CN108883572A - 用于3d打印的水凝胶材料的方法和装置 - Google Patents

用于3d打印的水凝胶材料的方法和装置 Download PDF

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CN108883572A
CN108883572A CN201780020996.4A CN201780020996A CN108883572A CN 108883572 A CN108883572 A CN 108883572A CN 201780020996 A CN201780020996 A CN 201780020996A CN 108883572 A CN108883572 A CN 108883572A
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C.W.赫尔
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Abstract

提供了用于物体的3D打印的3D打印系统、方法和材料,所述材料包括固化的水凝胶材料、未固化的水凝胶材料和载体材料。固化的水凝胶材料可限定用于器官或其它生物结构的支架。该3D打印系统选择性地沉积水凝胶材料和载体材料、干燥水凝胶材料和选择性地将催化剂施加至水凝胶材料,以选择性地固化水凝胶材料。一旦3D打印已完成,可排出未固化的水凝胶材料并可使载体材料熔融或溶解,留下固化的水凝胶材料的支架,可用所需器官或生物结构的活细胞对其进行输注。

Description

用于3D打印的水凝胶材料的方法和装置
相关申请的交叉引用
本申请依据35 U.S.C. § 119对2016年1月28日提交的美国临时专利申请序列号62/288,043要求优先权,其通过引用以其全部并入本文。
发明领域
本发明涉及水凝胶材料的3D打印,且更具体涉及后续可用活细胞输注的支架的3D打印。
发明背景
对功能性生物结构(例如肺和其它器官)存在着需求,并且迄今为止对于3D打印此类结构或支架的尝试尚不充分。
发明简述
通过提供用于产生3D打印的水凝胶材料支架的3D打印系统、方法和材料,本发明的各种实施方案致力于以上需求并实现其它优点。在本发明的一种实施方案中,3D打印系统包括:(a)平台,在3D打印过程期间其上可承载3D打印的物体;(b)打印部分,其选择性地在平台上沉积一种或更多种水凝胶材料和载体材料;(c)干燥器部分,其包括干燥器并且平台可经过干燥器部分,以干燥平台上的材料的至少一部分;和(d)引发部分,其包括催化剂源,该催化剂源选择性地将催化剂施加至平台上的材料,以在水凝胶材料的至少一部分中引起反应,其中将催化剂选择性地施加至平台上的一些但非全部的暴露的水凝胶材料。
进一步的实施方案包括通过以下步骤来3D打印3D物体的方法:(a)在平台上选择性地沉积水凝胶材料层和载体材料;(b)干燥水凝胶材料层的至少一部分;(c)选择性地将催化剂施加至水凝胶材料层的至少一部分;和(d)重复针对3D打印的物体的多个层的沉积、干燥和施加。
仍进一步的实施方案包括3D打印的物体,其包括支架部分,其包括固化的水凝胶材料;在支架部分中的通道,其包括未固化的水凝胶材料;以及载体结构,其包括载体材料。可将未固化的水凝胶从固化的水凝胶材料中除去,以在支架内提供通道,并可将载体材料从支架中除去。因此,本发明的各种实施方案提供了对于可用活细胞输注以提供有生存力的生物结构的支架的结构、可制造性和性能的改善。可使用本发明的3D打印系统、方法和材料来制备还有其它的3D打印的物体。
附图的若干视图的简述
已经如此概括地描述了本发明,现在将参考附图,其不必需按比例绘制,并且意在例示而非限制,其中:
图1是根据本发明的一种实施方案的3D打印系统的示意性侧视图,其中包在载体材料中的3D打印的支架示于高分辨率成像区域与喷墨打印区域之间的干燥区域中。
发明详述
现在将参考附图在下文中更加充分地描述本发明,在附图中显示了本发明的一些但非全部的实施方案。实际上,本发明可按许多不同的形式来体现,并且不应被解释为局限于本文中所阐述的实施方案;相反,提供这些实施方案以致本公开将满足适用的法律要求。虽然针对生物结构(包括器官、皮肤组织等等)的支架的特定类型在附图中描述并显示了用于提供3D打印的水凝胶结构的装置和方法,但是设想各种装置和方法的功能性可应用于其中期望提供3D打印的水凝胶物体的任何现在已知的或今后设计的3D打印技术和材料。通篇中相同的数字指代相同的元素。
参考图1,例示了根据本发明的一种实施方案的3D打印系统10。3D打印系统10包括喷墨打印区域16,其在本例示实施方案中与本领域已知的固体沉积成型(SDM)或多喷嘴成型(MJM)系统(例如美国专利第6,136,252、6,270,335、6,305,769、6,347,257和6,841,116号,其公开内容通过引用以其全部并入本文)类似。平台12在一个或更多个喷墨打印头24下方移动,自喷墨打印头24沉积水凝胶材料并沉积载体材料,以形成一层3D打印的物体14,3D打印的物体14 在图1中包括支架和载体。基于由控制器基于表示待产生的3D打印的物体14的设计数据而提供的指令来选择性地沉积材料。控制器使用设计数据来指导打印头沉积水凝胶材料和载体材料中的每一种。
本发明的某些实施方案的一个或更多个喷墨打印头24包括多个第一孔(a firstplurality of orifices)和多个第二孔(a second plurality of orifices),通过多个第一孔可将一种或更多种水凝胶材料选择性地沉积在平台上,通过多个第二孔可将载体材料选择性地沉积在平台上。各材料的单独小滴的位置基于表示3D打印的物体的设计数据。在一些实施方案中,可选择性地沉积两种或更多种水凝胶材料。在水凝胶和载体材料的沉积期间,或者在部分层、完全层之后,或者在多个层之后,平台12在平坦化装置(planarizer)26下方移动,该平坦化装置26在本例示实施方案中是SDM/MJM技术中所用类型的加热辊。平坦化装置除去过量的沉积材料,以确保在进一步沉积水凝胶和/或载体材料之前,或在平台12移动至干燥区域18之前的层厚度是正确的。
一些实施方案中的水凝胶材料是I型或II型胶原(在某些优选的实施方案中使用I型)或形成用于所得3D打印的物体(例如支架)的原材料的类似材料。另外或替代地,水凝胶材料可为原纤蛋白,例如原纤维性的(Fibrillar)(优选I、II、III、V、XI型)、 任何非原纤维性的(non-Fibrillar);或弹性蛋白。在某些实施方案中使用弹性蛋白,以为所得3D打印的物体提供弹性。本发明的仍进一步的实施方案使用水凝胶PEG-藻酸盐(单独的或作为增强材料),添加或不添加CaSO4•2H2O,以及引发剂I-2959,如由Hong, Sungmin等人于2015年在Advanced Materials(先进材料)上发表的题为“3D Printing of Highly Stretchableand Tough Hydrogels into Complex, Cellular Structures (高度可拉伸且坚韧的水凝胶3D打印成复杂的、多孔的结构)”的文章中所公开的,该文章的公开内容通过引用以其全部并入本文。本发明的进一步的实施方案使用本领域中已知的或今后设计的替代水凝胶。针对特定的3D打印的物体14选择的特别水凝胶基于一个或更多个参数,所述参数包括但不限于水凝胶的物理性质(遵循3D打印方法和某些后处理)、以及水凝胶经历光引发而不增加或引起细胞毒性的能力、或将使得所得支架或其它物体不适于预期目的或者要求相对大量的后处理以降低或消除细胞毒性的其它性质。本发明的一些实施方案中的水凝胶包括引发剂,其由如下文所解释的光化辐射(催化剂)活化。
将一种或更多种水凝胶材料溶解到水中,以便水凝胶可通过本例示实施方案的喷墨打印头喷射。在一些实施方案中,将水凝胶材料以大约30:1的比率溶解在水中。本发明的进一步的实施方案使用替代的水凝胶材料与水的比率,以便于实现从特定的喷墨打印头或其它沉积装置喷射的必需粘度,例如在10.0至19.0厘泊范围内、或更优选在11.0至14.0厘泊范围内、且仍更优选在11.3和11.8厘泊范围内的粘度(在进一步的实施方案中,可包括粘度调节剂以实现所需粘度)。将水凝胶材料溶解到水中用于本发明的某些实施方案的至少以下两个目的:1)在水中稀释使得粘度能够足够低以用于喷墨打印,和2)当在干燥过程(见下文)期间提取过量的水时,层高度从大约25-30微米(喷墨打印层的典型高度)收缩至大约0.8-1微米,这是提供使某些生物结构有效所必需的支架精细度(detail)所要求的厚度(沿着z-轴)。
本发明的一种实施方案包括可喷墨打印的水凝胶材料,其包括在大约3的pH下的乙酸中以及在含水溶液(30:1水)中溶解的胶原,以及作为光引发剂的核黄素。从喷墨打印头的第一组喷嘴选择性地沉积该实施方案的水凝胶材料,以形成层,同时从该喷墨打印头的第二组喷嘴(或另一喷墨打印头)选择性地沉积缓冲剂,以导致水凝胶胶凝(在其中沉积缓冲剂的三维像素处)。该实施方案的缓冲剂是磷酸盐缓冲盐水(“PBS”),其比率足以将沉积的胶原的pH从大约3移至6到8。例如,使用1倍(1X)浓度的PBS,沉积的胶原的pH提高至大约6.8,使用10倍(10X)浓度的PBS,沉积的胶原的pH提高至大约7.4。通过提高沉积的胶原的pH,胶原自组装回到凝胶。
根据本发明的该实施方案,一旦已沉积一层或更多层的水凝胶材料、缓冲剂和载体材料,就将该一层或更多层运送至干燥区域18,以从凝胶中除去过量的水,并随后将该一层或更多层运送至引发部分20,其中高分辨率UV(254 nm下)图像曝光选择性地使部分的胶凝胶原交联。针对3D打印的物体的基本上所有层重复该过程,并随后后处理3D打印的物体,以除去载体材料和未交联的胶凝胶原(可用乙酸溶液来除去未交联的胶凝胶原)。根据本发明的一些实施方案的进一步后处理步骤包括在最终部件(例如支架)上沉积京尼平,以进一步使胶原交联。在进一步的实施方案中,可使用戊二醛代替京尼平来后处理最终部件;但是,由于戊二醛的细胞毒性,此类用于生物医药应用的经后处理的部件(例如支架)可能要求在使用该部件之前进行进一步洗涤,以除去任何细胞毒素。
返回至图1的例示实施方案,载体材料可为蜡材料,例如烃蜡或烃基醇蜡或本领域已知的其它基于蜡的载体材料,例如美国专利第8,575,258、8,642,692和8,975,352号中已知的(那些),所述专利的公开内容通过引用以其全部并入本文。本发明的替代实施方案使用载体材料,例如不要求通过UV辐射或其它光化辐射进行固化的其它相变载体材料。
载体材料在3D打印过程期间承载水凝胶材料。在本发明的一些实施方案中,围绕水凝胶材料层的各部分的边界打印载体材料。该载体材料边界在打印3D打印物体时充当容纳固化的和未固化的水凝胶材料的“缸”。在本发明的一些实施方案中,通常在载体边界和支架之间打印I型胶原(或类似的)材料的区域。该中间区域不用UV或可见光曝光且不聚合,并因此在3D打印过程期间仅通过载体材料边界和下面的固化的水凝胶材料来维持。
一旦一层或更多层的水凝胶材料和载体材料已选择性地沉积在打印部分16中,在图1的实施方案中,平台12沿着x-轴移动至干燥器部分16(也称作干燥区域)。包括热源、风扇、真空或其组合的干燥器28导致水凝胶材料中的过量水被除去。
一旦水凝胶已被干燥至适当的粘度,在图1的实施方案中,平台12再次沿着x-轴移动至包括催化剂源22的引发部分20,所述催化剂源22选择性地将催化剂施加至平台上的材料,以在水凝胶的至少一部分中引起反应。在图1的实施方案中,催化剂源22是光化辐射源,例如UV或可见光,其活化水凝胶材料中的引发剂。光化辐射源包括但不限于激光装置、数字镜装置(DMD/DLP)、光栅光阀装置(GLV)、LED、MEMS、掩模成像装置和可在表面上选择性地投射光的任何其它光发射装置。在本发明的其它实施方案中,催化剂源是将催化剂物理沉积到水凝胶材料层的选择性部分上的催化剂施加装置。
在本发明的某些实施方案中,成像器是DMD或DMD阵列或类似的掩模成像器,其经缩微以致像素间距小于1微米。例如,如果DMD芯片像素间距为5.4微米,则缩微大于5.4(倍)。通常DMD或DMD阵列在水凝胶材料层上方扫描,且DMD经编程以在图像平面中的各像素位置处开启或关闭(或处于中间强度下)。
对于本发明3D打印用于生物结构(例如用于肺)的支架的实施方案,组合的喷墨成像和高分辨率掩模成像经编程来实施,以致形成在空气通道和血液通道之间的区域中具有非常高的精细度的I型胶原(或类似的)材料,所述区域要求大约1微米的分辨率。支架的总体机械强度和弹性必须大于单独的胶原可提供的机械强度和弹性,以便肺在呼吸时弹回原形。因此,在一些实施方案中,其它更硬的水凝胶样材料必须是交织或以其它方式并入基础胶原结构中。一种或更多种坚韧的弹性材料的精细度由分辨率较低的喷墨打印来确定。所有的水凝胶材料都将通过喷墨打印沉积。在I型胶原(或类似的)材料的本体(bulk)内的区域将容纳坚韧的弹性材料,但是没有一种坚韧的弹性材料将通常在直至空气通道和血液通道的区域中打印。水凝胶材料的整个横截面将用UV或可见光成像器曝光,空气通道和血液通道区域、后续将用活细胞输注的区域和在支架设计中保持中空的任何其它区域除外。
通常针对3D打印的物体的各层重复以上过程。一旦3D打印过程已完成,使3D打印的物体经受后处理操作,以除去载体材料和未固化的水凝胶材料。在除去载体材料之前或之后,可将未固化的水凝胶材料(其未经催化剂引发)从固化的水凝胶中排掉。在一些实施方案中,如本领域通常已知的,可通过热除去载体材料,同时小心不要破坏水凝胶材料。可使用本领域已知的用于除去载体材料的还有其它的技术。在后续使用之前,彻底清洁其余的固化的水凝胶材料。在涉及生物结构的产生的本发明实施方案中,3D打印的水凝胶材料一旦经适当清洁,就可用针对其设计支架的特定的器官或组织的活细胞进行输注。支架的设计可基于所需的生物结构的类型、得自生物结构意欲针对的个体患者的扫描数据和/或确定支架的适当形状和结构的其它因素。
在享有前述说明书和相关附图中所呈现的教导的益处的情况下,本发明所属领域的技术人员将想到本文所阐述的本发明的许多修改和其它实施方案。因此应理解,本发明并不局限于所公开的具体实施方案,并且意欲将修改和其它实施方案包括在随附的权利要求书的范围内。意图是,只要本发明的修改和变化落入随附的权利要求书及其等同物的范围内,本发明就涵盖所述修改和变化。虽然本文中采用了具体的术语,但是仅以通用且描述性的意义并且不是出于限制的目的而使用它们。
因此,本发明提供了具有改善的构造(build)和载体材料的三维物体的制造。在享有前述说明书和相关附图中所呈现的教导的益处的情况下,本发明所属领域的技术人员将想到本文所阐述的本发明的许多修改和其它实施方案。因此应理解,本发明并不局限于所公开的具体实施方案,并且意欲将修改和其它实施方案包括在随附的权利要求书的范围内。意图是,只要本发明的修改和变化落入随附的权利要求书及其等同物的范围内,本发明就涵盖所述修改和变化。虽然本文中采用了具体的术语,但是仅以通用且描述性的意义并且不是出于限制的目的而使用它们。
除非本文中另外指出或上下文明显抵触,术语“一种/个("a"和"an")”和“所述/该”以及类似指示语在描述本发明的上下文中(尤其在以下的权利要求书的上下文中)的使用应解释为涵盖单数和复数两者。除非另外指出,术语“包含/包括(comprising)”、“具有”、“包括(including)”和“含有”应解释为开放式术语(即,表示“包括但不限于”)。除非本文中另外指出,本文中值的范围的记载仅意欲充当分别指代落入所述范围中的各单独的值的简写方法,并且每个单独的值如同其在本文中单独记载般并入说明书中。除非本文中另外指出或上下文另外明显抵触,本文描述的所有方法均可以任何合适的次序实施。除非另外要求保护,本文中提供的任何和所有实例,或示例性语言(如,“例如”)的使用仅意欲更好地阐明本发明并且不对本发明的范围造成限制。不应将说明书中的语言解释为表示任何未要求保护的元素对于本发明的实施是必需的。

Claims (27)

1.用于产生3D打印的物体的3D打印系统,所述3D打印系统包括:
平台,在3D打印过程期间其上可承载所述3D打印的物体;
打印部分,其选择性地在所述平台上沉积水凝胶材料和载体材料;
干燥器部分,其包括干燥器并且所述平台可经过所述干燥器部分,以干燥所述平台上的所述材料的至少一部分;和
引发部分,其包括催化剂源,所述催化剂源选择性地将催化剂施加至所述平台上的所述材料,以在所述水凝胶材料的至少一部分中引起反应,
其中将所述催化剂选择性地施加至所述平台上的一些暴露的水凝胶材料。
2.根据权利要求1所述的3D打印系统,其中所述打印部分包括喷墨打印头,所述喷墨打印头包括多个第一孔和多个第二孔,通过所述多个第一孔可将所述水凝胶材料选择性地沉积在所述平台上,通过所述多个第二孔可将所述载体材料选择性地沉积在所述平台上。
3.根据权利要求1所述的3D打印系统,其中所述干燥器部分包括加热器、风扇和真空中的至少一种。
4.根据权利要求1所述的3D打印系统,其中所述引发部分包括光化辐射源。
5.根据权利要求1所述的3D打印系统,其中所述引发部分包括激光装置和数字镜装置(DMD/DLP)中的至少一种。
6.根据权利要求1所述的3D打印系统,其中所述引发部分包括催化剂施加装置,以在所述水凝胶材料上物理沉积催化剂。
7.根据权利要求1所述的3D打印系统,其中所述打印部分还包括平坦化装置,以从由所述平台承载的最上层材料中去除任何过量的水凝胶材料或载体材料。
8.根据权利要求1所述的3D打印系统,其中所述平台在x-方向、y-方向和z-方向中的至少两者上是可移动的。
9.根据权利要求1所述的3D打印系统,其中所述打印部分选择性地沉积两种或更多种水凝胶材料和所述载体材料。
10.根据权利要求1所述的3D打印系统,其中所述3D打印的物体是用于生物结构的支架。
11.用于产生3D打印的物体的方法,所述方法包括:
在平台上选择性地沉积水凝胶材料层和载体材料;
干燥所述水凝胶材料层的至少一部分;
选择性地将催化剂施加至所述水凝胶材料层的至少一部分;和
重复针对所述3D打印的物体的多个层的所述沉积、干燥和施加。
12.根据权利要求11所述的方法,其还包括后处理所述3D打印的物体,以将所述催化剂选择性地施加于其上的所述水凝胶材料与其余的水凝胶材料以及与所述载体材料分离。
13.根据权利要求12所述的方法,其中分离所述催化剂选择性地施加于其上的所述水凝胶材料包括排出所述其余的水凝胶材料以及使所述载体材料熔融和/或溶解。
14.根据权利要求11所述的方法,其中选择性地沉积所述水凝胶材料层和载体材料包括从喷墨打印头沉积水凝胶材料小滴和载体材料小滴。
15.根据权利要求11所述的方法,其还包括在选择性地沉积之后并在干燥之前,使所述水凝胶材料和载体材料平坦化。
16.根据权利要求11所述的方法,其中干燥所述水凝胶材料层的至少一部分包括使所述水凝胶材料经受热、空气流和真空中的至少一种。
17.根据权利要求11所述的方法,其中选择性地将催化剂施加至所述水凝胶材料层的至少一部分包括使用光化辐射选择性地辐照所述水凝胶材料层。
18.根据权利要求18所述的方法,其中使用光化辐射选择性地辐照所述水凝胶材料层包括投射来自激光装置、数字镜装置(DMD/DLP)、光栅光阀装置(GLV)、LED、MEM和掩模成像装置中的至少一种的光化辐射。
19.根据权利要求11所述的方法,其中选择性地将催化剂施加至所述水凝胶材料层的至少一部分包括在所述水凝胶材料上物理沉积催化剂。
20.根据权利要求12所述的方法,其还包括清洗所述3D打印的物体并用预定的器官或组织中的至少一种的活细胞输注所述3D打印的物体。
21.根据权利要求20所述的方法,其中清洗所述3D打印的物体包括使用京尼平和戊二醛中的至少一种清洗所述3D打印的物体。
22.根据权利要求21所述的方法,其还包括从所述3D打印的物体中去除细胞毒素。
23.3D打印的物体,其包括:
支架部分,其包括固化的水凝胶材料;
在所述支架部分中的通道,其包括未固化的水凝胶材料;和
载体结构,其包括载体材料。
24.根据权利要求23所述的3D打印的物体,其中所述水凝胶是I型胶原、原纤蛋白、弹性蛋白和PEG-藻酸盐中的至少一种。
25.根据权利要求23所述的3D打印的物体,其中所述载体材料是蜡材料。
26.根据权利要求23所述的3D打印的物体,其中所述未固化的水凝胶材料包括光引发剂。
27.根据权利要求23所述的3D打印的物体,其中所述固化的水凝胶材料包括缓冲剂,并且其中所述缓冲剂是磷酸盐缓冲盐水(“PBS”)。
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