CN102307596A - 伤口愈合用水凝胶细胞传送载体及其制备方法 - Google Patents
伤口愈合用水凝胶细胞传送载体及其制备方法 Download PDFInfo
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- CN102307596A CN102307596A CN2009801434363A CN200980143436A CN102307596A CN 102307596 A CN102307596 A CN 102307596A CN 2009801434363 A CN2009801434363 A CN 2009801434363A CN 200980143436 A CN200980143436 A CN 200980143436A CN 102307596 A CN102307596 A CN 102307596A
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Abstract
本发明涉及一种伤口愈合用水凝胶细胞传送载体组合物及其制备方法，更具体地涉及非离子表面活性剂及成长因子或P物质、人体派生细胞等分散在水性介质中形成的水凝胶细胞传送载体组合物，其伤口愈合用途及其制备方法。本发明的水凝胶组合物能将P物质和/或细胞适当传送到伤口部位，有润湿效果及抑制伤口收缩(contraction)的效果及保护细胞的效果，还有使用简单且方便的优点。因此，身体部分损伤时，通过涂布或注射本发明的组合物，使组合物中的细胞传送到损伤部位，有效治愈伤口。
Description
技术领域
本发明涉及愈合伤口用的水凝胶细胞传送载体组合物及其制备方法，更具体地涉及非离子表面活性剂、成长因子或P物质及人体派生细胞等分散在水性介质中而形成的水凝胶细胞传送载体组合物及其伤口愈合用途及其制备方法。
背景技术
长期以来，许多人进行过关于身体组织受损伤时细胞重建的研究，比如通过药物的组织重建、利用细胞的组织重建等。但重要问题之一是如何将这些药物及细胞以什么组成方式如何传送到受损组织。传送这种药物与细胞的方法，包括：简单的使用溶液状态，或进一步使用如胶原的生物材料的片、海绵、无纺布的形态，也会使用纤维素粘合剂。
P物质(substance-p)是由11种氨基酸组成的神经肽，据报告发现于一些细胞及肉芽组织中。据一些研究报告P物质有助于重建损伤的角膜组织中的角膜。这些，由于是使用单纯的溶液状态，因此具有不能在组织损伤部位停留太久的缺点。
目前以几种多样的形态使用利用细胞的组织重建。片状是以片(sheet)状培养皮肤、软骨、心血管等的细胞并运用于受损部位，因从培养皿中以片状分离出来，从而由于酶(enzyme)引起的细胞损伤，被指出具有干扰细胞分裂能力的缺点。由于这些问题，而使得程序简单且能轻易植入移植困难部位的细胞悬浮液(suspension)形态备受瞩目。但是，细胞悬浮液也具有不能停留在组织受损部位而流动的缺点，因此要与如纤维素(fibrin)等的生物粘合剂一起使用。因此需要一种不妨碍细胞植入于受损部位且能稳定适用的方法。
非离子表面活性剂虽然溶于水后不会离子化，但由于具有良好的润湿性且刺激性小，因此作为化妆水的增溶剂、面霜的乳化剂及洁面霜的洗涤剂而被使用。而且，部分非离子表面活性剂还可以使用为医疗附庸剂。虽然非离子表面活性剂对细胞毒性小、物性好，但由于存在其阻碍细胞附着能力的认识，而被认为无法用作细胞治疗剂的载体。
根据非离子表面活性剂的亲油基与亲水基的程度不同，其溶解度、润湿力、渗透力、乳化力及增溶能力等性质也不同。利用这些特性，能根据药物及细胞的类型和受损组织的位置，利用非离子表面活性剂的类型、调节浓度及添加合适的生物材料等可以轻松制备出合适的组合物。
公开的现有的技术有包含骨髓间充质干细胞和/或P物质的愈合伤口用组合物(韩国专利公布第10-2006-0037176号)。但是，上述专利以一种物质或混合两种物质，容易脱离伤口部位，难以达到其效果，且使用不便。因此，需要将这些组合物适当传送到伤口部位的方法。
本发明的发明人在研究如何有效地传送细胞的方法的过程中，使用虽然用于整个产业中、但未被用于细胞治愈等的非离子表面活性剂制备出水凝胶组合物进行试验的结果，发现其很适合用于细胞传送。
本发明的发明人发现以含有IGF或P物质的水凝胶处理的受伤老鼠相比未以水凝胶处理的老鼠其伤口治愈更快；使用含有骨髓间充质干细胞的水凝胶处理的老鼠相比没有用水凝胶处理的老鼠其伤口愈合更快；使用含有皮肤细胞的水凝胶处理的老鼠相比没有用水凝胶处理的老鼠其伤口愈合更快。因此，本发明的发明人发现了水凝胶作为细胞传送载体的新用途而完成了本发明。
发明内容
由此，本发明的主要目的是提供使用非离子表面活性物制成的水凝胶细胞传送载体组合物。
本发明另一目的是提供除上述的非离子表面活性剂外，还包含成长因子、P物质或细胞等的愈合伤口用水凝胶组合物。
本发明再一目的是提供所述本发明组合物的制备方法。
根据本发明的一个实施方式，本发明提供非离子表面活性剂分散于水介质而形成的水凝胶细胞传送(delivery)载体组合物。
一般来说，水凝胶是指亲水性高分子由共价键和非共价键架桥而成的三维网状结构物。虽然根据组成物质的亲水性，在水溶液内及水环境下吸收大量水而膨胀，但因其架桥结构而具有不溶于水的性质。本发明中，水凝胶由作为一种亲水性高分子的非离子表面活性剂分散于水介质内制备而成的。
本发明中，细胞传送(delivery)是指将组合物中的细胞以治愈伤口为目的传送到适用部位如皮肤等人体，此时所述组合物起到装载细胞载体或媒介的作用。
在本发明的组合物中，所述水介质(aqueous medium)可以是对人体无害且使亲水性非离子表面活性剂得以分散的任何水介质，但优选的是选自生理盐水、磷酸盐缓冲液(PBS)及细胞培养液。
在本发明组合物中，虽然所述非离子表面活性剂没有带电荷的部分，但是由羟基或环氧乙烷基的引起的、和水产生的氢键而具有亲水性。非离子表面活性剂可以用例如高价醇，如烷基酚的环氧乙烷附属物聚乙二醇(Polyethylene glycol)衍生物、甘油(glycerine)、季戊四醇(pentaerytritol)、山梨醇(sorbitol)、蔗糖(saccharose)等的羟基(polyhydroxy)化合物部分酯类反应的多元醇(polyol)衍生物等。优选的是缩合型聚乙二醇，例如选自聚乙二醇脂肪酸缩合物(Niosol，Myrj)、聚乙二醇脂肪酸酰胺缩合物、聚乙二醇脂族醇缩合物(Leonil，Peregal C)、聚乙二醇脂族胺缩合物、聚乙二醇脂族硫醇缩合物(Nyon 218)、烷基酚聚乙二醇缩合物(Igepal)及聚乙二醇与聚丙二醇缩合物(Pluronics)或由其混合物，其特征在于，更加优选的是聚乙二醇与聚丙二醇缩合物的泊洛沙姆(Poloxamer，Pluronic)。
本发明中非离子表面活性剂的烃链长为5000-20000分子量(MW)，EO的附加摩尔数优选的是50-80wt％。若烃链长过短，则不能充分形成网状结构；若过长，则不容易分散在水介质中。若EO的附加摩尔数过多，则不能形成胶；若过少，则亲水性减少。
在本发明组合物中，其特征在于所述非离子表面活性剂对水介质以15-50％重量比混合分散。若上述非离子表面活性剂的重量比(浓度)过低，则水凝胶不好形成；若过高，则不容易溶解在水介质中。
在本发明组合物中，其特征在于所述水凝胶还包含选自助伤口治愈的IGF、bFGF、EGF及GMCSF的成长因子或P物质(Substance-P)。所述成长因子或P物质在本发明组合物中有促进上皮细胞移动和成纤维细胞增殖的作用。
在本发明组合物中，其特征在于上述水凝胶还包含选自助伤口愈合用的胶原蛋白(Collagen)、透明质酸(Hyaluronic acid)、糖胺(Glycosaminoglycanes)、纤维连接蛋白(Fibronectin)或其混合物组成的群中的细胞间质(ECM)。所述细胞间质在本发明组合物中有增加细胞附着能力促进伤口治愈的作用。
本发明组合物中，其特征在于所述水凝胶还包含选自助愈合伤口用的所甲基纤维素(Carboxymethyl cellulose)、海藻酸钠(Alginate)、壳聚糖(Chitosan)、聚己内酯(Poly(e-caprolactone))、聚乳酸(Poly(lacticacid))、聚乙醇酸(Poly(glycolic acid))、羟基磷灰石(Hydroxyapatite)、磷酸三钙(Tricalcium phosphate)的生物材料，或由其混合物的生物材料(Biomaterials)。上述生物材料在本发明组成中有提升水凝胶的物性及提升生物相容性的作用。
本发明组合物中，其特征在于所述水凝胶还包含细胞。包含在所述组合物的细胞传送到人体适用部位用于治愈伤口等。所述细胞可以为例如皮肤角质细胞、成纤维细胞、色素细胞、骨髓间充质干细胞、间质干细胞、造血干细胞、骨髓细胞、神经细胞、上皮细胞或其混合物等。
在本发明组合物中，其特征在于所述细胞传送助治愈伤口。本发明中，治愈伤口是指治疗或缓解细胞损伤引起的伤口。由本发明组合物传送的细胞代替或补充伤口部位受损细胞而治愈伤口。
由于本发明组合物制备成水凝胶，因此可以直接涂布在伤口部位或由注射器等注入。上述组合物可以与在细胞治疗中常用的药剂学载体一起注入，这类载体例如为生理盐水。
为治愈伤口以治疗有效量使用本发明的组合物。术语“治疗有效量(therapeutically effective amount)”是指医学治疗中适用的合理受惠/危险比率能治疗疾病的充分含量，有效量要根据疾病的严重程度、年龄、性别、注入时间、注入途径及排放率，包括治疗期间同时使用的药物及其他医学领域公知的因素来决定。重要的是，斟酌上述所有要素，在无副作用的前提下使用最小量取得最大效果，本领域的普通技术人员能够容易确定，比如说，成人标准是一次使用本发明组合物1mg到1000mg。基于细胞比如说一次注入3×104到3×107细胞/kg的MSC。
本发明的实施例中，本发明组合物将成长因子、P物质和/或细胞适当传送到伤口部位，证明有润湿效果、防止伤口收缩(contraction)的效果(图2至图8)及保护细胞的效果(图9)。本发明的组合物还有使用简单方便的优点。而且，可以预见本发明组合物的非离子表面活性剂中混合胶原之类的生物材料就可以产生协同效应。最优选的是，本发明水凝胶的组合物可以将生理盐水或细胞培养液、非离子表面活性剂和生物材料适当混合而制成。
附图说明
图1是在20％、25％及30％浓度中随普朗尼克(Pluronic)F127的温度(15℃-30℃)而产生的粘度变化示意图；
图2是使用7天含有P物质(Substance-p)的水凝胶在后肉眼观察的结果示意图，其中(a)为对照群、(b)为实验群；
图3是使用14天含有骨髓间充质干细胞的水凝胶后肉眼观察的结果示意图，其中(a)为对照群、(b)为实验群；
图4是使用14天含有骨髓间充质干细胞的水凝胶后组织学观察的结果示意图，其中(a)为对照群、(b)为实验群；
图5是使用7天含有皮肤细胞的水凝胶后肉眼观察的结果示意图，其中(a)为对照群、(b)为实验群；
图6是使用7天含有皮肤细胞的水凝胶后组织学观察的结果示意图，其中(a)为对照群、(b)为实验群；
图7是使用7天含有IGF的水凝胶后肉眼观察的结果示意图，其中(a)为对照群、(b)为实验群；
图8是使用7天含有IGF的水凝胶后组织学观察的结果示意图，其中(a)为对照群、(b)为实验群；
图9是水凝胶皮肤细胞的稳定性实验结果示意图。
具体实施方式
下面，结合实施例对本发明进行详细说明。这些实施例仅用于说明本发明，并不用于限定本发明的保护范围。
实施例1
50μl的生理盐水中混入12pmole的P物质及100mg普朗尼克F127(BASF公司)制备水凝胶。Balb/c裸鼠(雄性，5周龄)的背上做出直径8mm的伤口后，使用制备的水凝胶。对照群使用了生理盐水。第7日肉眼比较了鼠背上的伤口。图2是使用7日含有P物质的水凝胶后肉眼观察的结果。肉眼观察对照群(a)和实验群(b)的结果，实验群相比于对照群具有润湿效果及抑制伤口收缩的效果，促进伤口治愈。
10ml的生理盐水中各溶解2g、2.5g及3g普朗尼克F127，制备20％、25％以及30％的水凝胶。用流变仪(CVO，BOHLIN Instruments)观察该水凝胶随温度(15℃-30℃)产生的粘度变化。图1是20％、25％及30％的浓度随普朗尼克F127的温度(15℃-30℃)产生粘度变化的结果示意图。可知水凝胶的特性随着非离子表面活性剂的浓度而变化。为组织再生而注入生物体时，随着温度能改变粘度的浓度更为有利，但是涂布或者附着在外部时随温度变化的粘度没什么作用。
实施例2
50μl骨髓间充质干细胞(mesenchymal stem cells，简称为MSC)培养液(MSCGM)中混合1×106个骨髓间充质干细胞及100mg普朗尼克F127制备水凝胶。Balb/c裸鼠(雄性，5周龄)的背上做出直径8mm的伤口后使用制备的水凝胶。对照群使用了生理盐水。使用后第6日，再使用相同组合物的水凝胶，第一次使用后第14日肉眼比较鼠背上的伤口再进行组织学观察。图3是使用14天含有骨髓间充质干细胞的水凝胶后肉眼观察的结果的示意图，其中(a)为对照群、(b)为实验群。图4是使用14天含有骨髓间充质干细胞的水凝胶后组织学观察的结果示意图，其中(a)为对照群、(b)为实验群。从肉眼观察的结果可知，实验群对比于对照群有润湿效果及抑制伤口收缩的效果，促进伤口愈合。而且，根据组织学观察的结果可知，实验群的表皮层和真皮层形成得更好。
实施例3
50μl皮肤细胞培养液(DMEM)中混合5×105个皮肤细胞(成纤维细胞、角质细胞及色素细胞)及100mg普朗尼克F127制备水凝胶。Balb/c裸鼠(雄性，5周龄)的背上做出直径8mm的伤口后，使用制备的水凝胶。第7日肉眼观察鼠背上的伤口再进行组织学观察。图5是使用7天含有皮肤细胞的水凝胶后肉眼观察的结果示意图，其中(a)为对照群、(b)为实验群。图6是使用7天含有皮肤细胞的水凝胶后组织学观察的结果示意图，其中(a)为对照群、(b)为实验群。从肉眼观察结果可知，实验群对比于对照群具有润湿效果及抑制伤口收缩的效果，促进伤口愈合。而且，根据组织学观察的结果可知，实验群的表皮层和真皮层形成得更好。
实施例4
50μl生理盐水中混合25μl/ml的IGF(Insuline like Growth factor)及100mg普朗尼克F127(BASF公司)制备水凝胶。在Balb/c裸鼠(雄性，5周龄)的背上做出直径8mm的伤口后使用制备的水凝胶。对照群使用了生理盐水。第7日肉眼比较鼠背上的伤口。图7是使用7天含有IGF的水凝胶后肉眼观察的结果的示意图，其中(a)为对照群、(b)为实验群。图8是使用7天含有IGF的水凝胶后组织学观察的结果的示意图，其中(a)为对照群、(b)为实验群。从肉眼观察结果可知，实验群对比于对照群具有润湿效果及抑制伤口收缩的效果，促进伤口愈合。而且，根据组织学观察的结果可知实验群的表皮层和真皮层形成得更好。
实施例5
96孔板(well plate)上接种2×104个皮肤细胞(成纤维细胞、角质细胞及色素细胞)，放入37℃孵化器里培育16小时。去掉培养液，各孔的水凝胶按浓度大小稀释放入到皮肤细胞培养液中，作为阴性对照群放入100μl 2.5mM EDTA。在4℃反应16小时后，去除。1∶9混合MTT溶液和细胞培养液在37℃反应4小时，用PBS洗涤后，与DMSO和乙醇1∶1混合的溶液搅拌20分钟，在540nm测OD值。图9是水凝胶皮肤细胞的稳定性实验结果的示意图。4℃下的细胞稳定性因添加了水凝胶的而相比对照群(DMEM)增加，特别是添加20％、25％时细胞稳定性相比对照群增加了约1.5倍。
如上所述，本发明的水凝胶组合物将成长因子，P物质和/或细胞适当地传送到伤口部位，具有润湿效果及抑制伤口收缩的效果(图2至图8)及保护细胞的效果(图9)，有使用简单方便的优点。因此，在身体部分损伤时，将本发明的组合物通过涂布或注射，使组合物中的细胞传送到损伤部位，能够有效愈合伤口。
Claims (11)
1.一种水凝胶细胞传送载体组合物，其中所述水凝胶细胞传送载体组合物是非离子表面活性剂分散于所述水介质中形成的。
2.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述水介质选自生理盐水、磷酸盐缓冲液及细胞培养基。
3.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述非离子表面活性剂选自聚乙二醇脂肪酸缩合物、聚乙二醇脂肪酸酰胺缩合物、聚乙二醇脂族醇缩合物、聚乙二醇脂族胺缩合物、聚乙二醇脂族硫醇缩合物、烷基酚聚乙二醇缩合物及聚乙二醇与聚丙二醇缩合物或其混合物。
4.根据权利要求3所述的水凝胶细胞传送载体组合物，其特征在于所述非离子表面活性剂为聚乙二醇与聚丙二醇缩合物的泊洛沙姆。
5.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述非离子表面活性剂相比水介质以15-50％重量比混合且分散。
6.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述水凝胶还包括助治愈伤口的成长因子或P物质，其中所述成长因子选自IGF、bFGF、EGF及GMCSF。
7.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述水凝胶还包括细胞间质，其中所述细胞间质选自愈合伤口用的胶原蛋白、透明质酸、糖胺、纤维连接蛋白或其混合物。
8.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述水凝胶还包括助愈合伤口用的生物材料，其中所述生物材料选自所甲基纤维素、海藻酸钠、壳聚糖、聚己内酯、聚乳酸、聚乙醇酸、羟基磷灰石、磷酸三钙或其混合物。
9.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述水凝胶还包括细胞。
10.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述细胞选自皮肤角质细胞、成纤维细胞、色素细胞、骨髓间充质干细胞、间质干细胞、造血干细胞、骨髓细胞、神经细胞、上皮细胞或其混合物。
11.根据权利要求1所述的水凝胶细胞传送载体组合物，其特征在于所述细胞传送是用于治愈伤口。
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| PCT/KR2009/006425 WO2010062059A2 (ko) | 2008-11-03 | 2009-11-03 | 상처 치유를 위한 하이드로 겔 형태의 세포전달용 비히클 및 그 제조방법 |
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| KR101101321B1 (ko) | 2012-01-02 |
| JP2012507510A (ja) | 2012-03-29 |
| WO2010062059A2 (ko) | 2010-06-03 |
| KR20100049341A (ko) | 2010-05-12 |
| WO2010062059A3 (ko) | 2010-08-19 |
| US20110256089A1 (en) | 2011-10-20 |
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