Tissue Adhesive Tattoos for Gastrointestinal Endoscopy

Approximately 3 million people are hospitalized for gastrointestinal (GI) indications in the US, resulting in costs of more than $135 billion every year. Early identification and detection of disease are key to saving lives, and nearly 11 million colonoscopies as well as 6 million upper GI endoscopies are carried out in the US annually. Suspect regions (e.g., polyps > 1cm) are often marked with tattoo inks in order to facilitate easy identification for longitudinal follow up, surgery, or additional procedures. Only one formulation of tattoo ink - a suspension of carbon particles - is currently approved for use in patients in the US. Clinically in humans and in preclinical animal models, this ink diffuses extensively throughout the tissue and the body, thus compromising spatial localization. This severely reduces performance in visualizing laterally diffusing, flat or depressed lesions and makes their resection very challenging, particularly in laparoscopic and robotic procedures. The ink can cause fibrosis, and extravasate to other tissues, which raises concerns of toxicity and inflammation at distant sites. Although use of carbon facilitates visualization under endoscopic light, this obviates multimodal imaging, which limits extensibility to other diagnostic, treatment, and follow-up procedures. We have developed next generation inks – Tissue-Adhesive Tattoos-generation 2 or TAT2 inks - that demonstrate excellent localization, high contrast under endoscopic light, high biocompatibility and multimodal imaging activity. Different biopolymer-nanoparticle formulations were generated and characterized using size, viscosity, injectability, surface charge, and electron microscopy analyses. Immunogenicity of TAT2 inks was investigated using reporter macrophages and their stability was determined over at least two months. Ex vivo studies using porcine intestinal tissue and sub-cutaneous administration studies, including histological analyses, in live mice were carried out to determine the efficacy of localization and biocompatibility. Multimodal imaging capability of TAT2 inks was investigated using post-mortem studies in mice. Finally, endoscopic administrations of TAT2 inks were carried out in live Yorkshire pigs and the localization efficacy was determined using endoscopic visualization immediately as well as two weeks after administration. Biocompatibility and toxicity of TAT2 inks in pigs were determined using clinical chemistry and histological analyses of the lung, liver, and kidneys. Our results indicate that TAT2 inks demonstrate significantly higher efficacies of localization than the existing ink. Further, their biocompatibility and multimodal imaging capabilities make them highly attractive for translational adoption for early marking and surveillance of disease in GI endoscopies and other indications.