Pre-clinical evaluation of OxyChip for long-term EPR oximetry
- 115 Downloads
Tissue oxygenation is a critical parameter in various pathophysiological situations including cardiovascular disease and cancer. Hypoxia can significantly influence the prognosis of solid malignancies and the efficacy of their treatment by radiation or chemotherapy. Electron paramagnetic resonance (EPR) oximetry is a reliable method for repeatedly assessing and monitoring oxygen levels in tissues. Lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) has been developed as a probe for biological EPR oximetry, especially for clinical use. However, clinical applicability of LiNc-BuO crystals is hampered by potential limitations associated with biocompatibility, biodegradation, or migration of individual bare crystals in tissue. To overcome these limitations, we have embedded LiNc-BuO crystals in polydimethylsiloxane (PDMS), an oxygen-permeable biocompatible polymer and developed an implantable/retrievable form of chip, called OxyChip. The chip was optimized for maximum spin density (40% w/w of LiNc-BuO in PDMS) and fabricated in a form suitable for implantation using an 18-G syringe needle. In vitro evaluation of the OxyChip showed that it is robust and highly oxygen sensitive. The dependence of its EPR linewidth to oxygen was linear and highly reproducible. In vivo efficacy of the OxyChip was evaluated by implanting it in rat femoris muscle and following its response to tissue oxygenation for up to 12 months. The results revealed preservation of the integrity (size and shape) and calibration (oxygen sensitivity) of the OxyChip throughout the implantation period. Further, no inflammatory or adverse reaction around the implantation area was observed thereby establishing its biocompatibility and safety. Overall, the results demonstrated that the newly-fabricated high-sensitive OxyChip is capable of providing long-term measurements of oxygen concentration in a reliable and repeated manner under clinical conditions.
KeywordsOxyChip EPR Oximetry PDMS Rat
This study was supported by National Institutes of Health (NIH) grant R01 EB004031-12.
- M. Dinguizli, S. Jeumont, N. Beghein, J. He, T. Walczak, P.N. Lesniewski, H. Hou, O.Y. Grinberg, A. Sucheta, H.M. Swartz, et al., Development and evaluation of biocompatible films of polytetrafluoroethylene polymers holding lithium phthalocyanine crystals for their use in EPR oximetry. Biosens. Bioelectron. 21, 1015–1022 (2006)CrossRefGoogle Scholar
- Dvornic, P.R. (2000). Thermal properties of Polysiloxanes at low temperatures, in Silicon-Containing Polymers - the Science and Technology of Their Synthesis and Applications. ed. by R.G. Jones, W. Ando, J. Chojnowski Kluwer Academic Publishers, Norwell, pp. 185–212Google Scholar
- H. Hou, N. Khan, J. Lariviere, S. Hodge, E.Y. Chen, L.A. Jarvis, A. Eastman, B.B. Williams, P. Kuppusamy, H.M. Swartz, Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: A longitudinal study by EPR oximetry using single-probe implantable oxygen sensors. Adv. Exp. Med. Biol. 812, 97–103 (2014)CrossRefGoogle Scholar
- H. Hou, V. Krishnamurthy Nemani, G. Du, R. Montano, R. Song, B. Gimi, H.M. Swartz, A. Eastman, N. Khan, Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry. Int. J. Cancer 136, 1688–1696 (2015)CrossRefGoogle Scholar
- M. Khan, I.K. Mohan, V.K. Kutala, S.R. Kotha, N.L. Parinandi, R.L. Hamlin, P. Kuppusamy, Sulfaphenazole protects heart against ischemia-reperfusion injury and cardiac dysfunction by overexpression of iNOS, leading to enhancement of nitric oxide bioavailability and tissue oxygenation. Antioxid. Redox Signal. 11, 725–738 (2009)CrossRefGoogle Scholar
- G. Meenakshisundaram, E. Eteshola, R.P. Pandian, A. Bratasz, K. Selvendiran, S.C. Lee, M.C. Krishna, H.M. Swartz, P. Kuppusamy, Oxygen sensitivity and biocompatibility of an implantable paramagnetic probe for repeated measurements of tissue oxygenation. Biomed. Microdevices 11, 817–826 (2009b)CrossRefGoogle Scholar
- I.K. Mohan, M. Khan, S. Wisel, K. Selvendiran, A. Sridhar, C.A. Carnes, B. Bognar, T. Kalai, K. Hideg, P. Kuppusamy, Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 296, H140–H151 (2009)CrossRefGoogle Scholar
- R.P. Pandian, Y.I. Kim, P.M. Woodward, J.L. Zweier, P.T. Manoharan, P. Kuppusamy, The open molecular framework of paramagnetic lithium octabutoxynaphthalocyanine: Implications for the detection of oxygen and nitric oxide using EPR spectroscopy. Mater. J. Chem. 16, 3609–3618 (2006)CrossRefGoogle Scholar
- M.A. Zullo, F. Plotti, F. Bellati, L. Muzii, R. Angioli, P.B. Panici, Transurethral polydimethylsiloxane implantation: A valid option for the treatment of stress urinary incontinence due to intrinsic sphincter deficiency without urethral hypermobility. J. Urol. 173, 898–902 (2005)CrossRefGoogle Scholar