Multifunctional Nanomaterials for Advancing Neural Interfaces: Recording, Stimulation, and Beyond.

ConspectusNeurotechnology has seen dramatic improvements in the last three decades. The major focus in the field has been to design electrical communication platforms with high spatial resolution, stability, and translatability for understanding and affecting neural pathways. The deployment of nanomaterials in bioelectronics has enhanced the capabilities of conventional approaches employing microelectrode arrays (MEAs) for electrical interfaces, allowing the construction of miniaturized, high-performance neuroelectronics (Garg, R.; et al. ACS Appl. Nano Mater. 2023, 6, 8495). While these advancements in the electrical neuronal interface have revolutionized neurotechnology both in scale and breadth, an in-depth understanding of neurons' interactions is challenging due to the complexity of the environments where the cells and tissues are laid. The activity of large, three-dimensional neuronal systems has proven difficult to accurately monitor and modulate, and chemical cell-cell communication is often completely neglected. Recent breakthroughs in nanotechnology have provided opportunities to use new nonelectric modes of communication with neurons and to significantly enhance electrical signal interface capabilities. The enhanced electrochemical activity and optical activity of nanomaterials owing to their nonbulk electronic properties and surface nanostructuring have seen extensive utilization. Nanomaterials' enhanced optical activity enables remote neural state modulation, whereas the defect-rich surfaces provide an enormous number of available electrocatalytic sites for neurochemical detection and electrochemical modulation of cell microenvironments through Faradaic processes. Such unique properties can allow multimodal neural interrogation toward generating closed-loop interfaces with access to more complete neural state descriptors. In this Account, we will review recent advances and our efforts spearheaded toward utilizing nanostructured electrodes for enhanced bidirectional interfaces with neurons, the application of unique hybrid nanomaterials for remote nongenetic optical stimulation of neurons, tunable nanomaterials for highly sensitive and selective neurotransmitter detection, and the utilization of nanomaterials as electrocatalysts toward electrochemically modulating cellular activity. We highlight applications of these technologies across cell types through nanomaterial engineering with a focus on multifunctional graphene nanostructures applied though several modes of neural modulation but also an exploration of broad material classes for maximizing the potency of closed-loop bioelectronics.

Intestinal retentive systems - recent advances and emerging approaches.

Intestinal retentive devices (IRDs) are devices designed to anchor within the lumen of the intestines for long-term residence in the gastrointestinal tract. IRDs can enable impactful medical device technologies including sustained oral drug delivery systems, indwelling sensors, or real-time diagnostics. The design and testing of IRDs present a myriad of challenges, including precise deployment of the device at desired intestinal locations, secure anchoring within the gastrointestinal tract to allow for natural function, and safe removal of the IRD at user-defined times. Advancing the state-of-the-art of IRD is an interdisciplinary effort that requires innovations such as new materials, novel anchoring mechanisms, and medical device design with consistent input from clinical practitioners and end-users. This perspective briefly reviews the current state-of-the-art for IRDs and charts a path forward to inform the design of future concepts. Specifically, this article will highlight materials, retention mechanisms, and test beds to measure the efficacy of IRDs and their mechanisms. Finally, potential synergies between IRD and other medical device technologies are presented to identify future opportunities.

Miniature battery-free bioelectronics.

Miniature wireless bioelectronic implants that can operate for extended periods of time can transform how we treat disorders by acting rapidly on precise nerves and organs in a way that drugs cannot. To reach this goal, materials and methods are needed to wirelessly transfer energy through the body or harvest energy from the body itself. We review some of the capabilities of emerging energy transfer methods to identify the performance envelope for existing technology and discover where opportunities lie to improve how much-and how efficiently-we can deliver energy to the tiny bioelectronic implants that can support emerging medical technologies.

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices.

Intestinal retentive devices have applications ranging from sustained oral drug delivery systems to indwelling ingestible medical devices. Current strategies to retain devices in the small intestine primarily focus on chemical anchoring using mucoadhesives or mechanical coupling using expandable devices or structures that pierce the intestinal epithelium. Here, the feasibility of intestinal retention using devices containing villi-inspired structures that mechanically interlock with natural villi of the small intestine is evaluated. First the viability of mechanical interlocking as an intestinal retention strategy is estimated by estimating the resistance to peristaltic shear between simulated natural villi and devices with various micropost geometries and parameters. Simulations are validated in vitro by fabricating micropost array patches via multistep replica molding and performing lap-shear tests to evaluate the interlocking performance of the fabricated microposts with artificial villi. Finally, the optimal material and design parameters of the patches that can successfully achieve retention in vivo are predicted. This study represents a proof-of-concept for the viability of micropost-villi mechanical interlocking strategy to develop nonpenetrative multifunctional intestinal retentive devices for the future.

Poisson-Nernst-Planck framework for modelling ionic strain and temperature sensors.

Ionically conductive hydrogels are gaining traction as sensing and structural materials for use bioelectronic devices. Hydrogels that feature large mechanical compliances and tractable ionic conductivities are compelling materials that can sense physiological states and potentially modulate the stimulation of excitable tissue because of the congruence in electro-mechanical properties across the tissue-material interface. However, interfacing ionic hydrogels with conventional DC voltage-based circuits poses several technical challenges including electrode delamination, electrochemical reaction, and drifting contact impedance. Utilizing alternating voltages to probe ion-relaxation dynamics has been shown to be a viable alternative for strain and temperature sensing. In this work, we present a Poisson-Nernst-Planck theoretical framework to model ion transport under alternating fields within conductors subject to varying strains and temperatures. Using simulated impedance spectra, we develop key insights about the relationship between frequency of the applied voltage perturbation and sensitivity. Lastly, we perform preliminary experimental characterization to demonstrate the applicability of the proposed theory. We believe this work provides a useful perspective that is applicable to the design of a variety of ionic hydrogel-based sensors for biomedical and soft robotic applications.

Gelatin-Based Ingestible Impedance Sensor to Evaluate Gastrointestinal Epithelial Barriers.

Low-profile and transient ingestible electronic capsules for diagnostics and therapeutics can replace widely used yet invasive procedures such as endoscopies. Several gastrointestinal diseases such as reflux disease, Crohn's disease, irritable bowel syndrome, and eosinophilic esophagitis result in increased intercellular dilation in epithelial barriers. Currently, the primary method of diagnosing and monitoring epithelial barrier integrity is via endoscopic tissue biopsies followed by histological imaging. Here, a gelatin-based ingestible electronic capsule that can monitor epithelial barriers via electrochemical impedance measurements is proposed. Toward this end, material-specific transfer printing methodologies to manufacture soft-gelatin-based electronics, an in vitro synthetic disease model to validate impedance-based sensing, and tests of capsules using ex vivo using porcine esophageal tissue are described. The technologies described herein can advance next generation of oral diagnostic devices that reduce invasiveness and improve convenience for patients.

Hysteresis-free and high sensitivity strain sensing of ionically conductive hydrogels.

Hydrogels are promising materials for soft and implantable strain sensors owing to their large compliance (E<100 kPa) and significant extensibility (εmax >500%) compared to other polymer networks. Further, hydrogels can be functionalized to seamlessly integrate with many types of tissues. However, most current methods attempt to imbue additional electronic functionality to structural hydrogel materials by incorporating fillers with orthogonal properties such as electronic or mixed ionic conduction. Although composite strategies may improve performance or facilitate heterogeneous integration with downstream hardware, composites complicate the path for regulatory approval and may compromise the otherwise compelling properties of the underlying structural material. Here we report hydrogel strain sensors composed of genipin-crosslinked gelatin and dopamine-functionalized poly(ethylene glycol) for in vivo monitoring of cardiac function. By measuring their impedance only in their resistive regime (>10 kHz), hysteresis is reduced and the resulting gauge factor is increased by ~50x to 1.02±0.05 and 1.46±0.05 from approximately 0.03-0.05 for PEG-Dopa and genipin-crosslinked gelatin respectively. Adhesion and in vivo biocompatibility are studied to support implementation of strain sensors for monitoring cardiac output in porcine models. Impedance-based strain sensing in the kilohertz regime simplifies the piezoresistive behavior of these materials and expands the range of hydrogel-based strain sensors.

Recent Progress in Materials Chemistry to Advance Flexible Bioelectronics in Medicine.

Designing bioelectronic devices that seamlessly integrate with the human body is a technological pursuit of great importance. Bioelectronic medical devices that reliably and chronically interface with the body can advance neuroscience, health monitoring, diagnostics, and therapeutics. Recent major efforts focus on investigating strategies to fabricate flexible, stretchable, and soft electronic devices, and advances in materials chemistry have emerged as fundamental to the creation of the next generation of bioelectronics. This review summarizes contemporary advances and forthcoming technical challenges related to three principal components of bioelectronic devices: i) substrates and structural materials, ii) barrier and encapsulation materials, and iii) conductive materials. Through notable illustrations from the literature, integration and device fabrication strategies and associated challenges for each material class are highlighted.