Tissue-Integrating Oxygen Sensors: Continuous Tracking of Tissue Hypoxia

Abstract

We describe a simple method of tracking oxygen in real-time with injectable, tissue-integrating microsensors. The sensors are small (500 μm × 500 μm × 5 mm), soft, flexible, tissue-like, biocompatible hydrogel s that have been shown to overcome the foreign body response for long-term sensing. The sensors are engineered to change luminescence in the presence of oxygen or other analytes and function for months to years in the body. A single injection followed by non-invasive monitoring with a hand-held or wearable Bluetooth optical reader enables intermittent or continuous measurements. Proof of concept for applications in high altitude, exercise physiology, vascular disease, stroke, tumors, and other disease states have been shown in mouse, rat and porcine models. Over 90 sensors have been studied to date in humans. These novel tissue-integrating sensors yield real-time insights in tissue oxygen fluctuations for research and clinical applications.

Keywords: Biosensor; Fluorescence; Hydrogel; Luminescence; Metabolism.

Figures

Fig. 49.1

Overview of tissue-integrating sensing system. (a) Miniature fluorescent hydrogel sensor. (b) Mobile health platform vision for continuous metabolic monitoring with a multi-analyte sensor. (c) Optical reader patch (black arrow) sits on the surface of skin and non-invasively interrogates the hydrogel sensor (white fiber) and sends data wirelessly to a computer interface or cell phone. (d) Tissue-integration without fibrous encapsulation of the soft, porous hydrogel sensor enables long term continuous monitoring of body analytes

Fig. 49.2

Sensor performance in vivo. Color shading in C, D, and G indicate periods at 1.00, 0.21 (1st grey bar) and <0.2 fiO2 (2nd grey bar). (a) Critical Limb Ischemia: Hindlimb sensor measured sudden changes in O2 upon application and release of a tourniquet (arrow). (b) Stroke Research: Sensor in mouse brain shows reduced tissue O2 due to induced stroke (carotid artery occlusion) and subsequent recovery after resolving the occlusion. (c) Tumor Metabolism: Sensors in a tumor (circles) and control tissue (line) measure oxygenation during hypoxia. Sensors can be utilized to measure the real-time action of oncological drugs on tumor metabolism and physiology. (d) Hypoxia Research in Pigs: Sensor in pig subcutis measures tissue O2 during acute hypoxia episodes with prototype handheld reader (described in 2.3). (e) Foot O2 in Humans (>2 years): Elevating (white area) and lowering (grey area) of foot causes change in tissue O2 monitored by sensors 2.5 years post-injection. Foot O2 is important to healing chronic wounds. (f) Exercise Physiology: Tissue deoxygenation from isotonic exercise is observed in sensors placed near tricep. (g) Comparison to OxyLite: O2 Sensors (open circle and filled square) respond similarly to a percutaneously inserted fiber optic sensor (Oxylite, Oxford Optronics) (solid line). (h) Glucose Sensor Prototype: Presented is the same O2-sensitive platform with the addition of glucose oxidase to measure glucose concentrations in a rat. The sensors were monitored 3 weeks post-injection. Capillary blood glucose is indicated with triangles. These preliminary data demonstrate the proof-of-concept application of the luminescent hydrogel sensor to extend beyond continuous measurement of oxygen