3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures.
3D Printing of Highly Stretchable and Tough Hydrogels into Complex, Cellularized Structures.
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DOI：
10.1002/adma.201501099
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发表时间：
2015-07-15
期刊：
影响因子：
--
通讯作者：
Zhao X
中科院分区：
文献类型：
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作者：
Hong S;Sycks D;Chan HF;Lin S;Lopez GP;Guilak F;Leong KW;Zhao X
活组织通常具有高的断裂韧性，以承受大量的内部和外部机械载荷。[1]组织的高韧性要求研究人员设计能够实现类似韧性的水凝胶，以承受生理机械负荷。[2]尽管最近在开发坚韧的水凝胶方面取得了成功，[3-12]这些水凝胶的制造通常涉及有毒化学品和/或苛刻的反应，限制了它们封装细胞的能力。此外，期望制造具有有助于产生复杂组织的大孔结构的细胞包埋水凝胶。虽然3D打印提供了快速原型[13-17]，并且可以将水凝胶打印成复杂的3D结构，用于血管网络[14，16]和主动脉瓣[18，19]等功能，但除了简单和平坦的结构（如狗骨样品）之外，还不可能将坚韧的水凝胶打印成复杂的结构。[15]在这里，我们选择了生物相容性材料海藻酸钠和聚乙二醇（PEG）来构成互穿网络（图1）。共价交联的PEG和离子交联的藻酸盐的所得水凝胶具有高断裂韧性并允许细胞包封（图2和3）。（水凝胶的详细配方描述于实验部分中。我们假设这种生物相容性水凝胶的增韧依赖于两种机制的组合：藻酸盐的可逆Ca 2+交联消耗机械能，而PEG的共价交联在大变形下保持弹性（图1）。为了检验这一假设，我们改变了水凝胶中PEG的分子量（6000-20 000 Da）和Ca 2+的浓度（每1 mL预凝胶PEG-藻酸盐混合物中加入25 μL 0或1 M CaSO 4溶液），并使用纯剪切测试来测量所得水凝胶的断裂能。[20]（纯剪切试验的详细信息见图S1，支持信息。）如图S2 a（支持性信息）所示，不含Ca 2+的水凝胶的断裂能始终较低（低于211 J m− 2），并且它们显示出可忽略的应力-应变滞后（图S2 b，支持性信息）。在水凝胶中引入可逆的Ca 2+交联显著增加了它们的断裂能。断裂能的增加还伴随着应力-应变滞后的显著增加，这表明水凝胶在变形下的机械耗散（图S2 b，支持性信息）。此外，含钙水凝胶的断裂能随着PEG分子量的增加而急剧增加，因为PEG的较长聚合物链允许水凝胶具有更高的拉伸性（图S2 a，c，支持性信息）。这些结果验证了机械能耗散和高弹性的组合机制对PEG-海藻酸盐水凝胶的增韧至关重要的假设。为了进一步验证这一假设，我们制备了一组具有不同分子量和PEG浓度的纯PEG水凝胶，并测量了它们的断裂能。从图S2 a和S3（支持信息）可以看出，
Living tissues usually have high fracture toughness in order to withstand substantial internal and external mechanical loads.[1] The high toughness of tissues challenges researchers to design hydrogels capable of achieving similar toughness in order to withstand physiological mechanical loads.[2] Despite recent success in developing tough hydrogels,[3–12] the fabrication of these hydrogels often involves toxic chemicals and/or harsh reactions, limiting their capability to encapsulate cells. In addition, it is desirable to fabricate cell-embedded hydrogels with macroporous architecture conducive to generation of complex tissues. While 3D printing offers rapid prototyping [13–17] and can print hydrogels into complex 3D structures for functions such as vascular networks [14, 16] and aortic valves,[18, 19] it has not been possible to print tough hydrogels into complex structures other than simple and flat ones such as dog-bone samples.[15]Here, we chose the biocompatible materials sodium alginate and poly (ethylene glycol)(PEG) to constitute an interpenetrating network (Figure 1). The resultant hydrogel of covalently crosslinked PEG and ionically crosslinked alginate possesses high fracture toughness and allows cell encapsulation (Figures 2 and 3).(Detailed formulation of the hydrogel is described in the Experimental Section.) We hypothesize that the toughening of this biocompatible hydrogel relies on a combination of two mechanisms: the reversible Ca2+ crosslinking of alginate dissipates mechanical energy, while the covalent crosslinking of PEG maintains elasticity under large deformations (Figure 1). To test this hypothesis, we varied the molecular weight of PEG (6000–20 000 Da) and the concentrations of Ca2+(25 µL of either 0 or 1 M CaSO4 solution added per 1 mL of the pre-gel PEG–alginate mixture) in the hydrogels, and used pure-shear tests to measure the fracture energies of the resultant hydrogels.[20](Details of the pure-shear test are described in Figure S1, Supporting Information.) As shown in Figure S2a (Supporting Information), the fracture energies of hydrogels without Ca2+ are consistently low (below 211 J m− 2) and they display negligible stress–strain hysteresis (Figure S2b, Supporting Information). Introducing reversible Ca2+ crosslinking into the hydrogels significantly increases their fracture energies. The increase in fracture energy is also accompanied by significant increase in stress–strain hysteresis, which indicates mechanical dissipation in the hydrogels under deformation (Figure S2b, Supporting Information). In addition, the fracture energy of calcium-containing hydrogels increases drastically with the molecular weight of PEG, because the longer polymer chains of PEG allow for higher stretchability of the hydrogel (Figure S2a, c, Supporting Information). These results validate the hypothesis that the combined mechanisms of mechanical energy dissipation and high elasticity are critical to the toughening of the PEG–alginate hydrogels. To further test the hypothesis, we made a set of pure PEG hydrogels with different molecular weights and concentrations of PEG and measured their fracture energies. From Figures S2a and S3 (Supporting Information), it is evident that the fracture energies of