CAREER: Hybrid Biorobotic Matrices to Simulate Diaphragmatic and Myocardial Biomechanics

为了提高对器官系统的理解，研究人员经常建立物理/台式模型，充分模拟系统，以再现，观察和测量在体内评估具有挑战性的功能。尽管已经开发了许多这样的心血管和呼吸系统模型来模拟跳动的心脏和呼吸的运动，但没有一个模型忠实地复制隔膜的力学或忠实地模仿心脏的三维扭曲和压缩运动。因此，该项目的总体目标是建立一个逼真的台式模型，使用先进的机器人技术和实际的有机组织相结合，重现心脏和横膈膜的运动和功能。 该模型将提供对生理学，病理学和系统相互依赖性的见解，并作为一种创新和有效的教学工具，用于教育学生心血管和呼吸生理学和病理学。它还将作为植入式心脏设备的解剖学和生理学上准确的测试平台，代表了对现有模型的巨大改进，并最终降低了对动物模型中测试设备的要求。最后，它将作为一个有影响力的可视化工具，用于教育和吸引更广泛的社区（例如在博物馆和儿童医院）。PI将使用这种示范和教学模式作为多管齐下的招聘倡议的许多方法之一，培养和留住新一代的妇女在学术科学职位。该项目的目标是改变台式模拟器的范式，从一个呼吸和心血管系统是独立模拟与合成幻影或离体组织和运动是被动驱动的流体或外部从一个可编程的仿生软活性材料的功能性动态组织重建组件。 用于隔膜和心肌（心肌）的合成软机器人肌肉模拟器将与体外生物组织（分别是整个肺和心内结构）相结合，以创建“混合生物机器人”，这将能够准确表示肺和心脏运动，同时保留关键的解剖结构，从而在再现功能的同时保持形式。临床上获得的运动数据的隔膜和心脏将被用来开发算法，以“程序”的设计纤维增强仿生软执行器。随后，这些有源元件将被嵌入拟人矩阵中，以模仿隔膜和心脏的形式和功能。将使用加压解剖室和模拟循环回路重建隔膜驱动的呼吸机制和心血管血液动力学。 研究计划有三个目标。 第一个目标是创建一个模块化的、主动的生物机器人隔膜，其可以集成到体外试验台中，该体外试验台可以用于模拟生理和病理生物力学并产生离体肺通气。体外试验台将集成由可互换隔膜模拟物隔开的加压室，以复制胸腔和腹腔的生理压力。 将对软机器人致动器进行编程，以模拟从临床MRI数据中计算提取的所需横膈膜运动轨迹。这将是第一个功能性软机器人隔膜模拟器，用于复制各种临床衍生的隔膜运动。 第二个目标是创建一个心血管试验台，包括一个生物机器人心脏，重建心壁运动，并产生压力变化，以模拟血液动力学条件。一种新型的混合制造工艺将用于使用离体组织（猪心）或高分辨率3D打印来保存心脏的心内结构（内皮衬里、隔膜、瓣膜、乳头肌和腱索）。活动心肌将被一种含有纤维增强致动器的合成软材料所取代，这些致动器以所需的配置定向。生物机器人心脏将与部分顺应性血管流动回路集成，以模拟血液动力学。 这将是第一次实现将有机心内组织与软机器人心肌整合在一起的软生物机器人心脏，以及第一个心脏模拟器，其中心血管血流动力学完全由能够复制扭曲和压缩的心肌替代物驱动，这在医疗植入物的性能评估中至关重要。 第三个目标是集成组件以制作心肺平台，并证明其在模拟Fontan患者呼吸和血流动力学生物力学模型中的实用性。呼吸模拟器的物理腔将根据Fontan患者的CT和MRI数据进行设计。 基于以前的工作，将开发一种控制器，该控制器在全腔静脉旁路的Fontan患者的模拟胸腔中的呼吸周期期间致动生理压力曲线。 然后将呼吸模拟器与部分顺应性血管流动回路结合，以模拟Fontan患者的静脉压和流动模式。这将是第一个使用软机器人心脏和横膈膜的组合心肺模拟器，也是第一个重现Fontan生理学（包括跨脑压和腹压）的平台。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

In order to improve understanding of an organ system, researchers often build physical/benchtop models that mimic the system sufficiently to reproduce, observe, and measure functions that are challenging to evaluate in the body. Though many such models of the cardiovascular and respiratory systems have been developed to simulate the motions of the beating heart and breathing, none faithfully replicates the mechanics of the diaphragm or faithfully mimics the three-dimensional twisting and compressive motion of the heart. Thus, the overall goal of this project is to build a lifelike, benchtop model that recreates the motion and function of the heart and the diaphragm using a combination of advanced robotic techniques and actual organic tissue. This model will provide insights into physiology, pathology and interdependence of the systems and serve as an innovative and effective teaching tool for educating students on cardiovascular and respiratory physiology and pathology. It will also serve as an anatomically and physiologically accurate testbed for implantable cardiac devices, representing a vast improvement over existing models and ultimately reducing the requirement for testing devices in animal models. Finally, it will act as an impactful visualization tool for educating and engaging the broader community (for example in museums and in Children's hospitals). The PI will use this demonstration and teaching model as one of many approaches in a multi-pronged initiative to recruit, train and retain a new generation of women in academic scientific positions.The goal of this project is to shift the paradigm of benchtop simulators from one where the respiratory and cardiovascular systems are independently simulated with synthetic phantoms or ex vivo tissue and motion is passively driven by fluid or external components to one where functional dynamic tissue is recreated using programmable biomimetic soft active materials. Synthetic soft robotic muscular simulators for the diaphragm and heart muscle (myocardium) will be combined with ex vivo biological tissue (entire lungs and intracardiac structures respectively) to create "hybrid biorobots" that will enable accurate representation of lung and heart motion, while preserving key anatomical structures, thus maintaining form while recapitulating function. Clinically derived motion data of the diaphragm and heart will be used to develop algorithms to "program" the design of fiber reinforced biomimetic soft actuators. Subsequently, these active elements will be embedded in anthropomorphic matrices to mimic the form and function of the diaphragm and heart. Diaphragm-driven breathing mechanics and cardiovascular hemodynamics will be recreated using pressurized anatomical chambers and mock circulatory loops. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to create a modular, active biorobotic diaphragm that can be integrated into an in vitro testbed that can be used simulate physiological and pathological biomechanics and generate ex vivo lung ventilation. The in vitro testbed will integrate pressurized chambers separated by an interchangeable diaphragm mimic to replicate the physiologic pressures of the thoracic and abdominal cavities. Soft-robotic actuators will be programmed to mimic the desired diaphragm motion trajectory as computationally extracted from clinical MRI data. This will be the first functional soft robotic diaphragm mimic to replicate a variety of clinically derived diaphragm motions. The SECOND OBJECTIVE is to create a cardiovascular testbed including a biorobotic heart that recreates cardiac wall motion and generates pressure changes to simulate hemodynamic conditions. A novel hybrid fabrication process will be used to preserve the intracardiac structures (endothelial lining, septum, valves, papillary muscles and chordae tendinae) of the heart using ex vivo tissue (porcine hearts) or high-resolution 3D printing. The active heart muscle will be replaced with a synthetic soft material containing fiber-reinforced actuators oriented in desired configurations. The biorobotic heart will be integrated with a partially compliant vascular flow loop to simulate hemodynamics. This will be the first realization of a soft biorobotic heart that integrates organic intracardiac tissue with soft robotic myocardium and the first cardiac simulator where cardiovascular hemodynamics are driven completely by a myocardial substitute that is capable of replicating twist as well as compression, which is critically important in the performance assessment of medical implants. The THIRD OBJECTIVE is to integrate components to make a cardiorespiratory platform and to demonstrate its utility in a model to simulate respiratory and hemodynamic biomechanics of Fontan patients. Physical cavities of the respiratory simulator will be designed based on Fontan patients' CT and MRI data. Based on previous work, a controller that actuates physiological pressure profiles during a breathing cycle in a simulated chest cavity of a Fontan patient with total cavopulmonary bypass will be developed. The respiratory simulator will then be combined with a partially compliant vascular flow loop to simulate venous pressure and flow patterns of Fontan patients. This will be the first combined cardiorespiratory simulator using a soft robotic heart and diaphragm and the first platform to recreate the Fontan physiology including both trans-diaphragmatic pressures and abdominal pressure.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.