Implantable microdevices with integrated optical imaging for high-throughput in situ tumor response and drug sensitivity measurement

摘要：预测个体患者最佳治疗的能力是一个主要的未满足需求 用于治疗癌症和其他疾病。临床癌症治疗中的大多数疗法， 特别是细胞毒性药物以及多种药物的组合，没有可靠的反应预测因子。 这种不知情的治疗选择是非常低效的，并可能导致治疗成功率降低 增加的副作用和过度的经济支出。我发明了一种新颖的“病人实验室” 在人体组织内真实的时间内探测、监测并最终治疗疾病的技术。一个小小的， 微创设备将提供持续的信息输出，揭示疾病生物学 并告知治疗方案。 “病人实验室”技术有可能作为一个微观病理学实验室， 实时测量对多种治疗或其他化学干扰剂的反应 在病人体内。我们已经实现了释放大量微剂量药物的概念验证。 将不同的药物或分子“传感器”平行植入天然组织，并分析每种药物或分子“传感器”的作用。 这些化合物（Science Translational Medicine，284 ra 57，2015）。我们正在增强这项技术， 小型化检测方法，其使得能够对疾病状态进行光学原位实时监测， 每个药物储库附近的小分子和生物制剂的影响。这种高通量的混合 化学扰动和光学检测在一个单一的仪器将首次使， 以连续和非侵入性的方式监测和功能表征患病组织。 方式因此，它将提供前所未有的细节，精度和分析响应的速度， 通过信号传导途径、代谢物和其他物质的现场读数对治疗剂的抗性 分子标记 这种方法最终可能会使医学远离长期试错治疗。 宏观终点，并通过探测、治疗和 在微观层面进行局部监测。利用技术在当地提供生物（非生物） 治疗）探针进入天然组织创建了通过直接的基本洞察的能力， 刺激-反应测量与实时现场监测，特别是在 免疫学、代谢和癌症形成，其中局部组织微环境起关键作用 在疾病生物学基础的分子过程中的作用。随着时间的推移，这些设备可能 能够个性化和实时选择最佳疗法，并有助于合理设计 在众多癌症适应症中更有效的个性化治疗方案。拟建项目 跨越了支持最终商业化的持续技术和转化发展。

ABSTRACT: The ability to predict the optimal therapy for an individual patient is a major unmet need in the treatment of cancer and other diseases. The majority of therapies in clinical cancer treatment, particularly cytotoxics as well as combinations of multiple drugs, have no reliable predictor of response. This uninformed therapy selection is highly inefficient and likely leads to reduced therapeutic success rates, increased side effects and excessive economic expenditures. I develop novel “lab-in-a-patient” technology to probe, monitor, and eventually treat disease in real time within human tissue. A tiny, minimally invasive device will provide continuous output of information that reveals disease biology and informs treatment options. “Lab-in-a-patient” technology has the potential to act as a micro-pathology laboratory by allowing the real-time measurement of response to multiple therapies or other chemical perturbagens simultaneously within the patient. We have achieved proof-of-concept for release of microdoses of a large number of distinct drugs or molecular “sensors” in parallel into native tissue, with analysis of the effect for each such compound (Science Translational Medicine, 284ra57, 2015). We are augmenting this technology with miniaturized detection methods that enable optical in situ real-time monitoring of disease state and the effects of small molecules and biologics near each drug reservoir. This blend of high-throughput chemical perturbation and optical detection in a single instrument will, for the first time, enable diseased tissue to be monitored and functionally characterized in a continuous and noninvasive manner. It will thus provide unprecendented detail, precision and speed of analyzing response and resistance to therapeutics through live in situ readouts of signaling pathways, metabolites and other molecular markers. This approach may eventually push medicine away from trial-and-error treatments with longer-term macroscale endpoints and towards precision management of disease by probing, treating and monitoring locally at the microscale level. Use of the technology for local delivery of biological (non- therapeutic) probes into native tissue creates the capability for fundamental insights through direct stimulus-response measurements with real-time in situ monitoring, particularly in the areas of immunology, metabolism and cancer formation where the local tissue microenvironment plays a key role in the molecular processes underlying disease biology. In the fullness of time, these devices may enable individualized and real-time selection of optimal therapies and could facilitate rational design of more effective, personalized therapeutic regimens in numerous cancer indications. The proposed project spans continued technological and translational development that support eventual commercialization.