CN115175981A - 细胞培养基材及其制备方法 - Google Patents
细胞培养基材及其制备方法 Download PDFInfo
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- CN115175981A CN115175981A CN202080097540.XA CN202080097540A CN115175981A CN 115175981 A CN115175981 A CN 115175981A CN 202080097540 A CN202080097540 A CN 202080097540A CN 115175981 A CN115175981 A CN 115175981A
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Abstract
提供一种细胞培养基材。本发明一实施例的细胞培养基材包括：基材，具有无孔表面；以及细胞培养涂层，覆盖上述无孔表面的至少一部分，上述细胞培养涂层由多个颗粒集合而形成表面的至少一部分，上述多个颗粒由功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白形成。据此，尽管包含有助于细胞培养的蛋白质样物质，也可以在常温下长期保存数年，因此具有非常优异的保存稳定性，同时使得有助于细胞培养的物质的活性保持原样或仅略微降低，从而能够以初始设计水平培养细胞。并且，对细胞培养基材具有优异的细胞粘附性，可以稳定地增殖粘附的细胞，因此可以实现高细胞培养效率，从而可广泛应用于干细胞等各种细胞培养。
Description
技术领域
本发明涉及一种细胞培养基材及其制备方法。
背景技术
近年来，随着培养细胞在疾病治疗方面的使用扩大，对细胞培养的兴趣和研究正在增加。细胞培养是从活体中采集细胞并在活体外培养的技术，培养的细胞分化成皮肤、器官、神经等身体的各种组织，然后移植到人体或在分化前状态下移植到人体内，以同时进行移植存活及分化，从而可应用于治疗各种疾病。
哺乳动物细胞的培养是生命科学和健康科学中的众多过程之一。作为用于培养及分析伴随固定-依赖性细胞的哺乳动物细胞的细胞培养基材，多使用例如由高分子聚合物或玻璃制成的孔-板等容器或薄膜等板，但需要额外的表面处理以使细胞粘附到容器或板表面。这种表面处理可以包括例如通过吸附、接枝或等离子体聚合技术在表面上形成吸附层或呈现适当的表面形状。或者，上述表面处理可以通过容器或板表面本身的化学改性，例如大气电晕、射频真空等离子体(radio frequency vacuum plasma)、直流(DC)辉光放电(glow discharge)及微波等离子体处理(microwave plasma treatments)等进行。
另一方面，目前用于培养、分化、交叉分化和重编程包括例如成体干细胞(adultstem cells，ASCs)、多能干细胞(Pluriopotent stem cell)在内的各种干细胞及体细胞的方法通常利用复杂环境，例如细胞外基质蛋白质或其他有助于细胞增殖的多种蛋白质，在固体基材表面上形成涂层，从而形成类似于细胞外基质的微环境，从而培养干细胞。
另一方面，上述涂层是通过简单地用包含上述各种蛋白质的溶液处理容器或板等细胞粘附表面之后干燥而成的，由于涂层内蛋白质的活性稳定性非常低，因此存在涂层形成后在常温下数小时内容易失去活性的问题，进而存在难以预先制备形成涂层的细胞培养基材，即使制备也必须在低温下保存，并且即使在低温下保存，保存天数也非常短，不到30天的问题。并且，由于保存稳定性如此差，因此通常在进行细胞加载工作之前在细胞粘附表面形成涂层，这给细胞细胞培养工作带来不便，并延长细胞培养前的准备时间。
发明内容
技术问题
本发明考虑到如上所述的问题而提出，其目的在于，提供一种如下细胞培养基材及其制备方法：可以在常温下长期保存数年，因此具有非常优异的保存稳定性，即便如此，也使有助于细胞培养的物质的活性保持原样或仅略微降低，从而能够以初始设计水平培养细胞。
并且，本发明的再一目的在于，提供一种如下细胞培养基材及其制备方法：具有优异的细胞粘附性，可以稳定地增殖粘附的细胞，因此可以实现高细胞培养效率。
进一步地，本发明的另一目的在于，提供一种如下细胞培养涂层组合物：能够实现如上所述的优异特性。
解决问题的手段
为了解决上述问题，本发明提供一种细胞培养基材，其包括：基材，具有无孔表面；以及细胞培养涂层，覆盖上述无孔表面的至少一部分，上述细胞培养涂层由多个颗粒集合而成，上述多个颗粒由功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白形成。
根据本发明的一实施例，上述功能性肽可以具有促进细胞的粘附、迁移、增殖及分化中的一种以上的功能。
并且，上述基材可以由选自由聚碳酸酯、聚苯乙烯、聚酰亚胺、聚酯、聚氨酯及玻璃组成的组中的一种以上材质形成。
并且，上述贻贝粘蛋白可以是选自由序列号1至序列号14的氨基酸序列组成的组中的一种蛋白质，或连接有选自上述组中的一种以上的氨基酸序列的蛋白质。
并且，上述功能性肽可以包含RGD序列。
并且，上述功能性肽可以是选自由序列号15至序列号18的氨基酸序列组成的组中的一种以上肽，或连接有选自上述组中的一种以上的氨基酸序列的肽。
并且，本发明提供一种细胞培养基材的制备方法，其包括：步骤(1)，准备包含碳二亚胺偶联剂及反应剂的活性溶液和功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白；步骤(2)，将准备的活性溶液与细胞培养用融合蛋白混合来制备细胞培养涂层组合物；以及步骤(3)，用细胞培养涂层组合物处理无孔细胞培养基材表面来形成细胞培养涂层。
根据本发明的一实施例，上述碳二亚胺偶联剂可以是1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)或N,N’-二环己基碳二亚胺(DCC)，上述反应剂可以是N-羟基琥珀酰亚胺(NHS)或N-羟基磺基琥珀酰亚胺(Sulfo-NHS)，更优选地，可以是N-羟基磺基琥珀酰亚胺(Sulfo-NHS)。
并且，上述碳二亚胺偶联剂和反应剂以1：0.1～10的重量比包含在活性溶液中，在上述细胞培养涂层组合物中，相对于100重量份的细胞培养用融合蛋白，可以混合1～100重量份的碳二亚胺偶联剂。
并且，本发明提供一种细胞培养涂层组合物，上述细胞培养涂层组合物在无孔细胞培养基材表面形成细胞培养涂层，包含功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白、碳二亚胺偶联剂及反应剂。
以下，对本发明所使用的术语进行描述。
本发明的“细胞外基质(extracellular matrix，ECM)”是包围细胞外部的基质，占据细胞与细胞之间，是指具有主要由蛋白质和多糖类组成的网状结构。
发明的效果
根据本发明的细胞培养基材尽管包含有助于细胞培养的蛋白质样物质，也可以在常温下长期保存数年，因此具有非常优异的保存稳定性，同时使得有助于细胞培养的物质的活性保持原样或仅略微降低，从而能够以初始设计水平培养细胞。并且，对细胞培养基材具有优异的细胞粘附性，可以稳定地增殖粘附的细胞，因此可以实现高细胞培养效率，从而可广泛应用于干细胞等各种细胞培养。
附图说明
图1及图2为本发明实施例1和实施例2的细胞培养基材表面的SEM(扫描电子显微镜)照片。
图3为本发明比较例的细胞培养基材表面的SEM照片。
图4至图7为本发明实施例的细胞培养基材表面的SEM照片。
图8及图9为拍摄通过本发明一实施例的细胞培养基材以及比较例的细胞培养基材的细胞培养结果的照片。
图10为在本发明一实施例的细胞培养基材中采用多种培养基后分泵培养4种细胞的结果的照片。
图11至图13为进行加速实验后细胞培养结果的照片，以评价本发明一实施例的细胞培养基材和比较例的细胞培养基材的保存稳定性。
具体实施方式
以下，参照附图对本发明的实施例进行说明，使得本发明所属技术领域的普通技术人员能够容易实施。但是，本发明能够以多种不同的方式实现，而不局限于在此所说明的实施例。
根据本发明一实施例的细胞培养基材包括：基材，具有无孔表面；以及细胞培养涂层，覆盖上述无孔表面的至少一部分，上述细胞培养涂层包含功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白。
上述基材是用于培养细胞的支撑体，所有基材可以是无孔基材，或者至少配置有细胞培养涂层的后述表面具有无孔性。并且，作为上述基材，可以使用细胞培养时通常使用的基材而没有限制。例如，上述基材可以是通常被称为孔板的容器形式的基材或薄膜等板状板，但不限于此。并且，作为上述基材的材质，可以使用常规细胞培养时使用的基材而没有限制，例如，可以由选自由聚碳酸酯、聚苯乙烯、聚酰亚胺、聚酯、聚氨酯及玻璃组成的组中的一种以上材质形成。
在上述基材中，待细胞培养涂层的表面可以是等离子体处理等公知的表面改性处理，但优选地，可以是未经过等离子体处理的表面。当后述的细胞培养涂层形成在未经过等离子体处理的基材表面时，与形成在经过等离子体处理的基材表面的情况相比，可以实现细胞培养效率上升的效果。
然后，对设置于上述基材表面上的细胞培养涂层进行说明。
上述细胞培养涂层是提供待培养的细胞在接种后置于其中并增殖的细胞粘附表面的层。上述细胞培养涂层形成为包含功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白，具体地，在上述细胞粘附表面设置有由上述细胞培养用融合蛋白形成的多个颗粒集合而成的细胞培养涂层。通过细胞培养用融合蛋白形成且涂层表面以多个颗粒集合的形式实现的细胞培养涂层在细胞培养效率方面非常优异，同时即使在常温下保存数年以上，也防止或最小化由于形成细胞培养涂层的细胞培养用融合蛋白分解、变性而引起的功能性肽的活性降低，从而具有保存稳定性显著提高的优点。并且，上述细胞培养涂层不使用聚合物类粘合剂成分，例如不是使用丙烯酸粘合剂成分，而是将功能性肽引入到细胞培养基材表面，因此没有细胞毒性，具有细胞细胞更具有生物相容性的优点。
上述细胞培养涂层通过功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白形成，上述功能性肽是一种具有有助于细胞培养的功能的物质，具体地，可以是执行促进细胞的粘附、迁移、增殖及分化中的一种以上功能的物质。作为上述功能性肽，可以使用执行这些功能的公知的肽，而没有限制。作为其非限制性示例，可以包括包含在选自由如下组成的组中的一种以上生长因子(GF)中的预定氨基酸序列：肾上腺髓质素(Adrenomedullin)、血管生成素(Angiopoietin)、骨形态发生蛋白(BMP)、脑源性神经营养因子(BDNF)、表皮生长因子(EGF)、红细胞生成素(Erythropoietin)、成纤维细胞生长因子(Fibroblast growthfactor)、胶质细胞源性神经营养因子(GDNF)、粒细胞集落刺激因子(Granulocyte colony-stimulating factor，G-CSF)、粒细胞巨噬细胞集落刺激因子(Granulocyte macrophagecolony-stimulating factor，GM-CSF)、生长分化因子-9(Growth differentiationfactor-9，GDF9)、肝细胞生长因子(HGF)、肝癌衍生生长因子(Hepatoma-derived growthfactor，HDGF)、胰岛素样生长因子(Insulin-like growth factor，IGF)、角质形成细胞生长因子(Keratinocyte growth factor，KGF)、迁移刺激因子(Migration-stimulatingfactor，MSF)、肌肉生长抑制素(Myostatin，GDF-8)、神经生长因子(Nerve growth factor，NGF)、血小板衍生生长因子(Platelet-derived growth factor，PDGF)、血小板生成素(Thrombopoietin，TPO)、T-细胞生长因子(T-cell growth factor，TCGF)、神经纤毛蛋白、转化生长因子-α(TGF-α)、转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)、血管内皮生长因子(VEGF)、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6及IL-7。或者，可以包括包含在选自由如下组成的组中的一种以上细胞外基质(extracellular matrix)中的预定氨基酸序列：透明质酸、硫酸肝素、硫酸软骨素、硫酸皮肤素、硫酸角质素、藻酸盐、纤维蛋白、纤维蛋白原、胶原、弹性蛋白、纤连蛋白、玻连蛋白、钙粘蛋白及层粘连蛋白。
例如，上述功能性肽可以包含氨基酸序列中的RGD序列。并且，上述功能性肽可以是选自由序列号15至序列号18的氨基酸序列组成的组中的一种以上肽或连接有选自上述组中的一种以上的氨基酸序列的肽。并且，上述功能性肽可以是玻连蛋白多肽、胶原多肽、层粘连蛋白多肽、纤连多肽或它们的变异体。
另一方面，上述功能性肽可以是例如具有3～100个氨基酸，更优选3～50个、例如3～30个氨基酸的肽，由此，即使在常温下以包含在涂层的状态长时间保存，也能够更有利于最小化或防止分解、变形等。
并且，上述功能性肽与贻贝粘蛋白结合，具体地，可以与贻贝粘蛋白的羧基末端、氨基末端或羧基末端和氨基末端这两端结合。在此情况下，上述结合为共价键，具体地，可以是氨基键。另一方面，功能性肽和贻贝粘蛋白可通过公知方法结合，例如，可以通过利用大肠杆菌的重组蛋白生产方法制备。另一方面，贻贝粘蛋白与功能性肽之间可以通过共价键直接结合，但不限于此，需要说明的是，可以通过介导诸如交联剂的预定物质来使贻贝粘蛋白与功能性肽之间间接结合。
将功能性肽与贻贝粘蛋白结合的原因是贻贝粘蛋白有利于将功能性肽固定在基材表面以提高粘附特性，并且如上所述，与上述聚合物基粘合剂成分相比，不会对培养细胞产生毒性，且生物相容性优异。并且，由于与接种的细胞之间的粘附特性优异，因此具有在将接种的细胞置于细胞粘附表面后可以最小化脱落的优点。
上述贻贝粘蛋白是从贻贝衍生的粘蛋白，可以使用统称为贻贝粘蛋白的公知粘蛋白而没有限制。优选地，上述贻贝粘蛋白可以是选自由序列号1至序列号14的氨基酸序列组成的组中的一种蛋白质或连接有选自上述组中的一种以上的氨基酸序列的蛋白质，例如，可以是序列号13。
并且，优选以适当的量形成颗粒，若聚集(aggregation)量大，即当粒径增加且颗粒数量减少时，存在细胞粘附及细胞增殖可能下降的隐患。
上述细胞培养涂层设置于基材表面的本发明一实施例的细胞培养基材可包括如下步骤来制备：步骤(1)，准备包含碳二亚胺偶联剂及反应剂的活性溶液和功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白；步骤(2)，将准备的活性溶液与细胞培养用融合蛋白混合来制备细胞培养涂层组合物；以及步骤(3)，用细胞培养涂层组合物处理无孔基材表面来形成细胞培养涂层。
首先，作为本发明的步骤(1)，执行准备包含碳二亚胺偶联剂及反应剂的活性溶液和功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白的步骤。
上述活性溶液包含碳二亚胺偶联剂和反应剂，还可以包含溶剂。活性溶液作为将细胞培养用融合蛋白引入基材表面的物质，与通过常规方法简单地用细胞培养用融合蛋白处理基材表面的情况相比，具有如下优点：提高细胞培养涂层与基材表面之间的粘附力，将细胞培养用融合蛋白凝集成颗粒状，受外部细菌感染的隐患少，即使温度变化也能够稳定地长期保存，并且细胞培养时偏差小。另一方面，很难看出由活性溶液诱导的融合蛋白凝集的颗粒形式是由融合蛋白之间的某种特定化学键，例如通过已知碳二亚胺偶联剂的羧基与胺基之间的氨基键引起的，这是因为贻贝粘蛋白中包含的多个羟基也可以与碳二亚胺偶联剂反应。因此，很难看出具有多个反应位点的本发明的融合蛋白所形成的颗粒形式是由某种特定反应及由此产生的化学键引起的，可以看作是根据活性溶液与本发明的融合蛋白之间的组合而发生的独特结果。
作为上述碳二亚胺偶联剂，可以使用允许融合蛋白之间相互结合的偶联剂而没有限制，例如，可以是1-[3-(二甲基氨基)丙基]-3-乙基碳亚胺盐酸盐(EDC)或N,N’-二环己基碳二亚胺(DCC)。
并且，具备上述反应剂是为了通过防止处于与碳二亚胺偶联剂偶联状态的融合蛋白水合，从而增加融合蛋白相互结合的效率，例如，可以是N-羟基磺基琥珀酰亚胺(Sulfo-NHS)。另一方面，在作为反应剂已知的N-羟基琥珀酰亚胺(NHS)的情况下，可能不易于实现本发明的期望效果。
上述活性溶液能够以1：0.1～10的重量比包含上述碳二亚胺偶联剂和反应剂。若不以适当比例包含它们，则难以实现本发明的期望效果，并且存在实现的细胞培养涂层中的细胞的粘附性显着降低的隐患。
并且，为了提高反应性，上述活性溶液还可以包含乙酸钠。在此情况下，相对于100重量份的碳二亚胺偶联剂，上述乙酸钠的含量可以是1～100重量份。
并且，上述活性溶液还可以包含溶剂，上述溶剂可以是水或有机溶剂，例如可以是水。
上述活性溶液的制备方法没有特别限制，但例如，将乙酸钠溶液分别放入碳二亚胺偶联剂溶液和反应剂溶液中，通过混合制备2种溶液后，以适当的比例混合2种溶液，然后诱导反应30～60分钟，然后在28～35℃恒温培养箱中再次反应25～40分钟来制备最终的活性溶液。
然后，作为本发明的步骤(2)，制造将准备的活性溶液与细胞培养用融合蛋白混合来制备细胞培养涂层组合物的步骤。
在此情况下，可以通过调节含量来混合上述细胞培养用融合蛋白和活性溶液，使得相对于100重量份的细胞培养用融合蛋白，包含1～100重量份的碳二亚胺偶联剂。若碳二亚胺偶联剂的含量小于1重量份，则细胞可能无法粘附或可能分化，若超过100重量份，则细胞可能在粘附后脱落，因此可能难以稳定培养细胞。
并且，将准备的活性溶液与细胞培养用融合蛋白混合后诱导反应大于0～2小时，即可制备成最终的细胞培养用涂层组合物。
然后，作为本发明的步骤(3)，执行用细胞培养涂层组合物处理无孔基材表面来形成细胞培养涂层的步骤。
用准备的细胞培养涂层组合物处理基材表面的方法可以采用常规涂布方法，例如，在孔板等基材的情况下，可以利用移液器进行分注。用细胞培养涂层组合物处理表面后，在4～60℃恒温培养箱中诱导反应大于0分钟～2小时，即可形成细胞培养涂层。
然后，可以进一步进行洗涤工序，例如，可以通过三次蒸馏水重复洗涤工序共2～5次，每次执行大于0分钟且小于或等于30分钟。在经过洗涤工序之后，可在空气中自然干燥，即可制备细胞培养基材。
下表1示出上述贻贝粘蛋白和功能性肽的氨基酸序列。
表1
本发明的实施方式
将通过以下实施例对本发明进行更具体的说明，但以下实施例并不用于限制本发明的范围，而是应解释为有助于理解本发明。
实施例1
准备了由无菌聚苯乙烯材质制成的6孔板作为基材。在此情况下，准备了未经过等离子体处理的6孔板。然后利用移液器将以下准备例中制备的细胞培养涂层组合物以每孔2ml进行分注，然后在恒温培养箱中进行反应来在基材表面形成细胞培养涂层。然后，利用三次蒸馏水洗涤3次，每次10分钟后，在洁净工作台中打开板盖并在空气中干燥，从而制备细胞培养基材。
*准备例-细胞培养涂层组合物的制备
通过使序列号15的功能性肽与序列号13贻贝粘蛋白的羧基末端的氨基末端结合来准备了细胞培养用融合蛋白。在此情况下，通过利用大肠杆菌的重组蛋白生产方法制备了融合蛋白。
另一方面，为了准备活性溶液，首先制备溶解在三次蒸馏水中的NaOAc、NaHCO3、2-(N-吗啉代)乙磺酸(2-(N-morpholino)ethanesu lfonic acid)溶液，然后分别放入分别分注有EDC和Sulfo-NHS试剂的微管中来制备EDC溶液和Sulfo-NHS。
为了制备细胞培养涂层组合物，将EDC溶液放入锥形管中，加入Sulfo-NHS溶液，在搅拌下将细胞培养用融合蛋白放入准备的活性溶液中，然后通过搅拌来制备细胞培养涂层组合物。在此情况下，相对于100重量份的细胞培养用融合蛋白，细胞培养涂层组合物包含1重量份的EDC，EDC和Sulfo-NHS以1：2的重量比混合，相对于100重量份的EDC，涂层组合物中包含的NaOAc的含量为100重量份。在此情况下，细胞培养涂层组合物中的细胞培养用融合蛋白的浓度为0.05㎎/ml。
实施例1的细胞培养涂层的表面SEM照片如图1所示，可以确认细胞培养涂层是由颗粒集合而成的。
实施例2
以与实施例1相同的方式实施来制备，但不同之处在于，将细胞培养用融合蛋白变更为使序列号19的功能性肽与序列号14的贻贝粘蛋白的羧基末端的氨基末端结合的细胞培养用融合蛋白来制备了细胞培养基材。实施例2的细胞培养涂层的表面SEM照片如图2所示，可以确认细胞培养涂层是由颗粒集合而成的。
比较例1
以与实施例1相同的方式实施来制备，但不同之处在于，将未涂布细胞培养涂层组合物且未经过等离子体处理的6孔板用作细胞培养基材。比较例2的细胞培养涂层的表面SEM照片如图3所示，可以确认具有平滑表面。
实施例3
以与实施例2相同的方式实施来制备，但不同之处在于，将细胞培养用融合蛋白变更为使序列号19的功能性肽与序列号14的贻贝粘蛋白的羧基末端的氨基末端结合的细胞培养用融合蛋白，细胞培养基材的材质变更为聚碳酸酯材质来制备细胞培养基材。实施例3的细胞培养涂层的表面SEM照片如图4所示，即使变更被覆基材的材质，也可以确认细胞培养涂层是由颗粒集合而成的。
实施例4～6
以与实施例1相同的方式实施来制备，但不同之处在于，使用通过将细胞培养涂层组合物中的细胞培养用融合蛋白的浓度分别变更为0.01㎎/ml、0.1㎎/ml、0.5㎎/ml而制备的细胞培养涂层组合物来制备细胞培养基材。实施例4至6的细胞培养涂层的表面SEM照片分别如图5、图6及图7所示，可以确认，随着细胞培养用融合蛋白的浓度的增加，形成的颗粒的粒径变大，粒子数量减少，根据粒子之间的结合，形成具有不规则颗粒形状的巨大颗粒。
比较例2
以与实施例1相同的方式实施来制备，但不同之处在于，使用相同浓度的序列号15的功能性肽代替细胞融合蛋白来制备细胞培养基材。
实验例1
将等量的诱导多能干细胞分注到实施例1及比较例2的细胞培养基材中，然后利用干细胞培养基(StemMACSTM)培养5天，然后使用细胞染色法观察细胞培养情况，细胞培养结果照片如图8及图9所示。
从图8可以确认，实施例1的细胞培养基材中细胞粘附和生长优异，但图9的比较例2的细胞培养基材中细胞未能正常粘附和生长。
实验例2
将hiPSC-1、hESO、hiPSC-2、hiPSC-3分注到实施例1的细胞培养基材上的每个培养基中，然后利用mTeSR1TM、TeSR2TM、StemMACSTM、E8TM培养基培养5天，然后使用细胞染色法观察细胞培养情况，细胞培养结果照片如图10所示。
从图10可以确认，实施例1的细胞培养基材适用于多种细胞培养，与多种培养基的相容性也很优异。
比较例3～4
根据制造商的方案，通过将作为细胞培养用涂层组合物市售中的Matrigel、Vitronectin-XFTM涂布在由作为基材的无菌聚苯乙烯材质制成的6孔板中来制备细胞培养基材。
实验例3
通过以下方法，将实施例1、比较例3及比较例4的细胞培养基材按照医疗器械保质期和稳定性评价的指南进行加速老化试验，然后培养诱导多能干细胞来评价保存稳定性。
具体地，为了在缩短的时间内重现细胞培养基材的实时老化，在高温(60℃)下将细胞培养基材保存0个月、1个月、2个月、3个月，并将细胞培养基材准备为使其老化期为0年、1年、2年、3年。
将等量的诱导多能干细胞分注到每个实施例及比较例中分别准备的4个细胞培养基材中，然后利用干细胞培养基(StemMACSTM)培养5天后，用光学显微镜拍摄来观察细胞培养情况，细胞培养结果照片如图11(实施例1)、图12(比较例3)及图13(比较例4)所示，对培养的细胞数量进行计数来示于下表2中。
表2
从图11至图13及表2可以确认，
在实施例1的细胞培养基材的情况下，即使将老化期加速至0年、1年、2年、3年，也可知均可以培养细胞，并且细胞培养性能优异。但是在比较例3的情况下，老化期为0年时细胞培养性能优异，但在将老化期加速至1年～3年的试片中未培养细胞。并且，在比较例4的情况下，在加速至0年～3年的试片中培养细胞，但与实施例1的试片相比，培养的细胞数量显着减少，由此可知实施例1的细胞培养基材的保存稳定性及细胞培养性能非常优异。
以上，对本发明的一实施例进行了说明，但本发明的思想不限于本说明书所提出的的实施例，理解本发明思想的本领域技术人员可在相同思想范围内，通过结构要素的附加、变更、删除、增加等可以容易地提出其他实施例，但这也将落入本发明的思想范围内。
序列表
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Claims (10)
1.一种细胞培养基材，其特征在于，包括：
基材，具有无孔表面；以及
细胞培养涂层，覆盖上述无孔表面的至少一部分，
上述细胞培养涂层由多个颗粒集合而成，上述多个颗粒由功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白形成。
2.根据权利要求1所述的细胞培养基材，其特征在于，上述功能性肽具有促进细胞的粘附、迁移、增殖及分化中的一种以上的功能。
3.根据权利要求1所述的细胞培养基材，其特征在于，上述基材由选自由聚碳酸酯、聚苯乙烯、聚酰亚胺、聚酯、聚氨酯及玻璃组成的组中的一种以上材质形成。
4.根据权利要求1所述的细胞培养基材，其特征在于，上述贻贝粘蛋白为选自由序列号1至序列号14的氨基酸序列组成的组中的一种蛋白质，或连接有选自上述组中的一种以上的氨基酸序列的蛋白质。
5.根据权利要求1所述的细胞培养基材，其特征在于，上述功能性肽包含RGD序列。
6.根据权利要求1所述的细胞培养基材，其特征在于，上述功能性肽为选自由序列号15至序列号18的氨基酸序列组成的组中的一种以上肽，或连接有选自上述组中的一种以上的氨基酸序列的肽。
7.一种细胞培养基材的制备方法，其特征在于，包括：
步骤(1)，准备包含碳二亚胺偶联剂及反应剂的活性溶液和功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白；
步骤(2)，将准备的活性溶液与细胞培养用融合蛋白混合来制备细胞培养涂层组合物；以及
步骤(3)，用细胞培养涂层组合物处理无孔基材表面来形成细胞培养涂层。
8.根据权利要求7所述的细胞培养基材的制备方法，其特征在于，上述碳二亚胺偶联剂为1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐或N,N’-二环己基碳二亚胺，上述反应剂为N-羟基磺基琥珀酰亚胺。
9.根据权利要求7所述的细胞培养基材的制备方法，其特征在于，
上述碳二亚胺偶联剂和反应剂以1：0.1～10的重量比包含在活性溶液中，
在上述细胞培养涂层组合物中，相对于100重量份的细胞培养用融合蛋白，混合1～100重量份的碳二亚胺偶联剂。
10.一种无孔细胞培养基材用细胞培养涂层组合物，上述细胞培养涂层组合物在无孔细胞培养基材表面形成细胞培养涂层，其特征在于，包含功能性肽与贻贝粘蛋白结合的细胞培养用融合蛋白、碳二亚胺偶联剂及反应剂。
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| US7198855B2 (en) * | 2003-09-12 | 2007-04-03 | Becton, Dickinson And Company | Methods of surface modification of a flexible substrate to enhance cell adhesion |
| US9499593B2 (en) * | 2011-05-11 | 2016-11-22 | Children's Medical Center Corporation | Modified biotin-binding protein, fusion proteins thereof and applications |
| KR101384746B1 (ko) * | 2011-08-24 | 2014-04-14 | 포항공과대학교 산학협력단 | 홍합 접착 단백질을 이용한 다양한 기능성 생체분자의 표면 고정화 |
| KR101311325B1 (ko) | 2012-09-13 | 2013-09-30 | 이상재 | 합성 디자인된 3차원 미세환경 구조물 |
| KR101665941B1 (ko) | 2014-09-25 | 2016-10-17 | 한국생산기술연구원 | 패트리접시의 표면처리방법 및 이 방법으로 제조된 패트리접시 |
| JP6758616B2 (ja) * | 2016-02-23 | 2020-09-23 | 国立大学法人 新潟大学 | 細胞培養方法及び培養組織 |
| KR101856575B1 (ko) * | 2016-05-25 | 2018-06-19 | 주식회사 아모그린텍 | 세포배양 지지체용 원사 및 이를 포함하는 원단 |
| KR102119514B1 (ko) * | 2016-05-31 | 2020-06-05 | 주식회사 아모라이프사이언스 | 세포배양용 또는 조직공학용 지지체 |
| CN111065727B (zh) * | 2017-07-13 | 2023-09-12 | 阿莫生命科学有限公司 | 细胞培养容器 |
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2020
- 2020-12-27 US US17/788,868 patent/US20230340402A1/en active Pending
- 2020-12-28 JP JP2022539438A patent/JP7594306B2/ja active Active
- 2020-12-28 CN CN202080097540.XA patent/CN115175981A/zh active Pending
- 2020-12-28 KR KR1020200184988A patent/KR102486926B1/ko active Active
- 2020-12-28 WO PCT/KR2020/019213 patent/WO2021133142A1/ko unknown
- 2020-12-28 EP EP20905500.3A patent/EP4095225A4/en active Pending
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|---|---|
| EP4095225A1 (en) | 2022-11-30 |
| WO2021133142A1 (ko) | 2021-07-01 |
| KR102486926B1 (ko) | 2023-01-10 |
| US20230340402A1 (en) | 2023-10-26 |
| JP2023508476A (ja) | 2023-03-02 |
| KR20210084329A (ko) | 2021-07-07 |
| EP4095225A4 (en) | 2024-01-17 |
| JP7594306B2 (ja) | 2024-12-04 |
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