Nanotransducers for Wireless Neuromodulation

Abstract

Understanding the signal transmission and processing within the central nervous system (CNS) is a grand challenge in neuroscience. The past decade has witnessed significant advances in the development of new tools to address this challenge. Development of these new tools draws diverse expertise from genetics, materials science, electrical engineering, photonics and other disciplines. Among these tools, nanomaterials have emerged as a unique class of neural interfaces due to their small size, remote coupling and conversion of different energy modalities, various delivery methods, and mitigated chronic immune responses. In this review, we will discuss recent advances in nanotransducers to modulate and interface with the neural system without physical wires. Nanotransducers work collectively to modulate brain activity through optogenetic, mechanical, thermal, electrical and chemical modalities. We will compare important parameters among these techniques including the invasiveness, spatiotemporal precision, cell-type specificity, brain penetration, and translation to large animals and humans. Important areas for future research include a better understanding of the nanomaterials-brain interface, integration of sensing capability for bidirectional closed-loop neuromodulation, and genetically engineered functional materials for cell-type specific neuromodulation.

Keywords: magnetic stimulation; nanotransducers; neuromodulation; optical stimulation; ultrasound modulation.

Figure 1.. Working principles and evolution of nanotransducers enabled wireless neuromodulation.

(A) working principles of nanotransducers for neuromodulation and (B) representative developments in nanotransducer-based and related neuromodulation techniques. Yellow for sono-neuromodulation, green for magneto-neuromodulation, cyan for optical neuromodulation, and pink for electrical neuromodulation. References for each technique: Caged compounds; Deep brain stimulation; Transcranial magnetic stimulation (TMS); Optogenetics^–; Infrared neural stimulation; Optoelectrical stimulation; Magnetothermal modulation; Transcranial ultrasound stimulation (TUS); Optogenetics using upconversion nanoparticles (UCNPs); Photovoltaic neuromodulation; Optothermal stimulation; Magnetomechanical stimulation; Opto-uncaging; Sonogenetics; Sonoelectrical stimulation; Magnetoelectrical modulation; Magnetogenetics^–; Transcranial magneto-acoustic stimulation (TMAS); Magneto- uncaging; Sono-uncaging; Sonochemogenetics; Sonooptogenetics.

Figure 2.. Collection of recently reported nanotransducers for neuromodulation.

(A) Nanotransducers for optogenetics^, ; (B) Optical^{, –} and magnetic transducers^{, , , –} for thermal modulation; (C) Nanotransducers for mechanical modulation, Left, optomechanical transducers^{, –}; Middle, Magnetomechanical transducers^, ; right, genetically encoded transducers^{–, –}. (D) Nanotransducers for electrical modulation; Left, optoelectronic transducers^{, –}; Middle, Magnetoelectric transducers^, ; Right, Piezoelectric transducers^, ; (E) Nanotransducers for chemical modulation. Left, transducers for opto-uncaging^{, –}; transducers for magneto- uncaging^{, –}; transducers for Sono-uncaging^{, –}. MLNPs, mechanoluminescent nanoparticles; SPNs, semiconducting polymer nanoconjugates, MNPs, magnetic nanoparticles; QDs, quantum dots; PFCs, fluorocarbons, e.g. perfluorobutane (PFB) and perfluoropentane (PFP).

Figure 3. Light delivery for neuromodulation.

(A) intracranial light delivery via optical fiber; (B) extracranial delivery of near-infrared light, the penetration depth of near-infrared light in the brain: ~3.5 mm; (C) upconversion nanoparticles (UCNPs) convert near-infrared light to visible light; (D) mechanoluminescent nanoparticles (MLNPs) converts UV light into green light upon ultrasound activation.

Figure 4. Proposed working mechanisms of magnetogenetics.

Magnetic field stimulation of the ferritin protein directly coupled to TRPV1/TRPV4 induces calcium transients through a heat-(A), force-^–, (B) or reactive oxygen species (ROS)-^–(C) based mechanism.

Figure 5. Nano-brain interface.

(A) Multi-scale brain-materials interface including nanotransducers. Modified from. Schematic for flexible electrodes. (B) Aspects of nano-brain interface: (1) Delivery of nanotransducers to the brain. (2) Cellular tropism of nanomaterials in the brain. (3) Passive diffusion of nanomaterials in extracellular space and active transport of nanomaterials in the brain. (4) The immune response following traditional electrode implantation and nanomaterials. (5) Brain clearance of nanomaterials via the perivascular pathway. L3-L4, lumbar segment 3–4; ECS, extracellular space; TNT, tunneling tube.