Guosong Hong

All Publications

• Force-Based Neuromodulation. Accounts of chemical research Cooper, L., Malinao, M. G., Hong, G. 2024

  Abstract

  ConspectusTechnologies for neuromodulation have rapidly developed in the past decade with a particular emphasis on creating noninvasive tools with high spatial and temporal precision. The existence of such tools is critical in the advancement of our understanding of neural circuitry and its influence on behavior and neurological disease. Existing technologies have employed various modalities, such as light, electrical, and magnetic fields, to interface with neural activity. While each method offers unique advantages, many struggle with modulating activity with high spatiotemporal precision without the need for invasive tools. One modality of interest for neuromodulation has been the use of mechanical force. Mechanical force encapsulates a broad range of techniques, ranging from mechanical waves delivered via focused ultrasound (FUS) to torque applied to the cell membrane.Mechanical force can be delivered to the tissue in two forms. The first form is the delivery of a mechanical force through focused ultrasound. Energy delivery facilitated by FUS has been the foundation for many neuromodulation techniques, owing to its precision and penetration depth. FUS possesses the potential to penetrate deeply (∼centimeters) into tissue while maintaining relatively precise spatial resolution, although there exists a trade-off between the penetration depth and spatial resolution. FUS may work synergistically with ultrasound-responsive nanotransducers or devices to produce a secondary energy, such as light, heat, or an electric field, in the target region. This layered technology, first enabled by noninvasive FUS, overcomes the need for bulky invasive implants and also often improves the spatiotemporal precision of light, heat, electrical fields, or other techniques alone. Conversely, the second form of mechanical force modulation is the generation of mechanical force from other modalities, such as light or magnetic fields, for neuromodulation via mechanosensitive proteins. This approach localizes the mechanical force at the cellular level, enhancing the precision of the original energy delivery. Direct interaction of mechanical force with tissue presents translational potential in its ability to interface with endogenous mechanosensitive proteins without the need for transgenes.In this Account, we categorize force-mediated neuromodulation into two categories: 1) methods where mechanical force is the primary stimulus and 2) methods where mechanical force is generated as a secondary stimulus in response to other modalities. We summarize the general design principles and current progress of each respective approach. We identify the key advantages of the limitations of each technology, particularly noting features in spatiotemporal precision, the need for transgene delivery, and the potential outlook. Finally, we highlight recent technologies that leverage mechanical force for enhanced spatiotemporal precision and advanced applications.

  View details for DOI 10.1021/acs.accounts.4c00074

  View details for PubMedID 38657038

• Mechanoluminescent Light Sources Based on Nanostructured Systems for Biomedical Applications: A Review ACS APPLIED NANO MATERIALS Yang, M., Ge, X., Zheng, L., Huang, Y., Zhong, J., Tu, D., Hong, G., Yang, F. 2024

  View details for DOI 10.1021/acsanm.4c00675

  View details for Web of Science ID 001241705700001

• Near-infrared II fluorescence imaging NATURE REVIEWS METHODS PRIMERS Schmidt, E., Ou, Z., Ximendes, E., Cui, H., Keck, C. C., Jaque, D., Hong, G. 2024; 4 (1)

  View details for DOI 10.1038/s43586-024-00301-x

  View details for Web of Science ID 001197506300002

• Mechanoluminescence and Mechanical Quenching of Afterglow Luminescent Particles for Wearable Photonic Display ADVANCED FUNCTIONAL MATERIALS Kim, S., Yang, F., Jung, H., Hong, G., Hahn, S. 2024

  View details for DOI 10.1002/adfm.202314861

  View details for Web of Science ID 001159756000001

• Activation of mechanoluminescent nanotransducers by focused ultrasound enables light delivery to deep-seated tissue in vivo. Nature protocols Jiang, S., Wu, X., Yang, F., Rommelfanger, N. J., Hong, G. 2023

  Abstract

  Light is used extensively in biological and medical research for optogenetic neuromodulation, fluorescence imaging, photoactivatable gene editing and light-based therapies. The major challenge to the in vivo implementation of light-based methods in deep-seated structures of the brain or of internal organs is the limited penetration of photons in biological tissue. The presence of light scattering and absorption has resulted in the development of invasive techniques such as the implantation of optical fibers, the insertion of endoscopes and the surgical removal of overlying tissues to overcome light attenuation and deliver it deep into the body. However, these procedures are highly invasive and make it difficult to reposition and adjust the illuminated area in each animal. Here, we detail a noninvasive approach to deliver light (termed 'deLight') in deep tissue via systemically injected mechanoluminescent nanotransducers that can be gated by using focused ultrasound. This approach achieves localized light emission with sub-millimeter resolution and millisecond response times in any vascularized organ of living mice without requiring invasive implantation of light-emitting devices. For example, deLight enables optogenetic neuromodulation in live mice without a craniotomy or brain implants. deLight provides a generalized method for applications that require a light source in deep tissues in vivo, such as deep-brain fluorescence imaging and photoactivatable genome editing. The implementation of the entire protocol for an in vivo application takes ~1-2 weeks.

  View details for DOI 10.1038/s41596-023-00895-8

  View details for PubMedID 37914782

• A Nanozyme-Based Electrode for High-Performance Neural Recording. Advanced materials (Deerfield Beach, Fla.) Liu, S., Wang, Y., Zhao, Y., Liu, L., Sun, S., Zhang, S., Liu, H., Liu, S., Li, Y., Yang, F., Jiao, M., Sun, X., Zhang, Y., Liu, R., Mu, X., Wang, H., Zhang, S., Yang, J., Xie, X., Duan, X., Zhang, J., Hong, G., Zhang, X., Ming, D. 2023: e2304297

  Abstract

  Implanted neural electrodes have been widely used to treat brain diseases that require high sensitivity and biocompatibility at the tissue-electrode interface. However, currently used clinical electrodes cannot meet both these requirements simultaneously, which hinders the effective recording of electronic signals. Herein, nanozyme-based neural electrodes incorporating bioinspired atomically precise clusters were developed as a general strategy with a heterogeneous design for multiscale and ultrasensitive neural recording via quantum transport and biocatalytic processes. Owing to the dual high-speed electronic and ionic currents at the electrode-tissue interface, the impedance of nanozyme electrodes was 26 times lower than that of state-of-the-art metal electrodes, and the acquisition sensitivity for the local field potential was 10 times higher than that of clinical PtIr electrodes, enabling a signal-to-noise ratio (SNR) of up to 14.7dB for single-neuron recordings in rats. The electrodes provided more than 100-fold higher antioxidant and multi-enzyme-like activities, which effectively decreased 67% of the neuronal injury area by inhibiting glial proliferation and allowing sensitive and stable neural recording. Moreover, nanozyme electrodes can considerably improve the SNR of seizures in acute epileptic rats and is expected to achieve precise localization of seizure foci in clinical settings. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/adma.202304297

  View details for PubMedID 37882151

• Wireless deep-brain neuromodulation using photovoltaics in the second near-infrared spectrum. Device Cui, H., Zhao, S., Hong, G. 2023; 1 (4)

  Abstract

  Conventional electrical neuromodulation techniques are constrained by the need for invasive implants in neural tissues, whereas methods using optogenetic are subjected to genetic alterations and hampered by the poor tissue penetration of visible light. Photovoltaic neuromodulation using light from the second near-infrared (NIR-II) spectrum, which minimizes scattering and enhances tissue penetration, shows promise as an alternative to existing neuromodulation technologies. NIR-II light has been used in deep-tissue imaging and in deep-brain photothermal neuromodulation via nanotransducers. This Perspective will provide an overview for the underpinning mechanisms of photovoltaic neuromodulation and identify avenues for future research in materials science and bioengineering that can further advance NIR-II photovoltaic neuromodulation methods.

  View details for DOI 10.1016/j.device.2023.100113

  View details for PubMedID 37990694

• Laminin-coated electronic scaffolds with vascular topography for tracking and promoting the migration of brain cells after injury. Nature biomedical engineering Yang, X., Qi, Y., Wang, C., Zwang, T. J., Rommelfanger, N. J., Hong, G., Lieber, C. M. 2023

  Abstract

  In the adult brain, neural stem cells are largely restricted into spatially discrete neurogenic niches, and hence areas of neuron loss during neurodegenerative disease or following a stroke or traumatic brain injury do not typically repopulate spontaneously. Moreover, understanding neural activity accompanying the neural repair process is hindered by a lack of minimally invasive devices for the chronic measurement of the electrophysiological dynamics in damaged brain tissue. Here we show that 32 individually addressable platinum microelectrodes integrated into laminin-coated branched polymer scaffolds stereotaxically injected to span a hydrogel-filled cortical lesion and deeper regions in the brains of mice promote neural regeneration while allowing for the tracking of migrating host brain cells into the lesion. Chronic measurements of single-unit activity and neural-circuit analyses revealed the establishment of spiking activity in new neurons in the lesion and their functional connections with neurons deeper in the brain. Electronic implants mimicking the topographical and surface properties of brain vasculature may aid the stimulation and tracking of neural-circuit restoration following injury.

  View details for DOI 10.1038/s41551-023-01101-6

  View details for PubMedID 37814007

  View details for PubMedCentralID 4800432

• Bioinspired nanotransducers for neuromodulation NANO RESEARCH Yang, F., Wu, X., Cai, S., Hong, G. 2023

  View details for DOI 10.1007/s12274-023-6136-6

  View details for Web of Science ID 001076987400003

• Direct-print three-dimensional electrodes for large- scale, high-density, and customizable neural inter- faces. bioRxiv : the preprint server for biology Wang, P., Wu, E. G., Uluşan, H., Phillips, A. J., Rose Hays, M., Kling, A., Zhao, E. T., Madugula, S., Vilkhu, R. S., Vasireddy, P. K., Hier-Lemann, A., Hong, G., Chichilnisky, E. J., Melosh, N. A. 2023

  Abstract

  Silicon-based planar microelectronics is a powerful tool for scalably recording and modulating neural activity at high spatiotemporal resolution, but it remains challenging to target neural structures in three dimensions (3D). We present a method for directly fabricating 3D arrays of tissue-penetrating microelectrodes onto silicon microelectronics. Leveraging a high-resolution 3D printing technology based on 2-photon polymerization and scalable microfabrication processes, we fabricated arrays of 6,600 microelectrodes 10-130 μm tall and at 35-μm pitch onto a planar silicon-based microelectrode array. The process enables customizable electrode shape, height and positioning for precise targeting of neuron populations distributed in 3D. As a proof of concept, we addressed the challenge of specifically targeting retinal ganglion cell (RGC) somas when interfacing with the retina. The array was customized for insertion into the retina and recording from somas while avoiding the axon layer. We verified locations of the microelectrodes with confocal microscopy and recorded high-resolution spontaneous RGC activity at cellular resolution. This revealed strong somatic and dendritic components with little axon contribution, unlike recordings with planar microelectrode arrays. The technology could be a versatile solution for interfacing silicon microelectronics with neural structures and modulating neural activity at large scale with single-cell resolution.

  View details for DOI 10.1101/2023.05.30.542925

  View details for PubMedID 37398164

  View details for PubMedCentralID PMC10312573

• Nanotransducer-Enabled Deep-Brain Neuromodulation with NIR-II Light. ACS nano Wu, X., Yang, F., Cai, S., Pu, K., Hong, G. 2023

  Abstract

  The second near-infrared window (NIR-II window), which ranges from 1000 to 1700 nm in wavelength, exhibits distinctive advantages of reduced light scattering and thus deep penetration in biological tissues in comparison to the visible spectrum. The NIR-II window has been widely employed for deep-tissue fluorescence imaging in the past decade. More recently, deep-brain neuromodulation has been demonstrated in the NIR-II window by leveraging nanotransducers that can efficiently convert brain-penetrant NIR-II light into heat. In this Perspective, we discuss the principles and potential applications of this NIR-II deep-brain neuromodulation technique, together with its advantages and limitations compared with other existing optical methods for deep-brain neuromodulation. We also point out a few future directions where the advances in materials science and bioengineering can expand the capability and utility of NIR-II neuromodulation methods.

  View details for DOI 10.1021/acsnano.2c12068

  View details for PubMedID 37079455

• 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

  Abstract

  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

• Advanced Light Delivery Materials and Systems for Photomedicines. Advanced drug delivery reviews Kim, S., Lee, G., Hong, G., Hyun Yun, S., Kwang Hahn, S. 2023: 114729

  View details for DOI 10.1016/j.addr.2023.114729

  View details for PubMedID 36764457

• 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

  Abstract

  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

  Abstract

  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

  Abstract

  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

• Systemically Delivered, Deep-Tissue Nanoscopic Light Sources PROGRESS IN ELECTROMAGNETICS RESEARCH-PIER Wu, X., Yang, F., Cai, S., Hong, G. 2023; 177: 33-42

  View details for Web of Science ID 000968675700001

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

  Abstract

  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

• Controlled afterglow luminescent particles for photochemical tissue bonding. Light, science & applications Kim, S., Choi, M., Hong, G., Hahn, S. K. 2022; 11 (1): 314

  Abstract

  Upconversion materials (UCMs) have been developed to convert tissue-penetrating near-infrared (NIR) light into visible light. However, the low energy conversion efficiency of UCMs has limited their further biophotonic applications. Here, we developed controlled afterglow luminescent particles (ALPs) of ZnS:Ag,Co with strong and persistent green luminescence for photochemical tissue bonding (PTB). The co-doping of Ag+ and Co2+ ions into ZnS:Ag,Co particles with the proper vacancy formation of host ions resulted in high luminescence intensity and long-term afterglow. In addition, the ALPs of ZnS:Ag,Co could be recharged rapidly under short ultraviolet (UV) irradiation, which effectively activated rose bengal (RB) in hyaluronate-RB (HA-RB) conjugates for the crosslinking of dissected collagen layers without additional light irradiation. The remarkable PTB of ZnS:Ag,Co particles with HA-RB conjugates was confirmed by in vitro collagen fibrillogenesis assay, in vivo animal wound closure rate analysis, and in vivo tensile strength evaluation of incised skin tissues. Taken together, we could confirm the feasibility of controlled ALPs for various biophotonic applications.

  View details for DOI 10.1038/s41377-022-01011-3

  View details for PubMedID 36302759

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• Cooling the pain. Science (New York, N.Y.) Jiang, S., Hong, G. 2022; 377 (6601): 28-29

  Abstract

  A miniaturized, flexible cooling device can be used for precise analgesia.

  View details for DOI 10.1126/science.abm8159

  View details for PubMedID 35771916

• Scalable Three-Dimensional Recording Electrodes for Probing Biological Tissues. Nano letters Lee, J. M., Lin, D., Hong, G., Kim, K., Park, H., Lieber, C. M. 2022

  Abstract

  Electrophysiological recording technologies can provide critical insight into the function of the nervous system and other biological tissues. Standard silicon-based probes have limitations, including single-sided recording sites and intrinsic instabilities due to the probe stiffness. Here, we demonstrate high-performance neural recording using double-sided three-dimensional (3D) electrodes integrated in an ultraflexible bioinspired open mesh structure, allowing electrodes to sample fully the 3D interconnected tissue of the brain. In vivo electrophysiological recording using 3D electrodes shows statistically significant increases in the number of neurons per electrode, average spike amplitudes, and signal to noise ratios in comparison to standard two-dimensional electrodes, while achieving stable detection of single-neuron activity over months. The capability of these 3D electrodes is further shown for chronic recording from retinal ganglion cells in mice. This approach opens new opportunities for a comprehensive 3D interrogation, stimulation, and understanding of the complex circuitry of the brain and other electrogenic tissues in live animals over extended time periods.

  View details for DOI 10.1021/acs.nanolett.2c01444

  View details for PubMedID 35583378

• Pristine carbon nanotubes are efficient absorbers at radio frequencies. Nanotechnology Rommelfanger, N. J., Brinson, K., Bailey, J. E., Bancroft, A. M., Ou, Z., Hong, G. 2022

  Abstract

  Radio frequency ablation and microwave hyperthermia are powerful tools for destroying dysfunctional biological tissues, but wireless application of these techniques is hindered by the inability to focus the electromagnetic energy to small targets. The use of locally injected radio frequency- or microwave-absorbing nanomaterials can help to overcome this challenge by confining heat production to the injected region. Previous theoretical work suggests that high-aspect-ratio conducting nanomaterials, such as carbon nanotubes, offer powerful radio frequency and microwave absorption. While carbon nanotubes have been previously studied for radio frequency and microwave hyperthermia enhancement, these studies have employed sonication for sample preparation, reducing the volume fraction and average length within the carbon nanotube suspensions. In this manuscript, we use a sonication-free preparation technique to preserve both the length of carbon nanotubes and the high volume fraction of their bundled state. We measure the heating of these samples at 2 GHz compared to the heating of a biological tissue reference using infrared thermography. We report an increase in heating by 4.5 fold compared to the tissue reference, with localized heating clearly observable within a three-dimensional biological tissue phantom. Numerical simulations further aid in producing a temperature map within the phantom and demonstrating localized heating. Due to their significant differential heating ratio, we believe that sonication-free carbon nanotube samples may bring unforeseen opportunities to the fields of radio frequency ablation and microwave hyperthermia.

  View details for DOI 10.1088/1361-6528/ac6cf8

  View details for PubMedID 35512668

• Shedding light on neurons: optical approaches for neuromodulation NATIONAL SCIENCE REVIEW Jiang, S., Wu, X., Rommelfanger, N. J., Ou, Z., Hong, G. 2022

  View details for DOI 10.1093/nsr/nwac007

  View details for Web of Science ID 000805252300001

• 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

  Abstract

  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

• Sub-10-nm graphene nanoribbons with atomically smooth edges from squashed carbon nanotubes NATURE ELECTRONICS Chen, C., Lin, Y., Zhou, W., Gong, M., He, Z., Shi, F., Li, X., Wu, J., Lam, K., Wang, J., Yang, F., Zeng, Q., Guo, J., Gao, W., Zuo, J., Liu, J., Hong, G., Antaris, A. L., Lin, M., Mao, W. L., Dai, H. 2021

  View details for DOI 10.1038/s41928-021-00633-6

  View details for Web of Science ID 000692947500001

• Learning from the brain's architecture: bioinspired strategies towards implantable neural interfaces. Current opinion in biotechnology Rommelfanger, N. J., Keck, C. H., Chen, Y., Hong, G. 2021; 72: 8-12

  Abstract

  While early neural interfaces consisted of rigid, monolithic probes, recent implantable technologies include meshes, gels, and threads that imitate various properties of the neural tissue itself. Such mimicry brings new capabilities to the traditional electrophysiology toolbox, with benefits for both neuroscience studies and clinical treatments. Specifically, by matching the multi-dimensional mechanical properties of the brain, neural implants can preserve the endogenous environment while functioning over chronic timescales. Further, topological mimicry of neural structures enables seamless integration into the tissue and provides proximal access to neurons for high-quality recordings. Ultimately, we envision that neuromorphic devices incorporating functional, mechanical, and topological mimicry of the brain may facilitate stable operation of advanced brain machine interfaces with minimal disruption of the native tissue.

  View details for DOI 10.1016/j.copbio.2021.07.020

  View details for PubMedID 34365114

• On the feasibility of wireless radio frequency ablation using nanowire antennas APL MATERIALS Rommelfanger, N. J., Hong, G. 2021; 9 (7): 071103

  Abstract

  Radio frequency ablation (RFA) is a proven technique for eliminating cancerous or dysfunctional tissues in the body. However, the delivery of RFA electrodes to deep tissues causes damage to overlying healthy tissues, while a minimally invasive RFA technique would limit damage to targeted tissues alone. In this manuscript, we propose a wireless RFA technique relying on the absorption of radio frequencies (RFs) by gold nanowires in vivo and the deep penetration of RF into biological tissues. Upon optimizing the dimensions of the gold nanowires and the frequency of the applied RF for breast cancer and myocardium tissues, we find that heating rates in excess of 2000 K/s can be achieved with high spatial resolution in vivo, enabling short heating durations for ablation and minimizing heat diffusion to surrounding tissues. The results suggest that gold nanowires can act as "radiothermal" agents to concentrate heating within targeted tissues, negating the need to implant bulky electrodes for tissue ablation.

  View details for DOI 10.1063/5.0053189

  View details for Web of Science ID 000669088500001

  View details for PubMedID 34262798

  View details for PubMedCentralID PMC8259129

• Nanotransducers for Wireless Neuromodulation. Matter Li, X., Xiong, H., Rommelfanger, N., Xu, X., Youn, J., Slesinger, P. A., Hong, G., Qin, Z. 2021; 4 (5): 1484-1510

  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.

  View details for DOI 10.1016/j.matt.2021.02.012

  View details for PubMedID 33997768

• Differential Heating of Metal Nanostructures at Radio Frequencies PHYSICAL REVIEW APPLIED Rommelfanger, N. J., Ou, Z., Keck, C. C., Hong, G. 2021; 15 (5)

  View details for DOI 10.1103/PhysRevApplied.15.054007

  View details for Web of Science ID 000656834900002

• Differential heating of metal nanostructures at radio frequencies. Physical review applied Rommelfanger, N. J., Ou, Z., Keck, C. H., Hong, G. 2021; 15 (5)

  Abstract

  Nanoparticles with strong absorption of incident radio frequency (RF) or microwave irradiation are desirable for remote hyperthermia treatments. While controversy has surrounded the absorption properties of spherical metallic nanoparticles, other geometries such as prolate and oblate spheroids have not received sufficient attention for application in hyperthermia therapies. Here, we use the electrostatic approximation to calculate the relative absorption ratio of metallic nanoparticles in various biological tissues. We consider a broad parameter space, sweeping across frequencies from 1 MHz to 10 GHz, while also tuning the nanoparticle dimensions from spheres to high-aspect-ratio spheroids approximating nanowires and nanodiscs. We find that while spherical metallic nanoparticles do not offer differential heating in tissue, large absorption cross sections can be obtained from long prolate spheroids, while thin oblate spheroids offer minor potential for absorption. Our results suggest that metallic nanowires should be considered for RF- and microwave-based wireless hyperthermia treatments in many tissues going forward.

  View details for DOI 10.1103/physrevapplied.15.054007

  View details for PubMedID 36268260

  View details for PubMedCentralID PMC9581340

• All-Tissue-like Multifunctional Optoelectronic Mesh for Deep-Brain Modulation and Mapping. Nano letters Lee, J. M., Lin, D., Kim, H., Pyo, Y., Hong, G., Lieber, C. M., Park, H. 2021

  Abstract

  The development of a multifunctional device that achieves optogenetic neuromodulation and extracellular neural mapping is crucial for understanding neural circuits and treating brain disorders. Although various devices have been explored for this purpose, it is challenging to develop biocompatible optogenetic devices that can seamlessly interface with the brain. Herein, we present a tissue-like optoelectronic mesh with a compact interface that enables not only high spatial and temporal resolutions of optical stimulation but also the sampling of optically evoked neural activities. An in vitro experiment in hydrogel showed efficient light propagation through a freestanding SU-8 waveguide that was integrated with flexible mesh electronics. Additionally, an in vivo implantation of the tissue-like optoelectronic mesh in the brain of a live transgenic mouse enabled the sampling of optically evoked neural signals. Therefore, this multifunctional device can aid the chronic modulation of neural circuits and behavior studies for developing biological and therapeutic applications.

  View details for DOI 10.1021/acs.nanolett.1c00425

  View details for PubMedID 33734716

• 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

  Abstract

  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

• An "All-in-One" Catheter: Surgery of the Future MATTER Chen, Y., Yin, R., Hong, G. 2020; 3 (6): 1829–31

  View details for DOI 10.1016/j.matt.2020.11.005

  View details for Web of Science ID 000596943200008

• Conjugated Polymers Enable a Liquid Retinal Prosthesis TRENDS IN CHEMISTRY Rommelfanger, N. J., Hong, G. 2020; 2 (11): 961–64

  View details for DOI 10.1016/j.trechm.2020.08.004

  View details for Web of Science ID 000583272100003

• Conjugated Polymers Enable a Liquid Retinal Prosthesis. Trends in chemistry Rommelfanger, N. J., Hong, G. 2020; 2 (11): 961-964

  View details for DOI 10.1016/j.trechm.2020.08.004

  View details for PubMedID 36268538

  View details for PubMedCentralID PMC9581341

• Bioinspired Materials for In Vivo Bioelectronic Neural Interfaces. Matter Woods, G. A., Rommelfanger, N. J., Hong, G. 2020; 3 (4): 1087–1113

  Abstract

  The success of in vivo neural interfaces relies on their long-term stability and large scale in interrogating and manipulating neural activity after implantation. Conventional neural probes, owing to their limited spatiotemporal resolution and scale, face challenges for studying the massive, interconnected neural network in its native state. In this review, we argue that taking inspiration from biology will unlock the next generation of in vivo bioelectronic neural interfaces. Reducing the feature sizes of bioelectronic neural interfaces to mimic those of neurons enables high spatial resolution and multiplexity. Additionally, chronic stability at the device-tissue interface is realized by matching the mechanical properties of bioelectronic neural interfaces to those of the endogenous tissue. Further, modeling the design of neural interfaces after the endogenous topology of the neural circuitry enables new insights into the connectivity and dynamics of the brain. Lastly, functionalization of neural probe surfaces with coatings inspired by biology leads to enhanced tissue acceptance over extended timescales. Bioinspired neural interfaces will facilitate future developments in neuroscience studies and neurological treatments by leveraging bidirectional information transfer and integrating neuromorphic computing elements.

  View details for DOI 10.1016/j.matt.2020.08.002

  View details for PubMedID 33103115

• Seeing the sound. Science (New York, N.Y.) Hong, G. n. 2020; 369 (6504): 638

  View details for DOI 10.1126/science.abd3636

  View details for PubMedID 32764064

• Atomic-Precision Gold Clusters for NIR-II Imaging. Advanced materials (Deerfield Beach, Fla.) Liu, H., Hong, G., Luo, Z., Chen, J., Chang, J., Gong, M., He, H., Yang, J., Yuan, X., Li, L., Mu, X., Wang, J., Mi, W., Luo, J., Xie, J., Zhang, X. 2019: e1901015

  Abstract

  Near-infrared II (NIR-II) imaging at 1100-1700 nm shows great promise for medical diagnosis related to blood vessels because it possesses deep penetration and high resolution in biological tissue. Unfortunately, currently available NIR-II fluorophores exhibit slow excretion and low brightness, which prevents their potential medical applications. An atomic-precision gold (Au) cluster with 25 gold atoms and 18 peptide ligands is presented. The Au25 clusters show emission at 1100-1350 nm and the fluorescence quantum yield is significantly increased by metal-atom doping. Bright gold clusters can penetrate deep tissue and can be applied in in vivo brain vessel imaging and tumor metastasis. Time-resolved brain blood-flow imaging shows significant differences between healthy and injured mice with different brain diseases in vivo. High-resolution imaging of cancer metastasis allows for the identification of the primary tumor, blood vessel, and lymphatic metastasis. In addition, gold clusters with NIR-II fluorescence are used to monitor high-resolution imaging of kidney at a depth of 0.61 cm, and the quantitative measurement shows 86% of the gold clusters are cleared from body without any acute or long-term toxicity at a dose of 100 mg kg-1 .

  View details for DOI 10.1002/adma.201901015

  View details for PubMedID 31576632

• Light-sheet microscopy in the near-infrared II window NATURE METHODS Wang, F., Wan, H., Ma, Z., Zhong, Y., Sun, Q., Tian, Y., Qu, L., Du, H., Zhang, M., Li, L., Ma, H., Luo, J., Liang, Y., Li, W., Hong, G., Liu, L., Dai, H. 2019; 16 (6): 545-+

  View details for DOI 10.1038/s41592-019-0398-7

  View details for Web of Science ID 000469455200024

• Novel electrode technologies for neural recordings NATURE REVIEWS NEUROSCIENCE Hong, G., Lieber, C. M. 2019; 20 (6): 330–45

  View details for DOI 10.1038/s41583-019-0140-6

  View details for Web of Science ID 000468530600005

• Light-sheet microscopy in the near-infrared II window. Nature methods Wang, F., Wan, H., Ma, Z., Zhong, Y., Sun, Q., Tian, Y., Qu, L., Du, H., Zhang, M., Li, L., Ma, H., Luo, J., Liang, Y., Li, W. J., Hong, G., Liu, L., Dai, H. 2019

  Abstract

  Non-invasive deep-tissue three-dimensional optical imaging of live mammals with high spatiotemporal resolution is challenging owing to light scattering. We developed near-infrared II (1,000-1,700nm) light-sheet microscopy with excitation and emission of up to approximately 1,320nm and 1,700nm, respectively, for optical sectioning at a penetration depth of approximately 750mum through live tissues without invasive surgery and at a depth of approximately 2mm in glycerol-cleared brain tissues. Near-infrared II light-sheet microscopy in normal and oblique configurations enabled in vivo imaging of live mice through intact tissue, revealing abnormal blood flow and T-cell motion in tumor microcirculation and mapping out programmed-death ligand 1 and programmed cell death protein 1 in tumors with cellular resolution. Three-dimensional imaging through the intact mouse head resolved vascular channels between the skull and brain cortex, and allowed monitoring of recruitment of macrophages and microglia to the traumatic brain injury site.

  View details for PubMedID 31086342

• Novel electrode technologies for neural recordings. Nature reviews. Neuroscience Hong, G., Lieber, C. M. 2019

  Abstract

  Neural recording electrode technologies have contributed considerably to neuroscience by enabling the extracellular detection of low-frequency local field potential oscillations and high-frequency action potentials of single units. Nevertheless, several long-standing limitations exist, including low multiplexity, deleterious chronic immune responses and long-term recording instability. Driven by initiatives encouraging the generation of novel neurotechnologies and the maturation of technologies to fabricate high-density electronics, novel electrode technologies are emerging. Here, we provide an overview of recently developed neural recording electrode technologies with high spatial integration, long-term stability and multiple functionalities. We describe how these emergent neurotechnologies can approach the ultimate goal of illuminating chronic brain activity with minimal disruption of the neural environment, thereby providing unprecedented opportunities for neuroscience research in the future.

  View details for PubMedID 30833706

• Nanoenabled Direct Contact Interfacing of Syringe-Injectable Mesh Electronics. Nano letters Lee, J. M., Hong, G. n., Lin, D. n., Schuhmann, T. G., Sullivan, A. T., Viveros, R. D., Park, H. G., Lieber, C. M. 2019

  Abstract

  Polymer-based electronics with low bending stiffnesses and high flexibility, including recently reported macroporous syringe-injectable mesh electronics, have shown substantial promise for chronic studies of neural circuitry in the brains of live animals. A central challenge for exploiting these highly flexible materials for in vivo studies has centered on the development of efficient input/output (I/O) connections to an external interface with high yield, low bonding resistance, and long-term stability. Here we report a new paradigm applied to the challenging case of injectable mesh electronics that exploits the high flexibility of nanoscale thickness two-sided metal I/O pads that can deform and contact standard interface cables in high yield with long-term electrical stability. First, we describe the design and facile fabrication of two-sided metal I/O pads that allow for contact without regard to probe orientation. Second, systematic studies of the contact resistance as a function of I/O pad design and mechanical properties demonstrate the key role of the I/O pad bending stiffness in achieving low-resistance stable contacts. Additionally, computational studies provide design rules for achieving high-yield multiplexed contact interfacing in the case of angular misalignment such that adjacent channels are not shorted. Third, the in vitro measurement of 32-channel mesh electronics probes bonded to interface cables using the direct contact method shows a reproducibly high yield of electrical connectivity. Finally, in vivo experiments with 32-channel mesh electronics probes implanted in live mice demonstrate the chronic stability of the direct contact interface, enabling consistent tracking of single-unit neural activity over at least 2 months without a loss of channel recording. The direct contact interfacing methodology paves the way for scalable long-term connections of multiplexed mesh electronics neural probes for neural recording and modulation and moreover could be used to facilitate a scalable interconnection of other flexible electronics in biological studies and therapeutic applications.

  View details for DOI 10.1021/acs.nanolett.9b03019

  View details for PubMedID 31361503

• 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

  Abstract

  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

• Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes. Neuron Tran, N. M., Shekhar, K. n., Whitney, I. E., Jacobi, A. n., Benhar, I. n., Hong, G. n., Yan, W. n., Adiconis, X. n., Arnold, M. E., Lee, J. M., Levin, J. Z., Lin, D. n., Wang, C. n., Lieber, C. M., Regev, A. n., He, Z. n., Sanes, J. R. 2019

  Abstract

  Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

  View details for DOI 10.1016/j.neuron.2019.11.006

  View details for PubMedID 31784286

• Tissue-like Neural Probes for Understanding and Modulating the Brain BIOCHEMISTRY Hong, G., Viveros, R. D., Zwang, T. J., Yang, X., Lieber, C. M. 2018; 57 (27): 3995–4004

  Abstract

  Electrophysiology tools have contributed substantially to understanding brain function, yet the capabilities of conventional electrophysiology probes have remained limited in key ways because of large structural and mechanical mismatches with respect to neural tissue. In this Perspective, we discuss how the general goal of probe design in biochemistry, that the probe or label have a minimal impact on the properties and function of the system being studied, can be realized by minimizing structural, mechanical, and topological differences between neural probes and brain tissue, thus leading to a new paradigm of tissue-like mesh electronics. The unique properties and capabilities of the tissue-like mesh electronics as well as future opportunities are summarized. First, we discuss the design of an ultraflexible and open mesh structure of electronics that is tissue-like and can be delivered in the brain via minimally invasive syringe injection like molecular and macromolecular pharmaceuticals. Second, we describe the unprecedented tissue healing without chronic immune response that leads to seamless three-dimensional integration with a natural distribution of neurons and other key cells through these tissue-like probes. These unique characteristics lead to unmatched stable long-term, multiplexed mapping and modulation of neural circuits at the single-neuron level on a year time scale. Last, we offer insights on several exciting future directions for the tissue-like electronics paradigm that capitalize on their unique properties to explore biochemical interactions and signaling in a "natural" brain environment.

  View details for DOI 10.1021/acs.biochem.8b00122

  View details for Web of Science ID 000438652900004

  View details for PubMedID 29529359

  View details for PubMedCentralID PMC6039269

• A method for single-neuron chronic recording from the retina in awake mice SCIENCE Hong, G., Fu, T., Qiao, M., Viveros, R. D., Yang, X., Zhou, T., Lee, J., Park, H., Sanes, J. R., Lieber, C. M. 2018; 360 (6396): 1447-+

  Abstract

  The retina, which processes visual information and sends it to the brain, is an excellent model for studying neural circuitry. It has been probed extensively ex vivo but has been refractory to chronic in vivo electrophysiology. We report a nonsurgical method to achieve chronically stable in vivo recordings from single retinal ganglion cells (RGCs) in awake mice. We developed a noncoaxial intravitreal injection scheme in which injected mesh electronics unrolls inside the eye and conformally coats the highly curved retina without compromising normal eye functions. The method allows 16-channel recordings from multiple types of RGCs with stable responses to visual stimuli for at least 2 weeks, and reveals circadian rhythms in RGC responses over multiple day/night cycles.

  View details for DOI 10.1126/science.aas9160

  View details for Web of Science ID 000436598000073

  View details for PubMedID 29954976

  View details for PubMedCentralID PMC6047945

• Mesh electronics: a new paradigm for tissue-like brain probes CURRENT OPINION IN NEUROBIOLOGY Hong, G., Yang, X., Zhou, T., Lieber, C. M. 2018; 50: 33–41

  Abstract

  Existing implantable neurotechnologies for understanding the brain and treating neurological diseases have intrinsic properties that have limited their capability to achieve chronically-stable brain interfaces with single-neuron spatiotemporal resolution. These limitations reflect what has been dichotomy between the structure and mechanical properties of living brain tissue and non-living neural probes. To bridge the gap between neural and electronic networks, we have introduced the new concept of mesh electronics probes designed with structural and mechanical properties such that the implant begins to 'look and behave' like neural tissue. Syringe-implanted mesh electronics have led to the realization of probes that are neuro-attractive and free of the chronic immune response, as well as capable of stable long-term mapping and modulation of brain activity at the single-neuron level. This review provides a historical overview of a 10-year development of mesh electronics by highlighting the tissue-like design, syringe-assisted delivery, seamless neural tissue integration, and single-neuron level chronic recording stability of mesh electronics. We also offer insights on unique near-term opportunities and future directions for neuroscience and neurology that now are available or expected for mesh electronics neurotechnologies.

  View details for DOI 10.1016/j.conb.2017.11.007

  View details for Web of Science ID 000436225100006

  View details for PubMedID 29202327

  View details for PubMedCentralID PMC5984112

• 3D NIR-II Molecular Imaging Distinguishes Targeted Organs with High-Performance NIR-II Bioconjugates ADVANCED MATERIALS Zhu, S., Herraiz, S., Yue, J., Zhang, M., Wan, H., Yang, Q., Ma, Z., Wang, Y., He, J., Antaris, A. L., Zhong, Y., Diao, S., Feng, Y., Zhou, Y., Yu, K., Hong, G., Liang, Y., Hsueh, A. J., Dai, H. 2018; 30 (13): e1705799

  Abstract

  Greatly reduced scattering in the second near-infrared (NIR-II) region (1000-1700 nm) opens up many new exciting avenues of bioimaging research, yet NIR-II fluorescence imaging is mostly implemented by using nontargeted fluorophores or wide-field imaging setups, limiting the signal-to-background ratio and imaging penetration depth due to poor specific binding and out-of-focus signals. A newly developed high-performance NIR-II bioconjugate enables targeted imaging of a specific organ in the living body with high quality. Combined with a home-built NIR-II confocal set-up, the enhanced imaging technique allows 900 µm-deep 3D organ imaging without tissue clearing techniques. Bioconjugation of two hormones to nonoverlapping NIR-II fluorophores facilitates two-color imaging of different receptors, demonstrating unprecedented multicolor live molecular imaging across the NIR-II window. This deep tissue imaging of specific receptors in live animals allows development of noninvasive molecular imaging of multifarious models of normal and neoplastic organs in vivo, beyond the traditional visible to NIR-I range. The developed NIR-II fluorescence microscopy will become a powerful imaging technique for deep tissue imaging without any physical sectioning or clearing treatment of the tissue.

  View details for PubMedID 29446156

  View details for PubMedCentralID PMC5931222

• A bright organic NIR-II nanofluorophore for three-dimensional imaging into biological tissues NATURE COMMUNICATIONS Wan, H., Yue, J., Zhu, S., Uno, T., Zhang, X., Yang, Q., Yu, K., Hong, G., Wang, J., Li, L., Ma, Z., Gao, H., Zhong, Y., Su, J., Antaris, A. L., Xia, Y., Luo, J., Liang, Y., Dai, H. 2018; 9: 1171

  Abstract

  Fluorescence imaging of biological systems in the second near-infrared (NIR-II, 1000-1700 nm) window has shown promise of high spatial resolution, low background, and deep tissue penetration owing to low autofluorescence and suppressed scattering of long wavelength photons. Here we develop a bright organic nanofluorophore (named p-FE) for high-performance biological imaging in the NIR-II window. The bright NIR-II >1100 nm fluorescence emission from p-FE affords non-invasive in vivo tracking of blood flow in mouse brain vessels. Excitingly, p-FE enables one-photon based, three-dimensional (3D) confocal imaging of vasculatures in fixed mouse brain tissue with a layer-by-layer imaging depth up to ~1.3 mm and sub-10 µm high spatial resolution. We also perform in vivo two-color fluorescence imaging in the NIR-II window by utilizing p-FE as a vasculature imaging agent emitting between 1100 and 1300 nm and single-walled carbon nanotubes (CNTs) emitting above 1500 nm to highlight tumors in mice.

  View details for PubMedID 29563581

• Mesh Nanoelectronics: Seamless Integration of Electronics with Tissues ACCOUNTS OF CHEMICAL RESEARCH Dai, X., Hong, G., Gao, T., Lieber, C. M. 2018; 51 (2): 309–18

  Abstract

  Nanobioelectronics represents a rapidly developing field with broad-ranging opportunities in fundamental biological sciences, biotechnology, and medicine. Despite this potential, seamless integration of electronics has been difficult due to fundamental mismatches, including size and mechanical properties, between the elements of the electronic and living biological systems. In this Account, we discuss the concept, development, key demonstrations, and future opportunities of mesh nanoelectronics as a general paradigm for seamless integration of electronics within synthetic tissues and live animals. We first describe the design and realization of hybrid synthetic tissues that are innervated in three dimensions (3D) with mesh nanoelectronics where the mesh serves as both as a tissue scaffold and as a platform of addressable electronic devices for monitoring and manipulating tissue behavior. Specific examples of tissue/nanoelectronic mesh hybrids highlighted include 3D neural tissue, cardiac patches, and vascular constructs, where the nanoelectronic devices have been used to carry out real-time 3D recording of electrophysiological and chemical signals in the tissues. This novel platform was also exploited for time-dependent 3D spatiotemporal mapping of cardiac tissue action potentials during cell culture and tissue maturation as well as in response to injection of pharmacological agents. The extension to simultaneous real-time monitoring and active control of tissue behavior is further discussed for multifunctional mesh nanoelectronics incorporating both recording and stimulation devices, providing the unique capability of bidirectional interfaces to cardiac tissue. In the case of live animals, new challenges must be addressed, including minimally invasive implantation, absence of deleterious chronic tissue response, and long-term capability for monitoring and modulating tissue activity. We discuss each of these topics in the context of implantation of mesh nanoelectronics into rodent brains. First, we describe the design of ultraflexible mesh nanoelectronics with size features and mechanical properties similar to brain tissue and a novel syringe-injection methodology that allows the mesh nanoelectronics to be precisely delivered to targeted brain regions in a minimally invasive manner. Next, we discuss time-dependent histology studies showing seamless and stable integration of mesh nanoelectronics within brain tissue on at least one year scales without evidence of chronic immune response or glial scarring characteristic of conventional implants. Third, armed with facile input/output interfaces, we describe multiplexed single-unit recordings that demonstrate stable tracking of the same individual neurons and local neural circuits for at least 8 months, long-term monitoring and stimulation of the same groups of neurons, and following changes in individual neuron activity during brain aging. Moving forward, we foresee substantial opportunities for (1) continued development of mesh nanoelectronics through, for example, broadening nanodevice signal detection modalities and taking advantage of tissue-like properties for selective cell targeting and (2) exploiting the unique capabilities of mesh nanoelectronics for tackling critical scientific and medical challenges such as understanding and potentially ameliorating cell and circuit level changes associated with natural and pathological aging, as well as using mesh nanoelectronics as active tissue scaffolds for regenerative medicine and as neuroprosthetics for monitoring and treating neurological diseases.

  View details for DOI 10.1021/acs.accounts.7b00547

  View details for Web of Science ID 000426014500013

  View details for PubMedID 29381054

  View details for PubMedCentralID PMC5820158

• Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fu, T., Hong, G., Viveros, R. D., Zhou, T., Lieber, C. M. 2017; 114 (47): E10046–E10055

  Abstract

  Implantable electrical probes have led to advances in neuroscience, brain-machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases.

  View details for DOI 10.1073/pnas.1717695114

  View details for Web of Science ID 000416503700008

  View details for PubMedID 29109247

  View details for PubMedCentralID PMC5703340

• Syringe-Injectable Electronics with a Plug-and-Play Input/Output Interface NANO LETTERS Schuhmann, T. G., Yao, J., Hong, G., Fu, T., Lieber, C. M. 2017; 17 (9): 5836–42

  Abstract

  Syringe-injectable mesh electronics represent a new paradigm for brain science and neural prosthetics by virtue of the stable seamless integration of the electronics with neural tissues, a consequence of the macroporous mesh electronics structure with all size features similar to or less than individual neurons and tissue-like flexibility. These same properties, however, make input/output (I/O) connection to measurement electronics challenging, and work to-date has required methods that could be difficult to implement by the life sciences community. Here we present a new syringe-injectable mesh electronics design with plug-and-play I/O interfacing that is rapid, scalable, and user-friendly to nonexperts. The basic design tapers the ultraflexible mesh electronics to a narrow stem that routes all of the device/electrode interconnects to I/O pads that are inserted into a standard zero insertion force (ZIF) connector. Studies show that the entire plug-and-play mesh electronics can be delivered through capillary needles with precise targeting using microliter-scale injection volumes similar to the standard mesh electronics design. Electrical characterization of mesh electronics containing platinum (Pt) electrodes and silicon (Si) nanowire field-effect transistors (NW-FETs) demonstrates the ability to interface arbitrary devices with a contact resistance of only 3 Ω. Finally, in vivo injection into mice required only minutes for I/O connection and yielded expected local field potential (LFP) recordings from a compact head-stage compatible with chronic studies. Our results substantially lower barriers for use by new investigators and open the door for increasingly sophisticated and multifunctional mesh electronics designs for both basic and translational studies.

  View details for DOI 10.1021/acs.nanolett.7b03081

  View details for Web of Science ID 000411043500097

  View details for PubMedID 28787578

• Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhou, T., Hong, G., Fu, T., Yang, X., Schuhmann, T. G., Viveros, R. D., Lieber, C. M. 2017; 114 (23): 5894–99

  Abstract

  Implantation of electrical probes into the brain has been central to both neuroscience research and biomedical applications, although conventional probes induce gliosis in surrounding tissue. We recently reported ultraflexible open mesh electronics implanted into rodent brains by syringe injection that exhibit promising chronic tissue response and recording stability. Here we report time-dependent histology studies of the mesh electronics/brain-tissue interface obtained from sections perpendicular and parallel to probe long axis, as well as studies of conventional flexible thin-film probes. Confocal fluorescence microscopy images of the perpendicular and parallel brain slices containing mesh electronics showed that the distribution of astrocytes, microglia, and neurons became uniform from 2-12 wk, whereas flexible thin-film probes yield a marked accumulation of astrocytes and microglia and decrease of neurons for the same period. Quantitative analyses of 4- and 12-wk data showed that the signals for neurons, axons, astrocytes, and microglia are nearly the same from the mesh electronics surface to the baseline far from the probes, in contrast to flexible polymer probes, which show decreases in neuron and increases in astrocyte and microglia signals. Notably, images of sagittal brain slices containing nearly the entire mesh electronics probe showed that the tissue interface was uniform and neurons and neurofilaments penetrated through the mesh by 3 mo postimplantation. The minimal immune response and seamless interface with brain tissue postimplantation achieved by ultraflexible open mesh electronics probes provide substantial advantages and could enable a wide range of opportunities for in vivo chronic recording and modulation of brain activity in the future.

  View details for DOI 10.1073/pnas.1705509114

  View details for Web of Science ID 000402703800043

  View details for PubMedID 28533392

  View details for PubMedCentralID PMC5468665

• Live imaging of follicle stimulating hormone receptors in gonads and bones using near infrared II fluorophore CHEMICAL SCIENCE Feng, Y., Zhu, S., Antaris, A. L., Chen, H., Xiao, Y., Lu, X., Jiang, L., Diao, S., Yu, K., Wang, Y., Herraiz, S., Yue, J., Hong, X., Hong, G., Cheng, Z., Dai, H., Hsueh, A. J. 2017; 8 (5): 3703-3711

  Abstract

  In vivo imaging of hormone receptors provides the opportunity to visualize target tissues under hormonal control in live animals. Detecting longer-wavelength photons in the second near-infrared window (NIR-II, 1000-1700 nm) region affords reduced photon scattering in tissues accompanied by lower autofluorescence, leading to higher spatial resolution at up to centimeter tissue penetration depths. Here, we report the conjugation of a small molecular NIR-II fluorophore CH1055 to a follicle stimulating hormone (FSH-CH) for imaging ovaries and testes in live mice. After exposure to FSH-CH, specific NIR-II signals were found in cultured ovarian granulosa cells containing FSH receptors. Injection of FSH-CH allowed live imaging of ovarian follicles and testicular seminiferous tubules in female and male adult mice, respectively. Using prepubertal mice, NIR-II signals were detected in ovaries containing only preantral follicles. Resolving earlier controversies regarding the expression of FSH receptors in cultured osteoclasts, we detected for the first time specific FSH receptor signals in bones in vivo. The present imaging of FSH receptors in live animals using a ligand-conjugated NIR-II fluorophore with low cell toxicity and rapid clearance allows the development of non-invasive molecular imaging of diverse hormonal target cells in vivo.

  View details for DOI 10.1039/c6sc04897h

  View details for Web of Science ID 000400553000048

  View details for PubMedCentralID PMC5465568

• Live imaging of follicle stimulating hormone receptors in gonads and bones using near infrared II fluorophore. Chemical science Feng, Y., Zhu, S., Antaris, A. L., Chen, H., Xiao, Y., Lu, X., Jiang, L., Diao, S., Yu, K., Wang, Y., Herraiz, S., Yue, J., Hong, X., Hong, G., Cheng, Z., Dai, H., Hsueh, A. J. 2017; 8 (5): 3703-3711

  Abstract

  In vivo imaging of hormone receptors provides the opportunity to visualize target tissues under hormonal control in live animals. Detecting longer-wavelength photons in the second near-infrared window (NIR-II, 1000-1700 nm) region affords reduced photon scattering in tissues accompanied by lower autofluorescence, leading to higher spatial resolution at up to centimeter tissue penetration depths. Here, we report the conjugation of a small molecular NIR-II fluorophore CH1055 to a follicle stimulating hormone (FSH-CH) for imaging ovaries and testes in live mice. After exposure to FSH-CH, specific NIR-II signals were found in cultured ovarian granulosa cells containing FSH receptors. Injection of FSH-CH allowed live imaging of ovarian follicles and testicular seminiferous tubules in female and male adult mice, respectively. Using prepubertal mice, NIR-II signals were detected in ovaries containing only preantral follicles. Resolving earlier controversies regarding the expression of FSH receptors in cultured osteoclasts, we detected for the first time specific FSH receptor signals in bones in vivo. The present imaging of FSH receptors in live animals using a ligand-conjugated NIR-II fluorophore with low cell toxicity and rapid clearance allows the development of non-invasive molecular imaging of diverse hormonal target cells in vivo.

  View details for DOI 10.1039/c6sc04897h

  View details for PubMedID 28626555

  View details for PubMedCentralID PMC5465568

• Molecular imaging of biological systems with a clickable dye in the broad 800-to 1,700-nm near-infrared window PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhu, S., Yang, Q., Antaris, A. L., Yue, J., Ma, Z., Wang, H., Huang, W., Wan, H., Wang, J., Diao, S., Zhang, B., Li, X., Zhong, Y., Yu, K., Hong, G., Luo, J., Liang, Y., Dai, H. 2017; 114 (5): 962-967

  Abstract

  Fluorescence imaging multiplicity of biological systems is an area of intense focus, currently limited to fluorescence channels in the visible and first near-infrared (NIR-I; ∼700-900 nm) spectral regions. The development of conjugatable fluorophores with longer wavelength emission is highly desired to afford more targeting channels, reduce background autofluorescence, and achieve deeper tissue imaging depths. We have developed NIR-II (1,000-1,700 nm) molecular imaging agents with a bright NIR-II fluorophore through high-efficiency click chemistry to specific molecular antibodies. Relying on buoyant density differences during density gradient ultracentrifugation separations, highly pure NIR-II fluorophore-antibody conjugates emitting ∼1,100 nm were obtained for use as molecular-specific NIR-II probes. This facilitated 3D staining of ∼170-μm histological brain tissues sections on a home-built confocal microscope, demonstrating multicolor molecular imaging across both the NIR-I and NIR-II windows (800-1,700 nm).

  View details for DOI 10.1073/pnas.1617990114

  View details for PubMedID 28096386

• Near-infrared fluorophores for biomedical imaging NATURE BIOMEDICAL ENGINEERING Hong, G., Antaris, A. L., Dai, H. 2017; 1 (1)

  View details for DOI 10.1038/s41551-016-0010

  View details for Web of Science ID 000418850600010

• Stable long-term chronic brain mapping at the single-neuron level NATURE METHODS Fu, T., Hong, G., Zhou, T., Schuhmann, T. G., Viveros, R. D., Lieber, C. M. 2016; 13 (10): 875-+

  Abstract

  Stable in vivo mapping and modulation of the same neurons and brain circuits over extended periods is critical to both neuroscience and medicine. Current electrical implants offer single-neuron spatiotemporal resolution but are limited by such factors as relative shear motion and chronic immune responses during long-term recording. To overcome these limitations, we developed a chronic in vivo recording and stimulation platform based on flexible mesh electronics, and we demonstrated stable multiplexed local field potentials and single-unit recordings in mouse brains for at least 8 months without probe repositioning. Properties of acquired signals suggest robust tracking of the same neurons over this period. This recording and stimulation platform allowed us to evoke stable single-neuron responses to chronic electrical stimulation and to carry out longitudinal studies of brain aging in freely behaving mice. Such advantages could open up future studies in mapping and modulating changes associated with learning, aging and neurodegenerative diseases.

  View details for DOI 10.1038/nmeth.3969

  View details for Web of Science ID 000385194600026

  View details for PubMedID 27571550

• Traumatic Brain Injury Imaging in the Second Near-Infrared Window with a Molecular Fluorophore. Advanced materials Zhang, X., Wang, H., Antaris, A. L., Li, L., Diao, S., Ma, R., Nguyen, A., Hong, G., Ma, Z., Wang, J., Zhu, S., Castellano, J. M., Wyss-Coray, T., Liang, Y., Luo, J., Dai, H. 2016; 28 (32): 6872-6879

  Abstract

  Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. A bright, renal-excreted, and biocompatible near-infrared II fluorophore for in vivo imaging of TBI is designed. A transient hypoperfusion in the injured cerebral region, followed by fluorophore leakage, is observed. NIR-II fluorophores can provide noninvasive assessment of TBI.

  View details for DOI 10.1002/adma.201600706

  View details for PubMedID 27253071

• IN VIVO VASCULAR IMAGING OF TRAUMATIC BRAIN INJURY IN THE SECOND NEAR-INFRARED WINDOW Zhang, X., Wang, H., Antaris, A., Li, L., Diao, S., Ma, R., Nguyen, A., Hong, G., Ma, Z., Wang, J., Zhu, S., Castellano, J., Wyss-Coray, T., Liang, Y., Luo, J., Dai, H. MARY ANN LIEBERT, INC. 2016: A48

  View details for Web of Science ID 000378336200127

• A small-molecule dye for NIR-II imaging NATURE MATERIALS Antaris, A. L., Chen, H., Cheng, K., Sun, Y., Hong, G., Qu, C., Diao, S., Deng, Z., Hu, X., Zhang, B., Zhang, X., Yaghi, O. K., Alamparambil, Z. R., Hong, X., Cheng, Z., Dai, H. 2016; 15 (2): 235-?

  Abstract

  Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)-a clinically approved NIR-I dye-in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery.

  View details for DOI 10.1038/NMAT4476

  View details for Web of Science ID 000368766100030

• A small-molecule dye for NIR-II imaging. Nature materials Antaris, A. L., Chen, H., Cheng, K., Sun, Y., Hong, G., Qu, C., Diao, S., Deng, Z., Hu, X., Zhang, B., Zhang, X., Yaghi, O. K., Alamparambil, Z. R., Hong, X., Cheng, Z., Dai, H. 2016; 15 (2): 235-42

  Abstract

  Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)-a clinically approved NIR-I dye-in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery.

  View details for DOI 10.1038/nmat4476

  View details for PubMedID 26595119

• In Vivo Fluorescence Imaging in the Second Near-Infrared Window Using Carbon Nanotubes IN VIVO FLUORESCENCE IMAGING: METHODS AND PROTOCOLS Hong, G., Dai, H., Bai, M. 2016; 1444: 167–81

  Abstract

  In vivo fluorescence imaging in the second near-infrared window (NIR-II window, 1000-1700 nm) is a powerful imaging technique that emerged in recent years. This imaging tool allows for noninvasive, deep-tissue visualization and interrogation of anatomical features and functions with improved imaging resolution and contrast at greater tissue penetration depths than traditional fluorescence imaging. Here, we present the detailed protocol for conducting NIR-II fluorescence imaging in live animals, including the procedures for preparation of biocompatible and NIR-II fluorescent carbon nanotube solution, live animal administration and NIR-II fluorescence image acquisition.

  View details for PubMedID 27283426

• Dispersion of High-Purity Semiconducting Arc-Discharged Carbon Nanotubes Using Backbone Engineered Diketopyrrolopyrrole (DPP)-Based Polymers ADVANCED ELECTRONIC MATERIALS Lei, T., Pitner, G., Chen, X., Hong, G., Park, S., Hayoz, P., Weitz, R. T., Wong, H. P., Bao, Z. 2016; 2 (1)

  View details for DOI 10.1002/aelm.201500299

  View details for Web of Science ID 000370335000018

• Single Chirality (6,4) Single-Walled Carbon Nanotubes for Fluorescence Imaging with Silicon Detectors SMALL Antaris, A. L., Yaghi, O. K., Hong, G., Diao, S., Zhang, B., Yang, J., Chew, L., Dai, H. 2015; 11 (47): 6325-6330

  Abstract

  Postsynthetic single-walled carbon nanotube (SWCNT) sorting methods such as density gradient ultracentrifugation, gel chromatography, and electrophoresis have all been inspired by established biochemistry separation techniques designed to separate subcellular components. Biochemistry separation techniques have been refined to the degree that parameters such as pH, salt concentration, and temperature are necessary for a successful separation, yet these conditions are only now being applied to SWCNT separation methodologies. Slight changes in pH produce radically different behaviors of SWCNTs inside a density gradient, allowing for the facile separation of ultrahigh purity (6,4) SWCNTs from as-synthesized carbon nanotubes. The (6,4) SWCNTs are novel fluorophores emitting below ≈900 nm and can be easily detected with conventional silicon-based charge-coupled device detectors without the need for specialized InGaAs cameras. The (6,4) SWCNTs are used to demonstrate their potential as a clinically relevant NIR-I fluorescence stain for the immunohistochemical staining of cells and cancer tissue sections displaying high endothelial growth factor receptor levels.

  View details for DOI 10.1002/smll.201501530

  View details for Web of Science ID 000367916600010

• Single Chirality (6,4) Single-Walled Carbon Nanotubes for Fluorescence Imaging with Silicon Detectors. Small (Weinheim an der Bergstrasse, Germany) Antaris, A. L., Yaghi, O. K., Hong, G., Diao, S., Zhang, B., Yang, J., Chew, L., Dai, H. 2015; 11 (47): 6325-30

  Abstract

  Postsynthetic single-walled carbon nanotube (SWCNT) sorting methods such as density gradient ultracentrifugation, gel chromatography, and electrophoresis have all been inspired by established biochemistry separation techniques designed to separate subcellular components. Biochemistry separation techniques have been refined to the degree that parameters such as pH, salt concentration, and temperature are necessary for a successful separation, yet these conditions are only now being applied to SWCNT separation methodologies. Slight changes in pH produce radically different behaviors of SWCNTs inside a density gradient, allowing for the facile separation of ultrahigh purity (6,4) SWCNTs from as-synthesized carbon nanotubes. The (6,4) SWCNTs are novel fluorophores emitting below ≈900 nm and can be easily detected with conventional silicon-based charge-coupled device detectors without the need for specialized InGaAs cameras. The (6,4) SWCNTs are used to demonstrate their potential as a clinically relevant NIR-I fluorescence stain for the immunohistochemical staining of cells and cancer tissue sections displaying high endothelial growth factor receptor levels.

  View details for DOI 10.1002/smll.201501530

  View details for PubMedID 26529611

• Fluorescence Imaging In Vivo at Wavelengths beyond 1500 nm ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Diao, S., Blackburn, J. L., Hong, G., Antaris, A. L., Chang, J., Wu, J. Z., Zhang, B., Cheng, K., Kuo, C. J., Dai, H. 2015; 54 (49): 14758-14762

  Abstract

  Compared to imaging in the visible and near-infrared regions below 900 nm, imaging in the second near-infrared window (NIR-II, 1000-1700 nm) is a promising method for deep-tissue high-resolution optical imaging in vivo mainly owing to the reduced scattering of photons traversing through biological tissues. Herein, semiconducting single-walled carbon nanotubes with large diameters were used for in vivo fluorescence imaging in the long-wavelength NIR region (1500-1700 nm, NIR-IIb). With this imaging agent, 3-4 μm wide capillary blood vessels at a depth of about 3 mm could be resolved. Meanwhile, the blood-flow speeds in multiple individual vessels could be mapped simultaneously. Furthermore, NIR-IIb tumor imaging of a live mouse was explored. NIR-IIb imaging can be generalized to a wide range of fluorophores emitting at up to 1700 nm for high-performance in vivo optical imaging.

  View details for DOI 10.1002/anie.201507473

  View details for Web of Science ID 000367723400025

• Fluorescence Imaging In Vivo at Wavelengths beyond 1500 nm. Angewandte Chemie (International ed. in English) Diao, S., Blackburn, J. L., Hong, G., Antaris, A. L., Chang, J., Wu, J. Z., Zhang, B., Cheng, K., Kuo, C. J., Dai, H. 2015; 54 (49): 14758-62

  Abstract

  Compared to imaging in the visible and near-infrared regions below 900 nm, imaging in the second near-infrared window (NIR-II, 1000-1700 nm) is a promising method for deep-tissue high-resolution optical imaging in vivo mainly owing to the reduced scattering of photons traversing through biological tissues. Herein, semiconducting single-walled carbon nanotubes with large diameters were used for in vivo fluorescence imaging in the long-wavelength NIR region (1500-1700 nm, NIR-IIb). With this imaging agent, 3-4 μm wide capillary blood vessels at a depth of about 3 mm could be resolved. Meanwhile, the blood-flow speeds in multiple individual vessels could be mapped simultaneously. Furthermore, NIR-IIb tumor imaging of a live mouse was explored. NIR-IIb imaging can be generalized to a wide range of fluorophores emitting at up to 1700 nm for high-performance in vivo optical imaging.

  View details for DOI 10.1002/anie.201507473

  View details for PubMedID 26460151

• Carbon Nanomaterials for Biological Imaging and Nanomedicinal Therapy CHEMICAL REVIEWS Hong, G., Diao, S., Antaris, A. L., Dai, H. 2015; 115 (19): 10816-10906

  View details for DOI 10.1021/acs.chemrev.5b00008

  View details for Web of Science ID 000363002300009

  View details for PubMedID 25997028

• Syringe Injectable Electronics: Precise Targeted Delivery with Quantitative Input/Output Connectivity NANO LETTERS Hong, G., Fu, T., Zhou, T., Schuhmann, T. G., Huang, J., Lieber, C. M. 2015; 15 (10): 6979–84

  Abstract

  Syringe-injectable mesh electronics with tissue-like mechanical properties and open macroporous structures is an emerging powerful paradigm for mapping and modulating brain activity. Indeed, the ultraflexible macroporous structure has exhibited unprecedented minimal/noninvasiveness and the promotion of attractive interactions with neurons in chronic studies. These same structural features also pose new challenges and opportunities for precise targeted delivery in specific brain regions and quantitative input/output (I/O) connectivity needed for reliable electrical measurements. Here, we describe new results that address in a flexible manner both of these points. First, we have developed a controlled injection approach that maintains the extended mesh structure during the "blind" injection process, while also achieving targeted delivery with ca. 20 μm spatial precision. Optical and microcomputed tomography results from injections into tissue-like hydrogel, ex vivo brain tissue, and in vivo brains validate our basic approach and demonstrate its generality. Second, we present a general strategy to achieve up to 100% multichannel I/O connectivity using an automated conductive ink printing methodology to connect the mesh electronics and a flexible flat cable, which serves as the standard "plug-in" interface to measurement electronics. Studies of resistance versus printed line width were used to identify optimal conditions, and moreover, frequency-dependent noise measurements show that the flexible printing process yields values comparable to commercial flip-chip bonding technology. Our results address two key challenges faced by syringe-injectable electronics and thereby pave the way for facile in vivo applications of injectable mesh electronics as a general and powerful tool for long-term mapping and modulation of brain activity in fundamental neuroscience through therapeutic biomedical studies.

  View details for DOI 10.1021/acs.nanolett.5b02987

  View details for Web of Science ID 000363003100105

  View details for PubMedID 26317328

• Biological imaging without autofluorescence in the second near-infrared region NANO RESEARCH Diao, S., Hong, G., Antaris, A. L., Blackburn, J. L., Cheng, K., Cheng, Z., Dai, H. 2015; 8 (9): 3027-3034

  View details for DOI 10.1007/s12274-015-0808-9

  View details for Web of Science ID 000361057000025

• Diketopyrrolopyrrole-Based Semiconducting Polymer Nanoparticles for In Vivo Photoacoustic Imaging. Advanced materials Pu, K., Mei, J., Jokerst, J. V., Hong, G., Antaris, A. L., Chattopadhyay, N., Shuhendler, A. J., Kurosawa, T., Zhou, Y., Gambhir, S. S., Bao, Z., Rao, J. 2015; 27 (35): 5184-5190

  Abstract

  Diketopyrrolopyrrole-based semiconducting polymer nanoparticles with high photostability and strong photoacoustic brightness are designed and synthesized, which results in 5.3-fold photoacoustic signal enhancement in tumor xenografts after systemic administration.

  View details for DOI 10.1002/adma.201502285

  View details for PubMedID 26247171

  View details for PubMedCentralID PMC4567488

• Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis. ACS nano Nakayama, K. H., Hong, G., Lee, J. C., Patel, J., Edwards, B., Zaitseva, T. S., Paukshto, M. V., Dai, H., Cooke, J. P., Woo, Y. J., Huang, N. F. 2015; 9 (7): 6900-6908

  Abstract

  The objective of this study was to enhance the angiogenic capacity of endothelial cells (ECs) using nanoscale signaling cues from aligned nanofibrillar scaffolds in the setting of tissue ischemia. Thread-like nanofibrillar scaffolds with porous structure were fabricated from aligned-braided membranes generated under shear from liquid crystal collagen solution. Human ECs showed greater outgrowth from aligned scaffolds than from nonpatterned scaffolds. Integrin α1 was in part responsible for the enhanced cellular outgrowth on aligned nanofibrillar scaffolds, as the effect was abrogated by integrin α1 inhibition. To test the efficacy of EC-seeded aligned nanofibrillar scaffolds in improving neovascularization in vivo, the ischemic limbs of mice were treated with EC-seeded aligned nanofibrillar scaffold; EC-seeded nonpatterned scaffold; ECs in saline; aligned nanofibrillar scaffold alone; or no treatment. After 14 days, laser Doppler blood spectroscopy demonstrated significant improvement in blood perfusion recovery when treated with EC-seeded aligned nanofibrillar scaffolds, in comparison to ECs in saline or no treatment. In ischemic hindlimbs treated with scaffolds seeded with human ECs derived from induced pluripotent stem cells (iPSC-ECs), single-walled carbon nanotube (SWNT) fluorophores were systemically delivered to quantify microvascular density after 28 days. Near infrared-II (NIR-II, 1000-1700 nm) imaging of SWNT fluorophores demonstrated that iPSC-EC-seeded aligned scaffolds group showed significantly higher microvascular density than the saline or cells groups. These data suggest that treatment with EC-seeded aligned nanofibrillar scaffolds improved blood perfusion and arteriogenesis, when compared to treatment with cells alone or scaffold alone, and have important implications in the design of therapeutic cell delivery strategies.

  View details for DOI 10.1021/acsnano.5b00545

  View details for PubMedID 26061869

• Syringe-injectable electronics NATURE NANOTECHNOLOGY Liu, J., Fu, T., Cheng, Z., Hong, G., Zhou, T., Jin, L., Duvvuri, M., Jiang, Z., Kruskal, P., Xie, C., Suo, Z., Fang, Y., Lieber, C. M. 2015; 10 (7): 629-+

  Abstract

  Seamless and minimally invasive three-dimensional interpenetration of electronics within artificial or natural structures could allow for continuous monitoring and manipulation of their properties. Flexible electronics provide a means for conforming electronics to non-planar surfaces, yet targeted delivery of flexible electronics to internal regions remains difficult. Here, we overcome this challenge by demonstrating the syringe injection (and subsequent unfolding) of sub-micrometre-thick, centimetre-scale macroporous mesh electronics through needles with a diameter as small as 100 μm. Our results show that electronic components can be injected into man-made and biological cavities, as well as dense gels and tissue, with >90% device yield. We demonstrate several applications of syringe-injectable electronics as a general approach for interpenetrating flexible electronics with three-dimensional structures, including (1) monitoring internal mechanical strains in polymer cavities, (2) tight integration and low chronic immunoreactivity with several distinct regions of the brain, and (3) in vivo multiplexed neural recording. Moreover, syringe injection enables the delivery of flexible electronics through a rigid shell, the delivery of large-volume flexible electronics that can fill internal cavities, and co-injection of electronics with other materials into host structures, opening up unique applications for flexible electronics.

  View details for DOI 10.1038/NNANO.2015.115

  View details for Web of Science ID 000357485600019

  View details for PubMedID 26053995

  View details for PubMedCentralID PMC4591029

• Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis ACS NANO Nakayarna, K. H., Hong, G., Lee, J. C., Patel, J., Edwards, B., Zaitseva, T. S., Paukshto, M. V., Dai, H., Cooke, J. P., Woo, Y. J., Huang, N. F. 2015; 9 (7): 6900-6908

  Abstract

  The objective of this study was to enhance the angiogenic capacity of endothelial cells (ECs) using nanoscale signaling cues from aligned nanofibrillar scaffolds in the setting of tissue ischemia. Thread-like nanofibrillar scaffolds with porous structure were fabricated from aligned-braided membranes generated under shear from liquid crystal collagen solution. Human ECs showed greater outgrowth from aligned scaffolds than from nonpatterned scaffolds. Integrin α1 was in part responsible for the enhanced cellular outgrowth on aligned nanofibrillar scaffolds, as the effect was abrogated by integrin α1 inhibition. To test the efficacy of EC-seeded aligned nanofibrillar scaffolds in improving neovascularization in vivo, the ischemic limbs of mice were treated with EC-seeded aligned nanofibrillar scaffold; EC-seeded nonpatterned scaffold; ECs in saline; aligned nanofibrillar scaffold alone; or no treatment. After 14 days, laser Doppler blood spectroscopy demonstrated significant improvement in blood perfusion recovery when treated with EC-seeded aligned nanofibrillar scaffolds, in comparison to ECs in saline or no treatment. In ischemic hindlimbs treated with scaffolds seeded with human ECs derived from induced pluripotent stem cells (iPSC-ECs), single-walled carbon nanotube (SWNT) fluorophores were systemically delivered to quantify microvascular density after 28 days. Near infrared-II (NIR-II, 1000-1700 nm) imaging of SWNT fluorophores demonstrated that iPSC-EC-seeded aligned scaffolds group showed significantly higher microvascular density than the saline or cells groups. These data suggest that treatment with EC-seeded aligned nanofibrillar scaffolds improved blood perfusion and arteriogenesis, when compared to treatment with cells alone or scaffold alone, and have important implications in the design of therapeutic cell delivery strategies.

  View details for DOI 10.1021/acsnano.5b00545

  View details for Web of Science ID 000358823200027

• Diketopyrrolopyrrole (DPP)-Based Donor-Acceptor Polymers for Selective Dispersion of Large-Diameter Semiconducting Carbon Nanotubes SMALL Lei, T., Lai, Y., Hong, G., Wang, H., Hayoz, P., Weitz, R. T., Chen, C., Dai, H., Bao, Z. 2015; 11 (24): 2946-2954

  Abstract

  Low-bandgap diketopyrrolopyrrole (DPP)-based polymers are used for the selective dispersion of semiconducting single-walled carbon nanotubes (s-SWCNTs). Through rational molecular design to tune the polymer-SWCNT interactions, highly selective dispersions of s-SWCNTs with diameters mainly around 1.5 nm are achieved. The influences of the polymer alkyl side-chain substitution (i.e., branched vs linear side chains) on the dispersing yield and selectivity of s-SWCNTs are investigated. Introducing linear alkyl side chains allows increased polymer-SWCNT interactions through close π-π stacking and improved C-H-π interactions. This work demonstrates that polymer side-chain engineering is an effective method to modulate the polymer-SWCNT interactions and thereby affecting both critical parameters in dispersing yield and selectivity. Using these sorted s-SWCNTs, high-performance SWCNT network thin-film transistors are fabricated. The solution-deposited s-SWCNT transistors yield simultaneously high mobilities of 41.2 cm(2) V(-1) s(-1) and high on/off ratios of greater than 10(4) . In summary, low-bandgap DPP donor-acceptor polymers are a promising class of polymers for selective dispersion of large-diameter s-SWCNTs.

  View details for DOI 10.1002/smll.201403761

  View details for PubMedID 25711378

• General Strategy for Biodetection in High Ionic Strength Solutions Using Transistor-Based Nanoelectronic Sensors NANO LETTERS Gao, N., Zhou, W., Jiang, X., Hong, G., Fu, T., Lieber, C. M. 2015; 15 (3): 2143–48

  Abstract

  Transistor-based nanoelectronic sensors are capable of label-free real-time chemical and biological detection with high sensitivity and spatial resolution, although the short Debye screening length in high ionic strength solutions has made difficult applications relevant to physiological conditions. Here, we describe a new and general strategy to overcome this challenge for field-effect transistor (FET) sensors that involves incorporating a porous and biomolecule permeable polymer layer on the FET sensor. This polymer layer increases the effective screening length in the region immediately adjacent to the device surface and thereby enables detection of biomolecules in high ionic strength solutions in real-time. Studies of silicon nanowire field-effect transistors with additional polyethylene glycol (PEG) modification show that prostate specific antigen (PSA) can be readily detected in solutions with phosphate buffer (PB) concentrations as high as 150 mM, while similar devices without PEG modification only exhibit detectable signals for concentrations ≤10 mM. Concentration-dependent measurements exhibited real-time detection of PSA with a sensitivity of at least 10 nM in 100 mM PB with linear response up to the highest (1000 nM) PSA concentrations tested. The current work represents an important step toward general application of transistor-based nanoelectronic detectors for biochemical sensing in physiological environments and is expected to open up exciting opportunities for in vitro and in vivo biological sensing relevant to basic biology research through medicine.

  View details for DOI 10.1021/acs.nanolett.5b00133

  View details for Web of Science ID 000351188000107

  View details for PubMedID 25664395

  View details for PubMedCentralID PMC4594804

• Graphene nanoribbons under mechanical strain. Advanced materials Chen, C., Wu, J. Z., Lam, K. T., Hong, G., Gong, M., Zhang, B., Lu, Y., Antaris, A. L., Diao, S., Guo, J., Dai, H. 2015; 27 (2): 303-309

  Abstract

  Uniaxial strains are introduced into individual graphene nanoribbons (GNRs) with highly smooth edges to investigate the strain effects on Raman spectroscopic and electrical properties of GNRs. It is found that uniaxial strain downshifts the Raman G-band frequency of GNRs linearly and tunes their bandgap significantly in a non-monotonic manner. The strain engineering of GNRs is promising for potential electronics and photonics applications.

  View details for DOI 10.1002/adma.201403750

  View details for PubMedID 25355690

• Through-skull fluorescence imaging of the brain in a new near-infrared window NATURE PHOTONICS Hong, G., Diao, S., Chang, J., Antaris, A. L., Chen, C., Zhang, B., Zhao, S., Atochin, D. N., Huang, P. L., Andreasson, K. I., Kuo, C. J., Dai, H. 2014; 8 (9): 723-730

  Abstract

  To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography with limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400-900 nm) is an alternative but currently requires craniotomy, cranial windows and skull thinning techniques, and the penetration depth is limited to 1-2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3-1.4 micrometre near-infrared window. Reduced photon scattering in this spectral region allows fluorescence imaging reaching a depth of >2 mm in mouse brain with sub-10 micrometre resolution. An imaging rate of ~5.3 frames/s allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of blood flow anomaly in a mouse middle cerebral artery occlusion stroke model.

  View details for DOI 10.1038/NPHOTON.2014.166

  View details for Web of Science ID 000342600100016

  View details for PubMedCentralID PMC5026222

• Through-skull fluorescence imaging of the brain in a new near-infrared window. Nature photonics Hong, G., Diao, S., Chang, J., Antaris, A. L., Chen, C., Zhang, B., Zhao, S., Atochin, D. N., Huang, P. L., Andreasson, K. I., Kuo, C. J., Dai, H. 2014; 8 (9): 723-730

  Abstract

  To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography with limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400-900 nm) is an alternative but currently requires craniotomy, cranial windows and skull thinning techniques, and the penetration depth is limited to 1-2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3-1.4 micrometre near-infrared window. Reduced photon scattering in this spectral region allows fluorescence imaging reaching a depth of >2 mm in mouse brain with sub-10 micrometre resolution. An imaging rate of ~5.3 frames/s allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of blood flow anomaly in a mouse middle cerebral artery occlusion stroke model.

  View details for DOI 10.1038/nphoton.2014.166

  View details for PubMedID 27642366

  View details for PubMedCentralID PMC5026222

• Tumor Metastasis Inhibition by Imaging-Guided Photothermal Therapy with Single-Walled Carbon Nanotubes ADVANCED MATERIALS Liang, C., Diao, S., Wang, C., Gong, H., Liu, T., Hong, G., Shi, X., Dai, H., Liu, Z. 2014; 26 (32): 5646-?

  Abstract

  Multi-modal imaging guided photothermal therapy with single-walled carbon nanotubes affords effective destruction of primary tumors together with cancer cells in sentinel lymph nodes. This results in remarkably prolonged mouse survival compared to mice treated by elimination of only the primary tumor by either surgery or conventional photothermal therapy.

  View details for DOI 10.1002/adma.201401825

  View details for Web of Science ID 000340900800007

  View details for PubMedID 24924258

• Diketopyrrolopyrrole (DPP)-based donor-acceptor polymers for scalable and selective dispersion of large-diameter carbon nanotubes Lei, T., Lai, Y., Hong, G., Wang, H., Dai, H., Bao, Z. AMER CHEMICAL SOC. 2014

  View details for Web of Science ID 000349167405040

• Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window NATURE COMMUNICATIONS Hong, G., Zou, Y., Antaris, A. L., Diao, S., Wu, D., Cheng, K., Zhang, X., Chen, C., Liu, B., He, Y., Wu, J. Z., Yuan, J., Zhang, B., Tao, Z., Fukunaga, C., Dai, H. 2014; 5

  Abstract

  In vivo fluorescence imaging in the second near-infrared window (1.0-1.7 μm) can afford deep tissue penetration and high spatial resolution, owing to the reduced scattering of long-wavelength photons. Here we synthesize a series of low-bandgap donor/acceptor copolymers with tunable emission wavelengths of 1,050-1,350 nm in this window. Non-covalent functionalization with phospholipid-polyethylene glycol results in water-soluble and biocompatible polymeric nanoparticles, allowing for live cell molecular imaging at >1,000 nm with polymer fluorophores for the first time. Importantly, the high quantum yield of the polymer allows for in vivo, deep-tissue and ultrafast imaging of mouse arterial blood flow with an unprecedented frame rate of >25 frames per second. The high time-resolution results in spatially and time resolved imaging of the blood flow pattern in cardiogram waveform over a single cardiac cycle (~200 ms) of a mouse, which has not been observed with fluorescence imaging in this window before.

  View details for DOI 10.1038/ncomms5206

  View details for Web of Science ID 000338839100002

• Near-Infrared II Fluorescence for Imaging Hindlimb Vessel Regeneration With Dynamic Tissue Perfusion Measurement. Circulation. Cardiovascular imaging Hong, G., Lee, J. C., Jha, A., Diao, S., Nakayama, K. H., Hou, L., Doyle, T. C., Robinson, J. T., Antaris, A. L., Dai, H., Cooke, J. P., Huang, N. F. 2014; 7 (3): 517-525

  Abstract

  Real-time vascular imaging that provides both anatomic and hemodynamic information could greatly facilitate the diagnosis of vascular diseases and provide accurate assessment of therapeutic effects. Here, we have developed a novel fluorescence-based all-optical method, named near-infrared II (NIR-II) fluorescence imaging, to image murine hindlimb vasculature and blood flow in an experimental model of peripheral arterial disease, by exploiting fluorescence in the NIR-II region (1000-1400 nm) of photon wavelengths.Because of the reduced photon scattering of NIR-II fluorescence compared with traditional NIR fluorescence imaging and thus much deeper penetration depth into the body, we demonstrated that the mouse hindlimb vasculature could be imaged with higher spatial resolution than in vivo microscopic computed tomography. Furthermore, imaging during 26 days revealed a significant increase in hindlimb microvascular density in response to experimentally induced ischemia within the first 8 days of the surgery (P<0.005), which was confirmed by histological analysis of microvascular density. Moreover, the tissue perfusion in the ischemic hindlimb could be quantitatively measured by the dynamic NIR-II method, revealing the temporal kinetics of blood flow recovery that resembled microbead-based blood flowmetry and laser Doppler blood spectroscopy.The penetration depth of millimeters, high spatial resolution, and fast acquisition rate of NIR-II imaging make it a useful imaging tool for murine models of vascular disease.

  View details for DOI 10.1161/CIRCIMAGING.113.000305

  View details for PubMedID 24657826

• Near-infrared II fluorescence for imaging hindlimb vessel regeneration with dynamic tissue perfusion measurement. Circulation. Cardiovascular imaging Hong, G., Lee, J. C., Jha, A., Diao, S., Nakayama, K. H., Hou, L., Doyle, T. C., Robinson, J. T., Antaris, A. L., Dai, H., Cooke, J. P., Huang, N. F. 2014; 7 (3): 517-525

  Abstract

  Real-time vascular imaging that provides both anatomic and hemodynamic information could greatly facilitate the diagnosis of vascular diseases and provide accurate assessment of therapeutic effects. Here, we have developed a novel fluorescence-based all-optical method, named near-infrared II (NIR-II) fluorescence imaging, to image murine hindlimb vasculature and blood flow in an experimental model of peripheral arterial disease, by exploiting fluorescence in the NIR-II region (1000-1400 nm) of photon wavelengths.Because of the reduced photon scattering of NIR-II fluorescence compared with traditional NIR fluorescence imaging and thus much deeper penetration depth into the body, we demonstrated that the mouse hindlimb vasculature could be imaged with higher spatial resolution than in vivo microscopic computed tomography. Furthermore, imaging during 26 days revealed a significant increase in hindlimb microvascular density in response to experimentally induced ischemia within the first 8 days of the surgery (P<0.005), which was confirmed by histological analysis of microvascular density. Moreover, the tissue perfusion in the ischemic hindlimb could be quantitatively measured by the dynamic NIR-II method, revealing the temporal kinetics of blood flow recovery that resembled microbead-based blood flowmetry and laser Doppler blood spectroscopy.The penetration depth of millimeters, high spatial resolution, and fast acquisition rate of NIR-II imaging make it a useful imaging tool for murine models of vascular disease.

  View details for DOI 10.1161/CIRCIMAGING.113.000305

  View details for PubMedID 24657826

• Graphite Oxide Nanoparticles with Diameter Greater than 20 nm Are Biocompatible with Mouse Embryonic Stem Cells and Can Be Used in a Tissue Engineering System. Small Wang, I. E., Robinson, J. T., Do, G., Hong, G., Gould, D. R., Dai, H., Yang, P. C. 2014; 10 (8): 1479-1484

  Abstract

  Graphite oxide sheets demonstrate size-dependent uptake and toxicity towards embryonic stem cells. Graphite oxide sheets larger than 20 nm are biocompatible and can be safely used with mouse embryonic stem cells, while graphite oxide sheets smaller than 20 nm in diameter reduced cell proliferation and increased cell toxicity.

  View details for DOI 10.1002/smll.201303133

  View details for PubMedID 24376186

• Plasmonic micro-beads for fluorescence enhanced, multiplexed protein detection with flow cytometry CHEMICAL SCIENCE Zhang, B., Yang, J., Zou, Y., Gong, M., Chen, H., Hong, G., Antaris, A. L., Li, X., Liu, C., Chen, C., Dai, H. 2014; 5 (10): 4070-4075

  View details for DOI 10.1039/c4sc01206b

  View details for Web of Science ID 000341195100048

• Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window. Nature communications Hong, G., Zou, Y., Antaris, A. L., Diao, S., Wu, D., Cheng, K., Zhang, X., Chen, C., Liu, B., He, Y., Wu, J. Z., Yuan, J., Zhang, B., Tao, Z., Fukunaga, C., Dai, H. 2014; 5: 4206-?

  Abstract

  In vivo fluorescence imaging in the second near-infrared window (1.0-1.7 μm) can afford deep tissue penetration and high spatial resolution, owing to the reduced scattering of long-wavelength photons. Here we synthesize a series of low-bandgap donor/acceptor copolymers with tunable emission wavelengths of 1,050-1,350 nm in this window. Non-covalent functionalization with phospholipid-polyethylene glycol results in water-soluble and biocompatible polymeric nanoparticles, allowing for live cell molecular imaging at >1,000 nm with polymer fluorophores for the first time. Importantly, the high quantum yield of the polymer allows for in vivo, deep-tissue and ultrafast imaging of mouse arterial blood flow with an unprecedented frame rate of >25 frames per second. The high time-resolution results in spatially and time resolved imaging of the blood flow pattern in cardiogram waveform over a single cardiac cycle (~200 ms) of a mouse, which has not been observed with fluorescence imaging in this window before.

  View details for DOI 10.1038/ncomms5206

  View details for PubMedID 24947309

• Biological Imaging Using Nanoparticles of Small Organic Molecules with Fluorescence Emission at Wavelengths Longer than 1000 nm. Angewandte Chemie (International ed. in English) Tao, Z., Hong, G., Shinji, C., Chen, C., Diao, S., Antaris, A. L., Zhang, B., Zou, Y., Dai, H. 2013; 52 (49): 13002-13006

  Abstract

  Embedded in a polymer: A hydrophobic organic molecule that fluoresces in the near-infrared II (NIR-II) region was made water-soluble and biocompatible by its embedment in a polymer nanoparticle, which was then coated with hydrophilic poly(ethylene glycol) chains. The resulting nanoparticles exhibit bright fluorescence in the NIR-II window and high photostability in aqueous media and were used for in vivo imaging in mice.

  View details for DOI 10.1002/anie.201307346

  View details for PubMedID 24174264

• Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice BIOMATERIALS Zhang, Y., Zhang, Y., Hong, G., He, W., Zhou, K., Yang, K., Li, F., Chen, G., Liu, Z., Dai, H., Wang, Q. 2013; 34 (14): 3639-3646

  Abstract

  Ag2S quantum dots (QDs) have been demonstrated as a promising near-infrared II (NIR-II, 1.0-1.4 μm) emitting nanoprobe for in vivo imaging and detection. In this work, we carefully study the long-term in vivo biodistribution of Ag2S QDs functionalized with polyethylene glycol (PEG) and systematically examine the potential toxicity of Ag2S QDs over time. Our results show that PEGylated-Ag2S QDs are mainly accumulated in the reticuloendothelial system (RES) including liver and spleen after intravenous administration and can be gradually cleared, mostly by fecal excretion. PEGylated-Ag2S QDs do not cause appreciable toxicity at our tested doses (15 and 30 mg/kg) to the treated mice over a period of 2 months as evidenced by blood biochemistry, hematological analysis and histological examinations. Our work lays a solid foundation for further biomedical applications of Ag2S QDs as an important in vivo imaging agent in the NIR-II region.

  View details for DOI 10.1016/j.biomaterials.2013.01.089

  View details for Web of Science ID 000317534200010

  View details for PubMedID 23415643

• Ultra-Low Doses of Chirality Sorted (6,5) Carbon Nanotubes for Simultaneous Tumor Imaging and Photothermal Therapy ACS NANO Antaris, A. L., Robinson, J. T., Yaghi, O. K., Hong, G., Diao, S., Luong, R., Dai, H. 2013; 7 (4): 3644-3652

  Abstract

  Single-walled carbon nanotubes (SWCNTs) exhibit intrinsic fluorescence and strong optical absorption in the near-infrared (NIR) biological window (0.7-1.4 μm), rendering them ideal for in vivo imaging and photothermal therapy. Advances in SWCNT sorting have led to improved nanoelectronics and are promising for nanomedicine. To date, SWCNTs used in vivo consist of heterogeneous mixtures of nanotubes and only a small subset of chirality nanotubes fluoresces or heats under a NIR laser. Here, we demonstrate that separated (6,5) SWCNTs exchanged into a biocompatible surfactant, C18-PMH-mPEG, are more than 6-fold brighter in photoluminescence on the per mass basis, afford clear tumor imaging, and reach requisite photothermal tumor ablation temperatures with a >10-fold lower injected dose than as-synthesized SWCNT mixtures while exhibiting relatively low (6,5) accumulation in the reticuloendothelial system. The intravenous injection of ∼4 μg of (6,5) SWCNTs per mouse (0.254 mg/kg) for dual imaging/photothermal therapy is, by far, the lowest reported dose for nanoparticle-based in vivo therapeutics.

  View details for DOI 10.1021/nn4006472

  View details for Web of Science ID 000318143300081

  View details for PubMedID 23521224

• Multiplexed cytokine detection on plasmonic gold substrates with enhanced near-infrared fluorescence NANO RESEARCH Zhang, B., Price, J., Hong, G., Tabakman, S. M., Wang, H., Jarrell, J. A., Feng, J., Utz, P. J., Dai, H. 2013; 6 (2): 113-120

  View details for DOI 10.1007/s12274-012-0286-2

  View details for Web of Science ID 000314763300004

• An integrated Peptide-antigen microarray on plasmonic gold films for sensitive human antibody profiling. PloS one Zhang, B., Jarrell, J. A., Price, J. V., Tabakman, S. M., Li, Y., Gong, M., Hong, G., Feng, J., Utz, P. J., Dai, H. 2013; 8 (7): e71043

  Abstract

  High-throughput screening for interactions of peptides with a variety of antibody targets could greatly facilitate proteomic analysis for epitope mapping, enzyme profiling, drug discovery and biomarker identification. Peptide microarrays are suited for such undertaking because of their high-throughput capability. However, existing peptide microarrays lack the sensitivity needed for detecting low abundance proteins or low affinity peptide-protein interactions. This work presents a new peptide microarray platform constructed on nanostructured plasmonic gold substrates capable of metal enhanced NIR fluorescence enhancement (NIR-FE) by hundreds of folds for screening peptide-antibody interactions with ultrahigh sensitivity. Further, an integrated histone peptide and whole antigen array is developed on the same plasmonic gold chip for profiling human antibodies in the sera of systemic lupus erythematosus (SLE) patients, revealing that collectively a panel of biomarkers against unmodified and post-translationally modified histone peptides and several whole antigens allow more accurate differentiation of SLE patients from healthy individuals than profiling biomarkers against peptides or whole antigens alone.

  View details for DOI 10.1371/journal.pone.0071043

  View details for PubMedID 23923050

  View details for PubMedCentralID PMC3726620

• An integrated peptide-antigen microarray on plasmonic gold films for sensitive human antibody profiling. PloS one Zhang, B., Jarrell, J. A., Price, J. V., Tabakman, S. M., Li, Y., Gong, M., Hong, G., Feng, J., Utz, P. J., Dai, H. 2013; 8 (7)

  Abstract

  High-throughput screening for interactions of peptides with a variety of antibody targets could greatly facilitate proteomic analysis for epitope mapping, enzyme profiling, drug discovery and biomarker identification. Peptide microarrays are suited for such undertaking because of their high-throughput capability. However, existing peptide microarrays lack the sensitivity needed for detecting low abundance proteins or low affinity peptide-protein interactions. This work presents a new peptide microarray platform constructed on nanostructured plasmonic gold substrates capable of metal enhanced NIR fluorescence enhancement (NIR-FE) by hundreds of folds for screening peptide-antibody interactions with ultrahigh sensitivity. Further, an integrated histone peptide and whole antigen array is developed on the same plasmonic gold chip for profiling human antibodies in the sera of systemic lupus erythematosus (SLE) patients, revealing that collectively a panel of biomarkers against unmodified and post-translationally modified histone peptides and several whole antigens allow more accurate differentiation of SLE patients from healthy individuals than profiling biomarkers against peptides or whole antigens alone.

  View details for DOI 10.1371/journal.pone.0071043

  View details for PubMedID 23923050

• Advanced zinc-air batteries based on high-performance hybrid electrocatalysts. Nature communications Li, Y., Gong, M., Liang, Y., Feng, J., Kim, J., Wang, H., Hong, G., Zhang, B., Dai, H. 2013; 4: 1805-?

  Abstract

  Primary and rechargeable Zn-air batteries could be ideal energy storage devices with high energy and power density, high safety and economic viability. Active and durable electrocatalysts on the cathode side are required to catalyse oxygen reduction reaction during discharge and oxygen evolution reaction during charge for rechargeable batteries. Here we developed advanced primary and rechargeable Zn-air batteries with novel CoO/carbon nanotube hybrid oxygen reduction catalyst and Ni-Fe-layered double hydroxide oxygen evolution catalyst for the cathode. These catalysts exhibited higher catalytic activity and durability in concentrated alkaline electrolytes than precious metal Pt and Ir catalysts. The resulting primary Zn-air battery showed high discharge peak power density ~265 mW cm(-2), current density ~200 mA cm(-2) at 1 V and energy density >700 Wh kg(-1). Rechargeable Zn-air batteries in a tri-electrode configuration exhibited an unprecedented small charge-discharge voltage polarization of ~0.70 V at 20 mA cm(-2), high reversibility and stability over long charge and discharge cycles.

  View details for DOI 10.1038/ncomms2812

  View details for PubMedID 23651993

• Advanced zinc-air batteries based on high-performance hybrid electrocatalysts. Nature communications Li, Y., Gong, M., Liang, Y., Feng, J., Kim, J., Wang, H., Hong, G., Zhang, B., Dai, H. 2013; 4: 1805-?

  Abstract

  Primary and rechargeable Zn-air batteries could be ideal energy storage devices with high energy and power density, high safety and economic viability. Active and durable electrocatalysts on the cathode side are required to catalyse oxygen reduction reaction during discharge and oxygen evolution reaction during charge for rechargeable batteries. Here we developed advanced primary and rechargeable Zn-air batteries with novel CoO/carbon nanotube hybrid oxygen reduction catalyst and Ni-Fe-layered double hydroxide oxygen evolution catalyst for the cathode. These catalysts exhibited higher catalytic activity and durability in concentrated alkaline electrolytes than precious metal Pt and Ir catalysts. The resulting primary Zn-air battery showed high discharge peak power density ~265 mW cm(-2), current density ~200 mA cm(-2) at 1 V and energy density >700 Wh kg(-1). Rechargeable Zn-air batteries in a tri-electrode configuration exhibited an unprecedented small charge-discharge voltage polarization of ~0.70 V at 20 mA cm(-2), high reversibility and stability over long charge and discharge cycles.

  View details for DOI 10.1038/ncomms2812

  View details for PubMedID 23651993

• Multifunctional in vivo vascular imaging using near-infrared II fluorescence NATURE MEDICINE Hong, G., Lee, J. C., Robinson, J. T., Raaz, U., Xie, L., Huang, N. F., Cooke, J. P., Dai, H. 2012; 18 (12): 1841-?

  Abstract

  In vivo real-time epifluorescence imaging of mouse hind limb vasculatures in the second near-infrared region (NIR-II) is performed using single-walled carbon nanotubes as fluorophores. Both high spatial (∼30 μm) and temporal (<200 ms per frame) resolution for small-vessel imaging are achieved at 1-3 mm deep in the hind limb owing to the beneficial NIR-II optical window that affords deep anatomical penetration and low scattering. This spatial resolution is unattainable by traditional NIR imaging (NIR-I) or microscopic computed tomography, and the temporal resolution far exceeds scanning microscopic imaging techniques. Arterial and venous vessels are unambiguously differentiated using a dynamic contrast-enhanced NIR-II imaging technique on the basis of their distinct hemodynamics. Further, the deep tissue penetration and high spatial and temporal resolution of NIR-II imaging allow for precise quantifications of blood velocity in both normal and ischemic femoral arteries, which are beyond the capabilities of ultrasonography at lower blood velocities.

  View details for DOI 10.1038/nm.2995

  View details for PubMedID 23160236

• Chirality Enriched (12,1) and (11,3) Single-Walled Carbon Nanotubes for Biological Imaging JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Diao, S., Hong, G., Robinson, J. T., Jiao, L., Antaris, A. L., Wu, J. Z., Choi, C. L., Dai, H. 2012; 134 (41): 16971-16974

  Abstract

  The intrinsic band gap photoluminescence of semiconducting single-walled carbon nanotubes (SWNTs) makes them promising biological imaging probes in the second near-infrared (NIR-II, 1.0-1.4 μm) window. Thus far, SWNTs used for biological applications have been a complex mixture of metallic and semiconducting species with random chiralities, preventing simultaneous resonant excitation of all semiconducting nanotubes and emission at a single well-defined wavelength. Here, we developed a simple gel filtration method to enrich semiconducting (12,1) and (11,3) SWNTs with identical resonance absorption at ~808 nm and emission near ~1200 nm. The chirality sorted SWNTs showed ~5-fold higher photoluminescence intensity under resonant excitation of 808 nm than unsorted SWNTs on a per-mass basis. Real-time in vivo video imaging of whole mouse body and tumor vessels was achieved using a ~6-fold lower injected dose of (12,1) and (11,3) SWNTs (~3 μg per mouse or ~0.16 mg/kg of body weight vs 1.0 mg/kg for unsorted SWNTs) than a previous heterogeneous mixture, demonstrating the first resonantly excited and chirality separated SWNTs for biological imaging.

  View details for DOI 10.1021/ja307966u

  View details for Web of Science ID 000309854700014

  View details for PubMedID 23033937

• Oxygen Reduction Electrocatalyst Based on Strongly Coupled Cobalt Oxide Nanocrystals and Carbon Nanotubes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Liang, Y., Wang, H., Diao, P., Chang, W., Hong, G., Li, Y., Gong, M., Xie, L., Zhou, J., Wang, J., Regier, T. Z., Wei, F., Dai, H. 2012; 134 (38): 15849-15857

  Abstract

  Electrocatalyst for oxygen reduction reaction (ORR) is crucial for a variety of renewable energy applications and energy-intensive industries. The design and synthesis of highly active ORR catalysts with strong durability at low cost is extremely desirable but remains challenging. Here, we used a simple two-step method to synthesize cobalt oxide/carbon nanotube (CNT) strongly coupled hybrid as efficient ORR catalyst by directly growing nanocrystals on oxidized multiwalled CNTs. The mildly oxidized CNTs provided functional groups on the outer walls to nucleate and anchor nanocrystals, while retaining intact inner walls for highly conducting network. Cobalt oxide was in the form of CoO due to a gas-phase annealing step in NH(3). The resulting CoO/nitrogen-doped CNT (NCNT) hybrid showed high ORR current density that outperformed Co(3)O(4)/graphene hybrid and commercial Pt/C catalyst at medium overpotential, mainly through a 4e reduction pathway. The metal oxide/carbon nanotube hybrid was found to be advantageous over the graphene counterpart in terms of active sites and charge transport. Last, the CoO/NCNT hybrid showed high ORR activity and stability under a highly corrosive condition of 10 M NaOH at 80 °C, demonstrating the potential of strongly coupled inorganic/nanocarbon hybrid as a novel catalyst system in oxygen depolarized cathode for chlor-alkali electrolysis.

  View details for DOI 10.1021/ja305623m

  View details for PubMedID 22957510

• In Vivo Fluorescence Imaging in the Second Near-Infrared Window with Long Circulating Carbon Nanotubes Capable of Ultrahigh Tumor Uptake JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Robinson, J. T., Hong, G., Liang, Y., Zhang, B., Yaghi, O. K., Dai, H. 2012; 134 (25): 10664-10669

  Abstract

  Cancer imaging requires selective high accumulation of contrast agents in the tumor region and correspondingly low uptake in healthy tissues. Here, by making use of a novel synthetic polymer to solubilize single-walled carbon nanotubes (SWNTs), we prepared a well-functionalized SWNT formulation with long blood circulation (half-life of ∼30 h) in vivo to achieve ultrahigh accumulation of ∼30% injected dose (ID)/g in 4T1 murine breast tumors in Balb/c mice. Functionalization dependent blood circulation and tumor uptake were investigated through comparisons with phospholipid-PEG solubilized SWNTs. For the first time, we performed video-rate imaging of tumors based on the intrinsic fluorescence of SWNTs in the second near-infrared (NIR-II, 1.1-1.4 μm) window. We carried out dynamic contrast imaging through principal component analysis (PCA) to immediately pinpoint the tumor within ∼20 s after injection. Imaging over time revealed increasing tumor contrast up to 72 h after injection, allowing for its unambiguous identification. The 3D reconstruction of the SWNTs distribution based on their stable photoluminescence inside the tumor revealed a high degree of colocalization of SWNTs and blood vessels, suggesting enhanced permeability and retention (EPR) effect as the main cause of high passive tumor uptake of the nanotubes.

  View details for DOI 10.1021/ja303737a

  View details for Web of Science ID 000305716700052

  View details for PubMedID 22667448

  View details for PubMedCentralID PMC3471786

• Short channel field-effect transistors from highly enriched semiconducting carbon nanotubes NANO RESEARCH Wu, J., Xie, L., Hong, G., Lim, H. E., Thendie, B., Miyata, Y., Shinohara, H., Dai, H. 2012; 5 (6): 388-394

  View details for DOI 10.1007/s12274-012-0219-0

  View details for Web of Science ID 000305529900002

• Ag2S Quantum Dot: A Bright and Biocompatible Fluorescent Nanoprobe in the Second Near-Infrared Window ACS NANO Zhang, Y., Hong, G., Zhang, Y., Chen, G., Li, F., Dai, H., Wang, Q. 2012; 6 (5): 3695-3702

  Abstract

  Ag(2)S quantum dots (QDs) emitting in the second near-infrared region (NIR-II, 1.0-1.4 μm) are demonstrated as a promising fluorescent probe with both bright photoluminescence and high biocompatibility for the first time. Highly selective in vitro targeting and imaging of different cell lines are achieved using biocompatible NIR-II Ag(2)S QDs with different targeting ligands. The cytotoxicity study illustrates the Ag(2)S QDs with negligible effects in altering cell proliferation, triggering apoptosis and necrosis, generating reactive oxygen species, and causing DNA damage. Our results have opened up the possibilities of using these biocompatible Ag(2)S QDs for in vivo anatomical imaging and early stage tumor diagnosis with deep tissue penetration, high sensitivity, and elevated spatial and temporal resolution owing to their high emission efficiency in the unique NIR-II imaging window.

  View details for DOI 10.1021/nn301218z

  View details for Web of Science ID 000304231700007

  View details for PubMedID 22515909

  View details for PubMedCentralID PMC3358570

• Three-dimensional imaging of single nanotube molecule endocytosis on plasmonic substrates NATURE COMMUNICATIONS Hong, G., Wu, J. Z., Robinson, J. T., Wang, H., Zhang, B., Dai, H. 2012; 3

  Abstract

  Investigating the cellular internalization pathways of single molecules or single nano objects is important to understanding cell-matter interactions, and to applications in drug delivery and discovery. Imaging and tracking the motion of single molecules on cell plasma membranes require high spatial resolution in three dimensions. Fluorescence imaging along the axial dimension with nanometre resolution has been highly challenging, but critical to revealing displacements in transmembrane events. Here, utilizing a plasmonic ruler based on the sensitive distance dependence of near-infrared fluorescence enhancement of carbon nanotubes on a gold plasmonic substrate, we probe ~10 nm scale transmembrane displacements through changes in nanotube fluorescence intensity, enabling observations of single nanotube endocytosis in three dimensions. Cellular uptake and transmembrane displacements show clear dependences to temperature and clathrin assembly on cell membrane, suggesting that the cellular entry mechanism for a nanotube molecule is via clathrin-dependent endocytosis through the formation of clathrin-coated pits on the cell membrane.

  View details for DOI 10.1038/ncomms1698

  View details for PubMedID 22426221

• Graphite-Coated Magnetic Nanoparticle Microarray for Few-Cells Enrichment and Detection ACS NANO Chen, Z., Hong, G., Wang, H., Welsher, K., Tabakman, S. M., Sherlock, S. P., Robinson, J. T., Liang, Y., Dai, H. 2012; 6 (2): 1094-1101

  Abstract

  Graphite-coated, highly magnetic FeCo core-shell nanoparticles were synthesized by a chemical vapor deposition method and solubilized in aqueous solution through a unique polymer mixture modification, which significantly improved the biocompatibility and stability of the magnetic nanoparticles (MNPs). Such functionalized MNPs were proven to be very stable in different conditions which would be significant for biological applications. Cell staining, manipulation, enrichment, and detection were developed with these MNPs. Under external magnetic manipulation, the MNP-stained cells exhibited directed motions. Moreover, MNPs were printed on substrates to modulate the magnetic field distribution on the surface. Capture and detection of sparse populations of cancer cells spiked into whole blood has been explored in a microarray fashion. Cancer cells from hundreds down to only two were able to be simply and efficiently detected from 1 mL of whole blood on the MNP microarray chips. Interestingly, the cells captured through the MNP microarray still showed viability and adhered to the MNP spots after incubation, which could be utilized for cancer cell detection, localized growth, and proliferation.

  View details for DOI 10.1021/nn2034692

  View details for Web of Science ID 000300757900013

  View details for PubMedID 22229344

• In Vivo Fluorescence Imaging with Ag2S Quantum Dots in the Second Near-Infrared Region ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Hong, G., Robinson, J. T., Zhang, Y., Diao, S., Antaris, A. L., Wang, Q., Dai, H. 2012; 51 (39): 9818-9821

  Abstract

  Hits the dot: Ag(2)S quantum dots (QDs) with bright near-infrared-II fluorescence emission (around 1200 nm) and six-arm branched PEG surface coating were synthesized for in vivo small-animal imaging. The 6PEG-Ag(2)S QDs afforded a tumor uptake of approximately 10 % injected dose/gram, owing to a long circulation half-life of approximately 4 h. Clearance of the injected 6PEG-Ag(2)S QDs occurs mainly through the biliary pathway in mice.

  View details for DOI 10.1002/anie.201206059

  View details for Web of Science ID 000308886800018

  View details for PubMedID 22951900

• Metal enhanced fluorescence of carbon nanotubes: Observation and application in enhanced cell imaging 242nd National Meeting of the American-Chemical-Society (ACS) Hong, G. AMER CHEMICAL SOC. 2011

  View details for Web of Science ID 000299378301821

• MoS2 Nanoparticles Grown on Graphene: An Advanced Catalyst for the Hydrogen Evolution Reaction JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Li, Y., Wang, H., Xie, L., Liang, Y., Hong, G., Dai, H. 2011; 133 (19): 7296-7299

  Abstract

  Advanced materials for electrocatalytic and photoelectrochemical water splitting are central to the area of renewable energy. In this work, we developed a selective solvothermal synthesis of MoS(2) nanoparticles on reduced graphene oxide (RGO) sheets suspended in solution. The resulting MoS(2)/RGO hybrid material possessed nanoscopic few-layer MoS(2) structures with an abundance of exposed edges stacked onto graphene, in strong contrast to large aggregated MoS(2) particles grown freely in solution without GO. The MoS(2)/RGO hybrid exhibited superior electrocatalytic activity in the hydrogen evolution reaction (HER) relative to other MoS(2) catalysts. A Tafel slope of ∼41 mV/decade was measured for MoS(2) catalysts in the HER for the first time; this exceeds by far the activity of previous MoS(2) catalysts and results from the abundance of catalytic edge sites on the MoS(2) nanoparticles and the excellent electrical coupling to the underlying graphene network. The ∼41 mV/decade Tafel slope suggested the Volmer-Heyrovsky mechanism for the MoS(2)-catalyzed HER, with electrochemical desorption of hydrogen as the rate-limiting step.

  View details for DOI 10.1021/ja201269b

  View details for PubMedID 21510646

• Near-Infrared-Fluorescence-Enhanced Molecular Imaging of Live Cells on Gold Substrates ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Hong, G., Tabakman, S. M., Welsher, K., Chen, Z., Robinson, J. T., Wang, H., Zhang, B., Dai, H. 2011; 50 (20): 4644-4648

  View details for DOI 10.1002/anie.201100934

  View details for PubMedID 21506225

• Biomimetic morphogenesis of micropottery: helical coiling of mesostructured silica nanofibers SOFT MATTER Zhou, L., Ye, J., Hong, G., Qi, L. 2011; 7 (20): 9624–27

  View details for DOI 10.1039/c1sm05593c

  View details for Web of Science ID 000295582000011

• LiMn1-xFexPO4 Nanorods Grown on Graphene Sheets for Ultrahigh-Rate-Performance Lithium Ion Batteries ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Wang, H., Yang, Y., Liang, Y., Cui, L., Casalongue, H. S., Li, Y., Hong, G., Cui, Y., Dai, H. 2011; 50 (32): 7364-7368

  View details for DOI 10.1002/anie.201103163

  View details for PubMedID 21710671

• Optical Properties of Single-Walled Carbon Nanotubes Separated in a Density Gradient: Length, Bundling, and Aromatic Stacking Effects JOURNAL OF PHYSICAL CHEMISTRY C Tabakman, S. M., Welsher, K., Hong, G., Dai, H. 2010; 114 (46): 19569-19575

  Abstract

  Single-walled carbon nanotubes (SWNTs) are promising materials for in vitro and in vivo biological applications due to their high surface area and inherent near infrared photoluminescence and Raman scattering properties. Here, we use density gradient centrifugation to separate SWNTs by length and degree of bundling. Following separation, we observe a peak in photoluminescence quantum yield (PL QY) and Raman scattering intensity where SWNT length is maximized and bundling is minimized. Individualized SWNTs are found to exhibit high PL QY and high resonance-enhanced Raman scattering intensity. Fractions containing long, individual SWNTs exhibit the highest PL QY and Raman scattering intensities, compared to fractions containing single, short SWNTs or SWNT bundles. Intensity gains of approximately ~1.7 and 4-fold, respectively, are obtained compared with the starting material. Spectroscopic analysis reveals that SWNT fractions at higher displacement contain increasing proportions of SWNT bundles, which causes reduced optical transition energies and broadening of absorption features in the UV-Vis-NIR spectra, and reduced PL QY and Raman scattering intensity. Finally, we adsorb small aromatic species on "bright," individualized SWNT sidewalls and compare the resulting absorption, PL and Raman scattering effects to that of SWNT bundles. We observe similar effects in both cases, suggesting aromatic stacking affects the optical properties of SWNTs in an analogous way to SWNT bundles, likely due to electronic structure perturbations, charge transfer, and dielectric screening effects, resulting in reduction of the excitonic optical transition energies and exciton lifetimes.

  View details for DOI 10.1021/jp106453v

  View details for Web of Science ID 000284287900003

  View details for PubMedCentralID PMC3023917

• Metal-Enhanced Fluorescence of Carbon Nanotubes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hong, G., Tabakman, S. M., Welsher, K., Wang, H., Wang, X., Dai, H. 2010; 132 (45): 15920-15923

  Abstract

  The photoluminescence (PL) quantum yield of single-walled carbon nanotubes (SWNTs) is relatively low, with various quenching effects by metallic species reported in the literature. Here, we report the first case of metal enhanced fluorescence (MEF) of surfactant-coated carbon nanotubes on nanostructured gold substrates. The photoluminescence quantum yield of SWNTs is observed to be enhanced more than 10-fold. The dependence of fluorescence enhancement on metal-nanotube distance and on the surface plasmon resonance (SPR) of the gold substrate for various SWNT chiralities is measured to reveal the mechanism of enhancement. Surfactant-coated SWNTs in direct contact with metal exhibit strong MEF without quenching, suggesting a small quenching distance for SWNTs on the order of the van der Waals distance, beyond which the intrinsically fast nonradiative decay rate in nanotubes is little enhanced by metal. The metal enhanced fluorescence of SWNTs is attributed to radiative lifetime shortening through resonance coupling of SWNT emission to the reradiating dipolar plasmonic modes in the metal.

  View details for DOI 10.1021/ja1087997

  View details for PubMedID 20979398

• Facile Fabrication of Two-Dimensionally Ordered Macroporous Silver Thin Films and Their Application in Molecular Sensing ADVANCED FUNCTIONAL MATERIALS Hong, G., Li, C., Qi, L. 2010; 20 (21): 3774–83

  View details for DOI 10.1002/adfm.201001177

  View details for Web of Science ID 000283999900020

• Optical Properties of Single-Walled Carbon Nanotubes Separated in a Density Gradient; Length, Bundling, and Aromatic Stacking Effects. The journal of physical chemistry. C, Nanomaterials and interfaces Tabakman, S. M., Welsher, K., Hong, G., Dai, H. 2010; 114 (46): 19569-19575

  Abstract

  Single-walled carbon nanotubes (SWNTs) are promising materials for in vitro and in vivo biological applications due to their high surface area and inherent near infrared photoluminescence and Raman scattering properties. Here, we use density gradient centrifugation to separate SWNTs by length and degree of bundling. Following separation, we observe a peak in photoluminescence quantum yield (PL QY) and Raman scattering intensity where SWNT length is maximized and bundling is minimized. Individualized SWNTs are found to exhibit high PL QY and high resonance-enhanced Raman scattering intensity. Fractions containing long, individual SWNTs exhibit the highest PL QY and Raman scattering intensities, compared to fractions containing single, short SWNTs or SWNT bundles. Intensity gains of approximately ~1.7 and 4-fold, respectively, are obtained compared with the starting material. Spectroscopic analysis reveals that SWNT fractions at higher displacement contain increasing proportions of SWNT bundles, which causes reduced optical transition energies and broadening of absorption features in the UV-Vis-NIR spectra, and reduced PL QY and Raman scattering intensity. Finally, we adsorb small aromatic species on "bright," individualized SWNT sidewalls and compare the resulting absorption, PL and Raman scattering effects to that of SWNT bundles. We observe similar effects in both cases, suggesting aromatic stacking affects the optical properties of SWNTs in an analogous way to SWNT bundles, likely due to electronic structure perturbations, charge transfer, and dielectric screening effects, resulting in reduction of the excitonic optical transition energies and exciton lifetimes.

  View details for DOI 10.1021/jp106453v

  View details for PubMedID 21258607

  View details for PubMedCentralID PMC3023917

• Facile Fabrication of Honeycomb-Patterned Thin Films of Amorphous Calcium Carbonate and Mosaic Calcite CHEMISTRY OF MATERIALS Li, C., Hong, G., Yu, H., Qi, L. 2010; 22 (10): 3206–11

  View details for DOI 10.1021/cm100363a

  View details for Web of Science ID 000277635000025

• Nanosphere Lithography at the Gas/Liquid Interface: A General Approach toward Free-Standing High-Quality Nanonets CHEMISTRY OF MATERIALS Li, C., Hong, G., Qi, L. 2010; 22 (2): 476–81

  View details for DOI 10.1021/cm9031946

  View details for Web of Science ID 000273580700026

• Seeding-Growth of Helical Mesoporous Silica Nanofibers Templated by Achiral Cationic Surfactant LANGMUIR Zhou, L., Hong, G., Qi, L., Lu, Y. 2009; 25 (11): 6040–44

  Abstract

  Helical mesoporous silica nanofibers with parallel nanochannels were synthesized in high yield via a novel seeding-growth method by using the achiral cationic surfactant cetyltrimethylammonium bromide (CTAB) as template without auxiliary additives. A general entropy-driven model taking into account the icelike structure water due to the hydrophobic effect was proposed to explain the formation of helical mesoporous silica nanofibers. It was indicated that helical silica mesostructures could result from a thick layer of highly ordered icelike water around thin silicate seed rods with a proper concentration, which was verified by the effect of various anions and organic additives on the formation of helical mesoporous silica.

  View details for DOI 10.1021/la901083u

  View details for Web of Science ID 000266604000009

  View details for PubMedID 19425562

• Wet Chemical Approaches to Patterned Arrays of Well-Aligned ZnO Nanopillars Assisted by Monolayer Colloidal Crystals CHEMISTRY OF MATERIALS Li, C., Hong, G., Wang, P., Yu, D., Qi, L. 2009; 21 (5): 891–97

  View details for DOI 10.1021/cm802839u

  View details for Web of Science ID 000263891700016