Multi-organ human-on-a-chip system to address overdose and acute and chronic efficacy and off-target toxicity

项目摘要 对止痛药，特别是鸦片类药物的上瘾，已经成为一个主要的健康问题，需要系统加以引导 对重复过量治疗的了解是必要的。我们的建议旨在建立过量用药的模型 四种药物(芬太尼、美沙酮、可待因和吗啡)在多器官系统中的应用，并评估急性和 重复剂量，或慢性作用，过量治疗，如纳洛酮，对过量恢复，疗效也 对心脏、肌肉、肾脏和肝脏的非靶标毒性。我们已经开发了一种使用人类的低成本系统 无泵多器官平台中的细胞，允许血液替代品持续循环多达28次 几天。该系统模拟母体化合物的分布和所有代谢物的形成 “器官”分区和预测药物的潜在毒性和疗效优于体外单个人体器官 或者动物模型。我们将为男性和女性开发两种不同的过量用药模型 伤害性感受器和B？tzinger复合体(B？TC)神经元，因为它们含有µ-阿片受体，但被认为 在应对过量用药和治疗方面有不同的作用。我们还将整合功能免疫组件 在UH3阶段，已经证明能够实现器官特异性或系统性单核细胞激活。在……里面 此外，将利用心肌病模型和感染模型来更准确地表示 治疗学对合并症的影响。我们将建立一种体外过量用药的PKPD模型 能够在临床环境中预测一系列变量，包括年龄和药物-药物相互作用。一次 建立的系统可用于评估新的疼痛疗法的有效性和非靶点毒性 以及在未来的研究中进行额外的过量治疗。具有连续再循环的互联系统 血液替代物允许在同一系统中同时评估母体化合物及其代谢物 因为它是一个低流量的平台。这种相互连接的系统更适合临床前药物测试，而不是 单器官系统的原因与人类和动物模型目前是 毒性和功效测定，因为它们允许体内器官系统之间的通信。至 构建一个定义良好的系统，我们将使用带有微电极阵列的普通无血清介质和 集成在芯片上的悬臂系统，允许非侵入性的电子和机械读数 器官功能。UCF和Hesperos与临床医生合作，寻求从根本上改变既定做法 在药物发现方面，绕过动物实验和广泛的临床试验，为疾病提供治疗 以及临床情况，如服药过量。我们已经在与监管部门合作，准备 最终接受该系统，以便在INDS中正常使用。因为Hesperos已经在提供多器官 评估作为对制药业和临床医生的一项服务，在 这项提议。

Project Summary Addiction to pain medications, especially opiates, has become a major health problem and systems to guide the understanding of repeat overdose treatments are needed. Our proposal seeks to build overdose models for four drugs (fentanyl, methadone, codeine, and morphine) in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments such as Naloxone on overdose recovery, efficacy as well as off-target toxicity for cardiac, muscle, kidney and liver. We have developed a low cost system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. This system emulates the distribution of a parental compound and the formation of metabolites among all “organ” compartments and predicts potential toxicity and efficacy of drugs better than in vitro single human organ or animal models. We will develop two different overdose models for both male and female phenotypes based on nociceptors and B?tzinger Complex (B?tC) neurons as they contain µ-opioid receptors but are thought to have different roles in response to overdose and treatment. We will also integrate functional immune components in the UH3 Phase that has been demonstrated to enable organ specific or systemic monocyte actuation. In addition, models for cardiomyopathy and an infection model will be utilized to more accurately represent the effects of therapeutics on comorbidities. We will establish a PKPD in vitro model of overdose and treatment to enable prediction in clinical environments for a range of variables including age and drug-drug interactions. Once established the system could be used to evaluate novel pain therapeutics for efficacy and off-target toxicity as well as additional overdose treatments in future studies. Interconnected systems with continuous recirculation of a blood surrogate allows both the parent compound and its metabolites to be evaluated in the same system since it is a low volume platform. This interconnected system is better suited for preclinical drug testing than single organ systems for the same reason that human and animal models are currently the gold standards for toxicity and efficacy determination as they allow communication between the organ systems in the body. To construct a well defined system we will use a common serum free medium with microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts of organ function. UCF and Hesperos in collaboration with clinicians seek to radically change established practice in drug discovery by bypassing animal experiments and extensive clinical trials to provide treatments for diseases and clinical conditions such as overdose. We have already been working with regulatory authorities to prepare for eventual acceptance of the systems for regular use in INDs. Since Hesperos is already offering multi-organ evaluations as a service to the pharmaceutical industry and clinicians there is a direct translational element in the proposal.