Region-specific targeting of microglia in vivo using direct delivery of tamoxifen metabolites via microfluidic polymer fibers.

Region-specific genetic manipulation of glial cells remains challenging due to the lack of anatomically selective transgenic models. Although local transduction is achievable with viral vectors, uniform recombination can be challenging in larger brain regions. We investigated the efficacy of intraparenchymal delivery of the tamoxifen metabolite endoxifen using inducible cre reporter mice. After observing localized reporter induction following stereotaxic injections of endoxifen in CX3CR1creERT2 mice, we carried out chronic delivery via osmotic pumps attached to bilateral cannulas made of stainless steel or microfluidic polymer fibers. Analysis of reporter expression in sections or iDISCO-cleared brains from TMEM119creERT2 mice revealed widespread induction following chronic infusion. Neuronal damage and gliosis were more prevalent around steel cannulas than polymer fibers, and glial reactivity was further attenuated when devices were implanted two months before drug delivery. In summary, region-specific recombination is achievable in glia with minimal tissue damage after endoxifen delivery via microfluidic polymer implants.

Multifunctional fibers enable modulation of cortical and deep brain activity during cognitive behavior in macaques.

Recording and modulating neural activity in vivo enables investigations of the neurophysiology underlying behavior and disease. However, there is a dearth of translational tools for simultaneous recording and localized receptor-specific modulation. We address this limitation by translating multifunctional fiber neurotechnology previously only available for rodent studies to enable cortical and subcortical neural recording and modulation in macaques. We record single-neuron and broader oscillatory activity during intracranial GABA infusions in the premotor cortex and putamen. By applying state-space models to characterize changes in electrophysiology, we uncover that neural activity evoked by a working memory task is reshaped by even a modest local inhibition. The recordings provide detailed insight into the electrophysiological effect of neurotransmitter receptor modulation in both cortical and subcortical structures in an awake macaque. Our results demonstrate a first-time application of multifunctional fibers for causal studies of neuronal activity in behaving nonhuman primates and pave the way for clinical translation of fiber-based neurotechnology.

Fatigue-resistant hydrogel optical fibers enable peripheral nerve optogenetics during locomotion.

We develop soft and stretchable fatigue-resistant hydrogel optical fibers that enable optogenetic modulation of peripheral nerves in naturally behaving animals during persistent locomotion. The formation of polymeric nanocrystalline domains within the hydrogels yields fibers with low optical losses of 1.07 dB cm-1, Young's modulus of 1.6 MPa, stretchability of 200% and fatigue strength of 1.4 MPa against 30,000 stretch cycles. The hydrogel fibers permitted light delivery to the sciatic nerve, optogenetically activating hindlimb muscles in Thy1::ChR2 mice during 6-week voluntary wheel running assays while experiencing repeated deformation. The fibers additionally enabled optical inhibition of pain hypersensitivity in an inflammatory model in TRPV1::NpHR mice over an 8-week period. Our hydrogel fibers offer a motion-adaptable and robust solution to peripheral nerve optogenetics, facilitating the investigation of somatosensation.

Multifunctional microelectronic fibers enable wireless modulation of gut and brain neural circuits.

Progress in understanding brain-viscera interoceptive signaling is hindered by a dearth of implantable devices suitable for probing both brain and peripheral organ neurophysiology during behavior. Here we describe multifunctional neural interfaces that combine the scalability and mechanical versatility of thermally drawn polymer-based fibers with the sophistication of microelectronic chips for organs as diverse as the brain and the gut. Our approach uses meters-long continuous fibers that can integrate light sources, electrodes, thermal sensors and microfluidic channels in a miniature footprint. Paired with custom-fabricated control modules, the fibers wirelessly deliver light for optogenetics and transfer data for physiological recording. We validate this technology by modulating the mesolimbic reward pathway in the mouse brain. We then apply the fibers in the anatomically challenging intestinal lumen and demonstrate wireless control of sensory epithelial cells that guide feeding behaviors. Finally, we show that optogenetic stimulation of vagal afferents from the intestinal lumen is sufficient to evoke a reward phenotype in untethered mice.

Magnetically Actuated Fiber-Based Soft Robots.

Broad adoption of magnetic soft robotics is hampered by the sophisticated field paradigms for their manipulation and the complexities in controlling multiple devices. Furthermore, high-throughput fabrication of such devices across spatial scales remains challenging. Here, advances in fiber-based actuators and magnetic elastomer composites are leveraged to create 3D magnetic soft robots controlled by unidirectional fields. Thermally drawn elastomeric fibers are instrumented with a magnetic composite synthesized to withstand strains exceeding 600%. A combination of strain and magnetization engineering in these fibers enables programming of 3D robots capable of crawling or walking in magnetic fields orthogonal to the plane of motion. Magnetic robots act as cargo carriers, and multiple robots can be controlled simultaneously and in opposing directions using a single stationary electromagnet. The scalable approach to fabrication and control of magnetic soft robots invites their future applications in constrained environments where complex fields cannot be readily deployed.

Magnetoelectric Nanodiscs Enable Wireless Transgene-Free Neuromodulation.

Deep-brain stimulation (DBS) with implanted electrodes revolutionized treatment of movement disorders and empowered neuroscience studies. Identifying less invasive alternatives to DBS may further extend its clinical and research applications. Nanomaterial-mediated transduction of magnetic fields into electric potentials offers an alternative to invasive DBS. Here, we synthesize magnetoelectric nanodiscs (MENDs) with a core-double shell Fe3O4-CoFe2O4-BaTiO3 architecture with efficient magnetoelectric coupling. We find robust responses to magnetic field stimulation in neurons decorated with MENDs at a density of 1 µg/mm2 despite individual-particle potentials below the neuronal excitation threshold. We propose a model for repetitive subthreshold depolarization, which combined with cable theory, corroborates our findings in vitro and informs magnetoelectric stimulation in vivo. MENDs injected into the ventral tegmental area of genetically intact mice at concentrations of 1 mg/mL enable remote control of reward behavior, setting the stage for mechanistic optimization of magnetoelectric neuromodulation and inspiring its future applications in fundamental and translational neuroscience.

Probing Neuro-Endocrine Interactions Through Remote Magnetothermal Adrenal Stimulation.

Exposure to stressful or traumatic stimuli may alter hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal-medullary (SAM) reactivity. This altered reactivity may be a component or cause of mental illnesses. Dissecting these mechanisms requires tools to reliably probe HPA and SAM function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis and SAM changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of SAM, HPA, and other neuro-endocrine axes and could help elucidate changes across stress and disease models.

Building a culture of responsible neurotech: Neuroethics as socio-technical challenges.

Scientists around the globe are joining the race to achieve engineering feats to read, write, modulate, and interface with the human brain in a broadening continuum of invasive to non-invasive ways. The expansive implications of neurotechnology for our conception of health, mind, decision-making, and behavior has raised social and ethical considerations that are inextricable from neurotechnological progress. We propose "socio-technical" challenges as a framing to integrate neuroethics into the engineering process. Intentionally aligning societal and engineering goals within this framework offers a way to maximize the positive impact of next-generation neurotechnologies on society.

Changes in Brain Neuroimmunology Following Injury and Disease.

The nervous and immune systems are intimately related in the brain and in the periphery, where changes to one affect the other and vice-versa. Immune cells are responsible for sculpting and pruning neuronal synapses, and play key roles in neuro-development and neurological disease pathology. The immune composition of the brain is tightly regulated from the periphery through the blood-brain barrier (BBB), whose maintenance is driven to a significant extent by extracellular matrix (ECM) components. After a brain insult, the BBB can become disrupted and the composition of the ECM can change. These changes, and the resulting immune infiltration, can have detrimental effects on neurophysiology and are the hallmarks of several diseases. In this review, we discuss some processes that may occur after insult, and potential consequences to brain neuroimmunology and disease progression. We then highlight future research directions and opportunities for further tool development to probe the neuro-immune interface.

Thermally Drawn Highly Conductive Fibers with Controlled Elasticity.

Electronic fabrics necessitate both electrical conductivity and, like any textile, elastic recovery. Achieving both requirements on the scale of a single fiber remains an unmet need. Here, two approaches for achieving conductive fibers (107 S m-1 ) reaching 50% elongation while maintaining minimal change in resistance (<0.5%) in embedded metallic electrodes are introduced. The first approach involves inducing a buckling instability in a metal microwire within a cavity of a thermally drawn elastomer fiber. The second approach relies on twisting an elastomer fiber to yield helical metal electrodes embedded in a stretchable yarn. The scalability of both approaches is illustrated in apparatuses for continuous buckling and twisting that yield tens of meters of elastic conducting fibers. Through experimental and analytical methods, it is elucidated how geometric parameters, such as buckling pre-strain and helical angle, as well as materials choice, control not only the fiber's elasticity but also its Young's modulus. Links between mechanical and electrical properties are exposed. The resulting fibers are used to construct elastic fabrics that contain diodes, by weaving and knitting, thus demonstrating the scalable fabrication of conformable and stretchable antennas that support optical data transmission.

The preference for sugar over sweetener depends on a gut sensor cell.

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.

Modulating cell signalling in vivo with magnetic nanotransducers.

Weak magnetic fields offer nearly lossless transmission of signals within biological tissue. Magnetic nanomaterials are capable of transducing magnetic fields into a range of biologically relevant signals in vitro and in vivo. These nanotransducers have recently enabled magnetic control of cellular processes, from neuronal firing and gene expression to programmed apoptosis. Effective implementation of magnetically controlled cellular signalling relies on careful tailoring of magnetic nanotransducers and magnetic fields to the responses of the intended molecular targets. This primer discusses the versatility of magnetic modulation modalities and offers practical guidelines for selection of appropriate materials and field parameters, with a particular focus on applications in neuroscience. With recent developments in magnetic instrumentation and nanoparticle chemistries, including those that are commercially available, magnetic approaches promise to empower research aimed at connecting molecular and cellular signalling to physiology and behaviour in untethered moving subjects.

Customizing MRI-Compatible Multifunctional Neural Interfaces through Fiber Drawing.

Fiber drawing enables scalable fabrication of multifunctional flexible fibers that integrate electrical, optical and microfluidic modalities to record and modulate neural activity. Constraints on thermomechanical properties of materials, however, have prevented integrated drawing of metal electrodes with low-loss polymer waveguides for concurrent electrical recording and optical neuromodulation. Here we introduce two fabrication approaches: (1) an iterative thermal drawing with a soft, low melting temperature (Tm) metal indium, and (2) a metal convergence drawing with traditionally non-drawable high Tm metal tungsten. Both approaches deliver multifunctional flexible neural interfaces with low-impedance metallic electrodes and low-loss waveguides, capable of recording optically-evoked and spontaneous neural activity in mice over several weeks. We couple these fibers with a light-weight mechanical microdrive (1g) that enables depth-specific interrogation of neural circuits in mice following chronic implantation. Finally, we demonstrate the compatibility of these fibers with magnetic resonance imaging (MRI) and apply them to visualize the delivery of chemical payloads through the integrated channels in real time. Together, these advances expand the domains of application of the fiber-based neural probes in neuroscience and neuroengineering.

Modular Integration of Hydrogel Neural Interfaces.

Thermal drawing has been recently leveraged to yield multifunctional, fiber-based neural probes at near kilometer length scales. Despite its promise, the widespread adoption of this approach has been impeded by (1) material compatibility requirements and (2) labor-intensive interfacing of functional features to external hardware. Furthermore, in multifunctional fibers, significant volume is occupied by passive polymer cladding that so far has only served structural or electrical insulation purposes. In this article, we report a rapid, robust, and modular approach to creating multifunctional fiber-based neural interfaces using a solvent evaporation or entrapment-driven (SEED) integration process. This process brings together electrical, optical, and microfluidic modalities all encased within a copolymer comprised of water-soluble poly(ethylene glycol) tethered to water-insoluble poly(urethane) (PU-PEG). We employ these devices for simultaneous optogenetics and electrophysiology and demonstrate that multifunctional neural probes can be used to deliver cellular cargo with high viability. Upon exposure to water, PU-PEG cladding spontaneously forms a hydrogel, which in addition to enabling integration of modalities, can harbor small molecules and nanomaterials that can be released into local tissue following implantation. We also synthesized a custom nanodroplet forming block polymer and demonstrated that embedding such materials within the hydrogel cladding of our probes enables delivery of hydrophobic small molecules in vitro and in vivo. Our approach widens the chemical toolbox and expands the capabilities of multifunctional neural interfaces.

Magnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice.

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson's disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.

Capturing 3D atomic defects and phonon localization at the 2D heterostructure interface.

The three-dimensional (3D) local atomic structures and crystal defects at the interfaces of heterostructures control their electronic, magnetic, optical, catalytic, and topological quantum properties but have thus far eluded any direct experimental determination. Here, we use atomic electron tomography to determine the 3D local atomic positions at the interface of a MoS2-WSe2 heterojunction with picometer precision and correlate 3D atomic defects with localized vibrational properties at the epitaxial interface. We observe point defects, bond distortion, and atomic-scale ripples and measure the full 3D strain tensor at the heterointerface. By using the experimental 3D atomic coordinates as direct input to first-principles calculations, we reveal new phonon modes localized at the interface, which are corroborated by spatially resolved electron energy-loss spectroscopy. We expect that this work will pave the way for correlating structure-property relationships of a wide range of heterostructure interfaces at the single-atom level.

Electrochemical Modulation of Carbon Monoxide-Mediated Cell Signaling.

Despite the critical role played by carbon monoxide (CO) in physiological and pathological signaling events, current approaches to deliver this messenger molecule are often accompanied by off-target effects and offer limited control over release kinetics. To address these challenges, we develop an electrochemical approach that affords on-demand release of CO through reduction of carbon dioxide (CO2 ) dissolved in the extracellular space. Electrocatalytic generation of CO by cobalt phthalocyanine molecular catalysts modulates signaling pathways mediated by a CO receptor soluble guanylyl cyclase. Furthermore, by tuning the applied voltage during electrocatalysis, we explore the effect of the CO release kinetics on CO-dependent neuronal signaling. Finally, we integrate components of our electrochemical platform into microscale fibers to produce CO in a spatially-restricted manner and to activate signaling cascades in the targeted cells. By offering on-demand local synthesis of CO, our approach may facilitate the studies of physiological processes affected by this gaseous molecular messenger.

Influence of Magnetic Fields on Electrochemical Reactions of Redox Cofactor Solutions.

Redox cofactors mediate many enzymatic processes and are increasingly employed in biomedical and energy applications. Exploring the influence of external magnetic fields on redox cofactor chemistry can enhance our understanding of magnetic-field-sensitive biological processes and allow the application of magnetic fields to modulate redox reactions involving cofactors. Through a combination of experiments and modeling, we investigate the influence of magnetic fields on electrochemical reactions in redox cofactor solutions. By employing flavin mononucleotide (FMN) cofactor as a model system, we characterize magnetically induced changes in Faradaic currents. We find that radical pair intermediates have negligible influence on current increases in FMN solution upon application of a magnetic field. The dominant mechanism underlying the observed current increases is the magneto-hydrodynamic effect. We extend our analyses to other diffusion-limited electrochemical reactions of redox cofactor solutions and arrive at similar conclusions, highlighting the opportunity to use this framework in redox cofactor chemistry.

Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity.

To understand the underlying mechanisms of progressive neurophysiological phenomena, neural interfaces should interact bi-directionally with brain circuits over extended periods of time. However, such interfaces remain limited by the foreign body response that stems from the chemo-mechanical mismatch between the probes and the neural tissues. To address this challenge, we developed a multifunctional sensing and actuation platform consisting of multimaterial fibers intimately integrated within a soft hydrogel matrix mimicking the brain tissue. These hybrid devices possess adaptive bending stiffness determined by the hydration states of the hydrogel matrix. This enables their direct insertion into the deep brain regions, while minimizing tissue damage associated with the brain micromotion after implantation. The hydrogel hybrid devices permit electrophysiological, optogenetic, and behavioral studies of neural circuits with minimal foreign body responses and tracking of stable isolated single neuron potentials in freely moving mice over 6 months following implantation.

Fiber-Based Electrochemical Biosensors for Monitoring pH and Transient Neurometabolic Lactate.

Developing tools that are able to monitor transient neurochemical dynamics is important to decipher brain chemistry and function. Multifunctional polymer-based fibers have been recently applied to monitor and modulate neural activity. Here, we explore the potential of polymer fibers comprising six graphite-doped electrodes and two microfluidic channels within a flexible polycarbonate body as a platform for sensing pH and neurometabolic lactate. Electrodes were made into potentiometric sensors (responsive to pH) or amperometric sensors (lactate biosensors). The growth of an iridium oxide layer made the fiber electrodes responsive to pH in a physiologically relevant range. Lactate biosensors were fabricated via platinum black growth on the fiber electrode, followed by an enzyme layer, making them responsive to lactate concentration. Lactate fiber biosensors detected transient neurometabolic lactate changes in an in vivo mouse model. Lactate concentration changes were associated with spreading depolarizations, known to be detrimental to the injured brain. Induced waves were identified by a signature lactate concentration change profile and measured as having a speed of ∼2.7 mm/min (n = 4 waves). Our work highlights the potential applications of fiber-based biosensors for direct monitoring of brain metabolites in the context of injury.