Technologies to non-invasively, continuously measure biochemical, metabolic, and biophysical changes in living tissues and organs have the capability to transform medical research and health care. Imaging and biopsies currently are the predominant methods to analyze disease status. Since these approaches provide only a limited number of snapshots over extended periods of time, researchers and clinicians may miss critical changes in physiology and disease status. We propose to overcome this fundamental medical problem by developing a new generation of ultra-low power, wireless, implantable, mm- scale biosensors for real-time, continuous monitoring of interstitial fluid pressure or extracellular pH n tumors. Elevated interstitial fluid pressure and acidic pH are characteristic features of almost al solid tumors, and prior studies suggest that changes in these parameters may be sensitive, early biomarkers for treatment response in many different malignancies. We will design sensors for percutaneous insertion into a tumor before starting chemotherapy. Sensors will remain in place over the multi-week course of treatment, continuously recording pressure or extracellular pH for periodic wireless transmission to an external readout device. We expect changes in interstitial pressure or pH in tumors will occur before alterations in tumor size and at least as soon as changes in tumor metabolism measured by clinical positron emission tomography (PET) imaging. To meet the challenge of extended tumor monitoring, we will advance our biosensor technology in four new areas: 1) through-tissue energy harvesting of infrared (IR) radiation, which will enable implantable devices to operate essentially perpetually in a non-invasive manner; 2) a new self-starting voltage converter to allow system charging after encapsulation is completed, facilitating high quality sealing of the electronics from the in vivo environment; 3) new pressure sensing and pH readout circuits for stable readout under unregulated sensor power supplies; and 4) pre-clinical studies to determine response to therapy in a mouse model of breast cancer. The combined expertise of our multi-disciplinary team uniquely positions us to develop transformative new biosensor technology for continuous monitoring of tumor environments, which will advance understanding of cancer biology and ultimately improve personalized cancer therapy. RELEVANCE (See instructions): We will develop mm-scale electronic biosensors that can be implanted into a tumor to continuously monitor response to several weeks of cancer therapy. By measuring changes in fluid pressure or acid-base balance in a tumor, we expect to detect success or failure of treatment within days of beginning chemotherapy. We expect this biosensor technology ultimately will provide a cheaper, more accurate method to determine efficacy of cancer therapy, allowing doctors to tailor chemotherapy protocols to individual patients and increase patients cured of cancer.