Adaptive Protocol Synthesis and Error Recovery in Micro-Electrode-Dot-Array (MEDA) Microfluidic Biochips

基于液滴的（“数字”）微流体生物芯片（DMFB）正在革新高通量DNA测序和即时临床诊断。使用DMFB，生物测定方案按比例缩小到液滴大小，并通过基于软件的控制图案化电极阵列上的纳升液滴来执行。然而，技术向工业的过渡一直是具有挑战性的，因为当今的DMFB受到几个关键限制：（1）对液滴尺寸的限制;（2）用于实时检测和监测的传感器集成的困难;以及（3）可靠性/产量问题。为了克服这些限制，最近开发了微电极点阵列（梅达）生物芯片，其在每个微电极上结合实时电容感测以检测液滴的性质和位置。这种“传感地图”开辟了网络物理梅达生物芯片的令人兴奋的机会，可以动态响应生物测定结果，执行实时错误恢复，并执行生物化学所需的“if-then-else”协议，以支持具有紧密集成的实验室芯片传感技术的下一代网络物理系统（CPS）。尽管如此巨大的前景，一个显着的障碍，在开发梅达现实的生物化学产生的需要手动控制生物芯片上的生化协议。因此，这项研究的动机是需要在可编程和网络物理梅达生物芯片上执行生物分子测定。为了充分利用梅达的动态自适应能力，需要一个综合和运行时优化框架，它可以灵活地响应实时传感器反馈。因此，该研究将为实现基于MEDA的CPS做出全面努力，从而带来新的应用，例如在癌症治疗或智能城市污染监测中的大气气溶胶测量方面取得突破，旨在为梅达开发包括硬件和软件进步的集成系统解决方案。具体研究产品包括以下创新：（1）建模和鲁棒控制器设计，其中将涉及基于离线模型的协议合成和基于在线学习的协议/模型自适应;（2）自适应和弹性合成技术，全面整合所有MED特定的液滴操作;（3）用于多反应物合成的优化方法，其将涉及芯片上样品制备和与稀释、混合和浓度梯度的产生;（4）通过基于实时感测、液滴跟踪和自适应MEDA特定流体操作的错误恢复的容错性;以及（5）梅达生物芯片设计、制造和试验台设置，以及在软件控制下用于个性化癌症治疗中的细胞分析的实时适应的演示。这些突破将使梅达从一个用于演示液滴操作的探索性平台发展成为一个成熟的平台，微生物学家和生物化学家可以使用它来实现现实的协议。该项目还有一个广泛的教育和推广组成部分，包括课程开发，扩大本科生和研究生的动手研究机会，以及国际合作。例如，MEDA-CPS将被用作一个重要的例子，展示在新的本科生和研究生课程的建模，设计和分析嵌入式控制和网络物理系统的实时适应。该奖项反映了NSF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。

Droplet-based ("digital") microfluidic biochips (DMFBs) are revolutionizing high-throughput DNA sequencing and point-of-care clinical diagnosis. Using DMFBs, bioassay protocols are scaled down to droplet size and executed through software-based control of nanoliter droplets on a patterned electrode array. However, technology transition to industry has been challenging as today's DMFBs suffer from several key limitations: (1) constraints on droplet size; (2) difficulty of sensor integration for real-time detection and monitoring; and (3) reliability/yield concerns. To overcome these limitations, micro-electrode-dot-array (MEDA) biochips have been recently developed, incorporating real-time capacitive sensing on every microelectrode to detect the property and location of a droplet. Such 'sensing maps' open up the exciting opportunity of cyber-physical MEDA biochips that can dynamically respond to bioassay outcomes, perform real-time error recovery, and execute "if-then-else" protocols from biochemistry necessary to support the next generation of cyber-physical systems (CPS) with tightly integrated lab-on-chip sensing technology. Despite such tremendous promise, a significant barrier in the exploitation of MEDA for realistic biochemistry arises from the need to manually control biochemical protocols on the biochip. This research is thus motivated by the need to enable the execution of biomolecular assays on programmable and cyber-physical MEDA biochips. To take full advantage of the dynamic adaptation capabilities of MEDA, there is a need for a synthesis and run-time optimization framework that can be agile in its ability to respond to real-time sensor feedback. The proposed research therefore constitutes a comprehensive effort towards the realization of MEDA-based CPS, resulting in new applications that would, for instance, enable breakthroughs in cancer treatment or atmospheric aerosol measurements for pollution monitoring in smart cities.This is aimed at developing an integrated system solution for MEDA that includes advances in both hardware and software. Specific research products include the following innovations: (1) Modeling and robust controller design, which will involve offline model-based protocol synthesis and online learning-based protocol/model adaptation; (2) Adaptive and elastic synthesis techniques that comprehensively incorporate all the MEDA-specific droplet operations; (3) Optimization methods for multiple-reactant synthesis, which will involve on-chip sample preparation and optimization of the fluidic steps associated with dilution, mixing, and the generation of concentration gradients; (4) Fault tolerance through error recovery based on real-time sensing, droplet tracking, and adaptive MEDA-specific fluidic operations; and (5) MEDA biochip design, fabrication, and testbed setup, and the demonstration of real-time adaptation under software control for cell analysis in personalized cancer treatment. These breakthroughs will advance MEDA from an exploratory platform used to demonstrate droplet manipulation, to a mature platform that microbiologists and biochemists can use for implementing realistic protocols. The project also has an extensive education and outreach component, including curriculum development, expansion of hands-on research opportunities for undergraduate and graduate students, and international collaboration. For instance, MEDA-CPS will be used as an important example to showcase real-time adaptation in new undergraduate and graduate courses on modeling, design, and analysis of embedded control and cyber-physical systems. Tutorials at top conferences and benchmark dissemination activities will benefit the broader research community.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.