CAREER: Secure Miniaturized Bio-Electronic Sensors for Real-Time In-Body Monitoring

实时体内监测可以为实现早期诊断和干预复杂疾病（如炎症性肠病）提供必要的健康信息。实时有效地跟踪这些炎症过程具有挑战性，因为胃肠道（GI）中的化学环境难以进入和采样。此外，许多炎症性疾病的关键介质在体内非常短暂。分析这些介导疾病和药物反应的短寿命生物分子将提高我们诊断、监测、治疗和预防胃肠道疾病的能力。目前监测胃肠道的金标准依赖于侵入性内窥镜生物间谍或非实时粪便分析。商业诊断药丸，如视频胶囊内窥镜，作为一种强大的技术，提供了一种非侵入性的实时替代方案。然而，纯电子系统功能有限，因为它们不能直接监测肠道化学环境。该项目旨在开发廉价且无创的小型化可消化传感器，以突破现有方法有限的准确性，进入体内生化领域。拟议的安全混合生物电子传感器将能够在家庭环境中实时准确地跟踪疾病进展，同时保护机密医疗信息。除了医疗保健之外，该平台技术还具有解决更广泛的社会挑战的变革潜力。它可以提供一种前所未有的工具，用于深入了解人体内部事件，促进早期发现水污染危机，并支持可持续生产实践。此外，该计划将教育纳入其核心使命。从K-12到研究生阶段的学生将接触和培训开发与其他不同领域（如生物医学工程）接口的半导体平台。通过超越传统的电气工程学科和促进跨学科学习，该计划旨在培养多元化和具有全球竞争力的半导体劳动力。该项目将创造首个安全混合生物电子传感器，从而建立网络安全生物系统（CSBS）领域，以实现准确、可靠和安全的实时体内监测。CSBS平台将使用带有安全集成电路的基因工程生物系统，用于生化传感，提供可靠的数据生成和通信能力。CSBS的工程化生命系统，如用于感知不同分析物的细菌细胞，在恶劣环境（如人类肠道）中具有高特异性和敏感性。该计划的核心智力贡献是：1)创造一种新型的安全小型化可摄取胶囊，用于测量胃肠道中极短寿命的疾病生物标志物；2)设计有效的信息传递机制，在严格的功率和尺寸限制下将细菌细胞传感器与集成电子器件耦合起来；3)开发一种超低功耗多模态传感器集成电路，用于交叉验证生物标志物检测，以实现高精度。4)通过在GI环境中收集能量来为这些混合生物电子传感器提供自供电；5)为资源受限的传感器开发一个物理层安全设计和评估框架，包括第一个模拟/射频（RF）安全原语的开源库和一个动态自适应安全协议，以最大限度地减少安全开销。CSBS的新领域是与合成生物学紧密耦合的半导体支持平台，用于精确的实时监测和控制，具有显著改变医学和环境科学研究的潜力。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Real-time in-body monitoring can provide essential health information for achieving early diagnosis and intervention of complex disorders, such as inflammatory bowel disease. Effective tracking of these inflammatory processes in real time is challenging because the chemical environment in the gastrointestinal (GI) tract is difficult to access and sample. Moreover, many key mediators of inflammatory diseases are extremely short-lived in the body. Profiling these short-lived biomolecules that mediate disease and response to medicine would enhance our ability to diagnose, monitor, treat, and prevent GI disorders. The current gold standard for monitoring the GI tract relies on invasive endoscopic biospies or non-real-time stool analysis. Commercial diagnostic pills such as the video capsule endoscopy provide a non-invasive real-time alternative as a powerful technology. However, electronic-only systems are functionally limited since they cannot directly monitor the gut chemical environment. This project aims to develop inexpensive and non-invasive miniaturized ingestible sensors that tap into the biochemical in-body domain to surpass the limited accuracy of existing methods. The proposed secure hybrid bio-electronic sensors will enable real-time and accurate tracking of disease progression in a home setting while protecting confidential medical information. Beyond healthcare, this platform technology has transformative potential for addressing broader societal challenges. It can provide an unprecedented tool for gaining insights into internal bodily events, facilitating early detection of water contamination crises, and supporting sustainable manufacturing practices. Furthermore, the program integrates education into its core mission. Students from K-12 to graduate levels will be exposed and trained to develop semiconductor-enabled platforms that interface with other diverse fields, such as Biomedical Engineering. By transcending traditional Electrical Engineering disciplines and fostering interdisciplinary learning, the program aims to cultivate a diverse and globally competitive semiconductor workforce. This project will create the first-of-its-kind secure hybrid bio-electronic sensors, thereby establishing the field of Cyber-Secure Biological Systems (CSBS), for accurate, reliable, and safe real-time in-body monitoring. CSBS platforms will use genetically engineered biological systems augmented with secure integrated circuits for biochemical sensing, providing reliable data generation and communication abilities. Engineered living systems of CSBS, such as bacterial cells made to sense different analytes, achieve high specificity and sensitivity in harsh environments, e.g., human gut. The core intellectual contributions of this program are to: 1) create a novel secure miniaturized ingestible capsule that measures extremely short-lived disease biomarkers in the GI tract, 2) design effective information transfer mechanisms to couple bacterial-cell sensors with integrated electronics under tight constraints of power and size, 3) develop an ultra-low-power multi-modal sensor integrated circuit for cross-validation of biomarker detection to achieve high accuracy, 4) self-power these hybrid bio-electronic sensors by harvesting energy in the GI environment, and 5) develop a physical-layer security design and evaluation framework for the resource-constrained sensors, including the first open-source library of analog/radio-frequency (RF) security primitives and a dynamically-adaptive security protocol to minimize the security overhead. The new field of CSBS, tightly coupling semiconductor-enabled platforms with synthetic biology for accurate real-time monitoring and control, has the potential for significantly transforming research in medicine and environmental science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.