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，以重现、观察和测量在体内难以评估的功能。虽然许多这样的心血管和呼吸系统模型已经被开发出来，以模拟心脏跳动和呼吸的运动，但没有一个能忠实地复制隔膜的力学，也没有一个能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，利用先进的机器人技术和实际的有机组织相结合，再现心脏和隔膜的运动和功能。该模型将提供对系统的生理学、病理学和相互依赖性的见解，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装置在解剖学和生理学上精确的测试平台，代表着对现有模型的巨大改进，并最终减少了对动物模型测试设备的需求。最后，它将作为一种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）。该项目将使用这种示范和教学模式，作为一项多管齐下的倡议的许多方法之一，以招募、培训和留住新一代的女性学术科学职位。这个项目的目标是改变台式模拟器的模式，从一个呼吸系统和心血管系统独立模拟合成的模型或离体组织，运动被动地由流体或外部组件驱动，到一个使用可编程的仿生软活性材料重建功能动态组织。用于膈肌和心肌（心肌）的合成软体机器人肌肉模拟器将与离体生物组织（分别为整个肺和心脏内结构）相结合，创造出“混合生物机器人”，它将能够准确地表示肺和心脏的运动，同时保留关键的解剖结构，从而在保持形状的同时再现功能。临床得到的膈肌和心脏的运动数据将用于开发算法来“编程”纤维增强仿生软驱动器的设计。随后，这些活动元素将被嵌入拟人化矩阵中，以模仿隔膜和心脏的形式和功能。膈膜驱动的呼吸力学和心血管血流动力学将使用加压解剖室和模拟循环回路重建。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，可以集成到一个体外试验台，可以用来模拟生理和病理生物力学，并产生体外肺通气。体外试验台将集成由可互换隔膜模拟器分隔的加压室，以复制胸腔和腹腔的生理压力。软机器人执行器将被编程来模拟从临床MRI数据中计算提取的所需隔膜运动轨迹。这将是第一个功能性的软体机器人膜片模拟来复制各种临床衍生的膜片运动。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，它可以重现心壁运动，并产生压力变化来模拟血液动力学条件。一种新的混合制造工艺将用于使用离体组织（猪心脏）或高分辨率3D打印来保存心脏的心内结构（内皮内膜、隔膜、瓣膜、乳头肌和腱索）。活跃的心脏肌肉将被一种含有纤维增强致动器的合成软材料取代。这种仿生心脏将与一个部分顺从的血管流动环相结合，以模拟血液动力学。这将是第一次实现将有机心脏内组织与软机器人心肌结合在一起的软生物心脏，也是第一个心脏模拟器，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品驱动，这在医疗植入物的性能评估中至关重要。第三个目标是将组件整合成一个心肺平台，并展示其在模型中的实用性，以模拟Fontan患者的呼吸和血液动力学生物力学。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。在以往工作的基础上，将开发一种控制器，用于在全腔室体外循环的Fontan患者的模拟胸腔内呼吸周期中驱动生理压力谱。然后，呼吸模拟器将与部分顺应的血管血流环结合，模拟Fontan患者的静脉压力和血流模式。这将是第一个使用软机器人心脏和隔膜的组合心肺模拟器，也是第一个重建Fontan生理学的平台，包括横膈膜压力和腹压。该奖项反映了美国国家科学基金会的法定使命，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。

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.