Platform for high-throughput biomechanical measurements using metallic islands on boron nitride nanosheets

摘要 该方案描述了一种用于高通量测量细胞中的机械现象的新平台。 该平台基于一种由六方硼支撑的金属纳米岛组成的应变传感器 氮化物。机械变形会引起电阻和光学散射的变化 这些传感器。这些过程允许检测变形≤1ppm(≤0.0001%应变)。这 史无前例的灵敏度水平允许测量细胞产生的微小作用力 使用现有方法测量，并且可以使用机器学习快速分析电信号 算法。虽然这种传感器在细胞生物学中有广泛的潜在应用，但我们在这里将其应用于 心血管医学和药物开发中普遍存在的挑战。特别是，收缩功能障碍 心肌细胞与一系列难以治疗的心肌病有关。在药物发现方面，心脏毒性 (肌病、心律失常或两者兼而有之)是药物在研发和售后市场失败的主要原因 发射。对于某些类别的药物--特别是那些用于化疗的药物--多达30%的患者经历了 心脏病与他们的治疗有关。事实上，心力衰竭是导致心力衰竭死亡的第二大原因 癌症患者。目前还没有既能预测心脏毒性又能充分预测心脏毒性的检测方法。 在药物开发早期实施的生产能力(即，在以下情况下可以选择更安全的药物先导 类似物)。我们建议使用诱导多能干细胞来源的心肌细胞(IPSC-CMS) 各种与疾病相关的突变，作为我们的纳米生物力学传感器的测试案例。特别是， 我们将构建一个基于“96孔”平板格式的阵列，并使用 专门设计的机器学习算法，以测量力和收缩的动力学 细胞。这样的平台将能够对疾病机制进行大规模评估，并加快治疗 通过允许高吞吐量、无偏见的测试来发现目标。这个应用程序提供了令人兴奋的可能性 在发现管道的早期引入人类心脏生物学的各个方面。更广泛地说，该平台 我们的描述提供了回答有关细胞中机械现象的深层次问题的潜力-- 机械体“--对人类健康起着至关重要的作用。

SUMMARY This proposal describes a new platform for high-throughput measurement of mechanical phenomena in cells. The platform is based on a type of strain sensor comprising metallic nanoislands supported by hexagonal boron nitride. Mechanical deformation produces a change in both the electrical resistance and the optical scattering of these sensors. These processes allow the detection of deformations ≤1 ppm (≤0.0001% strain). This unprecedented level of sensitivity permits the measurement of minute forces produced by cells that cannot be measured using existing methods, and the electrical signals can be analyzed rapidly using machine-learning algorithms. While this sensor has a broad range of potential applications in cell biology, we apply it here to a ubiquitous challenge in cardiovascular medicine and drug discovery. In particular, contractile dysfunction in cardiomyocytes is associated with a range of difficult-to-treat cardiomyopathies. In drug discovery, cardiotoxicity (myopathy, arrhythmia, or both) is a leading reason for the failure of drugs during development and aftermarket launch. For some classes of drugs—especially those used in chemotherapy—up to 30% of patients experience heart disease related to their treatment. Indeed, heart failure is the second most common reason for death of cancer patients. There are currently no assays that are both predictive of cardiotoxicity and are of sufficient throughput to implement early in drug development (i.e., when safer drug leads can be selected among analogues). We propose the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) bearing various disease-associated mutations as a test case of our nano-enabled biomechanical sensor. In particular, we will construct an array based on a “96-well” plate format combined with high-throughput analysis using a purpose-designed machine learning algorithm in order to measure the forces and kinetics of contractility of the cells. Such a platform would enable large-scale evaluation of disease mechanisms and accelerate therapeutic target discovery by permitting high-throughput, unbiased testing. This application offers the exciting possibility of introducing aspects of the biology of the human heart early in the discovery pipeline. More broadly, the platform we describe offers the potential of answering deep questions about mechanical phenomena in cells—“the mechanome”—which play critical roles in human health.