Simulation Tool to Rapidly Design Optimize and Prototype Microfluidic Devices

描述（由申请人提供）：微流体技术是实现NHGRI提出的目标的极好候选者，该目标是将总测序成本从目前测序人类大小的基因组的成本降低两个或四个数量级。微流控芯片能够大大减少样品/试剂的使用，并将从样品制备到分离和检测的所有测序步骤集成到单个分析仪器中。目前的芯片设计方法主要依赖于试错实验或采用昂贵的高保真计算分析。这些方法是耗时的，昂贵的，并需要实验或数值建模的专业知识，不能指望芯片设计师和制造商。此外，设计分析工具和微制造工艺之间缺乏直接接口，导致功能原型开发的额外成本和延迟。对于能够以低成本和快速周转时间提供具有上级性能的多功能微流体原型的设计工具存在明确且未满足的需求。我们建议开发一种新的，集成的，范式转换的微流体设计工具包，基于系统级仿真和降阶模型方法，以实现用于基因组分析的下一代微流体系统的快速仿真，优化和原型设计。在第二阶段，我们将开发用于液体填充、基因组样品提取和纯化以及DNA杂交的多物理、降阶模型，这些模型与我们在第一阶段的电泳和PCR模型相结合，将为关键的微流体基因组应用建立一个独立的、完整的设计能力。将为快速芯片设计开发使用非线性规划的基于约束的优化器。将开发和扩展弥合设计-微制造差距的接口，以适应无掩模和基于掩模的制造。新的功能和能力将纳入综合设计环境的开发，以提高易用性、集成性和自动化。通过工业和学术合作，我们将通过开发用于微流控PCR和DNA分离和测序的基因组微芯片的优化设计来验证和展示所提出的原型设计方法。在第二阶段之后，我们将开展软件工程和打包活动，并在执行效率、可靠性、界面多样性和易用性方面优化工具包性能，以便与Intellisense公司合作进行商业发布和销售。微流控制造和测试已经组装成功完成第二阶段的研究。开发的设计工具将在微流体，生命科学，生物医学和生物防御竞技场的关键应用。所提出的努力将有益地影响基因组分析和诊断社区，在缩小整体研发周期（从概念到优化的物理原型在~天内），并通过消除基于试错的设计和手动转移的布局信息的微细加工过程降低成本。公共卫生相关性：该项目旨在开发一种新型的，集成的，范式转换的微流体设计工具，以实现用于基因组分析的下一代微流体系统的快速模拟，优化和原型设计。第二阶段的最终产品将适用于整个生物技术市场的微流体/集成生物微系统部分，从事生命科学研究。开发技术的目标商业应用包括几个成熟和新兴的市场领域，包括制药，生物技术，临床诊断，医疗设备和药物输送。

DESCRIPTION (provided by applicant): Microfluidic technologies are an excellent candidate to achieve the goal set forth by NHGRI to reduce the total sequencing cost by two- or four-orders of magnitude from the current cost of sequencing a human-sized genome. Microfluidic chips enable highly reduced use of the sample/reagent and integration of all sequencing steps from sample preparation to separation and detection into a single analytical instrument. Current chip design methods rely primarily on trial-and-error experiments or employ prohibitively expensive high-fidelity computational analysis. These approaches are time consuming, costly, and require experimental or numerical modeling expertise that cannot be expected of chip designers and manufacturers. In addition, the lack of direct interfacing between design analysis tools and microfabrication processes leads to additional cost and delay in the development of functional prototypes. There is a clear and unmet need for design tool that can deliver multi-functional microfluidic prototypes with superior performance at a low cost and fast turn-around times. We propose to develop a novel, integrated, paradigm-transforming microfluidic design toolkit, based on system- level simulation and reduced-order model methodology to enable rapid simulation, optimization, and prototyping of next-generation microfluidic systems for genomic analysis. In Phase II, we will develop multi-physics, reduced-order models for liquid filling, genomic sample extraction and purification, and DNA hybridization, which in conjunction with our models of electrophoresis and PCR in Phase I will establish a self-contained, complete design capability for critical microfluidic genomic applications. Constraint-based optimizers using nonlinear programming will be developed for rapid chip design. Interfaces bridging the design-microfabrication gap will be developed and expanded to accommodate both maskless and mask-based fabrications. Novel functionalities and capabilities will be incorporated into the development of the integrated design environment for improved ease-of-use, integration, and automation. Through industrial and academic collaboration, we will validate and demonstrate the proposed prototyping methodology by developing optimized design of genomic microchips for microfluidic PCR and DNA separation and sequencing. Beyond Phase II, we will carry out software engineering and packaging activities and optimize the toolkit performance in terms of execution efficacy, reliability, interface diversity, and ease-of-use for commercial release and sales in partnership with Intellisense Corp. An experienced, multi-disciplinary team with expertise in all aspects of the proposed study - reduced-order modeling & simulation, optimization, software development, microfluidic fabrication and testing has been assembled for successful completion of the Phase II research. The developed design tool will have critical applications in microfluidics, life sciences, biomedical and biodefense arena. The proposed effort will beneficially impact the genomic analysis and diagnostics community in terms of shrinking the overall R&D cycles (from concepts to optimized physical prototype within ~days) and reducing the cost via elimination of trial-and-error-based design and manual transfer of the layout information to the microfabrication process. PUBLIC HEALTH RELEVANCE: The project is to develop a novel, integrated, paradigm-transforming microfluidic design tool to enable rapid simulation, optimization, and prototyping of next-generation microfluidic systems for genomic analysis. The Phase II end-product will find applicability in the microfluidic/integrated biomicrosystem section of the overall biotechnology market, engaged in life science research. Target commercial applications for the developed technology include several established and emerging market sectors including pharmaceutical, biotechnology, clinical diagnostics, medical devices, and drug delivery.