Normal tissue oxygen levels are critical to maintain homeostasis. Significant divergence from expected levels could serve as an indicator or confirmation of an underlying condition that may require intervention or more diligent monitoring. Despite the clinical significance and importance of tissue oxygenation levels in the diagnosis, prognosis, and treatment of several pathologies, there is clearly an unmet need for technologies to quantify tissue oxygen levels with a reasonable degree of accuracy, reliability, and robustness. The overall objective of this proposal is to bring the precision and consistency of electron paramagnetic resonance (EPR) oximetry to the clinical realm for easily-translatable measurements in cardiovascular, cancer, and cutaneous applications. In the past funding periods, we have discovered unique solid-state implants (probes) and procedures that enable unsurpassed accuracy and repeated interrogation of tissue oxygen levels at specific sites over a period of time, extending to months or longer. However, these measurements are limited primarily to laboratory research involving cells and small animals, the latter of which have known drawbacks in simulating human physiology. In the proposed funding period, we intend to build upon these innovations to translate this promising technology to the clinical realm. As a first ste toward this translation, we plan to develop at least three types of probes and procedures specifically intended for pO2 measurements in transcutaneous, subcutaneous, and deep tissue/organs. We will evaluate and validate the methods in pre- clinical, large animal models, and humans. We also propose to perform rigorous biocompatibility testing using a number of ISO/ASTM guidelines for implantable devices. The following specific aims are proposed: (i) Development of oxygen-sensing chips for continuous or long-term monitoring of pO2 in humans;(ii) Biocompatibility evaluation of oxygen-sensing chips for use in humans;(iii) Evaluation of oxygen-sensing chips for repeated pO2 measurements in preclinical animal models of disease and in humans;and (iv) Enabling technologies for making simultaneous oximetry measurements from multiple sites. When complete, the results from the proposed work will pave the way for subsequent clinical trials applying these innovative technologies for pO2 monitoring.

Public Health Relevance

Disease and injury produce numerous changes in homeostasis, or the maintenance of a normal, healthy condition. One such change is the oxygen level in the affected tissues. Measurement of tissue oxygen is important in terms of diagnosis, long-term tracking, and treatment in a number of applications, including wound healing, cancer, and myocardial infarction (a heart attack). In this proposal, we intend to characterize and test several new, topical and implantable sensors designed for use in human patients to obtain information on the local oxygen level in tissues and organs.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-X (02))
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Sastre, Antonio
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Dartmouth College
Schools of Medicine
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Hou, Huagang; Khan, Nadeem; Gohain, Sangeeta et al. (2018) Pre-clinical evaluation of OxyChip for long-term EPR oximetry. Biomed Microdevices 20:29
Hou, Huagang; Khan, Nadeem; Gohain, Sangeeta et al. (2017) Dynamic EPR Oximetry of Changes in Intracerebral Oxygen Tension During Induced Thromboembolism. Cell Biochem Biophys 75:285-294
Caston, Rose M; Schreiber, Wilson; Hou, Huagang et al. (2017) Development of the Implantable Resonator System for Clinical EPR Oximetry. Cell Biochem Biophys 75:275-283
Hou, H; Khan, N; Nagane, M et al. (2016) Skeletal Muscle Oxygenation Measured by EPR Oximetry Using a Highly Sensitive Polymer-Encapsulated Paramagnetic Sensor. Adv Exp Med Biol 923:351-357
Swartz, Harold M; Williams, Benjamin B; Hou, Huagang et al. (2016) Direct and Repeated Clinical Measurements of pO2 for Enhancing Cancer Therapy and Other Applications. Adv Exp Med Biol 923:95-104
Khan, Nadeem; Hou, Huagang; Swartz, Harold M et al. (2015) Direct and Repeated Measurement of Heart and Brain Oxygenation Using In Vivo EPR Oximetry. Methods Enzymol 564:529-52
Ohanyan, Vahagn; Yin, Liya; Bardakjian, Raffi et al. (2015) Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation. Circ Res 117:612-621
Khan, Nadeem; Hou, Huagang; Eskey, Clifford J et al. (2015) Deep-tissue oxygen monitoring in the brain of rabbits for stroke research. Stroke 46:e62-6
Swartz, Harold M; Hou, Huagang; Khan, Nadeem et al. (2014) Advances in probes and methods for clinical EPR oximetry. Adv Exp Med Biol 812:73-79
Swartz, Harold M; Williams, Benjamin B; Zaki, Bassem I et al. (2014) Clinical EPR: unique opportunities and some challenges. Acad Radiol 21:197-206

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