The objective of this research is to create computational foundation, methods, and tools for efficient and autonomous optical micromanipulation using microsphere ensembles as grippers. The envisioned system will utilize a holographic optical tweezer, which uses multiple focused optical traps to position microspheres in three-dimensional space. The proposed approach will focus on the following areas. First, it will provide an experimentally validated optical-tweezers based workstation for concurrent manipulation of multiple cells. Second, it will provide algorithms for on-line monitoring of workspace to support autonomous manipulation. Finally, it will provide real-time image-guided motion planning strategies for transporting microspheres ensembles. The proposed work will lead to a new way of autonomously manipulating difficult-to-trap or sensitive objects using microspheres ensembles as reconfigurable grippers. The proposed work will also lead to fundamental advances in several cyber physical systems areas by providing new approaches to micromanipulations, fast and accurate algorithms with known uncertainty bounds for on-line monitoring of moving microscale objects, and real-time motion planning algorithms to transport particle ensembles. The ability to quickly and accurately manipulate individual cells with minimal training will enable researchers to conduct basic research at the cellular scale. Control over cell-cell interactions will enable unprecedented insights into cell signaling pathways and open up new avenues for medical diagnosis and treatment. The proposed integration of research with education will train students with a strong background in emerging robotics technologies and the inner workings of cells. These students will be in a unique position to rapidly develop and deploy specialized robotics technologies.