A Completely New Camera for Cryo-EM

描述(申请人提供)：这个项目的总体目标是设计和建造一个最先进的摄像系统，基于直接检测有源像素探测器(APD)，为生物电子显微镜提供一种大大改进的胶片替代数据的直接数字记录。这样的系统将立即适用于大分子的冷冻电子显微镜(Cryo-EM)。新的雪佛兰将有一个非常统一的表面和格式的3500x4000像素在5微米x 5微米的间距。作为直接入射电子探测器，该设备不需要限制磷光闪烁屏幕的分辨率。Apd的每个像素都有一个二极管，它将收集入射电子通过敏感的p-外延层时沉积的电荷。它将在一段曝光期内整合收取的费用。在该帧结束时，传感器阵列的内容随后被读出、数字化并存储。所有的集成和读出电子都在0.25微米的芯片表面不到1微米的范围内实现，并且对入射电子是透明的。由于敏感的p-外延层位于读出电路的下方并且是连续的，因此，由于敏感的p-外延层位于读出电路下方并且是连续的，因此，即对入射电子敏感的每个像素区域的比例是100%。我们已经取得了重大突破，实现了一个512x550像素，间距5微米的雪崩光电二极管样机。对于每个入射电子(在100-400keV范围内)，该探测器产生的信噪比约为10/1(而使用电荷耦合器件时为1/1)。空间分辨率也更好(半高宽为2.5微米，而半高宽为30微米)。更好的空间分辨率使这种探测器能够以比ccd低得多的放大率拍摄照片。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)。还需要资金来试验更小的像素间距(3微米x 3微米)。建成后，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，大大提高所研究大分子的3D结构的分辨率。该探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。这些研究将在抗击疾病方面产生非常关键的结果。

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.