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

摘要：预测单个患者的最佳治疗方案的能力是一个尚未得到满足的主要需求。 用于治疗癌症和其他疾病。临床癌症治疗中的大多数治疗方法， 尤其是细胞毒性药物以及多种药物的组合，都没有可靠的反应预测指标。 这种不知情的治疗选择是非常低效的，可能会导致治疗成功率降低。 利率，增加的副作用和过度的经济支出。我开发了新的“病人实验室” 在人体组织内实时探测、监测并最终治疗疾病的技术。一个很小的， 微创设备将持续输出揭示疾病生物学的信息 并告知治疗方案。 “患者实验室”技术具有充当微观病理实验室的潜力，它允许 同时实时测量对多种疗法或其他化学干扰物的反应 在病人体内。我们已经实现了大量微量药物释放的概念验证 将不同的药物或分子“传感器”平行植入天然组织，并对每种药物或分子的作用进行分析。 这种化合物(《科学转化医学》，284ra57,2015)。我们正在用以下技术增强这项技术 小型化的检测方法，实现对疾病状态的光学原位实时监控 每个药物储备库附近的小分子和生物制剂的影响。这种混合的高吞吐量 在单一仪器中进行化学扰动和光学检测将首次使 要监测的病变组织和功能特征是连续和非侵入性的 举止。因此，它将提供无与伦比的详细、准确和快速的响应分析和 通过现场读出信号通路、代谢物和其他物质来抵抗治疗药物 分子标记。 这种方法可能最终会使药物远离长期反复试验的治疗方法。 宏观终点和通过探查、治疗和治疗实现疾病的精准管理 在当地进行微观层面的监测。利用技术在当地交付生物(非 治疗性)对天然组织的探索创造了通过直接 采用实时现场监测的刺激反应测量，特别是在下列领域 免疫学、新陈代谢与肿瘤形成--局部组织微环境起关键作用 在疾病生物学基础上的分子过程中的作用。随着时间的推移，这些设备可能会 支持个性化和实时选择最佳治疗方案，并可促进合理设计 在许多癌症适应症中更有效、更个性化的治疗方案。拟议中的项目 跨越持续的技术和翻译开发，支持最终的商业化。

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.