Microsensors to Study Electrical and Mechanical Coupling of Injured Myocardium

描述（由申请人提供）：尽管目前的治疗方案，心力衰竭仍然是美国和发达国家发病率和死亡率的主要原因，因为缺血引起的梗死不能充分替代失去的心室心肌。成年哺乳动物心室心肌细胞的分裂能力有限，这种增殖不足以克服心室损伤造成的心肌的显著损失。然而，斑马鱼（Danio rerio）具有在受伤心脏中再生大量心肌的非凡能力，因此代表了再生医学和心血管研究的新兴脊椎动物模型。虽然斑马鱼系统的小尺寸允许高通量研究，但小心脏尺寸（1-2毫米长）使其难以进行功能生理分析。为此，我们的合作努力使微电心电图（ECG）和高频超声换能器（>45 MHz）的应用能够进一步研究受损斑马鱼心脏再生心肌的电学和力学属性。我们观察到，在心室截肢后60天，尽管心肌完全再生，但心室复极（ST段和T波）未能正常化，这表明可能需要进一步的心脏重塑以使再生心肌与宿主心肌完全整合。我们假设，早期再生的心肌细胞可能缺乏电和机械的心脏表型，因此可能需要额外的心脏细胞重塑，以完全将电和机械整合到受伤的心脏中。为了评估心脏再生过程中心脏功能的恢复，我们建议将可植入的柔性微电极阵列与高频超声换能器和光学电压定位相结合，以测试传导和机械表型，然后通过有条件地阻断或激活Wnt/2-catenin和FGF信号通路进行机制评估。在干细胞和再生医学时代，可植入的柔性微电极阵列、高频超声换能器的开发和应用具有广阔的前景。总之，我们的共同努力可能会为心脏传导和机械表型提供新技术和新的机制见解，以响应与再生医学相关的遗传、表观遗传和药物扰动。

DESCRIPTION (provided by applicant): Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the US and developed world due to failure to adequately replace lost ventricular myocardium from ischemia- induced infarct. Adult mammalian ventricular cardiomyocytes have a limited capacity to divide, and this proliferation is insufficient to overcome the significant loss of myocardium from ventricular injury. However, zebrafish (Danio rerio) possess the remarkable capacity to regenerate a significant amount of myocardium in injured hearts, and thus, represent an emerging vertebrate model for regenerative medicine and cardiovascular research. While the small size of zebrafish system allows for high-throughput research, the small heart size (1-2 mm in length) renders it challenging to perform functional physiological analyses. Toward this end, our collaborated efforts have enabled the applications of the micro-electrical cardiogram (ECG) and high-frequency ultrasonic transducers (>45 MHz) to further investigate the electrical and mechanical attributes of regenerating myocardium in injured zebrafish hearts. We have observed that ventricular repolarization (ST intervals and T waves) failed to normalize despite fully regenerated myocardium at 60 days post ventricular amputation, suggesting further cardiac remodeling may be required to fully integrate regenerating myocardium with host myocardium. We hypothesize that early regenerating cardiomyocytes may lack the electrical and mechanical cardiac phenotypes, and thus may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts. To assess the restoration of cardiac function during cardiac regeneration, we propose to interface implantable flexible micro-electrode arrays with high- frequency ultrasonic transducers and optical voltage mapping to test the conduction and mechanical phenotypes, followed by mechanistic assessment by conditionally blocking or activating Wnt/2-catenin and FGF signaling pathways. The development and application of implantable and flexible micro-electrode arrays, high frequency ultrasonic transducers hold a great promise in the era of stem cell and regenerative medicine. In sum, our concerted efforts will likely provide both novel technology and new mechanistic insights into cardiac conduction and mechanical phenotypes in response to genetic, epigenetic, and pharmaceutical perturbations with relevance to regenerative medicine.