Anti-biofouling implantable catheter using thin-film magnetic microactuators.

Here we report on the development of polyimide-based flexible magnetic actuators for actively combating biofouling that occurs in many chronically implanted devices. The thin-film flexible devices are microfabricated and integrated into a single-pore silicone catheter to demonstrate a proof-of-concept for a self-clearing smart catheter. The static and dynamic mechanical responses of the thin-film magnetic microdevices were quantitatively measured and compared to theoretical values. The mechanical fatigue properties of these polyimide-based microdevices were also characterized up to 300 million cycles. Finally, the biofouling removal capabilities of magnetically powered microdevices were demonstrated using bovine serum albumin and bioconjugated microbeads. Our results indicate that these thin-film microdevices are capable of significantly reducing the amount of biofouling. At the same time, we demonstrated that these microdevices are mechanically robust enough to withstand a large number of actuation cycles during its chronic implantation.

Label-Free, Real-Time Monitoring of Cytochrome C Responses to Drugs in Microdissected Tumor Biopsies with a Multi-Well Aptasensor Platform.

Functional assays on intact tumor biopsies can potentially complement and extend genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key determinants of therapeutic response, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Currently, most of these assays rely on fluorescent labeling, a semi-quantitative method best suited to be a single-time-point terminal assay or labor-intensive terminal immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of increases of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity. The platform features a multi-well sensor layout and a multiplexed electronic setup. The aptasensors measure increases in cytochrome C in the supernatant of mouse or human microdissected tumors after exposure to various drug treatments. Since the aptamer probe can be easily exchanged to recognize different targets, the platform could be adapted for multiplexed monitoring of various biomarkers, providing critical information on the tumor and its microenvironment. This approach could not only help develop more advanced cancer disease models but also apply to other complex in vitro disease models, such as organs-on-chips and organoids.

Simple Fabrication of Flexible Biosensor Arrays Using Direct Writing for Multianalyte Measurement from Human Astrocytes.

Simultaneous measurements of glucose, lactate, and neurotransmitters (e.g., glutamate) in cell culture over hours and days can provide a more dynamic and longitudinal perspective on ways neural cells respond to various drugs and environmental cues. Compared with conventional microfabrication techniques, direct writing of conductive ink is cheaper, faster, and customizable, which allows rapid iteration for different applications. Using a simple direct writing technique, we printed biosensor arrays onto cell culture dishes, flexible laminate, and glass to enable multianalyte monitoring. The ink was a composite of PEDOT:PSS conductive polymer, silicone, activated carbon, and Pt microparticles. We applied 0.5% Nafion to the biosensors for selectivity and functionalized them with oxidase enzymes. We characterized biosensors in phosphate-buffered saline and in cell culture medium supplemented with fetal bovine serum. The biosensor arrays measured glucose, lactate, and glutamate simultaneously and continued to function after incubation in cell culture at 37 °C for up to 2 days. We cultured primary human astrocytes on top of the biosensor arrays and placed arrays into astrocyte cultures. The biosensors simultaneously measured glucose, glutamate, and lactate from astrocyte cultures. Direct writing can be integrated with microfluidic organ-on-a-chip platforms or as part of a smart culture dish system. Because we print extrudable and flexible components, sensing elements can be printed on any 3D or flexible substrate.

Printable Nonenzymatic Glucose Biosensors Using Carbon Nanotube-PtNP Nanocomposites Modified with AuRu for Improved Selectivity.

Nonenzymatic glucose biosensors have the potential for a more reliable in vivo functionality due to the reduced risk of biorecognition element degradation. However, these novel sensing mechanisms often are nanoparticle-based and have nonlinear responses, which makes it difficult to gauge their potential utility against more conventional enzymatic biosensors. Moreover, these nonenzymatic biosensors often suffer from poor selectivity that needs to be better addressed before being used in vivo. To address these problems, here we present an amperometric nonenzymatic glucose biosensor fabricated using one-step electrodeposition of Au and Ru nanoparticles on the surface of a carbon-nanotube-based platinum-nanoparticle hybrid in conductive polymer. Using benchtop evaluations, we demonstrate that the bimetallic catalyst of Au-Ru nanoparticles can enable the nonenzymatic detection of glucose with a superior performance and stability. Furthermore, our biosensor shows good selectivity against other interferents, with a nonlinear dynamic range of 1-19 mM glucose. The Au-Ru catalyst has a conventional linear range of 1-10 mM, with a sensitivity of 0.2347 nA/(µM mm2) ± 0.0198 (n = 3) and a limit of detection of 0.068 mM (signal-to-noise, S/N = 3). The biosensor also exhibits a good repeatability and stability at 37 °C over a 3 week incubation period. Finally, we use a modified Butler-Volmer nonlinear analytical model to evaluate the impact of geometrical and chemical design parameters on our nonenzymatic biosensor's performance, which may be used to help optimize the performance of this class of biosensors.

In Vivo Glutamate Sensing inside the Mouse Brain with Perovskite Nickelate-Nafion Heterostructures.

Glutamate, one of the main neurotransmitters in the brain, plays a critical role in communication between neurons, neuronal development, and various neurological disorders. Extracellular measurement of neurotransmitters such as glutamate in the brain is important for understanding these processes and developing a new generation of brain-machine interfaces. Here, we demonstrate the use of a perovskite nickelate-Nafion heterostructure as a promising glutamate sensor with a low detection limit of 16 nM and a response time of 1.2 s via amperometric sensing. We have designed and successfully tested novel perovskite nickelate-Nafion electrodes for recording of glutamate release ex vivo in electrically stimulated brain slices and in vivo from the primary visual cortex (V1) of awake mice exposed to visual stimuli. These results demonstrate the potential of perovskite nickelates as sensing media for brain-machine interfaces.

Fabrication and ex vivo evaluation of activated carbon-Pt microparticle based glutamate biosensor.

As one of the most abundant neurotransmitters in the brain and the spinal cord, glutamate plays many important roles in the nervous system. Precise information about the level of glutamate in the extracellular space of living brain tissue may provide new insights on fundamental understanding of the role of glutamate in neurological disorders as well as neurophysiological phenomena. Electrochemical sensor has emerged as a promising solution that can satisfy the requirement for highly reliable and continuous monitoring method with good spatiotemporal resolution for characterization of extracellular glutamate concentration. Recently, we published a method to create a simple printable glutamate biosensor using platinum nanoparticles. In this work, we introduce an even simpler and lower cost conductive polymer composite using commercially available activated carbon with platinum microparticles to easily fabricate highly sensitive glutamate biosensor using direct ink writing method. The fabricated biosensors are functionality superior than previously reported with the sensitivity of 5.73 ± 0.078 nA µM-1 mm-2, detection limit of 0.03 µM, response time less than or equal to 1 s, and a linear range from 1 µM up to 925 µM. In this study, we utilize astrocyte cell culture to demonstrate our biosensor's ability to monitor glutamate uptake process. We also demonstrate direct measurement of glutamate release from optogenetic stimulation in mouse primary visual cortex (V1) brain slices.

Ex vivo electrochemical measurement of glutamate release during spinal cord injury.

Excessive glutamate release following traumatic spinal cord injury (SCI) has been associated with exacerbating the extent of SCI. However, the mechanism behind sustained high levels of extracellular glutamate is unclear. Spinal cord segments mounted in a sucrose double gap recording chamber are an established model for traumatic spinal cord injury. We have developed a method to record, with micro-scale printed glutamate biosensors, glutamate release from ex vivo rat spinal cord segments following injury. This protocol would work equally well for similar glutamate biosensors.

Facile fabrication of flexible glutamate biosensor using direct writing of platinum nanoparticle-based nanocomposite ink.

Glutamate excitotoxicity is a pathology in which excessive glutamate can cause neuronal damage and degeneration. It has also been linked to secondary injury mechanisms in traumatic spinal cord injury. Conventional bioanalytical techniques used to characterize glutamate levels in vivo, such as microdialysis, have low spatiotemporal resolution, which has impeded our understanding of this dynamic event. In this study, we present an amperometric biosensor fabricated using a simple direct ink writing technique for the purpose of in vivo glutamate monitoring. The biosensor is fabricated by immobilizing glutamate oxidase on nanocomposite electrodes made of platinum nanoparticles, multi-walled carbon nanotubes, and a conductive polymer on a flexible substrate. The sensor is designed to measure extracellular dynamics of glutamate and other potential biomarkers during a traumatic spinal cord injury event. Here we demonstrate good sensitivity and selectivity of these rapidly prototyped implantable biosensors that can be inserted into a spinal cord and measure extracellular glutamate concentration. We show that our biosensors exhibit good flexibility, linear range, repeatability, and stability that are suitable for future in vivo evaluation.