Human in vitro models of neural tissue with controllable cellular identity, tunable microenvironment, and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing in jammed microgel supports (i.e., granular gels) holds great promise as it allows precise and programmable patterning of extremely soft and compliant tissue constructs. However, in contrast to the vast material landscape available for bulk hydrogels, granular printing support formulations are restricted to a handful of materials without the ability for facile adjustment of biofunctional properties of the cellular microenvironment. Therefore, there has been a need for novel materials that take advantage of versatile biomimicry of bulk hydrogels while providing high-fidelity support for embedded printing akin to granular gels. To address this need, we present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside Self-Healing Annealable Particle-Extracellular matrix (SHAPE) composites. SHAPE composites consist of soft microgels immersed in viscous extracellular-matrix solution to enable precise freeform patterning of human stem cells and consequent generation and long-term maintenance of mature subtype-specific neurons that extend projections within the volume of the annealed support. The developed approach further allows multi-ink deposition, live spatial and temporal monitoring of oxygen levels, as well as creation of vascular channels. Due to its modularity, SHAPE biomanufacturing toolbox not only offers a solution for functional modeling of mechanically sensitive neural constructs, but also has potential to be applied to a wide range of biomaterials with different crosslinking mechanisms to model tissues and diseases where recapitulation of complex architectural features and topological cues is essential.

中文翻译：

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嵌入自修复可退火复合材料中的 3D 打印，用于功能成熟的人类神经结构的精确图案化

人体外需要具有可控细胞特性、可调微环境和明确空间排列的神经组织模型来促进大脑发育和疾病的研究。为此，在堵塞的微凝胶支持物（即颗粒凝胶）中嵌入印刷具有很大的前景，因为它允许对极其柔软和顺从的组织结构进行精确和可编程的图案化。然而，与可用于散装水凝胶的广阔材料环境相比，颗粒印刷支持配方仅限于少数材料，无法轻松调整细胞微环境的生物功能特性。因此，需要能够利用块状水凝胶的多功能仿生学，同时为类似于颗粒凝胶的嵌入式打印提供高保真度支持的新型材料。为了满足这一需求，我们提出了一个用于神经元网络生物工程的模块化平台，该平台通过在自愈性可退火粒子-细胞外基质 (SHAPE) 复合材料中直接嵌入 3D 打印人类干细胞来实现。SHAPE 复合材料由浸入粘性细胞外基质溶液中的软微凝胶组成，以实现人类干细胞的精确自由图案化，以及随后生成和长期维持成熟的亚型特异性神经元，从而在退火支持的体积内扩展投影。开发的方法进一步允许多墨水沉积、实时空间和时间监测氧气水平，以及创建血管通道。由于其模块化，SHAPE 生物制造工具箱不仅为机械敏感神经结构的功能建模提供了解决方案，