Skip to main content

Advertisement

SpringerLink
Log in

Development of the Implantable Resonator System for Clinical EPR Oximetry

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Hypoxic tumors are more resistant to radiotherapy and chemotherapy, which decreases the efficacy of these common forms of treatment. We have been developing implantable paramagnetic particulates to measure oxygen in vivo using electron paramagnetic resonance. Once implanted, oxygen can be measured repeatedly and non-invasively in superficial tissues (<3 cm deep), using an electron paramagnetic resonance spectrometer and an external surface-loop resonator. To significantly extend the clinical applications of electron paramagnetic resonance oximetry, we developed an implantable resonator system to obtain measurements at deeper sites. This system has been used to successfully obtain oxygen measurements in animal studies for several years. We report here on recent developments needed to meet the regulatory requirements to make this technology available for clinical use. radio frequency heating is discussed and magnetic resonance compatibility testing of the device has been carried out by a Good Laboratory Practice-certified laboratory. The geometry of the implantable resonator has been modified to meet our focused goal of verifying safety and efficacy for the proposed use of intracranial measurements and also for future use in tissue sites other than the brain. We have encapsulated the device within a smooth cylindrical-shaped silicone elastomer to prevent tissues from adhering to the device and to limit perturbation of tissue during implantation and removal. We have modified the configuration for simultaneously measuring oxygen at multiple sites by developing a linear array of oxygen sensing probes, which each provide independent measurements. If positive results are obtained in additional studies which evaluate biocompatibility and chemical characterization, we believe the implantable resonator will be at a suitable stage for initial testing in human subjects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S., & Scott, O. C. (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. The British Journal of Radiology, 26(312), 638–648.

    Article  CAS  PubMed  Google Scholar 

  2. Cosse, J. P., & Michiels, C. (2008). Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti-Cancer Agents in Medicinal Chemistry, 8(7), 790–797.

    Article  CAS  PubMed  Google Scholar 

  3. Wouters, A., Pauwels, B., Lardon, F., & Vermorken, J. B. (2007). Review: Implications of in vitro research on the effect of radiotherapy and chemotherapy under hypoxic conditions. The Oncologist, 12(6), 690–712.

    Article  CAS  PubMed  Google Scholar 

  4. Moen, I., & Stuhr, L. E. (2012). Hyperbaric oxygen therapy and cancer-a review. Targeted Oncology, 7(4), 233–242.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lee, N. & Schoder, H. (2004) Using fluorine-18-labeled fluoro-misonidazole positron emission tomography to detect hypoxia in head and neck cancer patients. https://clinicaltrials.gov/ct2/show/NCT0060629. Bethesda: National Library of Medicine (USA).

  6. Baumann, M., Krause, M., & Cordes, N. (2016). Invasive assessment of tumour cell hypoxia, in molecular radio-oncology. Berlin, Heidelber: Springer 191–198.

    Google Scholar 

  7. Horsman, M., Busk, M., & Nielsen, T. (2013). Clinical Imaging of Hypoxia, in Hypoxia and Cancer: Biological Implications and Therapeutic Opportunities. New York: Humana 185.

    Google Scholar 

  8. Springett, R., & Swartz, H. M. (2007). Measurements of oxygen in vivo: Overview and perspectives on methods to measure oxygen within cells and tissues. Antioxidants and Redox Signaling, 9(8), 1295–1301.

    Article  CAS  PubMed  Google Scholar 

  9. Swartz, H. M. (2016). Using stable free radicals to obtain unique and clinically useful data in vivo in human subjects. Radiation Protection Dosimetry, 172(1–3), 3–15.

    Article  PubMed  Google Scholar 

  10. Swartz, H. M., & Walczak, T. (1998). Developing in vivo EPR oximetry for clinical use. Advances in Experimental Medicine and Biology, 454, 243–252.

    Article  CAS  PubMed  Google Scholar 

  11. Meenakshisundaram, G., Eteshola, E., Pandian, R. P., Bratasz, A., Selvendiran, K., Lee, S. C., Krishna, M. C., Swartz, H. M., & Kuppusamy, P. (2009). Oxygen sensitivity and biocompatibility of an implantable paramagnetic probe for repeated measurements of tissue oxygenation. Biomed Microdevices, 11, 817–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jarvis, L. A., Williams, B. B., Schaner, P. E., Chen, E. Y., Angeles, C. V., Hou, H., et al. (2016). Phase 1 clinical trial of OxyChip, an implantable absolute pO2 sensor for tumor oximetry. International Journal of Radiation Oncology, Biology, Physics, 96(Suppl. 2), S109–S110.

    Article  Google Scholar 

  13. Salikhov, I., Hirata, H., Walczak, T., & Swartz, H. M. (2003). An improved external loop resonator for in vivo L-band EPR spectroscopy. Journal of Magnetic Resonance, 164(1), 54–59.

    Article  CAS  PubMed  Google Scholar 

  14. Hou, H., Dong, R., Li, H., Williams, B., Lariviere, J. P., Hekmatyar, S. K., et al. (2012). Dynamic changes in oxygenation of intracranial tumor and contralateral brain during tumor growth and carbogen breathing: A multisite EPR oximetry with implantable resonators. Journal of Magnetic Resonance, 214(1), 22–28.

    Article  CAS  PubMed  Google Scholar 

  15. Hou, H., Li, H., Dong, R., Mupparaju, S., Khan, N., & Swartz, H. (2011). Cerebral oxygenation of the cortex and striatum following normobaric hyperoxia and mild hypoxia in rats by EPR oximetry using multi-probe implantable resonators. Advances in Experimental Medicine and Biology, 701, 61–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li, H., Hou, H., Sucheta, A., Williams, B. B., Lariviere, J. P., Khan, M. N., et al. (2010). Implantable resonators--a technique for repeated measurement of oxygen at multiple deep sites with in vivo EPR. Advances in Experimental Medicine and Biology, 662, 265–272.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Caston, RM. (2016). Developing and Implantable Resonator for EPR Oximetry (BA Honors Thesis). Dartmouth College.

  18. Hou, H., Khan, N., Nagane, M., Gohain, S., Chen, E. Y., Jarvis, L. A., et al. (2016). Skeletal muscle oxygenation measured by EPR oximetry using a highly sensitive polymer-encapsulated paramagnetic sensor. Advances in Experimental Medicine and Biology, 923, 351–357.

    Article  CAS  PubMed  Google Scholar 

  19. Hou, H., Khan, N., Lariviere, J., Hodge, S., Chen, E. Y., Jarvis, L. A., et al. (2014). Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: A longitudinal study by EPR oximetry using single-probe implantable oxygen sensors. Advances in Experimental Medicine and Biology, 812, 97–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Khan, N., Hou, H., Eskey, C. J., Moodie, K., Gohain, S., Du, G., et al. (2015). Deep-tissue oxygen monitoring in the brain of rabbits for stroke research. Stroke, 46(3), e62–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Swartz, H. M., Hou, H., Khan, N., Jarvis, L. A., Chen, E. Y., Williams, B. B., & Kuppusamy, P. (2014). Advances in probes and methods for clinical EPR oximetry. Advances in Experimental Medicine and Biology, 812, 73–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. BomBač, D., Brojan, M., Fajfar, P., Kosel, F., & Turk, R. (2007). Review of materials in medical applications. RMZ–Materials and Geoenvironment, 54(4), 471–499.

    Google Scholar 

  23. US Food and Drug Administration (2013) Investigational Device Exemptions (IDEs) for early feasibility medical device clinical studies, including certain First in Human (FIH) Studies, Guidance for Industry and Food and Drug Administration, Issued October 1.

Download references

Acknowledgements

Special thanks to a group of students at Thayer School of Engineering at Dartmouth College for their contributions to the development of the IR.

Funding

Research reported in this publication was supported by The National Institutes of Health awards P01 CA190193 from the National Cancer Institute and R01 EB4031 from the National Institute of Biomedical Imaging and Bioengineering. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. EPR Center for the Study of Viable Systems at Dartmouth College, Hanover, USA

    Rose M. Caston, Wilson Schreiber, Huagang Hou, Benjamin B. Williams, Eunice Y. Chen, Philip E. Schaner, Lesley A. Jarvis, Ann Barry Flood, Sergey V. Petryakov, Maciej M. Kmiec, Periannan Kuppusamy & Harold M. Swartz

Authors
  1. Rose M. Caston
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wilson Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huagang Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benjamin B. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eunice Y. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philip E. Schaner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lesley A. Jarvis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ann Barry Flood
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sergey V. Petryakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maciej M. Kmiec
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Periannan Kuppusamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Harold M. Swartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rose M. Caston.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caston, R.M., Schreiber, W., Hou, H. et al. Development of the Implantable Resonator System for Clinical EPR Oximetry. Cell Biochem Biophys 75, 275–283 (2017). https://doi.org/10.1007/s12013-017-0809-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-017-0809-2

Keywords

Search

Navigation