Injectable, thermosensitive, fast gelation, bioeliminable, and oxygen sensitive hydrogels

Abstract

The decrease of tissue oxygen content due to pathological conditions leads to severe cell death and tissue damage. Restoration of tissue oxygen content is the primary treatment goal. To accurately and efficiently assess efficacy of a treatment, minimally invasive, and long-term detection of oxygen concentration in the same tissue location represents a clinically attractive strategy. Among the different oxygen concentration measurement approaches, electron paramagnetic resonance (EPR) has the potential to accomplish this. Yet there lacks injectable EPR probes that can maintain a consistent concentration at the same tissue location during treatment period to acquire a stable EPR signal, and can finally be eliminated from body without retrieval. Herein, we developed injectable and bioeliminable hydrogel-based polymeric EPR probes that exhibited fast gelation rate, slow weight loss rate, and high oxygen sensitivity. The probe was based on N-Isopropylacrylamide (NIPAAm), 2-hydroxyethyl methacrylate (HEMA), dimethyl-γ-butyrolactone acrylate (DBA), and tetrathiatriarylmethyl (TAM) radical. The injectable probes can be implanted into tissues using a minimally invasive injection approach. The high gelation rate (~10 s) allowed the probes to quickly solidify upon injection to have a high retention in tissues. The polymeric probes overcame the toxicity issue of current small molecule EPR probes. The probes can be gradually hydrolyzed. Upon complete hydrolysis, the probes became water soluble at 37 °C, thus having the potential to be removed from the body by urinary system. The probes showed slow weight loss rate so as to maintain EPR signal intensity for extended periods while retaining in a certain tissue location. The probes remained their high oxygen sensitivity after in vitro hydrolysis and in vivo implantation for 4 weeks. These hydrogel-based EPR probes have attractive properties for in vivo oxygen detection.