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A detailed understanding of the anatomical and molecular architectures of brain cells and their brain-wide organization is essential for interrogating human brain function and dysfunction. Extensive efforts have been made toward mapping brain cells through various lenses, and have established invaluable databases yielding new insights. However, we still lack technologies that allow us to capture multi-scale multi-omic properties of individual brain cells in a holistic and scalable manner. To address this challenge, we developed a fully integrated technology platform for scalable three-dimensional (3D) mapping of human brain cells at subcellular resolution by simultaneously extracting brain-wide structure and high-dimensional features (e.g., spatial, molecular, morphological, and connectivity information) of individual cells from the same brain. We accomplished this by seamlessly integrating new chemical, mechanical, and computational tools to enable highly multiplexed multi-scale 3D proteomic imaging of human brain tissues with minimal information loss. We developed a novel microtome, termed MEGAtome, that enables ultra-precision slicing of a whole-mount intact human brain hemisphere and large arrays of animal organs with minimal loss of intra- and inter-slice information. To preserve structural and molecular information within intact human brain slabs and to enable highly multiplexed multiscale imaging, we developed a tissue-gel technology, termed mELAST, that transforms human brain tissues into an elastic, thermochemically stable, and reversibly expandable tissue-hydrogel. To reconstruct the intact brain to preserve the 3D connectivity information of neural fibers, we developed a semi-automatic tissue reconstruction computational pipeline termed HuBRIS. We demonstrated the utility and scalability of the technology platform by processing whole human brain hemispheres, investigating Alzheimer Disease (AD) pathology, and demonstrating the feasibility of projectome mapping.

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