Retrievable micro-inserts containing oxygen sensors for monitoring tissue oxygenation using EPR oximetry

Abstract

Tissue oxygenation is a crucial parameter in various physiopathological situations and can influence the therapeutic response of tumours. EPR oximetry is a reliable method for assessing and monitoring oxygen levels in vivo over long periods of time. Among the different paramagnetic oxygen sensors available for EPR oximetry, lithium phthalocyanine (LiPc) is a serious candidate for in vivo applications because of its narrow linewidth and its high signal-to-noise ratio. To enhance the biocompatibility of the sensors, fluoropolymer Teflon AF2400 was used to make cylindrical micro-inserts containing LiPc crystals. This new micro-pellet design has several advantages for in vivo studies, including the possibility of being able to choose the implant size, a high sensor content, the facility of in vivo insertion and complete protection with preservation of the oxygen sensor's characteristics. The response to oxygen and the kinetics of this response were tested using in vivo EPR: no differences were observed between micro-inserts and uncoated LiPc crystals. Pellets implanted in vivo in muscles conserved their responsiveness over a long period of time (approximately two months), which is much longer than the few days of stability observed using LiPc crystals without protection by the implant. Finally, evaluation of the biocompatibility of the implants revealed no inflammatory reaction around the implantation area.

Oxygen sensitivity and biocompatibility of an implantable paramagnetic probe for repeated measurements of tissue oxygenation

“…Although the mean pO 2 , at each measurement point during the experiment, was still within the range of normoxic murine gastrocnemius muscle pO 2 (10–25 mmHg) (Ilangovan et al 2004a; Ilangovan et al 2001; Ilangovan et al 2002a; Eteshola et al 2009; Ilangovan et al 2004b), there was an observable decrease in pO 2 during the initial few weeks following implantation. A similar, but unexplained, decrease in pO 2 , reported by retrievable TAF micro-inserts containing LiPc, was also observed by Dinguizli et al after 4 weeks of residence in mouse gastrocnemius muscle (Dinguizli et al 2008). We think that such a decrease in pO 2 could be due to increased oxygen consumption by polymorphonuclear lymphocytes (PMNs), which are the first line of defense in the body’s reaction to any implanted (foreign) biomaterial.…”

Fabrication and physical evaluation of a polymer-encapsulated paramagnetic probe for biomedical oximetry

“…Successful transformation of EPR oximetry into a powerful clinical tool requires stabilization of probes, in space, in tissue sites, protection of probes from degradative conditions in vivo , and sequestering probes and tissue to mitigate potential toxicity. We, and others, approach this set of challenges by encapsulating crystalline EPR probes in biocompatible, biostable, gas-permeable polymer matrices (Dinguizli et al 2006; Dinguizli et al 2008; Eteshola et al 2009; Gallez et al 1999; Gallez and Mader 2000; He et al 2001). …”

Clinical EPR

“…Although we have alternative probes, based on lithium phthalocyanine (LiPc) derivatives [33, 47, 66] that are much superior to India ink in terms on oxygen sensitivity, and other desirable properties their use in human awaits regulatory approval. One important consideration towards increasing the safety of the implanted probe material, which is usually in the form of microcrystalline powder, is to encapsulate it in a biocompatible, oxygen-permeable polymer [54, 55, 67–69]. The encapsulation will not only hold the probe particulates from smearing or migration over a period of time but also avoid direct contact of the probe with the cells.…”