Novel 3D bioprinted human cardiac tissue models for drug safety and efficacy testing

在人体临床试验中，很大比例的候选药物失败是因为它们不安全或无效。即使临床前的细胞和动物研究看起来是积极的，问题也会出现，因为在这些模型上用药物进行的测试通常不能预测人类会发生什么。这在很大程度上是由于不同物种在生物学上的显著差异。例如，离子通道(心脏细胞传导电流的膜蛋白)在人类和动物之间可能会有所不同。许多药物，包括非心血管药物，都以心脏中的这些离子通道为靶点，这可能会导致致命的心律失常。因此，使用能够紧密复制人类所发生的情况的临床前模型来更好地预测药物的安全性是至关重要的。为了简化治疗开发流程，我们将开发一种新的3D生物反应人体心脏组织模型，它将改进预测药物是否对人类安全有效的翻译科学过程。其目标是开发3D人类心脏组织结构(S)，该结构能够紧密模拟人类心脏的电生理特性，与脉冲传导和心律失常的产生有关。我们将使用商用的人类诱导多能干细胞(HiPSC)来源的心肌细胞和新的基于微流体的3D生物打印技术和方法来构建3D心脏组织。最终，这些模型有望取代使用动物来筛选药物的安全性和有效性。为了验证我们的模型，我们将评估一系列已知化合物的心脏毒性潜力，并将结果与使用当前标准分析获得的数据进行比较。开发一种新药并获得上市批准平均需要25亿美元以上。仅完成临床前研究就需要大约1亿美元。使用新的心肌组织生物打印模型有望显著减少将新药推向市场的成本和时间。

During human clinical trials, a large percentage of candidate drugs fail because they areunsafe or ineffective. Even when pre-clinical cell and animal studies seem positive, problemsoccur because tests done with drugs on these models are often not predictive of whathappens in humans. Much of this is due to significant differences in biology between species.For instance, ion channels (membrane proteins through which heart cells conduct electricalcurrents) can vary between humans and animals. Many drugs, including non-cardiovasculardrugs, target these ion channels in the heart, which can potentially result in lethal arrhythmias.Thus, it is critical to use preclinical models that can closely reproduce what happens inhumans to better predict drug safety.To streamline the therapeutic development pipeline, we will develop a novel 3D bioprintedhuman cardiac tissue model which will improve the translational science process forpredicting whether drugs will be safe and effective in humans. The goal is to develop 3Dhuman cardiac tissue structure(s) that closely model the electrophysiological properties of thehuman heart, relevant to impulse conduction and arrhythmia generation. We will usecommercially available human induced-pluripotent stem cells (hiPSC)-derived cardiomyocytesand novel microfluidic based 3D bioprinting technology and methodologies to build the 3Dcardiac tissue.Ultimately, these models are expected to replace the use of animals to screen drugs forsafety and efficacy.To validate our models, we will evaluate the cardiotoxicity potential of a range of knowncompounds, and compare the outcome with data obtained using current standard assays.It takes on average over $2.5 billion to develop and gain marketing approval for a new drug.About $100 million is required to complete the pre-clinical studies alone. Using novelbioprinted models of cardiac tissue is expected to significantly cut the cost and time ofbringing a new drug to market.