A Completely New Camera for Cryo-EM

描述（由申请人提供）：该项目的总体目标是设计和构建一个最先进的摄像系统，基于直接检测有源像素检测器（APD），为生物电子显微镜的数据直接数字记录提供一种大大改进的胶片替代品。这样的系统将立即适用于大分子的冷冻电子显微镜（cryo-EM）并且有益于大分子的冷冻电子显微镜（cryo-EM）。新的APD将有一个非常均匀的表面和格式的3500 x4000像素在5微米x5微米间距。作为直接入射电子检测器，该装置将不需要分辨率限制磷光闪烁屏。APD的每个像素将具有二极管，该二极管将收集由入射电子在其通过敏感的p-外延层的通道中沉积的电荷。它将在暴露期内整合收集的费用。在帧结束时，传感器阵列的内容然后被读出、数字化和存储。所有的集成和读出电子器件都在0.25微米CMOS芯片的表面的小于1微米内实现，并且对入射电子是透明的。“填充因子”，即对入射电子敏感的每个像素区域的比例，是100%，这是由于敏感的p-外延层位于读出电路下方并且是连续的这一事实。我们已经取得了很大的突破，实现了一个原型APD具有512 × 550像素的5微米间距。该探测器对每个入射电子（在100-400 keV范围内）产生约10/1的信噪比（相对于CCD的1/1）。空间分辨率也更好（2.5微米对30微米的FWHM）。更好的空间分辨率使该探测器能够以比CCD低得多的放大倍数拍摄照片。需要资金来制造更大的芯片（高达3.5K x 4K像素），芯片上的ADC允许非常高的帧读出（高达100帧/秒）。还要求提供资金，以试验更小的像素间距（3微米x3微米）。完成后，这种探测器将使研究人员能够快速收集数十万张图像的数据，大大提高所研究的大分子的3D结构的分辨率。该检测器将极大地帮助研究感染哺乳动物、昆虫和植物宿主的球形病毒。这些研究将在与疾病的斗争中产生非常重要的结果。

DESCRIPTION (provided by applicant): The overall aim of this project is to design and build a state-of-the-art camera system, based on a Direct Detection Active Pixel Detector (APD) to provide a vastly improved film substitute for direct digital recording of data for biological Electron Microscopy. Such a system will be immediately applicable and beneficial to cryo-Electron Microscopy (cryo-EM) of macromolecules. The new APD will have an extremely uniform surface and format of 3500x4000 pixels at 5 micron x 5 micron pitch. As a direct incident electron detector, this device will not require a resolution limiting phosphorescent scintillation screen. Each pixel of the APD will have a diode that will collect the charges deposited by an incident electron in its passage through a sensitive p-epitaxial layer. It will integrate the collected charges during an exposure period. At the conclusion of the frame, the contents of the sensor array are then read out, digitized and stored. All of the integration and read out electronics are implemented within less than 1 micron of the surface of a 0.25 micron CMOS chip, and are transparent to the incident electrons. The "fill factor" i.e. the proportion of each pixel area that is sensitive to the incident electrons, is 100% due to the fact that the sensitive p-epitaxial layer lies beneath the readout circuitry and is continuous. We have made a big breakthrough with the realization of a prototype APD having 512 x 550 pixels of 5 micron pitch. This detector yields a signal-to-noise ratio for each incident electron (in the 100-400 keV range) of 10/1 approximately (versus 1/1 with a CCD). The spatial resolution is also much better (2.5 micron versus 30 micron for FWHM). The better spatial resolution allows this detector to take pictures at a much lower magnification than with a CCD. Funding is requested to make larger chips (up to 3.5K x 4K pixels) with on chip ADC allowing very high frame readout (up to 100 frames/sec). Funding is requested also to experiment with even smaller pixel pitch (3 micron x 3 micron). When finished, this kind of detector will allow researchers to quickly gather data on hundreds of thousand of images, greatly improving the resolution of 3D structures of the studied macromolecules. This detector will greatly help the studies of spherical viruses that infect mammalian, insect, and plant hosts. These studies will yield very critical results in the fight against disease.