CN1277585C - 用于毛发组织工程的支架 - Google Patents

用于毛发组织工程的支架 Download PDF

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CN1277585C
CN1277585C CNB01816580XA CN01816580A CN1277585C CN 1277585 C CN1277585 C CN 1277585C CN B01816580X A CNB01816580X A CN B01816580XA CN 01816580 A CN01816580 A CN 01816580A CN 1277585 C CN1277585 C CN 1277585C
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托马斯·H·巴罗斯
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Abstract

本发明为用于人发毛囊组织工程的多孔的、可生物吸收的支架，用于生产它们的方法以及它们在产生新头发时的使用方法。

Description

用于毛发组织工程的支架
发明背景
男性型秃发为常见症状，常常通过毛发移植手术治疗。该方法将来自非光秃头皮区域内的毛囊切下并且再植入光秃区，以使整个头部充满毛发，事实上，由于该方法没有产生新的毛发，而且用于再分布的毛囊的数目有限，满头毛发只是一种错觉。因此，本发明提供一种刺激头皮中的大量新的毛囊生长的方法，满足了治疗秃头的需要。
发明内容
本发明涉及毛囊的组织工程再生中使用的可生物吸收的支架和生产它们的方法，以及它们在产生新毛发中的使用方法。更具体地说它涉及新的、有益的和可生物吸收的多孔结构，该结构能够促进合适的毛囊祖细胞发育成为正常的、功能性的、能够产生毛发的毛囊。本发明还涉及制备可生物吸收的支架、移植和促进新的毛囊在体内或体外生长的方法。
附图的简要描述
图1为模型(form)1的剖视图，其中多孔聚合物前体5涂敷在模型1末端4上。
图2为多孔支架8的剖视图，一层毛囊祖细胞9衬在该多孔支架的内表面10。
图3为可生物吸收的多孔聚合物材料的无纺织网12的侧面的三维视图。
图4为用于形成多孔支架的模型的截面侧视图，包括顶板14，该顶板的底面15具有从该顶板底面伸出的模型16，该模型还包括底板17，该底板上部18具有凹坑19，设计为在与顶板14的模型16对齐时可以接受模型16。
图5为无纺织网12’的俯视图，该网已经在图4模型中压模及加热，在无纺织网中形成凹坑。
图6为转入细胞培养皿小孔22后的支架组8’的剖视图。
发明的详细说明
在一个方面，本发明包括多孔的可生物吸收的支架，它具有近似正常毛囊发根的形状，目的是当种植毛囊细胞并且植入活的宿主皮内时促进毛发毛囊的形成。
本发明支架优选包括可生物吸收的聚合物，可以从用于临床实践和生物医学研究的各种合成的和天然的聚合物中选择。该支架由如下的聚合物中优选组成，其中包括聚(乳酸)，聚(羟基乙酸)，聚(三亚甲基碳酸酯)，聚(氨基酸)，酪氨酸衍生的聚(碳酸酯)，聚(碳酸酯)，聚(己内酯)，聚(对-二噁烷酮)，聚(酯)，聚(酯-氨基)，聚(酸酐)，聚(邻位酯)，聚(氨基酸)，胶原，凝胶，血清白蛋白，蛋白质，碳水化合物，聚(乙二醇)，聚(丙二醇)，聚(丙烯酸酯)，聚(甲基丙烯酸酯)，聚(乙烯醇)，和上述聚合物的共聚物、混合物。
该支架由合成聚合物组成时，该合成聚合物优选由下列单体中优选任何一个或组合形成：L-丙交酯，d，l-丙交酯，乙交酯，三亚甲基碳酸酯，己内酯，和对-二噁烷酮，还有其他优选的用于制备本发明支架的合成聚合物包括聚(乙二醇)，聚(乙烯醇)，聚(丙烯酸)及其他与可降解的交联物连接的水溶性聚合物和已经修饰并可支持细胞附着的可生物吸收的水凝胶。
当该支架由交联的或者不能溶解的天然存在的聚合物组成时，最好选用透明质酸，人血清白蛋白，胶原，凝胶，纤维素衍生物，淀粉，糊精，脱乙酰壳多糖，及其它的蛋白质，糖蛋白，脂蛋白，多糖和生物聚合物。
本发明的支架优选具有一个内表面，其形状适宜，刚好对应于毛发根的外表面。该支架的内表面优选为多孔物质，在例如细胞培养物溶液中与毛囊彼此接触时，该支架的多孔性优选足以使毛囊细胞被支架内表面吸附。
根据本发明的多孔的可生物吸收的支架的制备方法公开如下。该方法包括在可生物吸收的物质中产生孔隙的方法和将上述多孔支架模制、成形、或造型成为所需要的结构的方法。由于预期用本申请公开的方法的变化方法也可以产生的支架，或修改已知的用于生产多孔聚合物的方法产生支架，本发明不局限于根据以下本申请公开的具体的方法制造的支架。
可以用各种不同的方法来产生本发明支架的孔隙。产生孔隙的优选方法包括使用“发泡剂”。它们是化学添加剂，在已知温度分解，放出气体，在熔融聚合物中产生泡沫并且在所得的冷却的物质中产生孔隙。大量有用的发泡剂可从市场上买到，其商品名为CelogenTM(UniroyalChemical Co.公司出品)。一个传统发泡剂的例子是偶氮甲酰胺。另一种由于其与可生物吸收的聚合物的兼容性而对本发明特别有用的发泡剂是公开于美国专利4,104,195的脲二羧基酸酐，该文献作为参考编入本申请。使用发泡剂既可以产生开放泡沫也可以产生闭合泡沫。本发明需要开放泡沫，不需要闭合泡沫。因此用于生产多孔敷层的条件应适于产生“网状的”泡沫的开放结构。该支架的孔隙互相连通，孔隙的大小范围在0.1到1000微米，在1到500微米更好。
在另一个具体方案中，该支架的孔隙由支架具有的纤维结构产生。当该支架具有纤维结构时，纤维结合在一起。这些纤维由核和鞘结构组成，所述的鞘熔点比所述的核熔点低，并且通过该鞘中的接触点结合在一起。
一种优选的制备本发明支架的方法，(下文中称为“溶解法”)包括下列步骤：
1.提供一种可溶于溶剂(溶剂A)的可生物吸收的聚合物。
2.提供一种支架形状的模型，该物质可溶于不同的溶剂(溶剂B)而基本上不溶于溶剂A。
3.在支架上涂敷形成孔隙的物质颗粒，该物质可溶于溶剂B或可溶于第三种溶剂(溶剂C)。
4.将可生物吸收的聚合物溶解于溶剂A，并且将所得溶液涂敷于被颗粒覆盖的模型。
5.通过蒸发或其他合适的方法除去溶剂A。
6.使用溶剂B溶解上述模型和上述颗粒。
7.除去完成的多孔支架中的溶剂B。
8.如果需要的话，另外使用溶剂C去除上述颗粒。
图1图示了该溶解法，图1中显示涂有多孔聚合物前体5的具有末端4的模型1的横截面，前体5为形成孔隙物质的颗粒和该聚合物在溶剂A中的溶液的混合物。注意，模型1的末端4是球形的，并且包括大小足以使一些多孔聚合物前体5进入该腔的腔3。如上所述，一旦从图1中的多孔聚合物前体5形成多孔聚合物，该模型就已溶解，所得的多孔支架可以接种毛囊祖细胞以及按如下所述的方式使用。
图2是显示如上所述的通过溶解以及洗掉孔隙形成物质和模型而只剩下可生物吸收的聚合物、从而得到的多孔支架8的剖视图。所显示的支架8的内表面10上接种有毛囊祖细胞9，它具有适应该支架的形状。显示于图2的结构可以直接植入皮肤，促进从组织工程毛囊生长新的单个的毛发纤维。然而，为了更好地保证移植的工程毛囊的成熟，显示于图2的结构最好在植入之前使用另外的细胞培养。
如上所述，可用于产生模型的物质和可选择用作溶剂B的物质包括下列组合：聚(环氧乙烷)和水；石蜡和己烷；以及聚苯乙烯和丙酮。孔隙形成物质和模型物质必须选自在溶剂A中具有低溶解度，用于引导可生物吸收的聚合物进入该结构的物质。这些选择在以下表1中进一步举例说明，其中使用缩写PLGA为乳酸和乙醇酸的共聚物，PEO为聚(环氧乙烷)。
表1.
可生物吸收的聚合物 模型材料 孔隙形成物质   溶剂A   溶剂B   溶剂C
PLGAPLGA胶原 PEO蜡蜡 氯化钠葡萄糖聚苯乙烯   丙酮丙酮水   水己烷己烷   水水丙酮
溶解法的一种变型的例子是将建立所需要结构的步骤与用祖细胞接种的步骤的顺序颠倒。因此，多孔支架结构可以首先做成圆盘形状，例如将聚合物加入有机溶剂，将溶液倒入具有适当大小的盐粒的圆筒形容器，接着蒸发上述溶剂并且通过溶解和用水冲洗来除去盐。
然后可将所得到的高孔隙度支架灭菌，并且用微解剖的人类真皮乳头或其他合适来源的毛囊祖细胞接种和体外培养，直到整个多孔结构都繁殖了培养细胞。然后，可将该组织工程构造切成大量片段，每个约为正常人类真皮乳头大小。这些不规则形状的片段可以被悬浮在培养基中并且进一步培养，直到得到需要的平滑的表面结构。这些组织工程真皮乳头可以被植入或注入皮肤，启动用于毛发恢复的毛囊再生过程。
另外，本发明多孔支架还可以根据下列方法(下文中称为“溶解法”)制造，该方法包括下列步骤：
1.提供一种薄的、可生物吸收的纤维的无纺织网。
2、将上述的网放置在模型上，模型分两部分，在一部分具有空腔，另一部分具有配对造型，所述的空腔和造型提供所需支架需要的形状和大小。
3.合拢该模具并且提供足够的热和压力以便使该网成为所需多孔结构。
4.从模具中取出该网并且从该网冲切(die-cut)模制的支架。
该无纺织网包括具有核心/鞘结构的纤维和没有核心/鞘结构的纤维，具有该结构的纤维的核心具有比鞘更高的熔解温度。无纺织网中的纤维借助一种溶剂或溶于溶剂的另一个聚合物结合在一起。
图3-6图示了产生本发明支架的模制方法的应用。图3显示可生物吸收的纤维的无纺织网12。图4显示包括两部分的模型，包括顶板14和底板17。顶板的特征为底面15具有一系列从其中伸出的模型16。底板的顶面18具有容纳上述模型的许多凹坑19。图5为无纺织网12’的小角度俯视图，该网已经在图4的模子中被压缩和加热，从而产生了凹坑20，也就是说被模制成为用于组织工程毛发的支架所需要的形状。图6显示模制的支架8’，在通过冲切机从图5的无纺织网12’中的凹坑20剪下后，转入培养皿23的小孔22。小孔22用来容纳支架8或8’、培养基、以及细胞。
以上公开的模制生产方法特别适用于大规模和批量生产。例如，图4显示的两部分模型可以为双筒而非两个平面板。当通过两个反转滚筒压缩和加热时，网可以为连续的带状物，可以具有凸起图案。切割装置也可以安置在滚筒上以切割出支架结构。该自动装配流程的下一步骤为将该支架放进入预先在聚酯薄膜中形成的细胞培养小孔。载荷该支架的薄膜可以被切割及封装到托盘里，进行另外的封装和灭菌。
其他用可生物吸收的物质产生多孔支架的方法也可用于实施本发明。Y.S.Nam和T.G-Park的文章“Porous biodegradable Polymeric scaffoldsprepared by thermally induced phase separation(热诱导的相分离技术制备多孔的生物可降解的聚合物支架)”(刊载于The Journal of BiomedicalMaterials Research(生物医学材料研究)，1999年10月，vol.47，no.1，第8-17页)中论述了如乳剂冷冻干燥、高压缩气体中的扩张、3-D复制和相分离技术的方法。该文献作为参考加入本说明书中。
上述相分离技术方案使用聚(d，l-丙交酯-co-乙交酯)(PLGA)作为构架聚合物，使用聚(乙二醇)(PEG)作为多孔试剂(porogen)。因此PLGA和PEG的混合物可以被溶于二氯甲烷得到透明溶液，然后应用于由不溶于二氯甲烷却溶于水的物质，例如糖制成的支架模型。蒸发二氯甲烷，PEG通过结晶和PLGA分离。如果该模型由糖组成，水浸渍溶出PEG，该模型留下所得需要的多孔的PLGA支架。
本发明的支架可以很多方式用于制造新的毛囊。一般说来，可以将合适的细胞接种在该支架上，既可立即植入到头皮里，也可在植入之前将该支架在培养液中增殖。该植入方法与目前用于单个毛囊植入或“小移植”的毛发移植手术相同。例如，可使用激光在头皮中钻一个具有精确的预定深度的小孔，然后将接种细胞的支架简单地植入该小孔中。当这些植入的细胞生长时，它们构成新的毛囊的起源。当植入物发育成熟成为正常的，产生头发的毛囊后，该可生物吸收的支架降解。
用于接种该支架的细胞可以取自患者活体解剖的毛囊或器官捐献者的毛囊。根据近来的研究结果，选择后者是可行的。捐献者的毛囊祖细胞被成功地移植到无血缘关系的接受者上，在那里开始形成生长毛发的新的毛囊。该发现称为“Trans-gender induction ofhair follicles(毛囊的跨性别诱导)”，由A.M.Reynolds，C.Lawrence，P.B.Caerhalmi-Friedman，A.M.Christiano和C.A.B.Jahoda报道于Nature(《自然》)，402，33-34，1999年11月4日，该文献作为参考加入本说明书中。本发明与众不同的特点是在将细胞接种在支架之前就在培养液中增殖细胞。这既最大限度地增加了接种毛囊的支架的数目又最大限度地减少了得到需要的毛囊祖细胞的解剖工作。
实施例
实施例1：
将从Aldrich Chemical Co.公司(Milwaukee，WI 53201)购买的100,000分子量的聚环氧乙烷)(下文中，“PEO”)熔化延伸成为1.0mm直径的细丝并且切成2厘米长度。一根PEO细丝浸到水里，其表面水合并且产生粘性。然后将其浸到已经在电动咖啡豆磨床中研磨成微粒的氯化钠结晶里。抖落过量盐并且使涂层干燥。将10％(w/v)聚(d，l-丙交酯-co-50％-乙交酯)(PLGA)(Resomer RG504，Boehringer mgelheim，德国)在丙酮(Aldrich Chemical Co.公司)中的溶液滴在PEO细丝结壳的盐上并且允许过量溶液逸出。将另外的粉盐撒在该表面上直到它完全被覆盖。丙酮蒸发后，涂覆的PEO细丝置于水中直到所有盐和PEO溶解，剩下多孔PLGA空心丝，将其清理，压平，并且用锋利的刀刃切成细条。将该条卷在手指和大拇指之间并且切成2毫米长度。如上所述产生的多孔PLGA空心丝如下述用来制造用于本发明支架的模型。
本发明支架的生产过程如下。通过压模加热的约2毫米的PEO针状物，在另一个PEO细丝的末端产生直径0.3毫米的同心孔穴。这引起熔化的PEO堆积在该细丝侧面的周围。冷却后去掉该针。然后用上述卷着的多孔PLGA条充满该孔穴。如上所述，然后用盐和PLGA溶液涂敷所得PEO细丝的末端。蒸发丙酮并且将所有盐和PEO溶解在水中，进行干燥，得到需要的多孔的可生物吸收的聚合物支架。
实施例2：
解剖人发毛囊得到真皮乳头，转入含培养液的培养瓶。培养几个星期后，真皮乳头细胞增殖并且长满该细胞培养瓶的表面。通过用酶处理将这些细胞从该瓶分开并且离心浓缩。再悬浮后，通过移液管将该细胞转移进入实施例1的支架，并且将细胞接种的支架放入具有介质的培养瓶中，培养若干天，使细胞粘附在支架的表面。然后在轻柔的搅拌下在另一个瓶子的介质中继续培养细胞接种的支架，直到该支架充满了繁殖细胞。
实施例3：
将实施例2公开的接种细胞的支架植入缺失毛发的人的头皮。经过一段时间，随着新毛囊的产生，新的毛发从植入物中生长出来，并且该支架被生物吸收。

Claims (20)

1.一种包括可生物吸收聚合物和毛囊祖细胞的支架，其中所述支架具有大致毛囊的形状和多孔性。
2.权利要求1所述的支架，其中所述支架的内表面的形状与毛囊发根的外表面相同。
3.权利要求1或2所述的支架，其中所述的可生物吸收聚合物包括由一个或多个单体合成的聚合物，所述单体包括：L-丙交酯，d，l-丙交酯，乙交酯，三亚甲基碳酸酯，己内酯，和对二噁烷酮。
4.权利要求3所述的支架，其中所述的聚合物是d，l-丙交酯和乙交酯的共聚物。
5.权利要求1或2所述的支架，其中所述的可生物吸收的聚合物是胶原。
6.权利要求1或2所述的支架，其中所述的多孔性为大小范围为0.1到1000微米的连通的多个孔隙。
7.权利要求6所述的支架，其中所述的孔隙的大小范围为1到500微米。
8.权利要求1或2所述的支架，其中所述的支架具有纤维结构。
9.权利要求8所述的支架，其中所述的纤维结构包括结合在一起的纤维。
10.权利要求9所述的支架，其中所述的纤维包括核和鞘结构，所述的鞘熔点比核的熔点低，并且核和鞘通过联结点处纤维间缝结合在一起。
11.制备支架的方法，所述支架包括可生物吸收聚合物和毛囊祖细胞，并且具有大致毛囊的形状和多孔性，所述方法包括以下步骤：
a.提供一种溶于第一溶剂的可生物吸收的聚合物；
b.提供一模型，其具有大致毛囊的形状，并包括溶于第二溶剂而不溶于所述第一溶剂的物质；
c.在所述模型上涂敷一种孔隙形成物质的颗粒，该物质溶于第二溶剂或溶于第三溶剂；
d.将可生物吸收的聚合物溶解于第一溶剂，并且将所得溶液涂敷于所述颗粒涂敷的模型；
e.除去第一溶剂；
f.使用第二溶剂溶解上述模型和上述颗粒；
g.除去支架中的第二溶剂；
h.将毛囊祖细胞种植于支架中。
12.权利要求11所述的方法，进一步包括在种植毛囊祖细胞于支架前用第三溶剂移出所述颗粒的步骤。
13.权利要求11或12所述的制备支架的方法，其中所述的可生物吸收的聚合物是d，l-丙交酯和乙交酯的共聚物，所述的孔隙形成物质是聚乙二醇，所述的模型由糖制成，所述的第一溶剂是二氯甲烷，所述的第二溶剂是水。
14.制备支架的方法，所述支架包括可生物吸收聚合物和毛囊祖细胞，并且具有大致毛囊的形状和多孔性，所述方法包括以下步骤，
a.提供溶于第一溶剂并且不溶于第二溶剂的可生物吸收的聚合物；
b.提供大致毛囊的形状的模型，此模型由溶于第二溶剂而不溶于第一溶剂的物质制成；
c.提供溶于第一和第二溶剂的孔隙形成物质；
d.用将所述可生物吸收的聚合物和孔隙形成物质溶于第一溶剂而形成的溶液涂敷所述模型；
e.除去所述第一溶剂，以使上述孔隙形成物质与所述可生物吸收的聚合物进行相分离；
f.使用第二溶剂溶解所述模型和所述孔隙形成物质；
g.从完成的支架中除去所述第二溶剂；
h.将毛囊祖细胞种植于支架中。
15.权利要求14所述的制备支架的方法，其中所述的可生物吸收的聚合物是d，l-丙交酯和乙交酯的共聚物，所述的孔隙形成物质是聚乙二醇，所述的模型由糖制成，所述的第一溶剂是二氯甲烷，所述的第二溶剂是水。
16.制备支架的方法，所述支架包括可生物吸收聚合物和毛囊祖细胞，并且具有大致毛囊的形状和多孔性，所述方法包括以下步骤，
a.提供薄的、可生物吸收的纤维的无纺织网；
b.将上述的网放置在模型上，模型分两部分，其中一部分具有空腔，另一部分具有配对造型，所述的空腔和造型具有大致毛囊的形状；
c.合拢该模型并且提供足够的热和压力以便将所述网形成大致毛囊的形状；
d.从模型中取出所述网并且从该网中移出所述支架；及
e.将毛囊祖细胞种植于支架中。
17.产生新毛发的方法，包括
植入包括可生物吸收聚合物和毛囊祖细胞，并且具有大致毛囊的形状和多孔性的支架于需要生长新毛发的皮肤处。
18.权利要求17所述的方法，其中所述的毛囊祖细胞从正常的毛囊内的亚结构中获得，已知正常的毛囊包括毛囊祖细胞。
19.权利要求18所述的方法，其中所述的祖细胞在所述支架上接种前在培养液中增殖。
20.权利要求17所述的方法，其中所述的植入所述支架的方法相当于目前用于在头皮中植入单根头发的毛发移植手术的过程。
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