Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA.
Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, USA; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA.
Mater Sci Eng C Mater Biol Appl. 2019 Jun;99:1191-1198. doi: 10.1016/j.msec.2019.02.075. Epub 2019 Feb 20.
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.
由于病理状况导致的组织氧含量减少会导致严重的细胞死亡和组织损伤。恢复组织氧含量是主要的治疗目标。为了准确有效地评估治疗效果，在同一组织位置微创且长期检测氧浓度是一种具有吸引力的临床策略。在不同的氧浓度测量方法中，电子顺磁共振（EPR）有可能实现这一点。然而，目前还缺乏可在治疗期间保持同一组织位置的一致浓度以获得稳定的 EPR 信号的可注射 EPR 探针，并且最终可以无需取出而从体内消除。在这里，我们开发了可注射和可生物消除的水凝胶基聚合 EPR 探针，该探针具有快速凝胶化速率、缓慢的失重率和高氧灵敏度。该探针基于 N-异丙基丙烯酰胺（NIPAAm）、2-羟乙基甲基丙烯酸酯（HEMA）、二甲基-γ-丁内酯丙烯酸酯（DBA）和四硫代三芳基甲基（TAM）自由基。可通过微创注射将可注射探针植入组织中。高凝胶化速率（~10 s）使探针在注射后迅速固化，从而在组织中具有高保留率。聚合探针克服了当前小分子 EPR 探针的毒性问题。探针可以逐渐水解。完全水解后，探针在 37°C 下变成水溶性，因此有可能通过泌尿系统从体内清除。探针的失重率较慢，从而在保留在特定组织位置的同时延长了 EPR 信号强度的维持时间。探针在体外水解和体内植入 4 周后仍保持高氧灵敏度。这些水凝胶基 EPR 探针具有用于体内氧检测的有吸引力的特性。
