力、植入、增殖和分化而优化方法。
Haque等(Biotechnology Letters 27(5)(2005)，317-322))描述了藻酸盐-壳聚糖微胶囊作为治疗肝衰竭的肝细胞移植替代物的体外研究。Chandrasekaran等(Tissue Engineering 12(7)，(2006))公开了在静电产生的微珠中包埋的肝祖细胞。
尽管已经努力开发有效递送肝细胞至患者靶组织的治疗系统，但仍需要提供更可靠的治疗方式来治疗肝病，尤其是在靶机体中提供高活力和生理活性的肝细胞的方式。
本发明通过提供一种微胶囊来解决所述问题，所述微胶囊包含胶囊壳，优选生物相容性胶囊壳，所述胶囊壳包囊有与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞悬液。在优选的实施方式中，本发明提供了一种微胶囊，所述微胶囊包含胶囊壳和核，其中该胶囊壳在核中包囊治疗有效量的肝细胞悬液和肝细胞刺激量的促红细胞生成素，特别地，其中促红细胞生成素(以下称作EPO)与肝细胞彼此物理接触，以便提供EPO对肝细胞的刺激效果。
因而，在优选的实施方式中，本发明预见性提供了一种微胶囊，所述微胶囊包含胶囊壳和被所述胶囊壳包囊的核，所述胶囊壳优选由生物相容性胶囊壳材料所制。在本发明的一优选实施方式中，该核含有与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞悬液。
在另一优选实施方式中，所述核含有基质，所述基质优选由生物相容性基质材料所制，其中所述治疗有效量的肝细胞悬液包埋于所述基质中，与肝细胞刺激量的促红细胞生成素物理接触。优选地，基质材料与胶囊壳材料相同。在另一实施方式中，生物相容性基质材料可以是不同于胶囊壳材料的其他材料。
因而，本发明提供了将促红细胞生成素和肝细胞两者一起包囊于生物相容性壳中的方法，使得促红细胞生成素与肝细胞物理接触以发挥其对于肝细胞的至少一种生物学功能，尤其是刺激肝细胞。
本发明的一个优点是肝细胞包囊于胶囊壳中，从而不会在患者中引发任何副反应，尤其是过敏性或免疫学反应，所述患者中优选移植入微胶囊。进而，促红细胞生成素与肝细胞的紧密接触刺激所述肝细胞实施其生物学功能，以便提供给患者肝脏的生物学功能。
在特别优选的实施方式中，肝细胞以以便彼此物理接触的浓度包含于微胶囊中，在被促红细胞生成素刺激时提供甚至更显著的效果。因而，在特别优选的实施方式中，本发明预见到包含于微胶囊中的肝细胞彼此物理接触，并与促红细胞生成素物理接触。
在本发明上下文中，表述“肝细胞与促红细胞生成素物理接触”是指促红细胞生成素能对于肝细胞发挥其至少一种生物学功能，尤其是能够到达存在于肝细胞的促红细胞生成素受体并被其可逆地或不可逆地结合。
在本发明上下文中，表述“肝细胞彼此物理接触”是指肝细胞存在于本发明的微胶囊中，彼此紧密靠近使得细胞彼此触及，并提供几近类似肝脏中的天然生理状态的稳定环境。
在本发明上下文中，术语“刺激肝细胞”是指促红细胞生成素增加肝细胞的生物学功能(优选在移植了微胶囊的患者中)，增加肝细胞的活力，增加其储存稳定性和/或增加一旦被移植入受治疗者中成功实施其生物学功能的潜能。
在本发明上下文中，“生物相容性”是指材料、尤其是胶囊壳材料和/或基质材料能保持整合的肝细胞活力并允许促红细胞生成素与肝细胞间相互作用。在特别优选的实施方式中，术语“生物相容”是指材料允许在患者中的植入、优选长期植入，同时仍保留所包埋的肝细胞的功能，而不会在受治疗者中引发任何不良的局部或全身效应，尤其是过敏性和免疫学反应。在特别优选的实施方式中，术语“生物相容”是指材料能用作支持肝细胞活性的基质，包括肝细胞与EPO间的分子和机械类似系统的要求(solicitation)，优选地为了优化肝脏再生，而不在细胞和受治疗者中引发任何不良效应。
在本发明上下文中，术语“促红细胞生成素”指控制红细胞生成或血细胞产生的糖蛋白激素，优选的是，以适当的剂量控制干细胞经由成红血细胞至红细胞的生长、分化和成熟的物质。
促红细胞生成素是具有166个氨基酸，3个糖基化位点，分子量约为34,000Da的糖蛋白。在EPO诱导的红细胞祖细胞的分化过程中，珠蛋白合成被诱导，血红素复合物的合成放大，铁蛋白受体数量增加。从而细胞可以摄取更多的铁，并合成有功能的血红蛋白。在成熟的红细胞中，血红蛋白结合氧。因而红细胞和其中含有的血红蛋白在为机体供应氧中起到关键作用。这些过程通过EPO与红细胞祖细胞的细胞表面上的合适的受体相互作用而启动(Graber和Krantz，Ann.Rev.Med.29(1978)，51-56)。
在本发明上下文中，术语“促红细胞生成素”既包括野生型促红细胞生成素，尤其是人促红细胞生成素，又包括其衍生物。在本发明上下文中，促红细胞生成素衍生物是：重组促红细胞生成素蛋白，其特征在于至少一个氨基酸出现偏差，尤其是与野生型EPO相比，至少有一个氨基酸缺失、添加或置换；和/或与野生型EPO相比带有不同糖基化模式的促红细胞生成素蛋白。在特别优选的实施方式中，促红细胞生成素衍生物还是野生型促红细胞生成素或其衍生物的融合蛋白或截短蛋白。在特别优选的实施方式中，促红细胞生成素衍生物还是与野生型糖基化模式相比具有不同的糖基化模式的野生型促红细胞生成素。
本文所用的术语“促红细胞生成素”包括各种来源的EPO，特别是人或动物的EPO。本文所用术语因而不仅包括自然存在的，或换言之，EPO的野生型形式，还包括其衍生物，也称为变体、突变蛋白或突变体，只要它们呈现出野生型促红细胞生成素的生物学效应。
本发明所涉及的“衍生物”也可理解为通过一个或多个原子或分子基团或残基的取代，特别是通过诸如乙二醇的糖链取代获得的，同时保留了基本的促红细胞生成素结构的那些促红细胞生成素衍生物，和/或其氨基酸序列在至少一个位置上不同于天然存在的人或动物的促红细胞生成素蛋白的氨基酸序列，但基本上具有在氨基酸水平上的高度同源性且相当的生物学活性的那些促红细胞生成素衍生物。可应用的促红细胞生成素衍生物，例如本发明中的，可从WO 94/25055、EP 0148605 B1或WO 95/05465中得知。
“同源性”是指特别是具有至少80％、优选至少85％、特别优选至少超过90％、95％、97％和99％的序列同一性。因而，本领域技术人员熟知的术语“同源性”指两个或多个多肽分子之间的关系的度量。这通过序列间的一致性来确定。该一致性要么可以指相同的一致性，要么可以指氨基酸的保守性置换。
根据本发明，术语“衍生物”还包括融合蛋白，其中另一蛋白的功能域存在于N末端部分或C末端部分。在本发明的一种实施方式中，这另一蛋白可以是，例如，粒细胞-巨噬细胞集落刺激因子(GM-CSF)、血管内皮生长因子(VEGF)、PIGF、抑制素(statin)或对内皮祖细胞有刺激效应的另一因子。在本发明的进一步的实施方式中，该另一蛋白还可以是对肝细胞有刺激效应的因子。
促红细胞生成素衍生物和天然或野生型促红细胞生成素之间可以出现差异，例如，通过突变，诸如缺失、置换、插入、添加、碱基置换和/或编码促红细胞生成素氨基酸序列的核苷酸序列的重组。显然这样的差异还可以是天然存在的序列变异体，诸如来自其他生物的序列或有天然突变的序列，或利用诸如化学试剂和/或物理试剂的本领域公知的方式选择性引入编码促红细胞生成素的核酸序列的突变。从而，本发明所涉及的术语“衍生物”还包括突变的促红细胞生成素分子，或换言之，促红细胞生成素突变蛋白。
根据本发明，还可以使用促红细胞生成素的肽或蛋白类似物。本发明所涉及的术语“类似物”包括下述化合物：即，没有与促红细胞生成素氨基酸序列相同的任何氨基酸序列，但具有极其类似促红细胞生成素三维结构的，使得它们具有相当的生物学活性。促红细胞生成素类似物可以是，例如，在合适的构象中含有负责促红细胞生成素结合其受体的氨基酸残基的化合物，从而它们能模拟促红细胞生成素结合区的必要的表面特性。例如Wrighton等，Science，273(1996)，458中所记载的此类型化合物。
根据本发明所用的EPO能以各种方式产生，例如通过从人尿或从患有再生障碍性贫血的患者的尿或血浆(包括血清)中分离(Miyake等，J.B.C(《生物化学杂志》).252(1977)，5558)。作为示例，人EPO也能从人肾癌细胞的组织培养物中获得(JA未审查的专利申请55790/1979)，从能产生人EPO的人淋巴母细胞中获得(JA未审查的专利申请40411/1982)，以及从通过人细胞系的细胞融合得到的杂交瘤培养物中获得。EPO也能通过基因技术方法来生成，使用编码合适的EPO氨基酸序列的合适DNA或RNA通过基因工程(例如，在细菌、酵母或植物、动物或人细胞系中)来产生所需蛋白。这样的方法描述于例如，EP 0148605 B2或EP 0205564 B2以及EP 0411678 B1。
在优选的实施方式中，本发明所涉及的促红细胞生成素的衍生物是有功能的而且临床上证实的EPO衍生物，优选选自由依泊汀(Epoetin，也称作Procrit)、依普定(Epogen)、依泊汀α(Eprex)或依泊汀β(NeoRecormon)、依泊汀δ(Epoetin delta，也称作Dynepo)、达依泊汀(Darbepoetin，也称作Aranesp)、Pdpoetin、CERA(持续性促红细胞生成素受体拮抗剂)和甲氧聚乙二醇-依泊汀β(也称作Mircera)组成的组。
在本发明的优选实施方式中，微胶囊是一种由生物相容性胶囊壳材料制成的微珠，优选球形微珠，所述微珠含有包埋其中的与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞。在本发明说明书中，微胶囊优选为球形，优选直径10μm至10mm，优选140μm至10mm，优选50μm至1mm，优选60μm至800μm，优选100至700μm。在本发明的优选实施方式中，本发明的微胶囊由肝细胞、促红细胞生成素和生物相容性胶囊壳材料组成。优选的是，除以上三种元件外，还预知了微胶囊的包衣和/或微胶囊核中的生物相容性基质。
因而，在特别优选的实施方式中，本发明涉及一种微胶囊，所述微胶囊包含包囊于生物相容性基质材料的与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞。
在特别优选的实施方式中，肝细胞以悬液形式、优选细胞培养悬液形式，包埋在胶囊壳中。肝细胞悬液优选为包含在细胞培养基中或包含在生理学上可接受的水溶液中的肝细胞的形式。肝细胞悬液优选为在细胞培养基中的肝细胞的悬液。
在特别优选的实施方式中，肝细胞以悬液形式、优选细胞培养悬液形式、优选包含在细胞培养基中或包含在生理学上可接受的水溶液中的肝细胞的形式包埋在壳中含有的基质中。
在特别优选的实施方式中，本发明涉及微胶囊，其中肝细胞选自由肝祖细胞、肝干细胞、肝母细胞和肝细胞(hepatocyte)组成的组。
在特别优选的实施方式中，本发明涉及微胶囊，其中肝细胞选自由肝祖细胞、肝干细胞、肝母细胞、肝细胞和内皮细胞组成的组。
在另外的优选实施方式中，本发明涉及微胶囊，其中肝细胞从成人肝脏、胚肝、胎肝、新生肝或肝细胞培养物中获得。优选的是，肝细胞为活的肝细胞。在优选的实施方式中，肝细胞可以从活或死供体、特别是新近死亡的供体中获得。
在另外的优选实施方式中，本发明涉及微胶囊，其中肝细胞是人肝细胞、非人灵长类肝细胞、猪肝细胞、狗肝细胞、猫肝细胞、兔肝细胞、小鼠肝细胞或大鼠肝细胞。
在特别优选的实施方式中，本发明涉及微胶囊，其中微胶囊平均直径为100至700μm，优选200、300、400、500、600或650至700μm。
在特别优选的实施方式中，本发明涉及微胶囊，其中治疗有效量的肝细胞是104至108、优选105至107个肝细胞/ml悬液。
在特别优选的实施方式中，本发明涉及微胶囊，其中肝细胞平均直径为8至14μm，优选9至12μm。
在另外优选的实施方式中，本发明涉及微胶囊，其中促红细胞生成素的肝细胞刺激量为10-7至10-2U/ml悬液，优选10-7至10-3U/ml悬液，优选10-7至10-5U/ml悬液以及优选10-6到10-5U/ml悬液。
在另外优选的实施方式中，本发明涉及微胶囊，其中EPO是野生型促红细胞生成素或重组促红细胞生成素。
在另外优选的实施方式中，本发明涉及微胶囊，其中胶囊壳材料选自由藻酸盐、藻酸盐-壳聚糖(AC)、藻酸盐-聚L赖氨酸(APA)、热胶凝(thermogelation)-聚合物和PEG-水凝胶组成的组。
在另外优选的实施方式中，本发明涉及微胶囊，其中基质材料选自由藻酸盐、藻酸盐-壳聚糖(AC)、藻酸盐-聚L赖氨酸(APA)、热凝胶(thermogelation)-聚合物和PEG-水凝胶组成的组。
在另外的优选实施方式中，本发明涉及微胶囊，其中除肝细胞外，还有至少一种另外的细胞类型存在于微胶囊中。
在特别优选的实施方式中，存在于微胶囊中的至少一种另外的细胞类型选自由肝脏星状细胞、胆细胞、造血细胞、单核细胞、巨噬细胞系细胞、淋巴细胞和内皮细胞组成的组。
在本发明的另一优选实施方式中，预见到，除肝细胞和EPO外，微胶囊还包括至少一种另外的生长因子，优选选自HGH(人生长因子)、VEGF(血管内皮生长因子)、CSF(集落刺激因子)、促血小板生成素(thrombopoietin)、SCF复合物(包含Skpcollien、F-box的复合物)，SDF(间质细胞衍生因子-1)、NGF(神经生长因子)、PIGF(磷脂酰肌醇聚糖锚生物合成，F类)、HMG辅还原酶抑制剂、ACE(血管紧张素转化酶)抑制剂、AT-1抑制剂和NO供体组成的组。
在特别优选的实施方式中，本发明涉及微胶囊，其中所述微胶囊被包衣包覆。
在本发明的特别优选的实施方式中，包衣是聚合物包衣、糖包衣、糖醇包衣和/或脂或蜡包衣。
在另外的优选实施方式中，本发明涉及一种用于制备上文所述的微胶囊的方法，该方法包括：
a)提供治疗有效量的肝细胞悬液和肝细胞刺激量的促红细胞生成素，
b)混合所述肝细胞悬液和促红细胞生成素以使它们彼此物理接触，和
c)将所述肝细胞悬液和促红细胞生成素包囊于胶囊壳材料中以形成所述微胶囊。
在另外的优选实施方式中，本发明涉及一种方法，其中将步骤c)中获得的所述微胶囊冷冻保存。
在另外的优选实施方式中，本发明涉及一种用于预防性或治疗性治疗具有相应需要的受治疗者中的肝脏疾病的方法，该方法包括将本发明的所述微胶囊给药至所述受治疗者。
在特别优选的实施方式中，本发明涉及一种方法，其中肝脏疾病是肝炎、肝硬化、先天性代谢缺陷、急性肝衰竭、急性肝感染、急性化学毒性、慢性肝衰竭、胆管炎(cholangiocitis)、胆汁性肝硬化、Alagille综合征、α1-抗胰蛋白酶缺乏症、自身免疫性肝炎、胆道闭锁、肝癌、肝脏囊性疾病、脂肪肝、半乳糖血症、胆结石、吉尔伯特综合征(Gilbert’s syndrome)、血色素沉着症、甲型肝炎、乙型肝炎、丙型肝炎和其他肝炎病毒感染、卟啉病(poryphyria)、原发性硬化性胆管炎、瑞氏综合征(Reye’s syndrome)、结节病、酪氨酸血症、I型糖原贮积症或威尔森氏病(Wilson’s disease)。
在另外的优选实施方式中，本发明涉及一种方法，其中通过在肝包膜下将微胶囊导入脾脏、肝脏、肝浆(liver pulp)或脾动脉或门静脉而进行给药。
在另外的优选实施方式中，本发明涉及用于将肝细胞导入受治疗者的方法，该方法包括将本发明的微胶囊给药至所述受治疗者。
在本发明的特别优选的实施方式中，通过导入具有相应需要的受治疗者来进行给药，其中所述给药是局部、肠道或胃肠外给药。在优选的实施方式中，局部给药是表皮、吸入、阴道或鼻内给药。在优选的实施方式中，肠道给药是通过口腔、胃饲管或直肠。在优选的实施方式中，胃肠外给药是通过注射或输液，优选静脉内、动脉内、肌肉内、心脏内、皮下、骨内、皮内、鞘内、腹腔或膀胱内给药。在另外的优选实施方式中，胃肠外给药是透皮、透黏膜或吸入给药。
在另外的优选实施方式中，本发明涉及一种在培养基中培养肝细胞的方法，优选在体外，该方法包括在合适的培养基和在适于维持或增加肝细胞活力的条件下培养本发明的微胶囊。
在特别优选的实施方式中，本发明涉及一种在培养基中维持或增加肝细胞能量状态的方法，优选在体外，该方法包括在合适的培养基和在适于维持或增加肝细胞能量状态的条件下培养本发明的微胶囊。
本发明的另外的优选实施方式是从属权利要求的主题。
附图显示了包囊有EPO或未以EPO包囊的肝细胞培养后ATP/ADP比值(作为对于细胞能量状态的测量)。
实施例1
在EPO(5×10-3单位/ml)存在的条件下，用藻酸盐以104到108个细胞/ml的浓度包囊至平均直径为100至700μm的微珠中的肝细胞将优于除无EPO外同样地包囊的肝细胞。ATP/ADP比值用作细胞能量状态的测量。在实验过程中，如果ATP/ADP比值以较快速率增加或保持高于未处理的细胞，则该证据可支持推论。
肝细胞的包囊
利用静电微珠产生装置从冷冻保存的人肝细胞的单个原种实施肝细胞的细胞包囊。在常规培养基中悬浮肝细胞，并以1∶1的比例将其与2％藻酸钠混合。将所得到的含4百万个细胞/ml浓度的肝细胞的1％藻酸盐溶液吸入装有24号血管导管(angiocatheter)的1-cc注射器中。在静电铸造过程中，使用23号针头将血管导管穿在针座上作为正电极。注射器装在注射器泵(BraintreeScientific BS-8000，Braintree，MA)上，使得从留置针喷出的液滴垂直落在250ml玻璃烧杯中的125mM氯化钙(CaCl2)溶液表面上(含1％人白蛋白的常规缓冲液或Cytonet缓冲液，含5×10-3和5×10-6U/ml的EPO或不含EPO)。自留置针顶端至CaCl2表面的距离固定在大约2.5cm。泵流速设在0.75至1.5ml/分钟范围内。接地电极浸入CaCl2接收槽中。利用3.8至6kV范围内的高电压DC电源(Spellman model RHR30PF30，Hauppauge，NY)形成跨留置针顶端和CaCl2槽的静电势。通过调节所用电势控制微珠直径(500μm)。当在高静电电势存在条件下开启注射器泵时，挤压出的藻酸钠溶液被拉成细小的液滴，所述液滴当接触CaCl2溶液时立即聚合形成固体藻酸钙。
在包囊肝细胞后，将藻酸盐微珠保持在补有10％血清、244单位/ml青霉素、0.244mg/ml、5.5mM谷氨酰胺、0.195单位/ml胰岛素、0.017ug/ml胰高血糖素、0.73ug/ml泼尼松龙、0.54ug/ml地塞米松的威廉姆斯E培养基(William’s E)中，并培养2小时。
通过将微珠置于100mM柠檬酸中来进行去包囊化。当藻酸盐溶解时，用PBS洗涤细胞两遍，并通过200×G离心1分钟沉淀细胞。通过将4％高氯酸置于细胞上，并用手持微匀浆器匀浆20秒来提取代谢物。然后以14,000×G离心样品3分钟，并去除含代谢物的上清液。用KOH中和高氯酸，并通过离心去除不溶解的高氯酸钾。然后用记载于“哺乳动物细胞中的ATP测量(Measurements of ATP in Mammalian Cells)”(Manfredi等，Methods 2002(4)，317-326)的用于ATP、ADP分析的HPLC方法分析样品。三个平行的平板用于实施ATP/ADP水平测定。
结果
ATP/ADP比值是细胞能量的测量并代表基于细胞的代谢状态的所有生物化学通路的效果。所看到的包囊有EPO的肝细胞中的ATP/ADP比值(见附图)的维持清楚地显示，细胞能维持细胞的各个功能所需的能量产生通路。在该实验中，在EPO处理组中维持ATP/ADP比值，但在未处理对照中没有维持ATP/ADP比值。当EPO处理组能维持ATP/ADP比值时，对照中的ATP/ADP比值下降至0.5以下。这表明EPO可以通过非EPO受体驱动的通路来信号传导以赋予细胞营养刺激。
Claims (20)
1.一种微胶囊，其包含胶囊壳，所述胶囊壳包囊有与肝细胞刺激量的促红细胞生成素物理接触的治疗有效量的肝细胞悬液。
2.如权利要求1所述的微胶囊，其中，所述肝细胞选自由肝祖细胞、肝干细胞、肝母细胞、内皮细胞和肝细胞组成的组。
3.如权利要求1或2所述的微胶囊，其中，所述肝细胞从成人肝脏、胚肝、胎肝、新生肝或肝细胞培养物中获得。
4.如权利要求1至3任一项所述的微胶囊，其中，所述肝细胞是人肝细胞、非人灵长类肝细胞、猪肝细胞、狗肝细胞、猫肝细胞、兔肝细胞、小鼠肝细胞或大鼠肝细胞。
5.如上述权利要求任一项所述的微胶囊，其中，所述微胶囊具有100至700μm的平均直径。
6.如权利要求1至5任一项所述的微胶囊，其中，所述肝细胞具有8至14μm的平均直径。
7.如上述权利要求任一项所述的微胶囊，其中，所述治疗有效量的肝细胞为104至108个肝细胞/ml悬液。
8.如上述权利要求任一项所述的微胶囊，其中，所述肝细胞刺激量的促红细胞生成素为10-7至10-2U/ml悬液，优选为10-7至10-3U/ml悬液。
9.如上述权利要求任一项所述的微胶囊，其中，所述促红细胞生成素是野生型促红细胞生成素或重组促红细胞生成素。
10.如上述权利要求任一项所述的微胶囊，其中，所述胶囊壳由选自藻酸盐、藻酸盐-壳聚糖(AC)、藻酸盐-聚L赖氨酸(APA)、热胶凝-聚合物和PEG-水凝胶组成的组中的生物相容性材料制成。
11.如上述权利要求任一项所述的微胶囊，其中，除所述肝细胞外，还有至少一种另外的细胞类型存在于所述微胶囊中。
12.如上述权利要求任一项所述的微胶囊，其中，所述微胶囊被包衣包覆。
13.如上述权利要求任一项所述的微胶囊，其中，所述微胶囊含有包埋所述肝细胞和所述促红细胞生成素的生物相容性基质。
14.一种制备上述权利要求任一项所述的微胶囊的方法，其包括：
a)提供治疗有效量的肝细胞悬液和肝细胞刺激量的促红细胞生成素，
b)混合所述肝细胞悬液和所述促红细胞生成素以使它们彼此物理接触，和
c)将所述肝细胞悬液和所述促红细胞生成素包囊于生物相容性胶囊壳材料中以形成所述微胶囊。
15.如权利要求14所述的方法，其中，将步骤c)中获得的所述微胶囊进行冷冻保存。
16.一种预防性或治疗性治疗具有相应需要的受治疗者中的肝脏疾病的方法，其包括将权利要求1至13任一项所述的微胶囊给药至所述受治疗者。
17.如权利要求16所述的方法，其中，所述肝脏疾病是肝炎、肝硬化、先天性代谢缺陷、急性肝衰竭、急性肝感染、急性化学毒性、慢性肝衰竭、胆管炎、胆汁性胆硬化、Alagille综合征、α1-抗胰蛋白酶缺乏症、自身免疫性肝炎、胆道闭锁、肝癌、肝脏囊性疾病、脂肪肝、半乳糖血症、胆结石、吉尔伯特综合征(Gilbert’s syndrome)、血色素沉着症、甲型肝炎、乙型肝炎、丙型肝炎和其他肝炎病毒感染、卟啉病、原发性硬化性胆管炎、瑞氏综合征(Reye’s syndrome)、结节病、酪氨酸血症、I型糖原贮积症或威尔森氏病。
18.如权利要求15至17任一项所述的方法，其中，通过在肝包膜下将所述微胶囊导入脾脏、肝脏、肝浆或脾动脉或门静脉而进行给药。
19.一种在受治疗者中导入肝细胞的方法，其包括将权利要求1至13任一项所述的微胶囊给药至所述受治疗者。
20.一种在培养基中培养肝细胞的方法，其包括在合适的培养基中培养权利要求1至13任一项所述的微胶囊。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956128A (en) * | 1984-05-25 | 1990-09-11 | Connaught Laboratories Limited | Droplet generation |
| US5084350A (en) * | 1990-02-16 | 1992-01-28 | The Royal Institution For The Advance Of Learning (Mcgill University) | Method for encapsulating biologically active material including cells |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5455790A (en) | 1977-10-05 | 1979-05-04 | Tomoyuki Tajima | Production of erythropoetin |
| JPS6045849B2 (ja) | 1980-08-25 | 1985-10-12 | 林原 健 | ヒトエリトロポエチンの製造方法 |
| NZ210501A (en) | 1983-12-13 | 1991-08-27 | Kirin Amgen Inc | Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence |
| IL77081A (en) | 1984-12-04 | 1999-10-28 | Genetics Inst | AND sequence encoding human erythropoietin, a process for its preparation and a pharmacological preparation of human erythropoietin |
| HUT73876A (en) | 1993-04-29 | 1996-10-28 | Abbott Lab | Erythropoietin analog compositions and methods |
| IL192290A0 (en) | 1993-08-17 | 2008-12-29 | Kirin Amgen Inc | Erythropoietin analogs |
| RU94030310A (ru) * | 1994-08-16 | 1996-08-10 | Молдавский научно-исследовательский институт профилактической и клинической медицины МЗ Республики Молдова (MD) | Способ культивирования клеток человека и животных |
| US6281015B1 (en) | 1994-12-16 | 2001-08-28 | Children's Medical Center Corp. | Localized delivery of factors enhancing survival of transplanted cells |
| MXPA05000858A (es) | 2002-07-19 | 2005-10-19 | Vesta Therapeutics Inc | Metodo de obtener celulas hepaticas humanas viables, incluyendo celulas hepaticas troncales/progenitoras. |
| RU2392314C2 (ru) * | 2003-12-30 | 2010-06-20 | Аугустинус БАДЕР | Способ регенерации ткани |
| WO2005094162A2 (en) * | 2004-03-30 | 2005-10-13 | Fac8Cell Pty Limited | Culture and use of cells that secrete liver secretory factors |
| CN101312736B (zh) * | 2005-10-21 | 2013-03-20 | 生命细胞产品有限公司 | 包囊体系 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956128A (en) * | 1984-05-25 | 1990-09-11 | Connaught Laboratories Limited | Droplet generation |
| US5084350A (en) * | 1990-02-16 | 1992-01-28 | The Royal Institution For The Advance Of Learning (Mcgill University) | Method for encapsulating biologically active material including cells |
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