Advances in Implantable Microelectrode Array Insertion and Positioning.

OBJECTIVES: Microelectrode arrays offer a means to probe the functional circuitry of the brain and the promise of cortical neuroprosthesis for individuals suffering from paralysis or limb loss. These devices are typically comprised of one or more shanks incorporating microelectrode sites, where the shanks are positioned by inserting the devices along a straight path that is normal to the brain surface. The lack of consistent long-term chronic recording technology has driven interest in novel probe design and approaches that go beyond the standard insertion approach that is limited to a single velocity or axis. This review offers a description of typical approaches and associated limitations and surveys emergent methods for implantation of microelectrode arrays, in particular those new approaches that leverage embedded microactuators and extend the insertion direction beyond a single axis. MATERIALS AND METHODS: This review paper surveys the current technologies that enable probe implantation, repositioning, and the capability to record/stimulate from a tissue volume. A comprehensive literature search was performed using PubMed, Web of Science, and Google Scholar. RESULTS: There has been substantial innovation in the development of microscale and embedded technology that enables probe repositioning to maintain quality recordings in the brain. Innovations in material science have resulted in novel strategies for deployable structures that can record from or stimulate a tissue volume. Moreover, new developments involving magnetically steerable catheters and needles offer an alternative approach to "pull" rather than "push" a probe into the tissue. CONCLUSION: We envision the emergence of a new generation of probes and insertion methodologies for neuromodulation applications that enable reliable chronic performance from devices that can be positioned virtually anywhere in the brain.

Phenotypic Screening of Prospective Analgesics Among FDA-Approved Compounds using an iPSC-Based Model of Acute and Chronic Inflammatory Nociception.

Classical target-based drug screening is low-throughput, largely subjective, and costly. Phenotypic screening based on in vitro models is increasingly being used to identify candidate compounds that modulate complex cell/tissue functions. Chronic inflammatory nociception, and subsequent chronic pain conditions, affect peripheral sensory neuron activity (e.g., firing of action potentials) through myriad pathways, and remain unaddressed in regard to effective, non-addictive management/treatment options. Here, a chronic inflammatory nociception model is demonstrated based on induced pluripotent stem cell (iPSC) sensory neurons and glia, co-cultured on microelectrode arrays (MEAs). iPSC sensory co-cultures exhibit coordinated spontaneous extracellular action potential (EAP) firing, reaching a stable baseline after ≈27 days in vitro (DIV). Spontaneous and evoked EAP metrics are significantly modulated by 24-h incubation with tumor necrosis factor-alpha (TNF-α), representing an inflammatory phenotype. Compared with positive controls (lidocaine), this model is identified as an "excellent" stand-alone assay based on a modified Z' assay quality metric. This model is then used to screen 15 cherry-picked, off-label, Food and Drug Administration (FDA)-approved compounds; 10 of 15 are identified as "hits". Both hits and "misses" are discussed in turn. In total, this data suggests that iPSC sensory co-cultures on MEAs may represent a moderate-to-high-throughput assay for drug discovery targeting inflammatory nociception.

Liquid crystal elastomers as substrates for 3D, robust, implantable electronics.

New device architectures favorable for interaction with the soft and dynamic biological tissue are critical for the design of indwelling biosensors and neural interfaces. For the long-term use of such devices within the body, it is also critical that the component materials resist the physiological harsh mechanical and chemical conditions. Here, we describe the design and fabrication of mechanically and chemically robust 3D implantable electronics. This is achieved by using traditional photolithography to pattern electronics on liquid crystal elastomers (LCEs), a class of shape programmable materials. The chemical durability of LCE is evaluated under accelerated in vitro conditions simulating the physiological environment; for example, LCE exhibits less than 1% mass change under a hydrolytic medium simulating >1 year in vivo. By employing twisted nematic LCEs as dynamic substrates, we demonstrate electronics that are fabricated on planar substrates but upon release morph into programmed 3D shapes. These shapes are designed to enable intrinsically low failure strain materials to be extrinsically stretchable. For example, helical multichannel cables for electrode arrays withstand cyclic stretching and buckling over 10 000 cycles at 60% strain while being soaked in phosphate-buffered saline. We envision that these LCE-based electronics can be used for applications in implantable neural interfaces and biosensors.