Microsensors to Study Electrical and Mechanical Coupling of Injured Myocardium

描述(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，这是由于未能充分替换缺血引起的梗塞造成的丢失的心肌。成年哺乳动物的心肌细胞分裂能力有限，这种增殖能力不足以克服因心肌损伤而造成的心肌的显著损失。然而，斑马鱼(Danio Rerio)具有在受损心脏中再生大量心肌的显著能力，因此代表了再生医学和心血管研究的一种新兴脊椎动物模型。虽然斑马鱼系统的小尺寸允许高通量研究，但小的心脏尺寸(1-2毫米长)使其具有执行功能生理分析的挑战性。为此，我们的合作使微型心电图仪和高频超声换能器(&gt；45 MHz)的应用得以进一步研究受损斑马鱼心脏再生心肌的电和机械属性。我们观察到，在室性截肢后60天，尽管完全再生心肌，但心室复极(ST间期和T波)仍未恢复正常，提示可能需要进一步的心脏重塑才能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心脏的电和机械表型，因此可能需要额外的心脏细胞重塑才能完全电和机械地整合到受损的心脏中。为了评估心脏再生过程中心脏功能的恢复，我们建议将植入式柔性微电极阵列与高频超声换能器和光电压标测相结合，以测试心脏再生的传导和机械表型，然后通过有条件地阻断或激活Wnt/2-catenin和FGF信号通路来进行机械评估。可植入的柔性微电极阵列、高频超声换能器的发展和应用在干细胞和再生医学时代有着巨大的前景。总而言之，我们的共同努力可能会为心脏传导和机械表型提供新的技术和新的机械见解，以应对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.