Abstract 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 Fe 3 O 4 -CoFe 2 O 4 -BaTiO 3 architecture with efficient magnetoelectric coupling. We find robust responses to magnetic field stimulation in neurons decorated with MENDs at a density of 1 µg/mm 2 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.
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.
Supramolecular hyaluronic acid hydrogels formed via 2 : 1 homoternary complexes of coumarin and cucurbit[8]uril can reversibly toggle between physical and covalent states.
The rising prevalence of high throughput screening and the general inability of (1) two dimensional (2D) cell culture and (2)in vitrorelease studies to predictin vivoneurobiological and pharmacokinetic responses in humans has led to greater interest in more realistic three dimensional (3D) benchtop platforms. Advantages of 3D human cell culture over its 2D analogue, or even animal models, include taking the effects of microgeometry and long-range topological features into consideration. In the era of personalized medicine, it has become increasingly valuable to screen candidate molecules and synergistic therapeutics at a patient-specific level, in particular for diseases that manifest in highly variable ways. The lack of established standards and the relatively arbitrary choice of probing conditions has limitedin vitrodrug release to a largely qualitative assessment as opposed to a predictive, quantitative measure of pharmacokinetics and pharmacodynamics in tissue. Here we report the methods used in the rapid, low-cost development of a 3D model of a mucopolysaccharidosis type I patient’s corpus callosum, which may be used for cell culture and drug release. The CAD model is developed fromin vivobrain MRI tracing of the corpus callosum using open-source software, printed with poly (lactic-acid) on a Makerbot Replicator 5X, UV-sterilized, and coated with poly (lysine) for cellular adhesion. Adaptations of material and 3D printer for expanded applications are also discussed.
Abstract Deep brain stimulation with implanted electrodes has transformed neuroscience studies and treatment of neurological and psychiatric conditions. Discovering less invasive alternatives to deep brain stimulation could expand its clinical and research applications. Nanomaterial-mediated transduction of magnetic fields into electric potentials has been explored as a means for remote neuromodulation. Here we synthesize magnetoelectric nanodiscs (MENDs) with a core–double-shell Fe 3 O 4 –CoFe 2 O 4 –BaTiO 3 architecture (250 nm diameter and 50 nm thickness) with efficient magnetoelectric coupling. We find robust responses to magnetic field stimulation in neurons decorated with MENDs at a density of 1 µg mm −2 despite individual-particle potentials below the neuronal excitation threshold. We propose a model for repetitive subthreshold depolarization that, combined with cable theory, supports our observations in vitro and informs magnetoelectric stimulation in vivo. Injected into the ventral tegmental area or the subthalamic nucleus of genetically intact mice at concentrations of 1 mg ml −1 , MENDs enable remote control of reward or motor behaviours, respectively. These findings set the stage for mechanistic optimization of magnetoelectric neuromodulation towards applications in neuroscience research.
Abstract The engineering advantages of soft, nonaqueous, solvent‐free supramolecular materials have resulted in their emerging transition and adoption from a predominantly food, cosmetics, and paint industry‐driven technology to biocompatible matrices for parenteral drug delivery. Factors that have contributed to this trend are the drastic increase of hydrophobic and combination drugs in the pharmaceutical pipeline and the limitations of hydrated drug delivery materials with regard to poorly soluble drugs and biologics. This review highlights examples of nonaqueous, soft supramolecular materials, illustrates molecular engineering principles that may give rise to novel structures and unique properties, and explores emerging opportunities of application of these materials in parenteral drug delivery.
Background: Hyaluronic acid (HA) is the major component of the extracellular matrix in the central nervous system and the only supramolecular glycosaminoglycan. Much focus has been given to using this high molecular weight polysaccharide for tissue engineering applications. In the majority of cases, HA is covalently functionalized with moieties that can facilitate network formation through physical selfassembly, or photo-catalyzed covalent crosslinking as the polysaccharide does not gel on its own. However, these covalent crosslinks are not the driving force of HA self-assembly in biological tissues. Methods: Oscillatory rheology and dynamic light scattering were used to study albumin/HA structures. Dynamic light scattering and transmission electron microscopy were used to study albumin/chondroitin sulfate (CS) structures. UV-vis spectroscopy was used to study mass transfer of a hydrophilic small molecule into the albumin/HA/CS materials. Results: In this work we examine the intermolecular interactions of two major glycans found in the human brain, HA and the lower molecular weight CS , with the protein albumin. We report physiochemical properties of the resulting supramolecular micro- and nanomaterials. Albumin/HA mixtures formed supramolecular gels, and albumin/CS mixtures formed micro- and nanoparticles. We also summarize the concentrations of HA and CS found in various mammalian brains. Conclusions: Simple preparation and combination of commercially available charged biomacromolecules under short time-scales can result in interesting self-assembled materials with structures at the micron and nanometer length-scales. Such materials may have utility in serving as cost-effective and simple models of nervous system electrostatic interactions and as in vitro drug release and mass transfer quantification tools.
In article number 1800908, Anthony Tabet and Chun Wang review strategies to design supramolecular solvent-free gels that lack appreciable vapor pressure. These networks may consist of nanoparticles with tailored surfaces bridged by hydrophobic or amphiphilic polymer chains in the melt. Such oleogel-like solvent-free materials are distinctly different - both in structure and property - than hydrogels and organogels and have much potential in the local delivery of hydrophobic drugs and combination drug therapies.
<p>Understanding and modulating proton-mediated biochemical processes in living organisms have been impeded by the lack of tools to control local pH. Here, we design nanotransducers capable of converting non-invasive alternating magnetic fields (AMFs) into protons in physiological environments by combining magnetic nanoparticles (MNPs) with polymeric scaffolds. When exposed to AMFs, the heat dissipated by MNPs triggered a hydrolytic degradation of surrounding polyanhydride or polyester, releasing protons into the extracellular space. pH changes induced by these nanotransducers can be tuned by changing the polymer chemistry or AMF stimulation parameters. Remote magnetic control of local protons was shown to trigger acid-sensing ion channels and evoke intracellular calcium influx in neurons. By offering a wireless modulation of local pH, our approach can accelerate the mechanistic investigation of the role of protons in biochemical signalling in the nervous system.</p>
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