STTR Phase I: The AMBIT Organ-on-Chip Platform: Advanced Microphysiological Brain Injury Technology

这个小企业技术转让（STTR）第一阶段项目的更广泛影响将是完善创伤性脑损伤（TBI）和其他神经系统疾病引起的血脑屏障（BBB）的临床损伤阈值。这种新型平台是一种灵活的基于BBB的“器官芯片”，允许对TBI的细胞反应和药物治疗进行无动物测试。器官芯片是模拟组织、器官或器官系统的微流体细胞培养芯片。一般来说，器官芯片的设计和制造的改进最终可以取代动物模型，特别是啮齿动物模型，作为临床前药物评价的对象。该技术可以支持未来在BBB分解药物开发中的应用，或用作测试或设计药物以穿过BBB的平台。最后，所得到的数据可用于模拟运输，损伤和BBB功能障碍。拟议的项目将推进一种新的技术，用于研究TBI和其他神经系统疾病的长期影响。血脑屏障是一种高度选择性的半透膜，它将脑组织和血管系统分开，当创伤破坏其结构、生理和功能完整性时，血脑屏障可能会受损。然而，TBI介导的力学（幅度，减速，影响频率）的BBB结构和功能的调制的作用知之甚少。 到目前为止，很少有器官芯片模型能够进行这种类型的研究，并且没有一个将TBI作为输入变量。该技术为芯片的BBB组件提供了一种类似TBI的机械损伤，BBB组件是一种分离微血管内皮细胞和星形胶质细胞的柔性多孔膜。所提出的技术可以量化（1）跨膜的跨内皮电阻，（2）BBB渗透性，（3）上皮屏障系数，（4）紧密连接形成，和（5）细胞表型，所有这些都预期在TBI期间和之后改变。该项目将设计一个更强大的电极系统，通过用于将导电墨水直接3D打印到BBB膜上的微点胶技术，可重复地测量跨内皮电阻。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact of this Small Business Technology Transfer (STTR) Phase I project will be to refine clinical injury thresholds of the blood-brain barrier (BBB) resulting from traumatic brain injury (TBI) and other neurological diseases. This novel platform is a flexible BBB-based “organ-on-chip” to allow for animal-free testing of cell response and drug treatments for TBI. Organ-on-chips are microfluidic cell culture chips that simulate tissues, organs, or organ systems. In general, improvements in the design and manufacture of organ-on-chips can eventually replace animal models, especially rodent models, as subjects in preclinical drug evaluations. The proposed technology can support future applications in drug development for BBB breakdown, or be used as a platform to test or engineer drugs for transport across the BBB. Finally, the resulting data can be used for modeling transport, injury, and BBB dysfunction.The proposed project will advance a novel technology for studying long-term implications of TBI and other neurological diseases. The BBB is a highly selective semipermeable membrane that separates brain tissue and the vascular system, and it can be damaged when trauma disrupts its structural, physiological and functional integrity. However, the role of TBI-mediated mechanics (magnitude, deceleration, impact frequency) on the modulation of BBB structure and function is poorly known. To date few organ-on-chip models enablee this type of study, and none incorporates TBI as an input variable. The proposed technology provides a TBI-like mechanical insult to the chip’s BBB component, a flexible, porous membrane that separates microvascular endothelial cells and astrocytes. The proposed technology can quantify (1) transendothelial electrical resistance across the membrane, (2) BBB permeability, (3) epithelial barrier coefficient, (4) tight junction formation, and (5) cell phenotype, all of which are expected to change during and after TBI. This project will design a more robust electrode system to reproducibly measure transendothelial electrical resistance through micro-dispensing techniques used to 3D-print conductive ink directly onto the BBB membrane.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.