Tissue-Integrating Oxygen Sensors: Continuous Tracking of Tissue Hypoxia.

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.

Conditioning saliva for use in a microfluidic biosensor.

This report details an approach to saliva conditioning for compatibility of raw patient samples with microfluidic immunoassay components, principally biosensor surfaces susceptible to fouling. Stimulated whole human saliva spiked with a small molecule analyte (phenytoin, 252 Da) was first depleted of cells, debris and high molecular weight glycoproteins (mucins) using membrane filtration. This process significantly reduced but did not eliminate fouling of biosensor surfaces exposed to the sample. An H-filter, which separates solutes from mixed samples based on their diffusion in laminar flow, was used to extract the analyte from the remaining large molecular weight species in the filtered saliva sample. Patient samples treated in this way retained 23% of the analyte with 97% and 92% reduction in glycoproteins and proteins, respectively, and resulted in 3.6 times less surface fouling than either untreated or filtered saliva alone. These sample conditioning steps will enable the use of fouling-sensitive detection techniques in future studies using clinical saliva samples.

SPR imaging-based salivary diagnostics system for the detection of small molecule analytes.

Saliva is an underused fluid with considerable promise for biomedical testing. Its potential is particularly great for monitoring small-molecule analytes since these are often present in saliva at concentrations that correlate well with their free levels in blood. We describe the development of a prototype diagnostic device for the rapid detection of the antiepileptic drug (AED) phenytoin in saliva. The multicomponent system includes a hand-portable surface plasmon resonance (SPR) imaging instrument and a disposable microfluidic assay card.

Biofouling of polymer hydrogel materials and its effect on diffusion and enzyme-based luminescent glucose sensor functional characteristics.

BACKGROUND: Continuous glucose monitoring is crucial to developing a successful artificial pancreas. However, biofouling and host response make in vivo sensor performance difficult to predict. We investigated changes in glucose diffusivity and sensor response of optical enzymatic glucose sensors due to biological exposure. METHOD: Three hydrogel materials, poly(2-hydroxyethyl methacrylate) (pHEMA), poly(acrylamide) (pAM), and poly(2-hydroxyethyl methacrylate)-co-poly(acrylamide) (p(HEMA-co-AM)), were tested for glucose diffusivity before and after exposure to serum or implantation in rats for 1 month. Luminescent sensors based on these materials were measured to compare the response to glucose before and after serum exposure. RESULTS: Glucose diffusivity through the pHEMA [(8.1 ± 0.38) × 10(-8) cm(2)/s] slabs was much lower than diffusivity through pAM [(2.7 ± 0.15) × 10(-6) cm(2)/s] and p(HEMA-co-AM) [(2.5 ± 0.08) × 10(-6)]. As expected from these differences, sensor response was highly dependent on material type. The pHEMA sensors had a maximum sensitivity of 2.5%/(mg/dl) and an analytical range of 4.2-356 mg/dl, while the p(HEMA-co-AM) sensors had a higher sensitivity [14.9%/(mg/dl)] and a narrower analytical range (17.6-70.5 mg/dl). After serum exposure, the pHEMA sensors were unaffected, whereas the p(HEMA-co-AM) sensors exhibited significantly decreased sensitivity and increased analytical range. CONCLUSIONS: Decreases in glucose diffusivity in the polymers resulting from in vitro serum exposure and residence in vivo were shown to be similar, suggesting that serum incubation was a reasonable approximation of in vivo fouling. While biofouling is expected to affect the response of flux-based sensors, we have shown that this depended on the type of sensor and matrix used. Therefore, proper design and materials selection may minimize response alterations occurring upon implantation.

Biomechanics of the sensor-tissue interface-effects of motion, pressure, and design on sensor performance and the foreign body response-part I: theoretical framework.

The importance of biomechanics in glucose sensor function has been largely overlooked. This article is the first part of a two-part review in which we look beyond commonly recognized chemical biocompatibility to explore the biomechanics of the sensor-tissue interface as an important aspect of continuous glucose sensor biocompatibility. Part I provides a theoretical framework to describe how biomechanical factors such as motion and pressure (typically micromotion and micropressure) give rise to interfacial stresses, which affect tissue physiology around a sensor and, in turn, impact sensor performance. Three main contributors to sensor motion and pressure are explored: applied forces, sensor design, and subject/patient considerations. We describe how acute forces can temporarily impact sensor signal and how chronic forces can alter the foreign body response and inflammation around an implanted sensor, and thus impact sensor performance. The importance of sensor design (e.g., size, shape, modulus, texture) and specific implant location on the tissue response are also explored. In Part II: Examples and Application (a sister publication), examples from the literature are reviewed, and the application of biomechanical concepts to sensor design are described. We believe that adding biomechanical strategies to the arsenal of material compositions, surface modifications, drug elution, and other chemical strategies will lead to improvements in sensor biocompatibility and performance.

Biomechanics of the sensor-tissue interface-effects of motion, pressure, and design on sensor performance and foreign body response-part II: examples and application.

This article is the second part of a two-part review in which we explore the biomechanics of the sensor-tissue interface as an important aspect of continuous glucose sensor biocompatibility. Part I, featured in this issue of Journal of Diabetes Science and Technology, describes a theoretical framework of how biomechanical factors such as motion and pressure (typically micromotion and micropressure) affect tissue physiology around a sensor and in turn, impact sensor performance. Here in Part II, a literature review is presented that summarizes examples of motion or pressure affecting sensor performance. Data are presented that show how both acute and chronic forces can impact continuous glucose monitor signals. Also presented are potential strategies for countering the ill effects of motion and pressure on glucose sensors. Improved engineering and optimized chemical biocompatibility have advanced sensor design and function, but we believe that mechanical biocompatibility, a rarely considered factor, must also be optimized in order to achieve an accurate, long-term, implantable sensor.