Using India Ink as a Sensor for Oximetry: Evidence of its Safety as a Medical Device

Abstract

Clinical EPR spectroscopy is emerging as an important modality, with the potential to be used in standard clinical practice to determine the extent of hypoxia in tissues and whether hypoxic tissues respond to breathing enriched oxygen during therapy. Oximetry can provide important information useful for prognosis and to improve patient outcomes. EPR oximetry has many potential advantages over other ways to measure oxygen in tissues, including directly measuring oxygen in tissues and being particularly sensitive to low oxygen, repeatable, and non-invasive after an initial injection of the EPR-sensing material is placed in the tumor. The most immediately available oxygen sensor is India ink, where two classes of carbon (carbon black and charcoal) have been identified as having acceptable paramagnetic properties for oximetry. While India ink has a long history of safe use in tattoos, a systematic research search regarding its safety for marking tissues for medical uses and an examination of the evidence that differentiates between ink based on charcoal or carbon black has not been conducted. Methods Using systematic literature search techniques, we searched the PubMed and Food and Drug Administration databases, finding ~1000 publications reporting on adverse events associated with India/carbon based inks. The detailed review of outcomes was based on studies involving >16 patients, where the ink was identifiable as carbon black or charcoal. Results Fifty-six studies met these criteria. There were few reports of complications other than transient and usually mild discomfort and bleeding at injection, and there was no difference in charcoal vs. carbon black India ink. Conclusions India ink was generally well tolerated by patients and physicians reported that it was easy to use in practice and used few resources. The risk is low enough to justify its use as an oxygen sensor in clinical practice.

Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies

“…EPR oximetry requires the respective implantation of an exogenous particulate or the injection of a soluble agent into the tumor to quantify pO 2 (132)(133)(134)140). Detection is therefore limited to superficial tumors; however investigations to assess and put forth safer and more informative oxygen sensors that can work at any tissue depth are ongoing (133,(141)(142)(143), and some are being applied in clinical studies (144). Regarding EPRI, the recent introduction of nontoxic, water-soluble, and biocompatible paramagnetic probes could lead to its clinical translation, enabling the non-invasive, real-time quantification of pO 2 in a three-dimensional format (134,140,145).…”

OxyChip Implantation and Subsequent Electron Paramagnetic Resonance Oximetry in Human Tumors Is Safe and Feasible: First Experience in 24 Patients

“…EPR oximetry in humans has thus far been conducted using probes composed of ink particulates; these probes are limited in that they can only measure oxygen if placed within a few mm of the skin surface (9,10). Although ink particulates are tolerated well, this depth limitation hampers their clinical utility vis a vis human malignancies (11). In contrast, the OxyChip probe, a small paramagnetic oxygen sensor composed of oxygen-sensing lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) crystals embedded in a biocompatible polymer (12), can measure pO 2 up to a depth of at least 1.5 cm.…”

Circulating levels of hydroxylated bradykinin function as an indicator of tissue HIF-1α expression

“…However, changes in circulating factors in response to changes in HIF-1a-regulated genes may be useful as non-invasive indicators of tissue hypoxia. HIF-1a directly regulates prolyl-4-hydroxylase a1 (P4HA1) expression, catalyzes proline hydroxylation at X-Pro-Gly (X-P-G) triplets, which plays a critical role in collagen biogenesis [18,19] and is essential for normal collagen folding and stability during tumor remodeling [20][21][22]. Other molecules containing collagen-like sequences can also serve as substrates for P4H activity, including bradykinin (BK), a peptide involved in blood pressure regulation and inflammation [23].…”