CN1700915A - 生物的皮肤修复和增强 - Google Patents

生物的皮肤修复和增强 Download PDF

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CN1700915A
CN1700915A CNA038199637A CN03819963A CN1700915A CN 1700915 A CN1700915 A CN 1700915A CN A038199637 A CNA038199637 A CN A038199637A CN 03819963 A CN03819963 A CN 03819963A CN 1700915 A CN1700915 A CN 1700915A
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skin
sarcoplast
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serum
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彼得·K·罗
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Abstract

本发明提供了用于整修皮肤的肌细胞材料和方法。通过去除死细胞准备皮肤表面，并将成肌细胞添加到细胞营养液中。一个实施方案提供了来自将被处理的个体的自体的人成肌细胞、来自所述个体的血清以及用于刺激血管形成的血管生成因子。大6硫酸软骨素可用于所述成肌细胞的受控的快速细胞融合。也可以单独地或与成肌细胞组合地使用包皮成纤维细胞的悬浮液。在另一个实施方案中，可以将具有影响外源识别的双剔除突变的另一动物如猪的非免疫原性细胞添加到细胞表面。

Description

生物的皮肤修复和增强
本申请要求2002年8月23日提交的序号为60/405,301的美国临时申请的优先权，其全部在此引入，作为参考。
技术领域
本发明总的来说涉及皮肤的修复，更具体地说涉及使用活细胞来修复和/或增强皮肤。
背景技术
随着岁月流逝，皮肤自然衰老。阳光的作用加速老化，该过程被称为光老化，而且暴露于风、盐和其他因素也加速老化。随着老化，皮肤拥有或表现出各种问题，包括线纹、皱纹、缺乏坚实性和弹性、粗糙、不均匀角质层、老年斑和光线性角化病。
通过用不透明的化妆膜或涂层掩盖缺陷来暂时地增强皮肤的外观的化妆品已经使用了数千年。自古以来人们就知道或尝试了可改善裸露的、未经修饰的皮肤的质量和外观而非仅仅掩盖缺陷的处理。使用水果或乳酸、或醋漂洗的处理方法，如果长期一贯地保持的话，在暂时地阻止某些可见的老化效果方面或许已是成功的。近年来，人们在寻找对于老化皮肤难题的有效处理方法，并且存在着巨大且正在增长的、为老化皮肤的外观有效地提供结构改善的产品和服务的市场。
一类为皮肤提供结构改善的产品是皮肤更新酸(skin renewal acids)，尤其是α-羟基酸和视黄酸，或它们的酯。这些酸、酸性化合物或酯不是作用于细胞内就是作用于细胞间以刺激皮肤细胞增殖。在授予Yu和Van Scott的各种专利中公开了一些利用皮肤更新酸的处理方法，这些专利包括，例如，美国专利No.4,363,815、No.5,091,171和No.5,422,370，以及国际专利申请No.WO94/06640。类维生素A代表了另一类刺激皮肤更新的产品，例如如在Kligman的美国专利No.5,051,449中公开的那样。然而，这些产品只限于改变小规模的皮肤紊乱并且对许多人作用不够好。
皮肤更新酸提供了某些益处但易于引起刺激、起效慢且会引起干皮病问题。一种利用乳酸与水杨酸的新组合的刺激性特别低的处理方法公开于国际专利申请出版物No.WO/94/06640，其描述了可有效地提供对皮肤水屏障的持久并且显著破坏的屏障破坏处理的局部应用。将这种持久破坏保持足够长的时间以引起皮肤的结构改善。被破坏的水屏障是水蒸气通过皮肤的固体部分扩散或蒸发的天然障碍，而不涉及出汗。这种技术通常也只限于小规模的暂时改善并且对许多人不适用。
发明内容
本发明的一个实施方案是整修个体皮肤的方法，其包括从皮肤表面去除死细胞以形成准备好的表面并以成肌细胞营养液形式将成肌细胞涂到准备好的皮肤表面。本发明的另一个实施方案是用于个体皮肤改善的成肌细胞悬浮液，其包含得自个体的自体的人成肌细胞、得自个体的血清、血管生成因子和用于成肌细胞的受控快速细胞融合的大6硫酸软骨素(large 6 chondroitin sulfate)。本发明的另一个实施方案在类似的过程中利用包皮成纤维细胞悬浮液，单独或与成肌细胞组合。在又一个实施方案中，使用了来自具有影响外源识别，如影响加至细胞表面的α-1，3-半乳糖的双剔除(knockout)突变的另一动物如猪的非免疫原性细胞。
具体实施方式
已发现可以将来自乳膏样悬浮液的成肌细胞以薄层(一层或多层)的形式涂到准备好的皮肤表面以使成肌细胞存活、生长并且并入到皮肤中，从而填充裂缝及皮肤的其他裂隙。成肌细胞消除皮肤中的缺陷并提供更多的诸如弹性、甚至色泽和强度的性质。
在一个有利的实施方案中，首先处理要处理的个体的皮肤，优选用柔滑的研磨剂或用一种或多种化学品如乳酸处理。在去除死细胞的处理后，将含或不含包皮成纤维细胞的成肌细胞悬浮液，平抹到所希望的区域以填补瑕疵、皱纹和/或孔。然后，将温暖湿润的含氧空气，或更优选纯氧，吹到处理的地方至少0.1、1、3、6、12、24或更多小时。将该区域静置至少12、24至30或更多小时。可以按照间隔如1、2、3、6或12个月来重复所述整个过程，以得到更光滑和看起来更年轻的皮肤。
在另一个实施方案中，悬浮液包含来自另一动物的细胞如皮肤细胞，所述动物具有外源组织特异性抗原如加到细胞表面上的α-1，3-半乳糖所必需的基因的双剔除去除。
用于处理的成肌细胞
成肌细胞可以是自体的(从所处理的个体获得的)，可以从其他人获得，或者甚至从其他动物获得。如果不是自体的，优选预先给予环孢霉素。虽然可使用其他的免疫系统抑制剂，但优选使用环孢霉素5天，因为通过环孢霉素对某些淋巴细胞的作用而抑制皮肤中的炎症。通常，有严重皮肤病的病人服用环孢霉素最少几个月并多至数年，并且典型地以每天5mg/(kg体重)的口服剂量来使用环孢霉素。
如果得自正在接受处理的个体，优选在去除前用机械探针法(mechanicalprobing)刺激一或更多肌肉1天、2至3天、4至5天或更多天。例如，可刺激四个肌肉点：左、右三角肌和左、右四头肌，用Emgel局部麻醉2小时后使用2.5英寸的针(26规格)，每个点6次。2至3天后，对于总共获得的2.0g肌肉，可用针(穿孔器)刺法活检0.5g肌肉。将细胞分散并培养成10亿至500亿个成肌细胞的培养物。
将培养的成肌细胞悬浮于任何合适的介质中。特别是对于自体细胞，优选将细胞再悬浮于得自待处理的个体的血清或血中。例如，可从所述个体获得50至100ml的血并分离血清。连同其他因子一起，例如，NGF、胰岛素、VEGF165(血管生成因子)、TGF-β、血管紧张素、葡萄糖、胎球蛋白、脂质、白蛋白、大6硫酸软骨素和鸡胚提取物(或其他来源的生长因子)，优选以1亿个细胞/ml将希望量的成肌细胞悬浮在血清(优选至少25％、50％、75％或更多血清)中。熟练的技术人员会知道每种因子的使用量。常规的优化试验可使用，例如，0.01ng至1μg/ml的血管生成因子。更有营养的物质如葡萄糖、脂质、白蛋白和鸡胚提取物，可在更高的、1μg/ml至25mg/ml之间的浓度下优化。可使用最终浓度在0.01μg/ml至1mg/ml之间并更优选在1μg/ml和100μg/ml之间的大6硫酸软骨素。在室温下将悬浮介质滴定至pH 6.8-7.2。将细胞悬浮并优选在其后迅速地施用于准备好的皮肤。细胞的浓度应为1百万-10亿个细胞/ml，优选为1千万-5亿个细胞/ml，并且更优选为5千万-1.5亿个细胞/ml。
细胞悬浮液任选地包含一种或多种调节黏度的试剂，以适合机械地附着于皮肤表面。例如，可使用如U.S.6,387,413中描述的透明质酸和如U.S.6,365,149中描述的多孔组织支架及如U.S.6,306,424中描述的泡沫复合材料。在另一个用于除皮肤整修外的其他情况如血管修复和内脏修复的实施方案中，本文所描述的成肌细胞可用于被覆用作体内的支架的材料。这种材料可被处理以促进成肌细胞的附着，并且在一个实施方案中可以用硫酸软骨素被覆。用于这些进一步的方法的塑料和无机材料是已知的，例如在U.S.6,107,453、U.S.5,843,781和U.S.5,503,771中提及的。在另一个实施方案中，如本文中所述的成肌细胞层用作人造或生物器官的被覆层，包括用作实体瘤的被覆层。使用这种成肌细胞层既可以被覆又可以保护还可以机械地固定这样的器官，同时允许大分子甚至细胞如淋巴细胞移动进出被固定的器官。
在一个尤其用于填充大的皮肤区域如大皱纹的实施方案中，使用了个体成肌细胞和小肌管的混合物。肌管的存在帮助机械地桥接大缝隙，并且可以根据需要制备并调整混合物中的肌管的比率和平均大小，这可被熟练技术人员所理解。
在另一个实施方案中，可以单用包皮成纤维细胞或将其与成肌细胞和/或肌管合用来产生近似的结果。包皮成纤维细胞可有利地提供光滑细腻的肌理。
皮肤的准备
在使用成肌细胞前将死皮肤细胞去除。可以使用研磨处理，如用微粒状水滚石英卵砂和高级体霜按摩以去除死皮和碎屑。其他物理方法也可有效，例如，通过用胶带，或氰基丙烯酸酯粘合剂，或石蜡剥离皮肤的外层。其他破裂处理可以使用化学药品从角质层中去除屏障脂质。有机溶剂如己烷、丙酮或甲醇和强洗涤剂如十二烷基硫酸钠不能物理去除角质层的层，但对清洁表面有效，因为它们通过从角质层去除相当多的脂质物质来破坏水蒸气屏障。可以使用表皮脱落剂如α-羟基酸，独立地使用或与研磨剂按摩合用。在处理后，应该用水冲洗经过处理的皮肤，优选在体温下进行。
将成肌细胞应用到准备好的皮肤上
优选地，在洁净室(等级100、等级1000、或等级10,000)中，将成肌细胞，任选地与填充大范围皮肤的肌管和/或包皮成纤维细胞(或其他细胞)一起，平抹到准备好的表面上，以填充瑕疵、皱纹和孔。优选地将平抹的成肌细胞表面暴露于氧并静置至少6小时、12小时、18小时、24小时、30小时，或如果希望的话，甚至至少36小时。优选地将含有至少20％、35％、50％、70％或者甚至高于95％的氧的温暖湿润空气连续地吹到成肌细胞层至少4、6、9、12或更多小时。优选地至少在24、30、36、48或更多小时里不清洗所处理的区域。在一个实施方案中，通过喷雾或其他方法将抗菌剂添加到涂抹了成肌细胞的表面，或者可以在涂抹到皮肤表面之前添加到细胞悬浮液中。
对于本发明的实施方案的作用方式，不想受任何理论的约束，要指出的是成肌细胞可以在宽范围的培养物、应用溶液和环境条件中存活并生长。每一种这样的试剂都适合于本发明的实施方案。许多受处理的外皮层包括比成肌细胞大很多的成纤维细胞。涂敷的成肌细胞会发育成肌管，并可在皮肤表面形成肌纤维系统，使得至少一些成纤维细胞向外生长并从皮肤表面排出。而且，成肌细胞是运动的并可避开毛囊，因而保持皮肤的有毛的表面。又进一步，当涂敷的成肌细胞(其中很多永不会成熟为肌纤维)衰老并开始死亡时，它们变为结缔组织并可形成一些弹性物或胶原。也就是说，一些涂敷的成肌细胞悬浮液退化成在皮肤上形成坚固层的其他组织。因此，本发明的一些实施方案的一个特征是触感性的去除或降低。根据本发明的实施方案的使用成肌细胞的处理的另一个特征是可以产生更加(同质的)理想的皮肤颜色。在一个特别的实施方案中，在成肌细胞的体外培养期间或就在将成肌细胞涂抹到皮肤之前，在黑色素反应中涉及到的酪氨酸酶和/或其他酶的一个或多个基因被开启或调节。这个实施方案允许使用成肌细胞来校正皮肤的不均匀色素沉着。
在本文中引用的每一文件都明确地以其整体并入作为参考。
当然，在阅读本说明书之后，熟练的技术人员会容易理解对在本文中所提出的实施方案的改变和修改，而且，这样的改变和修改可在所附的权利要求的范围内实施。

Claims (16)

1.一种整修个体的皮肤的方法，其包括下列步骤：
a)从皮肤表面除去死的细胞，生成准备好的表面；
b)将在成肌细胞营养液中的成肌细胞涂到准备好的皮肤表面。
2.权利要求1的方法，其中所述成肌细胞是自体的并且是从所述个体的肌肉活检获得的。
3.权利要求1的方法，其中所述肌细胞是从非自体的人样品制备的。
4.权利要求1的方法，其中所述成肌细胞营养液包括血清、大6硫酸软骨素和至少一种血管生成因子。
5.权利要求4的方法，其中所述至少一种血管生成因子是VEGF165、TGFB或血管紧张素。
6.权利要求1的方法，进一步包括在洁净室中在涂敷成肌细胞之后将温暖、湿润的氧循环到所述皮肤表面的步骤。
7.权利要求1的方法，其中步骤a)是通过用微粒状水滚石英卵砂和高级体霜按摩以除去死皮和碎屑然后漂洗而完成的。
8.权利要求1的方法，其中所述成肌细胞营养液包括从所述个体获得的血清。
9.权利要求1的方法，其中以至少0.25亿个细胞/ml的浓度涂敷至少5亿个成肌细胞。
10.权利要求2的方法，其中所述成肌细胞是在刺激一块或多块所述个体的肌肉后通过穿刺活检而获得的。
11.一种用于个体的皮肤增强的成肌细胞悬浮液，其包括来自所述个体的自体人成肌细胞、来自所述个体的血清、血管生成因子和大6硫酸软骨素。
12.如权利要求11所述的用于个体的皮肤增强的成肌细胞悬浮液，其进一步包括NGF、胰岛素白蛋白和鸡胚提取物。
13.如权利要求11所述的用于个体的皮肤增强的成肌细胞悬浮液，其进一步包括胎球蛋白。
14.一种用于个体的皮肤增强的成肌细胞悬浮液，其在乳状悬浮液中包括成肌细胞、血清和大6硫酸软骨素，所述乳状悬浮液适合作为填充皮肤的缺陷并掩盖皮肤形态(skin mold)的黏性物来涂敷。
15.如权利要求14中所述的成肌细胞悬浮液，它进一步包括血管生成因子。
16.一种用于个体的皮肤增强的包皮成纤维细胞悬浮液，其在乳状悬浮液中包括包皮成纤维细胞、血清和大6硫酸软骨素，所述乳状悬浮液适合作为填充皮肤的缺陷并掩盖皮肤形态的黏性物来涂敷。
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