Biomolecule Crystallization Microarray

描述(申请人提供)：健康和医学研究的几个方面取决于对大分子结构的了解，而大分子结构的确定取决于高质量晶体的供应。生长高质量晶体的条件通常是由昂贵的反复试验研究确定的。拟议的创新是一种光刻制造的系统，用于自动、动态控制生长用于结晶学的生物分子晶体。它在结晶工艺开发应用中也很有用。一组结晶室，每个结晶室的体积为几微升，由一组泵供应，泵的进料速度由飞行时间流量计控制在亚NL/S范围内。这些泵分别用于缓冲液、生物分子溶液和沉淀剂溶液，由使用图像数据的控制算法控制。这些个别概念已在第一阶段研究中得到展示，即在数小时内向微反应室输送几微升溶液并在这种微反应室中生长晶体的能力、使用无移动部件的仪表以电子方式测量亚NL/S流量的能力，以及确定一种非常廉价的数字成像和分析方法的能力。第二阶段研究的具体目标是(1)将这些新组件集成到单个自动结晶系统中，以通过单个控制计算机进行所有功能的协调测试；(2)在此基础上，(1)通过光刻技术设计和制造包括光学、微流体和电子学在内的集成4腔阵列；以及(3)针对实际晶体生长问题测试该阵列，并改进基于图像的控制算法。这项技术使用液-液结晶方法的自动动力学控制作为一种手段来考察一系列化学条件，而不是使用大规模并行的谨慎筛选来提高这一相当昂贵的过程的产量。由此产生的产品是结晶器微阵列(CRYMA)，将向世界大型制药公司、设有结构生物学单位的大学实验室和政府空间研究机构销售--这是Shot公司熟悉的市场。它的实施。

DESCRIPTION (provided by applicant): Several aspects of health and medicinal research depend on the knowledge of macromolecular structures, the determination of which depends on a supply of high-quality crystals. Conditions for growing high-quality crystals are usually determined by expensive trial-and-error research. The proposed innovation is a lithography-fabricated system for automated, kinetically controlled growth of biomolecule crystals for crystallography. It is also useful in crystallization process development applications. An array of crystallization chambers, each with a volume of a few microlitres is served by an array of pumps whose feed rates are controlled in the sub-nL/s range by a time-of-flight flow meter. The pumps, one each for buffer, biomolecule solution and precipitant solution, are commanded by control algorithms that use image data. The individual concepts were demonstrated in Phase I research, namely, the ability to deliver a few microlitres of solution to a microreactor chamber over several hours and to grow crystals in such a chamber, the ability to electronically measure sub nL/s flow rates with a meter than has no moving parts, and the identification of a very inexpensive digital imaging and analysis method. The Phase II research specific aims are to (1) integrate these novel components into a single automated crystallization system to be tested for the coordination of all functions through a single control computer; (2) on the basis of (1) design and fabricate by lithography an integrated 4-chamber array including optics, microfluidics and electronics; and (3) test this array against real crystal-growth problems and refine image-based control algorithms. This technology uses automated kinetic control of the liquid-liquid crystallization method as a means of canvassing a continuum of chemical conditions rather than using massively paralleled discreet screening to enhance throughput in this rather expensive process. The resulting product, a crystallizer microarray ("CRYMA"), will be marketed to the world's large pharmaceutical firms, university laboratories with structural biology units and governmental space research agencies - a market with which SHOT, Inc. is familiar. Its implementation.