CN101530636A - 可注射人发角蛋白软组织填充材料的制备方法 - Google Patents
可注射人发角蛋白软组织填充材料的制备方法 Download PDFInfo
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Abstract
本发明涉及医学整形美容技术领域，根据人发对物理、化学因素有高度的抵抗力，性质稳定，耐酸碱，不易被组织吸收降解，获取方便，可以反复取材和便于加工等优点，克服现有的软组织填充材料的不足之处。利用固态的自体人发中段作为原材料，经过清洗、漂白、碾磨加工、冻干、包装、钴60辐照处理，将漂白人发制成不同粗细的粉体匀浆及液态人发角蛋白颗粒，提供一种来源于自体，便于获得，安全无毒，组织相容性好，易于人体耐受，且能够刺激胶原增生的适合于注射的人发角蛋白软组织填充材料。实现皮肤及软组织的长期修复，满足整形美容领域的软组织填充材料的需要。
Description
技术领域
本发明涉及一种医学整形美容用材料，尤其涉及一种来源于自体的适合于注射的可注射人发角蛋白软组织填充材料的制备方法。
背景技术
软组织填充材料在整形外科领域有着广泛而重要的应用。在组织缺损修复、改善面部及身体轮廓的治疗中，通过软组织填充材料可以达到理想的效果；与手术方法相比，注射软组织填充材料的方法简单实用、易于掌握、形态容易控制。
但是这种方法对填充材料的要求很高，理想的充填材料应当具有以下的特点：1)最好是自体的材料，不存在免疫排斥问题；2)能比较长期地存留，但不一定是永久性的；3)无痛苦且放置容易，质地接近正常组织；4)最好能通过注射法置入；5)价格不昂贵，副作用少，不出现皮肤青肿、刺激性、炎症、迁移等。理想的自体注射材料能够提供长期的矫正效果，不需要牺牲额外组织，仅需可以忽略的手术操作获得原始组织，通过适当的处理加工获得无限的产量。
1899年，Gersuny为一位睾丸切除后的年轻男性行阴囊内石蜡注射阴囊充填开始，诞生了注射充填的技术和科学。自从1977年胶原注射材料的出现，许多来源于人体、动物甚至是细菌的天然填充材料应用于临床，如：填充眼睛和唇周围的表浅皱纹和前额、眉间或鼻唇区可见的深层皱纹，矫正凹陷性疤痕或水痘凹窝，医源性或创伤性疤痕和真皮萎缩等。每一种材料都有它们本身的优缺点，如：透明质酸凝胶有较强的异源性且易被吸收；提纯精制的牛胶原，包括Zyderm I(含胶原35mg/mL)、ZydermII(含胶原65mg/mL)和Zyplast(含戊二醛交联的胶原35mg/mL)在组织内存留期仅有6～9月，且会导致1％～3％的健康病人注射区域发生局部过敏反应，表现为暂时性的红斑、搔痒症状、硬结和肿胀等；聚甲基丙烯酸甲酯(PMMA)微粒易导致如过敏反应、毛细血管扩张、肉芽肿形成并发症，且PMMA是惰性材料不能降解，置入后很难取出。注射硅胶的并发症则多见周边组织肉芽肿形成、硬化、皮肤变薄、溃疡形成等；聚丙烯酰胺水凝胶则易导致出血、血肿、感染、局部水肿、硬结和不对称等；膨体聚四氟乙烯(ePTFE)虽性质稳定，组织相容较好，但极易吸附杂质或吸入杂质贮留于其内部微孔之中，使其丧失了良好的组织相容性，且对手术操作要求较高，价格较昂贵；自体脂肪颗粒、自体成纤维细胞溶浆等作为软组织填充材料的远期疗效并不确切。其他异源性材料如Artecoll、透明质酸制剂、纯硅酮、Fibrel、Alloderm、Dermalogen等也面临类似情况，有的已经被美国FDA严令禁止使用。因此寻找一种长期、安全、有效的材料，依然是一个亟待解决的问题。
人发是真皮的演化物，主要成分多硫角质蛋白的肽链间存在着广泛的交联，呈现高度的稳定性，使其对物理、化学因素有高度的抵抗力、性质稳定、耐酸碱、不易被组织吸收降解。人发经戊二醛合剂处理后，角蛋白处于半解聚状态，在体内的降解产物为多种氨基酸，可为迁入的真皮细胞利用，为细胞的生长代谢提供营养。此外，网状的人发还提供了粗支架，利于细胞的迁入。将经特殊处理的人发与细胞共培养，发现人发与成纤维细胞相容性好，且对细胞有吸附性。将人发编织成网状掺入胶原中，在体外可抑制成纤维细胞收缩，同时机械张力还能促进弹性蛋白的表达。已有将人发植入人体填补面部软组织缺损以及应用人发角蛋白作为人工腱修复肌腱及韧带的缺损的临床应用成功的报导。
人发高度的稳定性，无免疫原性及良好的组织相容性，使其作为填充材料具有良好的前景；同时人发具有获取方便、可以反复取材和便于加工等优点，有望利用自体毛发制成填充材料应用于人体自身从而获得满意的填充效果。
发明内容
本发明提供一种可注射人发角蛋白软组织填充材料的制备方法，该填充材料可反复取材，安全无毒，组织相容性好，易于人体耐受，且能够刺激胶原增生。
本发明采用如下技术方案：
一种可注射人发角蛋白软组织填充材料的制备方法，步骤如下：
(1)清洗除杂质：室温下，取人发样品中段，蒸馏水反复清洗，晾干；
(2)脱脂：室温下，将清洗干净的人发浸入乙醇脱脂液，1.5～2h，蒸馏水清洗，干燥；
(3)氯化：NaClO和稀H2SO4，水浴比1:30，室温反应20分钟，流水冲洗；
(4)漂白：采用室温漂白法，清洗干净的人发毛发20～30质量份，质量体积浓度为H2O2 30质量份，焦磷酸钠质量8份，氨水质量60份，过硫酸钾3质量份，室温反应4小时；
(5)清洗烘干：待人发原料色泽变白后，蒸馏水反复清洗，去除残留物，过滤，烘干；
(6)人发角蛋白颗粒的制备：漂白烘干后的人发，按质量体积比为12～15：100的比例，将人发与生理盐水混合，经碾磨加工8～12h，形成粒径约60～80um的人发角蛋白颗粒匀浆，钴60辐照灭菌。
与现有技术相比，本发明具有如下优点：
人发对物理、化学因素有高度的抵抗力，性质稳定，耐酸碱，不易被组织吸收降解，获取方便，可以反复取材和便于加工等优点，克服现有的软组织填充材料的异源性且易被吸收、易过敏、易导致出血、血肿、感染、局部水肿、硬结和不对称等；且对手术操作要求较高，价格较昂贵或远期疗效并不确切等不足之处。本发明来源于自体，便于获得，安全无毒，组织相容性好，易于人体耐受，且能够刺激胶原增生的适合于注射的人发角蛋白软组织填充材料。从而实现皮肤及软组织的长期修复，满足整形美容领域的软组织填充材料的需要。
具体实施方式
一种可注射人发角蛋白软组织填充材料的制备方法，步骤如下：
(1)清洗除杂质：室温下，取人发样品中段，蒸馏水反复清洗，晾干；
(2)脱脂：室温下，将清洗干净的人发浸入乙醇脱脂液，1.5～2h，蒸馏水清洗，干燥；
(3)氯化：NaClO和稀H2SO4，水浴比1:30，室温反应20分钟，流水冲洗；
(4)漂白：采用室温漂白法，清洗干净的人发毛发20～30质量份，质量体积浓度为H2O2 30质量份，焦磷酸钠质量8份，氨水质量60份，过硫酸钾3质量份，室温反应4小时；
(5)清洗烘干：待人发原料色泽变白后，蒸馏水反复清洗，去除残留物，过滤，烘干；
(6)人发角蛋白颗粒的制备：漂白烘干后的人发，按质量体积比为12～15:100的比例，将人发与生理盐水混合，经碾磨加工8～12h，形成粒径约60～80um的人发角蛋白颗粒匀浆，钴60辐照灭菌。
取20g中段人发经脱脂洗涤烘干后，氯化(0.32％NaClO、0.5％H2SO4，水浴比1:30，20℃，20分钟)，流水冲洗，双蒸水浸泡3次后，漂白(30％H2O2，焦磷酸钠8g/l，过硫酸钾3g/l，氨水14g/l，浴比1:100，40℃水浴，3.5h。)在本实施例中，可以在将匀浆进行钴60辐照灭菌之前，将匀浆移至液氮罐中，冻干，钴60辐照后4℃保存。
实施例一
1.1 实验材料，试剂和仪器
CO2细胞培养箱(Heal Force BB16UV HongKong)，相差显微镜(NikonEclipse TS100日本)，96孔板，DMEM培养基(Gibco公司美国)，胎牛血清(杭州四季清)，PBS缓冲液，MTT(溴化-3-(4-5-二甲基噻唑基-2)2，5二苯基四唑，Sigma公司美国)浓度为5mg/ml(0.5％)，过滤除菌，DMSO(Sigma公司，美国)，生理盐水，高压灭菌，30％过氧化氢，浓氨水，过硫酸钾。
1.2 人发处理
取20g中段人发经脱脂洗涤烘干后，氯化(0.32％NaClO，0.5％H2SO4，水浴比1：30，20℃，20分钟)，流水冲洗，双蒸水浸泡3次后，漂白(30％H2O2，焦磷酸钠8g/l，过硫酸钾3g/l，氨水14g/l，水浴比1∶100，40℃水浴3.5h)，30℃烘干，称重并取1g试样用作制备粉体材料浸提液，其余分为两等份。取其中一半试样，按14％的浓度与生理盐水混合并分为3等份，分别加工8、6、4h，得到粗、中、细三种形态粉体匀浆。另一半试样制备人发角蛋白凝胶。
1.3 试样浸提液制备
人发角蛋白凝胶经液氮冷冻固化后粉碎，取1g加入10ml生理盐水中，振荡混匀后在细胞培养孵箱中37℃放置7d，离心后吸出上清液，制备凝胶浸提液原液(初始100％浓度材料∶浸液＝100mg/ml)；人发漂白试样取1g加入10ml生理盐水中，同法制备粉体浸提液原液，过滤除菌备用。
1.4 体外急性全身毒性试验
选用健康小白鼠24只，体重在20g左右，雌雄各半，随机分为3组，每组8只，记录初始体重.试验组小鼠腹腔分别注射凝胶和粉体的浸提液原液(100％)，上下午各1次，每次0.5ml/10g，连续7天；对照组小鼠取浸提介质生理盐水腹腔注射，方法同上。于每次注射后即刻，4h，24h，48h和72h观察小鼠一般状态及毒性表现和死亡数。并分别于实验开始之后第3天，第5天，第7天观察并记录各组小鼠体重变化。
1.5 小鼠骨髓嗜多染红细胞(PCE)微核试验
选体重在20g左右的健康小鼠20只，雌雄各半，随即分为4组，每组5只.分别为凝胶浸液组，粉体浸液组，阳性对照组和阴性对照组。两实验组按0.5ml/20g量分别腹腔注射凝胶组和粉体组浸提液原液；阴性对照组给予生理盐水(0.5ml/20g腹腔注射)；阳性对照组给予环磷酰胺(40mg/kg，腹腔注射)。各组均间隔24小时给样，第二次给样后6小时处死小鼠，胸骨骨髓涂片，吉姆萨染色，镜检。每只动物计数1000个骨髓的嗜多染红细胞(PCE)，记录含有微核的PCE细胞数，计算微核率。(微核率指含有微核的嗜多染红细胞数，以千分率(‰)表示)
1.6 MTT比色法测细胞毒性实验
受试液的制备：将浸提液原液(100％)和DMEM培养基1∶1混合稀释，为50％浓度；将浸提液原液和DMEM培养基1∶3混合稀释，为25％浓度；对照组加入浸提介质∶生理盐水。收集对数期L-929细胞，以5×104个/ml密度接种于96孔板，每孔100ul，分为4组(3个浓度组+对照组)，每组重复8孔。置37℃，5％CO2培养箱培养24小时，弃去原液，每孔换入100ul新培养液，实验组每组各孔再加入100ul 100％、50％、25％的相应受试液，对照组加同量的生理盐水。置37℃，5％CO2培养箱培养，于培养的第3天，第5天和第7天分别取出一块96孔板，弃去每孔上清110ul，加入10ulMTT(0.5％MTT)，置箱中培养4小时，取板，小心吸去孔内上清，每孔加入DMSO150ul，再放入37℃，5％CO2培养箱中孵育15分钟，尽快测定光度值(OD值)，测定波长为490nm，参考波长为540nm。
2 结果
2.1 人发材料的大体观察：
经漂白，不同球磨时间的人发粗、中、细三种粉体匀浆和液态人发角蛋白凝胶都具有较好的流动性和粘滞性，适合注射，且原发中的黑色素含量都已浅化，可以用来填充于面部等较为表浅的层次。
通过x20倍显微观察，除细态粉体材料中有部分人发断片细小，不易观察到之外，粗、中材料中的人发断片都保持人发原有稳定的束状结构，这将有利于延缓注入组织后的降解从而延长填充的持续时间。将人发材料通过不同方法制成粗细各异的粉体和角蛋白凝胶两种不同形式的材料，可在以后的动物皮下填充实验中互作对照，以寻求符合注射要求而又有最好填充效果的人发材料的形态。
2.2 小鼠急性全身毒性试验
小鼠一般情况较好，7天观察期内无死亡，72h观察期内各组动物未见中毒症状或不良反应，无死亡，体重增长正常，方差分析表明两试验组与生理盐水组之间小鼠体重变化不存在明显差异，这表明人发凝胶和粉体两种形式材料浸提液均无急性毒性作用。
2.3 小鼠骨髓嗜多染红细胞(PCE)微核试验
粉体组和凝胶组的微核发生率与阴性对照组无显著差异(P>0.05)，而与阳性对照组比较差异显著(P<0.01)，则两组受试物小鼠骨髓嗜多染红细胞微核实验呈阴性，说明人发凝胶组和粉体组无致染色体畸变毒性作用。结果：见表1
表1 骨髓嗜多染红细胞(PCE)微核试验结果
2.5MTT比色法测细胞毒性实验
按公式:RGR＝材料各浓度组吸光度/阴性对照组吸光度×100％计算细胞相对增殖度(RGR)，并依据细胞相对增殖率与细胞毒性分级的关系转换成细胞毒性分级。结果表明，人发凝胶和粉体两种形式材料的不同浓度浸提液在三个时间点测得的细胞相对增殖率均达80％以上，细胞毒性分级为一级，说明具有良好的细胞相容性，无细胞毒性。见表2
表2-1 凝胶MTT结果统计分析
表2-2 粉体MTT结果统计分析
实施例二
1 动物模型制备
在每只兔背部取毛区沿中轴线左右两侧标记5个注射部位，备皮后用8号针头在其皮下分别注射制备的A、B、C、D四种自体兔毛角蛋白粉体匀浆材料约2.5ml，使之形成直径约2cm的皮下隆起，另外一个部位注射生理盐水做对照。采用Marler等人设计的软组织填充材料注射动物模型对材料的体内吸收性进行考察。使用游标卡尺测量注射后第i月皮丘参数：皮丘长度ai、皮丘宽度bi、皮丘高度ci，计算皮丘体积Vi(式1)，及皮丘体积保持率δi(式2)。δ越高，表明材料的吸收率越低。计算A、B、C、D四种δ值，并记录其动态变化。
式1∶Vi＝2/3πaibici(i＝1，2，3，...)
式2：δi＝Vi/V0×100％(i＝1，2，3，...)
2 一般情况观察
动物活动及进食皆正常，背部材料注射区皮肤无红肿无渗液等炎症反应，皮丘触之皆软于正常皮肤组织；随观察时间的增长，A、B、C、D四种材料的皮丘质地也逐渐变韧，第12周时，触之已似正常皮肤组织；至注射后第28周后，材料A注射部位逐渐形成一个皮下硬结，而B，C、D三种皮丘质地较前变化并不明显。
3 材料吸收性观察
除生理盐水皮下注射后约3小时可完全吸收外，从总体趋势看，相比A、B、C三种材料，D材料吸收降解较快，注射14周后已基本被吸收。A、B、C三种材料则吸收相对缓慢。注射后12周时的数据表明D材料平均δ值(21％)远低于A、B、C三种(δ均值分别为77％，80％和73％)，统计分析表明，该差别具有显著性意义(P<0.001)，而各时段的A、B、C三种之间δ均值无显著差异(P>0.05)。
4 组织学观察
1周，A、B、C、D四种材料周围有少量炎性细胞浸润，以中性粒细胞为主，材料内部亦有少量成纤维细胞长入。
4周(1个月)，A、B、C、D四种材料周围组织内炎性细胞较前已明显减少，其周围有菲薄的纤维包膜形成，尤其以材料A为明显。
12周(3个月)，A、B、C、D四材料周围纤维增生，纤维包膜较前有所增厚，依然以材料A明显，且这四种材料内部纤维成份亦有所增多，周围未见炎性细胞浸润。
24周(6个月)，材料A周围有纤维包膜形成，B、C材料周围纤维包膜增厚不明显；材料D此时已基本被吸收。
以自体毛发为原料制备的四种填充材料，除颗粒A在后期之地较硬外，B、C、D三种粒径的毛发角蛋白颗粒填充局部的质地均接近正常软组织，有较好的填充效果。既保持了毛发原有的较稳定的结构，又能满足于注射填充的使用要求，局部组织反应轻，生物相容性好，其中B、C颗粒注射后有效的填充维持时间能达到大约为12个月，在12个月的观察周期后在动物皮下仍存留40％，并且吸收情况呈现平台期。
上述结果显示：在此部分我们已探索出一套毛发角蛋白颗粒匀浆的制备方法，并通过不同粒径毛发角蛋白颗粒的吸收情况的比较，寻找到了较为理想的作为填充材料和作为载体的毛发颗粒粒径范围，可以根据患者的要求并且根据具体情况，分别选取不同粒径的毛发角蛋白颗粒进行填充。
Claims (2)
1、一种可注射人发角蛋白软组织填充材料的制备方法，其特征在于，步骤如下：
(1)清洗除杂质：室温下，取人发样品中段，蒸馏水反复清洗，晾干；
(2)脱脂：室温下，将清洗干净的人发浸入乙醇脱脂液中1.5～2h，用蒸馏水清洗后干燥；
(3)氯化：NaClO和稀H2SO4，水浴比1∶30，室温反应20分钟，流水冲洗；
(4)漂白：采用室温漂白法，清洗干净的人发毛发20～30质量份，质量体积浓度为H2O230质量份，焦磷酸钠质量8份，氨水质量60份，过硫酸钾3质量份，室温反应4小时；
(5)清洗烘干：待人发原料色泽变白后，蒸馏水反复清洗，去除残留物，过滤，烘干；
(6)人发角蛋白颗粒的制备：漂白烘干后的人发，按质量体积比为12～15∶100的比例，将人发与生理盐水混合，经碾磨加工8～12h，形成粒径约60～80um的人发角蛋白颗粒匀浆，钴60辐照灭菌。
2、根据权利要求1所述的可注射人发角蛋白软组织填充材料的制备方法，其特征在于在将匀浆进行钴60辐照灭菌之前，将匀浆移至液氮罐中，冻干，钴60辐照后4℃保存。
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| CN1274567A (zh) * | 1999-05-25 | 2000-11-29 | 中国人民解放军第一军医大学 | 人发角蛋白人工腱的制作方法及其工艺 |
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