In this SBIR a powerful new tool for imaging biological samples with sub-nanometer resolution is proposed. This tool allows for information on cellular processes to be measured from the mechanical and thermal properties of living cells. To date there has been no concentrated effort by a private entity to use micromachined piezo-thermal atomic force microscopy probes as single cell disease markers. This SBIR Phase I aims to develop a novel method for single cell disease markers using a hybrid scanning piezo-thermal probe and its associated electronics. The probe will operate in aqueous environments and will include an embedded piezoresistive element (for viscoelastic measurements and z-axis sensing), and a thermal element (for thermal properties measurement such as thermal conductance and conductivity measurements to identify the specimen from its thermal signature). In this proposal key engineering and application challenges will be addressed. Micromachined scanning piezo-thermal probes, an interface circuit, and specialized software will be designed and developed. Finally the utility of the system will be demonstrated by producing thermal and topographical images of cells and by discriminating thermally and viscoelastically between healthy and diseased cells. This SBIR is a collaboration between PicoCal, Inc., the Dep. of Electrical Engineering of Michigan State University, and the Depts. of Medicine and Pharmacology & Toxicology of Michigan State University. This work will continue into Phase II with the aim of scaling the system and dramatically improving the scan rate to create a tool useful for temporal and high throughput imaging. Keywords: Cell biomechanics, viscoelasticity, cytoskeleton, indentation, stiffness, disease markers, scanning thermal microscopy, SThM, atomic force microscopy, AFM, scanning probe microscopy, SPM, conductance measurements, cell biology, nanomechanics, mechanotransduction, mechanobiology With the costs of clinical trials for new drug development and approval in the billion dollar range, single cell disease markers offer an inexpensive way to quickly and harmlessly test possible drug candidates on live human cells before testing the drugs on animals or humans. At the same time new personalized treatments tested on single live cells, rather than one-size-fits-all treatments like chemotherapy, have an excellent likelihood of effectively treating diseases in the future. The proposed instrument may contribute to the understanding of cell mechanisms and biology and may be sensitive to disease allowing for the use of such measurements as disease markers. This method may find clinical use and may add to the recognition, identification, and treatment of disease. [unreadable] [unreadable] [unreadable]