All Publications

  • Palette of Rechargeable Mechanoluminescent Fluids Produced by a Biomineral-Inspired Suppressed Dissolution Approach. Journal of the American Chemical Society Yang, F., Wu, X., Cui, H., Jiang, S., Ou, Z., Cai, S., Hong, G. 2022


    Mechanoluminescent materials, which emit light in response to mechanical stimuli, have recently been explored as promising candidates for photonic skins, remote optogenetics, and stress sensing. All mechanoluminescent materials reported thus far are bulk solids with micron-sized grains, and their light emission is only produced when fractured or deformed in bulk form. In contrast, mechanoluminescence has never been observed in liquids and colloidal solutions, thus limiting its biological application in living organisms. Here, we report the synthesis of mechanoluminescent fluids via a suppressed dissolution approach. We demonstrate that this approach yields stable colloidal solutions comprising mechanoluminescent nanocrystals with bright emissions in the range of 470-610 nm and diameters down to 20 nm. These colloidal solutions can be recharged and discharged repeatedly under photoexcitation and hydrodynamically focused ultrasound, respectively, thus yielding rechargeable mechanoluminescent fluids that can store photon energy in a reversible manner. This rechargeable fluid can facilitate a systemically delivered light source gated by tissue-penetrant ultrasound for biological applications that require light in the tissue, such as optogenetic stimulation in the brain.

    View details for DOI 10.1021/jacs.2c06724

    View details for PubMedID 36190898

  • A biomineral-inspired approach of synthesizing colloidal persistent phosphors as a multicolor, intravital light source. Science advances Yang, F., Wu, X., Cui, H., Ou, Z., Jiang, S., Cai, S., Zhou, Q., Wong, B. G., Huang, H., Hong, G. 2022; 8 (30): eabo6743


    Many in vivo biological techniques, such as fluorescence imaging, photodynamic therapy, and optogenetics, require light delivery into biological tissues. The limited tissue penetration of visible light discourages the use of external light sources and calls for the development of light sources that can be delivered in vivo. A promising material for internal light delivery is persistent phosphors; however, there is a scarcity of materials with strong persistent luminescence of visible light in a stable colloid to facilitate systemic delivery in vivo. Here, we used a bioinspired demineralization (BID) strategy to synthesize stable colloidal solutions of solid-state phosphors in the range of 470 to 650 nm and diameters down to 20 nm. The exceptional brightness of BID-produced colloids enables their utility as multicolor luminescent tags in vivo with favorable biocompatibility. Because of their stable dispersion in water, BID-produced nanophosphors can be delivered systemically, acting as an intravascular colloidal light source to internally excite genetically encoded fluorescent reporters within the mouse brain.

    View details for DOI 10.1126/sciadv.abo6743

    View details for PubMedID 35905189

  • Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nature biomedical engineering Wu, X., Jiang, Y., Rommelfanger, N. J., Yang, F., Zhou, Q., Yin, R., Liu, J., Cai, S., Ren, W., Shin, A., Ong, K. S., Pu, K., Hong, G. 2022


    Neural circuitry is typically modulated via invasive brain implants and tethered optical fibres in restrained animals. Here we show that wide-field illumination in the second near-infrared spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromolecular photothermal transducers activating neurons ectopically expressing the temperature-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromolecular transducers, ~40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71% at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400-1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal's head and at an incident power density of 10 mW mm-2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioural studies in small animals.

    View details for DOI 10.1038/s41551-022-00862-w

    View details for PubMedID 35314800

  • Sono-optogenetics facilitated by a circulation-delivered rechargeable light source for minimally invasive optogenetics. Proceedings of the National Academy of Sciences of the United States of America Wu, X. n., Zhu, X. n., Chong, P. n., Liu, J. n., Andre, L. N., Ong, K. S., Brinson, K. n., Mahdi, A. I., Li, J. n., Fenno, L. E., Wang, H. n., Hong, G. n. 2019


    Optogenetics, which uses visible light to control the cells genetically modified with light-gated ion channels, is a powerful tool for precise deconstruction of neural circuitry with neuron-subtype specificity. However, due to limited tissue penetration of visible light, invasive craniotomy and intracranial implantation of tethered optical fibers are usually required for in vivo optogenetic modulation. Here we report mechanoluminescent nanoparticles that can act as local light sources in the brain when triggered by brain-penetrant focused ultrasound (FUS) through intact scalp and skull. Mechanoluminescent nanoparticles can be delivered into the blood circulation via i.v. injection, recharged by 400-nm photoexcitation light in superficial blood vessels during circulation, and turned on by FUS to emit 470-nm light repetitively in the intact brain for optogenetic stimulation. Unlike the conventional "outside-in" approaches of optogenetics with fiber implantation, our method provides an "inside-out" approach to deliver nanoscopic light emitters via the intrinsic circulatory system and switch them on and off at any time and location of interest in the brain without extravasation through a minimally invasive ultrasound interface.

    View details for DOI 10.1073/pnas.1914387116

    View details for PubMedID 31811026

  • An optimized bioluminescent substrate for non-invasive imaging in the brain. Nature chemical biology Su, Y., Walker, J. R., Hall, M. P., Klein, M. A., Wu, X., Encell, L. P., Casey, K. M., Liu, L. X., Hong, G., Lin, M. Z., Kirkland, T. A. 2023


    Bioluminescence imaging (BLI) allows non-invasive visualization of cells and biochemical events in vivo and thus has become an indispensable technique in biomedical research. However, BLI in the central nervous system remains challenging because luciferases show relatively poor performance in the brain with existing substrates. Here, we report the discovery of a NanoLuc substrate with improved brain performance, cephalofurimazine (CFz). CFz paired with Antares luciferase produces greater than 20-fold more signal from the brain than the standard combination of D-luciferin with firefly luciferase. At standard doses, Antares-CFz matches AkaLuc-AkaLumine/TokeOni in brightness, while occasional higher dosing of CFz can be performed to obtain threefold more signal. CFz should allow the growing number of NanoLuc-based indicators to be applied to the brain with high sensitivity. Using CFz, we achieve video-rate non-invasive imaging of Antares in brains of freely moving mice and demonstrate non-invasive calcium imaging of sensory-evoked activity in genetically defined neurons.

    View details for DOI 10.1038/s41589-023-01265-x

    View details for PubMedID 36759751

  • Principles and applications of sono-optogenetics. Advanced drug delivery reviews Yang, F., Kim, S. J., Wu, X., Cui, H., Kwang Hahn, S., Hong, G. 2023: 114711


    Optogenetics has revolutionized neuroscience research through its spatiotemporally precise activation of specific neurons by illuminating light on opsin-expressing neurons. A long-standing challenge of in vivo optogenetics arises from the limited penetration depth of visible light in the neural tissue due to scattering and absorption of photons. To address this challenge, sono-optogenetics has been developed to enable spatiotemporally precise light production in a three-dimensional volume of neural tissue by leveraging the deep tissue penetration and focusing ability of ultrasound as well as circulation-delivered mechanoluminescent nanotransducers. Here, we present a comprehensive review of the sono-optogenetics method from the physical principles of ultrasound and mechanoluminescence to its emerging applications for unique neuroscience studies. We also discuss a few promising directions in which sono-optogenetics can make a lasting transformative impact on neuroscience research from the perspectives of mechanoluminescent materials, ultrasound-tissue interaction, to the unique neuroscience opportunities of "scanning optogenetics".

    View details for DOI 10.1016/j.addr.2023.114711

    View details for PubMedID 36708773

  • Ultrasound-activated luminescence with color tunability enabled by mechanoluminescent colloids and perovskite quantum dots. Nanoscale Yang, F., Cui, H., Wu, X., Kim, S., Hong, G. 2023


    Ultrasound represents a wireless and non-contact route for energy delivery and device control, owing to its ability to propagate and focus in various mediums including biological tissue. Specifically, ultrasound-activated mechanoluminescence from a colloidal suspension of mechanoluminescent (ML) nanocrystals offers a wireless means to remotely control a light source, such as wirelessly addressing a multicolor display. However, the limited color purity and tunability, as well as the large sizes of conventional ML materials prevent their use in an ultrasound-mediated flexible color display. Here, we apply a biomineral-inspired suppressed dissolution approach to synthesize ML colloids with bright blue emission under ultrasound and small sizes down to 20 nm. In addition, we leverage the bandgap engineering strategy of all-inorganic perovskite quantum dots (PQDs) to achieve wavelength tunability of the mechanoluminescence of ML colloid/PQD composites. Remarkably, the ultrasound-activated emission of the ML colloid/PQD composites exhibits a highly saturated color gamut covering the entire visible spectrum. Based on these advantages, we assembled a pixel array composed of different ML colloid/PQD composites in a silicone elastomer and demonstrated the proof-of-concept of a flexible and wireless multicolor display with each pixel individually addressed by scanning focused ultrasound.

    View details for DOI 10.1039/d2nr06129e

    View details for PubMedID 36625323

  • Ultrasound-Triggered In Situ Photon Emission for Noninvasive Optogenetics. Journal of the American Chemical Society Wang, W., Wu, X., Kevin Tang, K. W., Pyatnitskiy, I., Taniguchi, R., Lin, P., Zhou, R., Capocyan, S. L., Hong, G., Wang, H. 2023


    Optogenetics has revolutionized neuroscience understanding by allowing spatiotemporal control over cell-type specific neurons in neural circuits. However, the sluggish development of noninvasive photon delivery in the brain has limited the clinical application of optogenetics. Focused ultrasound (FUS)-derived mechanoluminescence has emerged as a promising tool for in situ photon emission, but there is not yet a biocompatible liquid-phase mechanoluminescence system for spatiotemporal optogenetics. To achieve noninvasive optogenetics with a high temporal resolution and desirable biocompatibility, we have developed liposome (Lipo@IR780/L012) nanoparticles for FUS-triggered mechanoluminescence in brain photon delivery. Synchronized and stable blue light emission was generated in solution under FUS irradiation due to the cascade reactions in liposomes. In vitro tests revealed that Lipo@IR780/L012 could be triggered by FUS for light emission at different stimulation frequencies, resulting in activation of opsin-expressing spiking HEK cells under the FUS irradiation. In vivo optogenetic stimulation further demonstrated that motor cortex neurons could be noninvasively and reversibly activated under the repetitive FUS irradiation after intravenous injection of lipid nanoparticles to achieve limb movements.

    View details for DOI 10.1021/jacs.2c10666

    View details for PubMedID 36606703

  • Protocol for wireless deep brain stimulation in freely behaving mice with infrared light. STAR protocols Wu, X., Hong, G. 2022; 4 (1): 101757


    Here, we present a protocol for deep brain stimulation in freely behaving mice using through-scalp wide-field illumination in the second near-infrared window (NIR-II). We first describe the injection of the TRPV1 (transient receptor potential cation channel subfamily V member 1)-expressing viruses and macromolecular infrared nanotransducers for deep brain stimulation (MINDS). We then detail NIR-II neuromodulation in a conditioned place preference test, followed by immunohistochemical studies. This approach is especially useful for tether-free deep brain stimulation in social interacting experiments involving multiple subjects. For complete details on the use and execution of this protocol, please refer to Wu etal. (2022).

    View details for DOI 10.1016/j.xpro.2022.101757

    View details for PubMedID 36538396

  • Shedding light on neurons: optical approaches for neuromodulation. National science review Jiang, S., Wu, X., Rommelfanger, N. J., Ou, Z., Hong, G. 2022; 9 (10): nwac007


    Today's optical neuromodulation techniques are rapidly evolving, benefiting from advances in photonics, genetics and materials science. In this review, we provide an up-to-date overview of the latest optical approaches for neuromodulation. We begin with the physical principles and constraints underlying the interaction between light and neural tissue. We then present advances in optical neurotechnologies in seven modules: conventional optical fibers, multifunctional fibers, optical waveguides, light-emitting diodes, upconversion nanoparticles, optical neuromodulation based on the secondary effects of light, and unconventional light sources facilitated by ultrasound and magnetic fields. We conclude our review with an outlook on new methods and mechanisms that afford optical neuromodulation with minimal invasiveness and footprint.

    View details for DOI 10.1093/nsr/nwac007

    View details for PubMedID 36196122

    View details for PubMedCentralID PMC9522429

  • Shedding light on neurons: optical approaches for neuromodulation NATIONAL SCIENCE REVIEW Jiang, S., Wu, X., Rommelfanger, N. J., Ou, Z., Hong, G. 2022
  • How is flexible electronics advancing neuroscience research? Biomaterials Chen, Y., Rommelfanger, N. J., Mahdi, A. I., Wu, X., Keene, S. T., Obaid, A., Salleo, A., Wang, H., Hong, G. 2020; 268: 120559


    Innovative neurotechnology must be leveraged to experimentally answer the multitude of pressing questions in modern neuroscience. Driven by the desire to address the existing neuroscience problems with newly engineered tools, we discuss in this review the benefits of flexible electronics for neuroscience studies. We first introduce the concept and define the properties of flexible and stretchable electronics. We then categorize the four dimensions where flexible electronics meets the demands of modern neuroscience: chronic stability, interfacing multiple structures, multi-modal compatibility, and neuron-type-specific recording. Specifically, with the bending stiffness now approaching that of neural tissue, implanted flexible electronic devices produce little shear motion, minimizing chronic immune responses and enabling recording and stimulation for months, and even years. The unique mechanical properties of flexible electronics also allow for intimate conformation to the brain, the spinal cord, peripheral nerves, and the retina. Moreover, flexible electronics enables optogenetic stimulation, microfluidic drug delivery, and neural activity imaging during electrical stimulation and recording. Finally, flexible electronics can enable neuron-type identification through analysis of high-fidelity recorded action potentials facilitated by its seamless integration with the neural circuitry. We argue that flexible electronics will play an increasingly important role in neuroscience studies and neurological therapies via the fabrication of neuromorphic devices on flexible substrates and the development of enhanced methods of neuronal interpenetration.

    View details for DOI 10.1016/j.biomaterials.2020.120559

    View details for PubMedID 33310538

  • A wearable helical organic-inorganic photodetector with thermoelectric generators as the power source JOURNAL OF MATERIALS CHEMISTRY C Sa, C., Xu, X., Wu, X., Chen, J., Zuo, C., Fang, X. 2019; 7 (42): 13097–103

    View details for DOI 10.1039/c9tc04696h

    View details for Web of Science ID 000494705100009

  • Mode-splitting based optofluidic sensing at exceptional points in tubular microcavities OPTICS COMMUNICATIONS Wang, Y., Li, S., Kiravittaya, S., Wu, X., Wu, K., Li, X., Mei, Y. 2019; 446: 128–33
  • Ultrathin Silicon Nanomembrane in a Tubular Geometry for Enhanced Photodetection ADVANCED OPTICAL MATERIALS Xu, C., Pan, R., Guo, Q., Wu, X., Li, G., Huang, G., An, Z., Li, X., Mei, Y. 2019
  • Rolled-up Nanotechnology: Materials Issue and Geometry Capability ADVANCED MATERIALS TECHNOLOGIES Xu, C., Wu, X., Huang, G., Mei, Y. 2019; 4 (1)
  • Infrared tubular microcavity based on rolled-up GeSn/Ge nanomembranes. Nanotechnology Wu, X., Tian, Z., Cong, H., Wang, Y., Edy, R., Huang, G., Di, Z., Xue, C., Mei, Y. 2018; 29 (42): 42LT02


    Germanium-Tin (GeSn) alloys have attracted great amounts of attention as these group IV semiconductors present direct band-gap behavior with high Sn content and are compatible with current complementary metal oxide semiconductor technology. In this work, three dimensional tubular GeSn/Ge micro-resonators with a diameter of around 7.3 μm were demonstrated by rolling up GeSn nanomembranes (NM) grown on a Ge-on-insulator wafer via molecular beam epitaxy. The microstructural properties of the resonators were carefully investigated and the strain distributions of the rolled-up GeSn/Ge microcavities along the radial direction were studied by utilizing micro-Raman spectroscopy with different excitation laser wavelengths. The values of the strains calculated from Raman shifts agree well with the theoretical prediction. Coupled with fiber tapers, as-fabricated devices present a high quality factor of up to 800 in the transmission spectral measurements. The micro-resonators fabricated via rolled-up nanotechnology and GeSn/Ge NMs in this work may have great potential in photonic micro- and nanodevices.

    View details for DOI 10.1088/1361-6528/aad66e

    View details for PubMedID 30052202