富勒烯研究站 | 富勒烯在护肤领域的研究与应用
富勒烯在护肤领域的研究与应用
富勒烯论文速递
一
富勒烯论文速递
自由基与皮肤
1956年Denham Harman教授提出了人体衰老的自由基学说。自由基的产生分为两个渠道 ：一是机体氧化代谢中产生自由基。二是辐射、 环境污染以及不良生活习惯等产生自由基。自由基又称游离基，是具有不成对电子的原子或基团，包括超氧阴离子自由基，羟自由基、过氧化氢、单线态氧及其衍生物等。自由基具有高度的活泼性和极强的氧化反应能力，能通过氧化作用攻击体内的生命大分子，如核酸、蛋白质、糖类和脂质等，使这些物质发生过氧化变性、交联和断裂，从而引起细胞结构和功能的破坏，导致机体的组织破坏和退行性变化。在正常情况下，机体会不断产生多种内源性抗自由基的活性物质，包括非酶类抗自由基物质（如：维生素C、β-胡萝卜素等）和抗自由基的酶类（如：SOD、过氧化氢酶、谷胱甘肽过氧化物酶）。他们能不断地清除自由基，因而使机体细胞和组织免受损害。但在内外环境异常的情况下，体内抗自由基系统的平衡就会被破坏，从而引起生物膜的脂质过氧化，破坏生物膜的功能和结构完整性，结果使机体更易于发生各种病变和老化1-7。
人类的皮肤是人体的重要器官之一，它覆盖着体表，具有保护、感受刺激，吸收、分泌、调节体温及维持平衡等多种功能。同时，皮肤也是人类健美的重要标志，一个体魄健康的人，其皮肤一定是滋润丰满、富有弹性的。但随着年龄的增加，人的皮肤，特别是暴露于衣服外部的皮肤，就会逐渐变得粗糙、发皱、变黑，并且长出老年斑。这些变化与氧自由基的代谢密切相关。
二
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自由基清除剂
自由基种类很多，其中OH·、O2－·、H2O2在体内的含量最多，过剩后损害也最大。OH·是最活泼、毒性最大的自由基，它可以与活细胞中的任何分子发生反应而造成损伤，而且反应速度极快，被破坏的分子遍及糖类、氨基酸、磷脂、核苷和有机酸等。O2－·可使核酸链断裂、多糖解聚及不饱和脂肪酸过氧化作用，进而造成膜损伤、线粒体氧化磷酸化作用的改变等。H2O2能使少数酶的-SH（巯基）氧化失活，因为H2O2能迅速穿过细胞膜，而O2－·不能，在细胞内的H2O2能与Fe2+ 或Cu2+ 离子反应生成OH·，这是H2O2毒性的真正原因。
自由基清除剂发挥作用必须满足三个条件：
1、自由基清除剂要有一定的浓度；
2、因为自由基活泼性极强，一旦产生马上就会与附近的生命大分子起作用，所以自由基清除剂必须能以极快的速度抢先与自由基结合，否则就起不到应有的效果；
3、在大多数情况下，清除剂与自由基反应后会变成新的自由基，这个新的自由基的毒性应小于原来自由基的毒性才有防御作用。
自由基清除剂是指能清除自由基或能阻断自由基氧化反应的物质。可分为酶类清除剂和非酶类清除剂两大类。酶类清除剂一般为抗氧化酶， 主要有超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPX）等几种。非酶类自由基清除剂一般包括黄酮类、多糖类、维生素C 、维生素E、β-胡萝卜素和还原型谷胱甘肽（GSH）等活性肽类。GPX、SOD和CAT协同作用，共同消除机体活性氧，减轻和阻止脂质过氧化作用。维生素Ｃ，又叫抗坏血酸，通过逐级供给电子而转变成半脱氢抗坏血酸和脱氢抗坏血酸，在转化的过程中达到清除O2-·、OH·、ROO·等自由基的作用。维生素Ｅ又称为生育酚，是强有效的自由基清除剂，它可将ROO·转化为化学性质不活泼的ROOH，中断了脂类过氧化的连锁反应，有效地抑制了脂类的过氧化作用。β-胡萝卜素具有较强的抗氧化用，能通过提供电子，抑制活性氧的生成，从而达到防止自由基产生的目的。
富勒烯是球形笼状分子，一个分子可同时容纳6个电子，具有庞大的共轭电子云，极易淬灭自由基的电子能量。它突出的抗氧化能力使其成为防晒、美白和抗衰老产品中重要的成分。Charles N. McEwen在研究富勒烯的质谱信号时发现了富勒烯可以连续结合多个甲基自由基，同时他们预测了富勒烯与自由基相互作用的一种机制：当富勒烯分子表面是奇数电子数时带电基团与富勒烯的电子云表面紧密结合，并在形成偶数电子物种时释放（图1），因此它被称为“自由基海绵”59。
图1：富勒烯与自由基相互作用原理
在更多的研究中也发现了富勒烯独特的电子学特性：富勒烯及其衍生物具有高的电子亲和势、低的电子重组能、较高的电子迁移率, 并且能够与多电子材料相容。中科院化学所王春儒研究员针对富勒烯清除自由基的性质进行了详细的研究，采用电子自旋捕获的方法对富勒烯清除羟基自由基的性能进行了检测，发现富勒烯及其衍生物可以快速、长效清除羟基自由基14、15、16、17、18。
富勒烯是纯碳材料，溶解性极差，需要采用一定方式进行改性以提高其溶解性和分散性，同时增加其生命系统的适用性。目前许多已知的提高富勒烯溶解性和分散性的方法可主要分为两大类：a）物理方式：包封、形成混悬液、形成复合物、将富勒烯溶解于油脂中等20-30；b）通过化学反应连接增溶附属物形成功能化富勒烯，例如添加氨基酸，类固醇，羟基，羧基，氨基等20-30。
富勒烯电子转移和抗氧化能力强 31-38，被认为是皮肤治疗药物和化妆品中重要的成分39-46，富勒烯及其衍生物所形成的的新型微粒在皮肤病学和皮肤护理技术领域已经取得良好的成绩。因此，许多制造商都渴望将它们用于化妆品和外用制剂。
三
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富勒烯对抗紫外线对皮肤的损伤
富勒烯作为一种多功能的新型碳纳米材料，许多研究评价了它在增加皮肤的抗氧化能力和保护皮肤免受紫外线损伤方面所起的作用。在体外研究中，针对不同人类皮肤细胞经受紫外线照射后，用富勒烯及其衍生物进行处理，然后评针对ROS的清除作用或细胞保护作用。数种富勒烯衍生物（高分子包裹的富勒烯、富勒醇、富勒烯羧基衍生物等）均获得了可喜的结果表现出了优异的清除自由基抗氧化的性能47-54，能够减少细胞凋亡以及细胞和形态学变化。尽管大多数研究表明富勒烯改善细胞和形态变化的作用是其抗氧化特性的结果，但村上隆等人53的研究表明，富勒烯还可以通过促进角质形成细胞的分化来实现其保护作用。这项研究还提供了一个证据说明富勒烯没有通过屏障机制显示其细胞保护作用，因为在UVB照射期间，在叠置的培养皿中使用富勒烯时未见细胞保护作用；而当直接应用于含有角质形成细胞的培养皿时，则具有细胞保护作用55。
富勒烯对紫外线引起皮肤损伤也有一定的保护作用，在Ito等人的一项体内研究中56，在紫外线照射前1小时，将富勒烯溶液涂于小鼠背部皮肤，虽然在使用富勒烯后只能看到很小的ROS减少效果（它只能减少UVB诱导的皮肤中的O2•，）但是当富勒烯和抗坏血酸（AA）一起使用时，红斑、ROS指数和细胞凋亡指数显著降低并且O2•、H• 、OH•与AA•的产生被显著抑制。这些结果说明富勒烯和其他抗氧化剂共用可以产生协同作用。此外，在该研究中，未发现富勒烯对细胞具有任何毒性或光毒性。
Xiao等人51在新鲜的人皮肤器官培养物中使用了高分子包裹的水溶性富勒烯材料（100μM），发现它可以明显减少UVA诱导的黑色素生成达20%以上。在Kato等人的另一项研究中57，评估了油溶性富勒烯对3D人皮肤组织模型的影响。在UVA照射之前和之后，用油溶性富勒烯重复处理3D皮肤模型，结果表明，UVA诱导的表皮异常缩放减少，真皮和基底层的I/IV型胶原纤维的破坏减少，异常细胞核和凋亡细胞减少。Inui等58评估了水溶性富勒烯对UVB诱导的人表皮中前列腺素E2（PGE2）合成的影响，并发现PGE2的产生受到了显著抑制，由于PGE2可激活酪氨酸酶，进而引起黑色素细胞大量分泌黑色素，因此富勒烯对PGE2较强的抑制作用，说明其在抑制黑色素生成方面有着显著的优势，这一发现也是富勒烯影响黑色素生成的潜在机制之一。这些研究均支持富勒烯对紫外线引起的皮肤损伤和氧化应激的保护作用，并证实了其可作为防晒霜，皮肤美白和嫩肤产品中的活性成分的巨大潜力。
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富勒烯治疗痤疮
寻常痤疮是一种涉及皮脂腺的慢性炎症性皮肤病。这种慢性复杂疾病的多种病因包括角化过度，皮脂囊阻塞，皮脂分泌增加，丙酸杆菌增殖和炎性反应59，此外，氧化应激（皮肤和全身性的）也是其发病机理的另一个重要因素60,61。作为一种新型的纳米材料，富勒烯由于其诸多优点而被引入痤疮治疗中。它具有很高的抗氧化活性，可以穿透表皮，并且可以作为递送载体改善药物体内过程62。此外，对一种富勒烯衍生物（C60（OH）24）的研究表明，它可以抑制皮脂生成63，并对痤疮丙酸杆菌具有抗菌活性64。
Inui等人研究了富勒烯在临床中的抗痤疮作用65,73。将含有富勒烯角鲨烷溶液（1%）的凝胶（富勒烯含量2ppm）涂抹在11例痤疮患者的面部皮肤上，每天两次并持续8周，结果表明治疗后病人的炎性病变和脓疱的平均数量在统计学上显著减少，粉刺的数量无统计学差异。在仓鼠皮脂细胞上使用75μM PVP-富勒烯，显示皮脂分泌量减少25％，中性粒细胞浸润减少（较少脓疱），但在病人身上未观察到皮脂减少，猜测可能是由于测试样品中富勒烯用量少。这些机制和富勒烯的抗氧化作用一起被认为是其控制痤疮的可能途径。另外，脂质体富勒烯对皮肤含水量显示出有益的作用，并且不影响毛孔的数量。总体来看，Inui的实验中，富勒烯添加量极少，这一点也有可能是未能达到更好的预期效果的一个环节65。因此，需要进一步研究才能得到更加可靠的结论。针对这个问题Wang等人（一种水溶性富勒烯外用组合物， CN201810871219；一种油溶性富勒烯外用组合物， CN201810777244；一种祛痘组合物，201810124686.3）进行了进一步研究，他们将富勒烯溶于霍霍巴籽油中，然后配制成痤疮治疗外用软膏剂，其中富勒烯添加量较Inui试验提高了30倍，针对轻、中、重度痤疮患者进行临床测试，治疗组结果显示对粉刺、炎性丘疹有着显著的效果（如图2）。同时发现，在第3天时，脸部红斑就有显著的改善，第7天时粉刺明显减少，第14天时炎性丘疹也得到明显缓解；最为显著的是治疗组在治疗后痤疮部位的印痕几乎没有显现。对比Inui的试验可以得出富勒烯在治疗痤疮方面是存在量效关系的，添加量提高后，富勒烯对痤疮的治疗效果显著提高。同时Wang等人的试验中发现，虽然富勒烯的添加量提高了几十倍，但是在受试人群中并没有发现皮肤过敏者，也从一个侧面证明了富勒烯的安全性。
图2
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富勒烯美白和细腻肌肤的功效
亚洲女性对皮肤的白皙度关注较多，富勒烯在这一领域也有其独特的功效和作用原理。紫外线会诱导产生活性氧，对人体皮肤细胞产生一系列生物效应，导致色素沉着等皮肤损伤，一般会用抗氧化剂来解决这个问题。但是，一旦色素形成后，表皮层是去除色素非常关键的一环。富勒烯具有持久稳定的抗氧化特性，除了可以抑制氧化应激带来的黑色素过度生成之外，同时研究还发现富勒烯可以促进角质形成细胞的分化和角质化，这一点可以促进黑色素代谢，并对角质层保水度有促进作用，角质层含水量搞了，皮肤白皙度也会提高。
在一项单盲临床研究中，Murakami等64评价了10名健康志愿者的前臂经胶带剥离后，再使用水溶性富勒烯后的皮肤屏障恢复情况。结果表明，志愿者表皮水分流失（TEWL）的情况显著改善，但角质层水化没有任何变化。根据分子水平检测，他们认为TEWL的改善可能是由于富勒烯促进角质形成细胞的分化和角质化包膜的合成。Inui等58研究了富勒烯在减少面部毛孔中的作用。使用含有水溶性富勒烯的润肤乳8周后，参与者的毛孔减少了17.6%（p<0.05）；约三分之二的受众对美容效果感到满意。在使用脂质富勒烯时发现皮肤的水合作用没有得到改善，该结果是否与富勒烯的类型有关，还是存在其他未知的原因，仍需进一步探索。
H.Takada65等研究了高分子包裹的水溶性富勒烯在HMV-II人类黑素瘤细胞和NHEM正常人类表皮黑素细胞中的作用。在高分子修饰的富勒烯(25mM)存在下培养黑素瘤细胞24小时，结果显示富勒烯可以抑制两种模型条件下皮肤细胞的黑素生成，没有体现出任何细胞毒性。富勒烯可以作为一种对年轻肌肤进行防护的很好的原料，同时也是修复衰老肌肤的很好的潜在活性成分。Takahiro66制备了一种含富勒烯（2ppm）的凝胶，对32名女性志愿者进行了临床试验， 6周后94%的受试者皮肤白皙度改善，没有任何炎症或刺激，表明富勒烯具有美白效果。Wang等人制备了富勒烯含量更高的水溶性和油溶性富勒烯原液，制备了富勒烯含量较高的面霜（临床添加量为 15ppm的富勒烯），并进行了临床测试（一种美白祛斑组合物，201810123967.7），受试者为45-55岁的女性，测试周期是4周，从统计结果可以看出受试者皮肤黑色素值显著降低，皮肤亮度有显著提高，细腻度显著提高。这些研究不仅说明了富勒烯具有美白功效，同时可缩小毛孔和细腻肌肤。
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富勒烯淡化皮肤皱纹
皱纹是指皮肤受到外界环境及自身影响，形成游离自由基，自由基破坏正常细胞膜组织内的胶原蛋白及活性物质，导致皮肤真皮层胶原蛋白含量逐渐减少。网状支撑体亦会变厚变硬、失去弹性，当真皮层的弹性与保水度降低，皮肤便会失去弹性并变薄老化，表皮即形成松垮的皱纹。关于皮肤水分与皱纹的关系，据报道，在皮肤模型中，角质层水分减少11%可使皱纹增大25-88%69。
NDA是4-羟基壬醛的类似物，是导致人体老化的主要原因之一，也是亲脂细胞损伤因子。Nobuhiko的研究指出富勒烯对2，4-非二烯醛（NDA）诱导的HaCaT角质形成细胞损伤和三维（3D）人体皮肤组织模型中皱纹形成有防御作用。同时Nobuhiko67进行的临床试验证明，使用添加有富勒烯的面霜，在第8周时可以有效的改善眼部皱纹，抚平眼部干燥，提高眼部水润度水平。他们还进行了一项双盲随机对照试验，要求23名健康女性每天两次使用富勒烯产品，试验周期共计8周67，并观察到治疗部位的皱纹较少（图3）。相比于安慰组来说，实验组得皱纹面积在第4周时就有了明显得降低，皱纹深度明显降低，皮肤表面粗糙度显著降低。皮肤白皙度指数TWEL在第4周时也有显著提高，皮肤弹性指数也得到提高，试验观察到的结果具有显著性差异，并且研究中未发现富勒烯的副作用。
皮脂膜是皮肤外层的一个屏障，角鲨烯是构成皮肤皮脂膜的重要组成部分，皮肤中的角鲨烯可有效抑制脂类过氧化反应的级联放大，进而帮助皮肤抵抗由于紫外照射和其它氧化反应导致的损伤。Nobuhiko67在文中指出，皮肤暴露在阳光下1.5小时表面会由于单线态氧而使过氧化角鲨烯增加60倍。我们皮肤的最上层，也就是皮肤表皮层，大部分是角质形成细胞构成了皮肤的主要屏障功能，是抵御环境物理、化学和生物制剂的前线，外部氧气压力对角质形成细胞和成纤维细胞的匹配培养至关重要。C60通过清除活性氧自由基或防止紫外线穿透人皮肤角质形成细胞，从而防止UVA-可见光或UVB照射引起的光损伤。
研究表明68、86富勒烯没有光细胞毒性和细菌逆转致突变性。富勒烯可以通过角质层进入表皮层，真皮层24小时的人体皮肤活检未检出富勒烯，表明没有必要考虑C60由于经真皮静脉的体循环造成的毒性。自由基被认为是通过破坏胶原蛋白和弹性蛋白网络导致细皱纹产生的主要因素，成纤维细胞和角质形成细胞的外表面布满抗氧化酶，而富勒烯可以进入皮肤表皮层，在角质形成细胞外作为抗氧化保护剂。抗氧化物质的应用与美容护肤、抗衰老有着密切的关系。
图三
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富勒烯论文速递
富勒烯和毛发生长
正常脱落的头发都是处于退行期及休止期的毛发，由于进入退行期与新进入生长期的毛发不断处于动态平衡，故能维持正常数量的头发。病理性脱发是指头发异常或过度的脱落，其原因很多。比如由于感染病菌、内分泌障碍、遗传因素、激素水平失调等74，75。社会中许多人都被脱发这个常见而棘手的难题所困扰，脱发可能带来心理问题并影响人们的身体形象和生活质量76-78。脱发背后的病因是多种多样的，从遗传、激素和环境因素（例如雄激素性脱发或端粒剥脱）到化疗、甲状腺疾病和营养缺乏等次要原因77-79。尽管脱发非常普遍，但其治疗方法却止步不前。治疗的第一步是消除任何潜在原因和避免使用任何会加重病情的药物。树立患者信心、压力控制以及缺铁患者补铁有时会对缓解症状有所帮助。米诺地尔和非那雄胺是唯一经FDA批准用于治疗雄激素性脱发的药物77，78，80，而外用皮质类固醇及其注射剂同局部用他克莫司和米诺地尔一起用于治疗斑秃81。然而，所有这些治疗方法都有其自身的局限性。
Zhou等人82研究了富勒烯作为头发生长刺激剂的作用。他们在小鼠和人类活皮肤样品上使用了富勒烯衍生物，发现皮内注射或局部给与富勒烯可以促进头发生长并引发从头开始的毛囊生成。富勒烯产生这种作用的机理尚不清楚，但作者推测它可能通过其抗氧化特性发挥作用，因为最近的数据表明，氧化应激也是引起头发损伤和脱发的重要原因83，84。
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富勒烯与皮肤刺激
当异物接触皮肤时，它有可能引起皮肤局部反应，例如皮炎70，或者通过皮肤屏障进入全身循环或淋巴系统，并在全身分布，这种情况下的安全风险可能会更高71,72。Luechtefeld等人分析了111项在REACH（化学品的注册，评估，授权和限制，欧洲法规化学品联盟）注册的皮肤致敏性研究，发现在我们日常生活或工业中遇到的常见化学品中，多达21%的化学品会引起皮炎85。富勒烯作为一种新的化妆品原料，也有可能存在潜在皮肤刺激或致敏性。文献中未见工作场所或环境中真皮对富勒烯定量暴露的报道。但根据目前已有的数据，如果采取适当的防护，工作场所中富勒烯原型似乎对人类健康威胁极小89。然而，工作和环境中所接触各种富勒烯衍生物的安全性研究尚需进一步加强。
Aoshima等人90使用高纯度的富勒烯在兔子和豚鼠上进行了实验。他们评价了在兔子皮肤上单次或重复施用富勒烯后红斑或水肿的情况，未发现刺激。他们还在22天的实验中评估了HPF注射和局部应用后豚鼠的皮肤致敏性，也没有发现皮肤反应。此外，在局部应用富勒烯后，他们用紫外线照射了豚鼠的皮肤，未见光敏化或接触光毒性。
Ema等人91在兔皮肤上涂抹了C60的橄榄油糊剂（10%富勒烯），在4小时内未发现红斑或水肿。同样，在为期30天的研究中，在豚鼠上局部施用富勒烯糊剂后，未见红斑或水肿。1999年，Huczko等人92对30名有刺激和过敏史的志愿者进行了贴片试验实验，使用了0-14.6 wt%富勒烯碳灰的水悬浮液，暴露96 h后未见任何皮肤刺激。Aoshima等人89还对21名男性和24名女性（22-56岁）进行了补丁测试。他们在闭塞条件下在手臂腹侧施加了0.01 g 高纯度富勒烯样品24小时，并在去除贴剂后1和24小时评估了皮肤反应，在任何受试者中均未发现刺激现象。
根据上述研究以及之前提到的评价富勒烯在皮肤护理和化妆品应用中的临床研究，似乎可以得出结论，富勒烯用于局部制剂不会增大皮炎的风险。但是，仍然需要对不同的富勒烯成分和不同的皮肤状况进行更细致的研究，才能得出更确切的结论。
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皮肤渗透性与细胞毒性
当我们面对一个新的化妆品成分时，评价其皮肤渗透性和细胞毒性是另一个需要关注的项目。实际上，在皮肤护理方案中引入新成分后，最重要的挑战之一是找到一种能够忍受诸如水、汗和温度等物理因素，同时减少经皮吸收的产品。旨在最大程度地降低皮肤或全身毒性的潜在风险。
一般而言，纳米粒子进入细胞的能力会受到诸如纳米粒的物理化学性质、载体效应、剂量、持续时间，暴露频率以及吸收和毒性的测定方法等因素的影响。透过皮肤进入体内还涉及其他因素，例如不同的皮肤表面状况和影响其完整性的因素，例如过敏性、刺激性或接触性皮炎或牛皮癣等；环境和外部因素，例如紫外线或机械变形；通过皮肤细胞与皮肤附件（例如毛囊，汗腺等）进入；最后还有皮肤表层脱落、剥落和洗清效应导致纳米粒的损失，使吸收过程更加复杂93、94、95。
小分子（<500-600 Da）物质，尤其是亲脂性的96、97，很容易穿透皮肤，其他一些大分子则很难以进入真皮。由于富勒烯的分子量为720Da，因此其在皮肤中的扩散速率远低于小分子物质98。
另一些研究采用分子动力学模型来评价C60在细胞膜模型中的相互作用和转运。Qiao等人103发现，在形成短暂的微孔后，富勒烯原型可以在几毫秒内穿透脂质双层，而C60(OH)20由于其亲水性表面仅吸附在膜上而非穿透膜。因为体外研究表明，富勒烯聚集体的尺寸范围可能很大，从20到26,000 nm以上不等，具体取决于分子的结构，浓度以及在介质中的放置时间59,99,101， Qiao等人的研究103未考虑富勒烯的聚集状态，因此对其结论应持审慎态度。Bedrov等人104经分子动力学模拟研究发现，富勒烯分子即使在处于水相时也可以轻松透过脂质膜。他们认为富勒烯不仅是一个小的1 nm分子，还具有高密度的表面原子，故可推断出它具有很强的范德华相互作用。这一独特的性质使富勒烯既不像传统的亲水分子，也不像疏水分子那样起作用，而是即使在水相中也具有高渗透性的分子。这种性质使富勒烯有望成为一种优良的药物载体。
关于富勒烯穿透细胞的机制，似乎没有证据表明有任何特定的C60转运系统存在，而是通过被动扩散来完成的104。这与计算机模拟研究105相符。在被动和自发过程中，富勒烯分子簇很容易渗透到脂质膜中，而不会对脂质膜造成任何机械损伤。由于在计算机模拟中仍未考虑富勒烯与其他细胞成分（如其他脂质，碳水化合物和蛋白质）的相互作用，因此仍需要深入研究。
在此计算机仿真研究中。Rouse等106的体内研究还表明，苯丙氨酸衍生的富勒烯（Baa）通过被动扩散来穿透真皮和表皮。他们还使用透射电子显微镜（TEM）观察到表皮细胞间隙中的Baa颗粒，这说明富勒烯能在细胞间隙中运动。
关于富勒烯吸收和渗透的其他体内/体外研究，评价了苯丙氨酸衍生的富勒烯（Baa）106，在角鲨烯中稀释的C60107， 脂质体富勒烯，在矿物油，甲苯，环己烷和氯仿中的富勒烯和高分子包裹富勒烯102进入表皮或真皮的能力和效果。结果表明，除了如不同类型富勒烯及其相关特征等因素101外，富勒烯的活组织吸收还涉及其他因素，例如溶剂效应98，紫外线暴露102和外部机械力106。上述结果提醒研究者有必要进一步考虑影响富勒烯吸收的其他方面，例如不同的环境因素对富勒烯皮肤吸收的影响。
但是，由于研究者使用的模型，富勒烯类型，粒径和评估毒性的机制方面受到很大限制。因此，需要进行更多的研究才能得出有关富勒烯皮肤吸收和毒性的确切结论。
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富勒烯化妆品产业发展现状
2014年富勒烯被列入了中国《已使用化妆品原料目录》中，第02372号。从2014年开始，国内陆续有化妆品品牌注册含有富勒烯的化妆品，从FDA注册信息查看，此类化妆品在命名时也大多含有“富勒烯”三个字，也足以证明了品牌商对富勒烯的重视和认可。2006年，中科院化学所王春儒团队开始推进国内富勒烯的产业化，始终以材料应用和产业规范为准则，研发了四代富勒烯制备技术和工业化纯化技术，并牵头制定了多项富勒烯检测国家标准（《[60]和[70]富勒烯的纯度测定 高效液相色谱法》 GB/T 44241-2022；《[60]和[70]富勒烯中残留溶剂测定 气相色谱法》 T/CSTM 00195-2021；《[60]和[70]富勒烯制品的含量测定 高效液相色谱法》 T/CSTM 00194-2021）。2015年，该团队突破了高纯度富勒烯批量制备的关键技术，实现了高纯度富勒烯的高产能，所生产的富勒烯纯度能够达到99.99%以上。国内北京福纳康生物技术有限公司推出了自主知识产权的富勒烯化妆品原料，打破了VC60公司多年的垄断地位。
如今，国内护肤品牌及工厂已经认可了富勒烯的功效及其在护肤品领域的地位。富勒烯在护肤领域强效的抗氧化能力所带来的保湿紧致、淡纹祛皱、祛黄淡斑、抗炎祛痘、抗敏舒缓等功效已经得到广泛认可。
需要强调的是，高纯富勒烯安全无毒无刺激性。在2021年，由中科院化学所王春儒研究员团队、北京福纳康公司和仁生泽发公司对高纯度富勒烯的遗传毒性进行测试，通过中国仓鼠卵巢细胞体外染色体畸变试验以及大鼠微核试验和细菌回复突变试验验证了福纳康的99.99%高纯度富勒烯没有基因毒性、无遗传毒性、无致癌性。测试依据（CFDA：Technical guidelines for drug genotoxicity studies；ICH：Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use，S2（R1）；OECD：OECD Guideline for the Testing of Chemicals (473): In Vitro Mammalian Chromosomal Aberration Test）。
经过中国科学家团队和企业的长期坚持以及在技术上的投入，在富勒烯研究方面中国已经遥遥领先，不但在制备和纯化技术方面取得突破，并建立了相关国家标准，而且在生物安全性研究和评价方面也进行了大量严谨而翔实的实验，证实了高纯度富勒烯的安全。
此外，随着研究的深入，富勒烯在化妆品应用中的其他领域价值也在逐渐被发掘。例如，2023年，有研究表明，富勒烯-羟基磷灰石复合物具有良好的定向吸油，持久锁妆的特性，能有效清除自由基，减少皮肤油脂氧化113。同时，富勒烯还具有抗炎、抗菌等作用，能够缓解皮肤炎症、改善痤疮等皮肤问题109。
实际上，富勒烯近年在医药领域同样显现了自己优异的发展潜力。2021年，富勒烯用于治疗溃疡性结肠炎取得新的突破，研究显示，C60FS可修复UC屏障功能障碍，有效促进愈合溃疡，为UC提供了新的治疗指导110。2022年，有研究表明，口服富勒烯片（OFT）可通过口服直接作用于结直肠部位，并减少肿瘤部位的炎症状态用于有效的CRC治疗111。2023年，有研究证实了富勒烯通过调节肠道屏障提供了一种新的治疗机制来减轻动脉粥样硬化112。
富勒烯的广阔应用前景不仅展现了科技的魅力，更坚定了我们的信念：秉持严谨的科学态度，运用科学的研究方法，必能推动科技不断前行，让科技成果更好地造福人类社会。
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17、Ying Zhang, Chunying Shu, Mingming Zhen, Jie Li, Tong Yu, Wang Jia, Xue Li, Ruijun Deng, Yue Zhou and Chunru Wang，A novel bone marrow targeted gadofullerene agent protect against oxidative injury in chemotherapy, Sci China Mater 2017, 60(9): 866–880
18、 Xue Li, Mingming Zhen, Chen Zhou, Ruijun Deng, Tong Yu, Yingjie Wu, Chunying Shu, Chunru Wang, and Chunli Bai, Gadofullerene Nanoparticles Reverse Dysfunctions of Pancreas and Improve Hepatic Insulin Resistance for Type 2 Diabetes Mellitus Treatment, ACS Nano, 2019, 13, 8597-8608
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22. Scrivens W, Tour J, Creek K, Pirisi L. Synthesis of 14C-labelled C60, its suspension in water, and its uptake by human keratinocytes. J Am Chem Soc, 1994;116:4517-8.
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25. Deguchi S, Alargova RG, Tsujii K. Stable dispersions of fullerenes, C60 and C70, in water. preparation and characterization. Langmuir, 2001;17:6013-7.
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31. Nakamura E, Isobe H. Functionalized fullerenes in water. The first 10 years of their chemistry, biology, and nanoscience. Acc Chem Res 2003;36:807-15.
32. Markovic Z, Trajkovic V. Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C60). Biomaterials 2008;29:3561-73.
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11. Markovic Z, Trajkovic V. Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C60). Biomaterials 2008;29:3561-73.
12、Yang X, Ebrahimi A, Li J, Cui Q. Fullerene-biomolecule conjugates and their biomedicinal applications. Nanomedicine 2014;9:77-92.
13. Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Investig, 2008;118:1532-43.
14、Jie Li, Mirong Guan, Taishan Wang, Mingming Zhen, Fuwen Zhao, Chunying Shu, and Chunru Wang, Gd@C82-(ethylenediamine)8 Nanoparticle: A New Haigh-Efficiency Water-Soluble ROS Scavenger ACS Appl. Mater. Interfaces 2016, 8, 25770-25776
15、Xue Li, Mingming Zhen*, Ruijun Deng, Tong Yu, Jie Li, Ying Zhang, Toujun Zou, Yue Zhou, Zhigao Lu, Mirong Guan, Hui Xu, Chunying Shu and Chunru Wang*, Biomaterials, 2018, 163, 142-153。3、）。
16、Yue Zhou, Mingming Zhen, Haijun Ma, Jie Li, Chunying Shu, Chunru Wang ，Inhalable Gadofullerenol/[70] Fullerenol as High-Efficiency ROS Scavengers for Pulmonary Fibrosis Therapy，NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE，2018，14， 1361-1369
17、Ying Zhang, Chunying Shu, Mingming Zhen, Jie Li, Tong Yu, Wang Jia, Xue Li, Ruijun Deng, Yue Zhou and Chunru Wang，A novel bone marrow targeted gadofullerene agent protect against oxidative injury in chemotherapy, Sci China Mater 2017, 60(9): 866–880
18、 Xue Li, Mingming Zhen, Chen Zhou, Ruijun Deng, Tong Yu, Yingjie Wu, Chunying Shu, Chunru Wang, and Chunli Bai, Gadofullerene Nanoparticles Reverse Dysfunctions of Pancreas and Improve Hepatic Insulin Resistance for Type 2 Diabetes Mellitus Treatment, ACS Nano, 2019, 13, 8597-8608
19. Aguilera-Granja F, Dorantes-Dávila J, Morán-López JL, OrtízSaavedra J. Electronic structure of some semiconductor fullerenes. Nanostructured Mater, 1993;3:469-77.
20. Wu H, Lin L, Wang P, Jiang S, Dai Z, Zou X. Solubilization of pristine fullerene by the unfolding mechanism of bovine serum albumin for cytotoxic application. Chem Commun, 2011;47:10659-61.
21. Andrievsky GV, Kosevich MV, Vovk OM, Shelkovsky VS, Vashchenko LA. On the production of an aqueous colloidal solution of fullerenes. J Chem Soc Chem Commun, 1995;1281-2.
22. Scrivens W, Tour J, Creek K, Pirisi L. Synthesis of 14C-labelled C60, its suspension in water, and its uptake by human keratinocytes. J Am Chem Soc, 1994;116:4517-8.
23. Krusic PJ, Wasserman E, Keizer PN, Morton JR, Preston KF. Radical reactions of c60. Science, 1991;254:1183-5.
24. Trpkovic A, Todorovic-Markovic B, Trajkovic V. Toxicity of pristine versus functionalized fullerenes: mechanisms of cell damage and the role of oxidative stress. Arch Toxicol, 2012;86:1809-27.
25. Deguchi S, Alargova RG, Tsujii K. Stable dispersions of fullerenes, C60 and C70, in water. preparation and characterization. Langmuir, 2001;17:6013-7.
26. Ruiz A, Coro J, Almagro L, Ruiz JA, Molero D, Maroto EE, et al. Diastereoselective synthesis of C60/steroid conjugates. J Org Chem, 2013;78:2819-26.
27. Yamakoshi YN, Yagami T, Fukuhara K, Sueyoshi S, Miyata N. Solubilization of fullerenes into water with polyvinylpyrrolidone applicable to biological tests. J Chem Soc Chem Commun, 1994;517-8.
28. Sijbesma R, Srdanov G, Wudl F, Castoro JA, Wilkins C, Friedman SH, et al. Synthesis of a fullerene derivative for the inhibition of HIV enzymes. J Am Chem Soc, 1993;115:6510-2.
29. Fumelli C, Marconi A, Salvioli S, Straface E, Malorni W, Offidani AM, et al. Carboxyfullerenes protect human keratinocytes from ultravioletB-induced apoptosis. J Invest Derm, 2000;115:835-41.
30. Partha R, Conyers JL. Biomedical applications of functionalized fullerene-based nanomaterials. Nanomedicine, 2009;4:261-75.
31. Nakamura E, Isobe H. Functionalized fullerenes in water. The first 10 years of their chemistry, biology, and nanoscience. Acc Chem Res 2003;36:807-15.
32. Markovic Z, Trajkovic V. Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C60). Biomaterials 2008;29:3561-73.
33. Dellinger A, Zhou Z, Connor J, Madhankumar AB, Pamujula S, Sayes CM, et al. Application of fullerenes in nanomedicine: an update. Nanomedicine, 2013;8:1191-208.
34. Dugan LL, Turetsky DM, Du C, Lobner D, Wheeler M, Almli CR, et al. Carboxyfullerenes as neuroprotective agents. S A ,1997;94:9434-9.
35. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol, 2009;7:65-74.
36. Droge W. Free radicals in the physiological control of cell function. Physiol Rev, 2002;82:47-95.
37. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Biochem Cell Biol, 2007;39:44-84.
38. Yang X, Ebrahimi A, Li J, Cui Q. Fullerene-biomolecule conjugates and their biomedicinal applications. Nanomedicine, 2014;9:77-92.
39. Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Investig, 2008;118:1532-43.
40. Gonzalez KA, Wilson LJ, Wu W, Nancollas GH. Synthesis and in vitro characterization of a tissue-selective fullerene: vectoring C(60)(OH)(16)AMBP to mineralized bone. Bioorg Med Chem, 2002;10:1991-7.
41. Berger CS, Marks JW, Bolskar RD, Rosenblum MG, Wilson LJ. Cell internalization studies of gadofullerene-(ZME-018) immunoconjugates into A375m melanoma cells. Transl Oncol, 2011;4:350-4.
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