Xuandi Hou
Postdoctoral Scholar, Materials Science and Engineering
Bio
Xuandi Hou's research focuses on integrating nanotools and physical stimuli to gain insights into neural circuits and achieve precise remote manipulation of neural activity. His ultimate aspiration is to develop comprehensive toolkits that facilitate the exploration of the biophysical mechanisms underlying non-invasive transcranial ultrasound brain stimulation, offering applications in both neuroscience and neurology.
Professional Education
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Doctor of Philosophy, Hong Kong Polytechnic University (2022)
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Postdoc fellow, Hong Kong Polytechnic University, Biomedical Engineering (2024)
All Publications
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Impact of endogenous sonosensation on in vivo sonogenetics.
iScience
2025; 28 (12): 114030
Abstract
Sonogenetics is a promising paradigm that uses non-invasive ultrasound to modulate neurons expressing sonosensitive proteins. However, the brain's varying endogenous sonosensitivity presents a challenge for its precise application. We first mapped this intrinsic sensitivity, identifying the somatosensory cortex as particularly responsive. Using an MscL-G22S-based approach in the somatosensory cortex, we found that ultrasound non-specifically activated both excitatory and inhibitory neurons in control mice, preventing behavioral output. In contrast, in MscL-expressing mice, ultrasound selectively activated excitatory neurons while suppressing inhibitory ones, thereby shifting the net neural response to successfully drive whisker movement. This effect was independent of auditory confounds or astrocytic involvement. Our study highlights that accounting for endogenous sonosensitivity is critical and demonstrates that optimized sonogenetic tools can achieve precise neuromodulation despite this inherent challenge.
View details for DOI 10.1016/j.isci.2025.114030
View details for PubMedID 41377656
View details for PubMedCentralID PMC12688701
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Precise modulation of cell activity using sono-responsive nano-transducers.
Biomaterials
2025; 314: 122857
Abstract
Ultrasound, as a form of mechanical energy, possesses a distinctive ability to deeply penetrate tissues, allowing for non-invasive manipulation of cellular activities. Utilizing nanomaterials in conjunction with ultrasound has enabled simple, efficient, spatiotemporally controllable, and minimally invasive regulation of cellular activities with ultrasound-generated electric, optical, acoustic, or chemical stimuli at the localized nanomaterials interface. This technology allows for precise and localized regulation of cellular activities, which is essential for studying and understanding complex biological processes, and also provides new opportunities for research, diagnostics, and therapeutics in the fields of biology and medicine. In this article, we review the state-of-the-art and ongoing developments in nanomaterials-enabled ultrasound cellular modulation, highlighting potential applications and advancements achieved through the integration of sono-responsive nanomaterials with ultrasound.
View details for DOI 10.1016/j.biomaterials.2024.122857
View details for PubMedID 39357155
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Nanobubble-actuated ultrasound neuromodulation for selectively shaping behavior in mice.
Nature communications
2024; 15 (1): 2253
Abstract
Ultrasound is an acoustic wave which can noninvasively penetrate the skull to deep brain regions, enabling neuromodulation. However, conventional ultrasound's spatial resolution is diffraction-limited and low-precision. Here, we report acoustic nanobubble-mediated ultrasound stimulation capable of localizing ultrasound's effects to only the desired brain region in male mice. By varying the delivery site of nanobubbles, ultrasound could activate specific regions of the mouse motor cortex, evoking EMG signaling and limb movement, and could also, separately, activate one of two nearby deep brain regions to elicit distinct behaviors (freezing or rotation). Sonicated neurons displayed reversible, low-latency calcium responses and increased c-Fos expression in the sub-millimeter-scale region with nanobubbles present. Ultrasound stimulation of the relevant region also modified depression-like behavior in a mouse model. We also provide evidence of a role for mechanosensitive ion channels. Altogether, our treatment scheme allows spatially-targetable, repeatable and temporally-precise activation of deep brain circuits for neuromodulation without needing genetic modification.
View details for DOI 10.1038/s41467-024-46461-y
View details for PubMedID 38480733
View details for PubMedCentralID PMC10937988
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Tracking adoptive natural killer cells via ultrasound imaging assisted with nanobubbles
ACTA BIOMATERIALIA
2023; 169: 542-555
Abstract
The recent years has witnessed an exponential growth in the field of natural killer (NK) cell-based immunotherapy for cancer treatment. As a prerequisite to precise evaluations and on-demand interventions, the noninvasive tracking of adoptive NK cells plays a crucial role not only in post-treatment monitoring, but also in offering opportunities for preclinical studies on therapy optimizations. Here, we describe an NK cell tracking strategy for cancer immunotherapy based on ultrasound imaging modality. Nanosized ultrasound contrast agents, gas vesicles (GVs), were surface-functionalized to label NK cells. Unlike traditional microbubble contrast agents, nanosized GVs with their unique thermodynamical stability enable the detection of labeled NK cells under nonlinear contrast-enhanced ultrasound (nCEUS), without a noticeable impact on cellular viability or migration. By such labeling, we were able to monitor the trafficking of systematically infused NK cells to a subcutaneous tumor model. Upon co-treatment with interleukin (IL)-2, we observed a rapid enhancement in NK cell trafficking at the tumor site as early as 3 h post-infusion. Altogether, we show that the proposed ultrasound-based tracking strategy is able to capture the dynamical changes of cell trafficking in NK cell-based immunotherapy, providing referencing information for early-phase monotherapy evaluation, as well as understanding the effects of modulatory co-treatment. STATEMENT OF SIGNIFICANCE: In cellular immunotherapies, the post-infusion monitoring of the living therapeutics has been challenging. Several popular imaging modalities have been explored the monitoring of the adoptive immune cells, evaluating their trafficking and accumulation in the tumor. Here we demonstrated, for the first time, the ultrasound imaging-based immune cell tracking strategy. We showed that the acoustic labeling of adoptive immune cells was feasible with nanosized ultrasound contrast agents, overcoming the size and stability limitations of traditional microbubbles, enabling dynamical tracking of adoptive natural killer cells in both monotherapy and synergic treatment with cytokines. This article introduced the cost-effective and ubiquitous ultrasound imaging modality into the field of cellular immunotherapies, with broad prospectives in early assessment and on-demand image-guided interventions.
View details for DOI 10.1016/j.actbio.2023.07.058
View details for Web of Science ID 001079728400001
View details for PubMedID 37536495
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Modulation of deep neural circuits with sonogenetics
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2023; 120 (22): e2220575120
Abstract
Noninvasive control of neuronal activity in the deep brain can be illuminating for probing brain function and treating dysfunctions. Here, we present a sonogenetic approach for controlling distinct mouse behavior with circuit specificity and subsecond temporal resolution. Targeted neurons in subcortical regions were made to express a mutant large conductance mechanosensitive ion channel (MscL-G22S), enabling ultrasound to trigger activity in MscL-expressing neurons in the dorsal striatum and increase locomotion in freely moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. Moreover, sonogenetic stimulation of the subthalamic nuclei of Parkinson's disease model mice improved their motor coordination and mobile time. Neuronal responses to ultrasound pulse trains were rapid, reversible, and repeatable. We also confirmed that the MscL-G22S mutant is more effective to sensitize neurons to ultrasound compared to the wild-type MscL. Altogether, we lay out a sonogenetic approach which can selectively manipulate targeted cells to activate defined neural pathways, affect specific behaviors, and relieve symptoms of neurodegenerative disease.
View details for DOI 10.1073/pnas.2220575120
View details for Web of Science ID 001038068000004
View details for PubMedID 37216521
View details for PubMedCentralID PMC10235981
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The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation.
Proceedings of the National Academy of Sciences of the United States of America
2023; 120 (18): e2300291120
Abstract
Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.
View details for DOI 10.1073/pnas.2300291120
View details for PubMedID 37098060
View details for PubMedCentralID PMC10161134
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Photonic Nanojet-Mediated Optogenetics
ADVANCED SCIENCE
2022; 9 (12): e2104140
Abstract
Optogenetics has become a widely used technique in neuroscience research, capable of controlling neuronal activity with high spatiotemporal precision and cell-type specificity. Expressing exogenous opsins in the selected cells can induce neuronal activation upon light irradiation, and the activation depends on the power of incident light. However, high optical power can also lead to off-target neuronal activation or even cell damage. Limiting the incident power, but enhancing power distribution to the targeted neurons, can improve optogenetic efficiency and reduce off-target effects. Here, the use of optical lenses made of polystyrene microspheres is demonstrated to achieve effective focusing of the incident light of relatively low power to neighboring neurons via photonic jets. The presence of microspheres significantly localizes and enhances the power density to the target neurons both in vitro and ex vivo, resulting in increased inward current and evoked action potentials. In vivo results show optogenetic stimulation with microspheres that can evoke significantly more motor behavior and neuronal activation at lowered power density. In all, a proof-of-concept of a strategy is demonstrated to increase the efficacy of optogenetic neuromodulation using pulses of reduced optical power.
View details for DOI 10.1002/advs.202104140
View details for Web of Science ID 000758089000001
View details for PubMedID 35187865
View details for PubMedCentralID PMC9036029
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Gas-filled protein nanostructures as cavitation nuclei for molecule-specific sonodynamic therapy.
Acta biomaterialia
2021; 136: 533-545
Abstract
Sonodynamic therapy (SDT) is a promising alternative for cancer therapy, understood to exert cytotoxicity through cavitation and subsequent production of large amounts of reactive oxygen species (ROS). Gas-filled protein nanostructures (gas vesicles or GVs) produced by cyanobacteria have a hollow structure similar to microbubbles and have demonstrated comparable enhancement of ultrasound imaging contrast. We thus hypothesized that GVs may act as stable nuclei for inertial cavitation to enhance SDT with improved enhanced permeability and retention (EPR) effects due to their nanometer scale. The function of GVs to mediate cavitation, ROS production, and cell-targeted toxicity under SDT was determined. In solution, we found that GVs successfully increased cavitation and enhanced ROS production in a dose- and time-dependent manner. Then, GV surfaces were modified (FGVs) to specifically target CD44+ cells and accumulate preferentially at the tumor site. In vitro sonodynamic therapy (SDT) showed ROS production and tumor cell toxicity substantially elevated in the presence of FGVs, and the addition of FGVs was found to enhance cavitation and subsequently inhibit tumor growth and exert greater damage to tumors under SDT in vivo. Our results thus demonstrate that FGVs can function as stable, nanosized, nuclei for spatially accurate and cell-targeted SDT. STATEMENT OF SIGNIFICANCE: The initiation of inertial cavitation is critical for ROS generation and subsequent cellular toxicity in SDT. Thus, precise control of the occurrence of cavitation is a key factor in increasing SDT's therapeutic efficacy. We explored nanometer-sized gas vesicles (GVs) as a new class of cavitation nuclei for molecule-specific sonodynamic therapy. Our results showed that GV-mediated SDT treatment enabled targeted disruption of specific cells expressing a known surface marker within the area of insonation, providing a spatially specific and targeted SDT treatment.
View details for DOI 10.1016/j.actbio.2021.09.010
View details for PubMedID 34530143
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Protocol for the sonogenetic stimulation of mouse brain by non-invasive ultrasound
STAR PROTOCOLS
2021; 2 (2): 100393
Abstract
Manipulating specific neural activity by targeted ultrasound intervention is a powerful method to gain causal insight into brain functions and treat brain disorders. The technique of sonogenetics enables controlling of cells that are genetically modulated with ultrasound-sensitive ion channels. Here, we detail the preparations, surgical procedures, ultrasound stimulation process, and simultaneous electromyogram (EMG) measurement necessary for successful sonogenetic stimulation in mice. For complete details on the use and execution of this protocol, please refer to Qiu et al. (2020).
View details for DOI 10.1016/j.xpro.2021.100393
View details for Web of Science ID 001049637900012
View details for PubMedID 33796870
View details for PubMedCentralID PMC7995654
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Precise Ultrasound Neuromodulation in a Deep Brain Region Using Nano Gas Vesicles as Actuators.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
2021: e2101934
Abstract
Ultrasound is a promising new modality for non-invasive neuromodulation. Applied transcranially, it can be focused down to the millimeter or centimeter range. The ability to improve the treatment's spatial resolution to a targeted brain region could help to improve its effectiveness, depending upon the application. The present paper details a neurostimulation scheme using gas-filled nanostructures, gas vesicles (GVs), as actuators for improving the efficacy and precision of ultrasound stimuli. Sonicated primary neurons display dose-dependent, repeatable Ca2+ responses, closely synced to stimuli, and increased nuclear expression of the activation marker c-Fos in the presence of GVs. GV-mediated ultrasound triggered rapid and reversible Ca2+ responses in vivo and could selectively evoke neuronal activation in a deep-seated brain region. Further investigation indicate that mechanosensitive ion channels are important mediators of this effect. GVs themselves and the treatment scheme are also found not to induce significant cytotoxicity, apoptosis, or membrane poration in treated cells. Altogether, this study demonstrates a simple and effective method to achieve enhanced and better-targeted neurostimulation with non-invasive low-intensity ultrasound.
View details for DOI 10.1002/advs.202101934
View details for PubMedID 34546652
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Targeted Neurostimulation in Mouse Brains with Non-invasive Ultrasound
CELL REPORTS
2020; 32 (7): 108033
Abstract
Recently developed brain stimulation techniques have significantly advanced our ability to manipulate the brain's function. However, stimulating specific neurons in a desired region without significant surgical invasion remains a challenge. Here, we demonstrate a neuron-specific and region-targeted neural excitation strategy using non-invasive ultrasound through activation of heterologously expressed mechanosensitive ion channels (MscL-G22S). Low-intensity ultrasound is significantly better at inducing Ca2+ influx and neuron activation in vitro and at evoking electromyogram (EMG) responses in vivo in targeted cells expressing MscL-G22S. Neurons in the cerebral cortex or dorsomedial striatum of mice are made to express MscL-G22S and stimulated ultrasonically. We find significant upregulation of c-Fos in neuron nuclei only in the regions expressing MscL-G22S compared with the non-MscL controls, as well as in various other regions in the same brain. Thus, we detail an effective approach for activating specific regions and cell types in intact mouse brains by sensitizing them to ultrasound using a mechanosensitive ion channel.
View details for DOI 10.1016/j.celrep.2020.108033
View details for Web of Science ID 000561274200006
View details for PubMedID 32814040
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Biogenic nanobubbles for effective oxygen delivery and enhanced photodynamic therapy of cancer.
Acta biomaterialia
2020
Abstract
Tumor hypoxia is believed to be a factor limiting successful outcomes of oxygen-consuming cancer therapy, thereby reducing patient survival. A key strategy to overcome tumor hypoxia is to increase the prevalence of oxygen at the tumor site. Oxygen-containing microbubbles/nanobubbles have been developed to supply oxygen and enhance the effects of therapies such as radiotherapy and photodynamic therapy. However, the application of these bubbles is constrained by their poor stability, requiring major workarounds to increase their half-lives. In this study, we explore the potential of biogenic gas vesicles (GVs) as a new kind of oxygen carrier to alleviate tumor hypoxia. GVs, which are naturally formed, gas-filled, protein-shelled compartments, were modified on the surface of their protein shells by a layer of liposome. A substantial improvement of oxygen concentration was observed in hypoxic solution, in hypoxic cells, as well as in subcutaneous tumors when lipid-GVs(O2) were added/tail-injected. Significant enhancement of tumor cell apoptosis and necrosis was also observed during photodynamic therapy (PDT) in the presence of lipid-GVs(O2) both in vitro and in vivo. Lipid-GVs(O2) alone induced no obvious change in cell viability in vitro or any apparent pathological abnormalities after mice were tail-injected with them. In all, lipid-GVs exhibited promising performance for intravenous gas delivery, enhanced PDT efficacy and low toxicity, a quality that may be applied to alleviate hypoxia in cancers, as well as hypoxia-related clinical treatments. STATEMENT OF SIGNIFICANCE: The development of stable oxygen-filled micro/nanobubbles capable of delivering oxygen to tumor sites is a major hurdle to enhancing the efficacy of cancer therapy. Currently, micro/nanobubbles are limited by their instability when oxygen is encapsulated, creating a large pressure gradient and surface tension. To improve stability, we modified the surfaces of GVs, a biogenic stable nanoscale hollow structure, as a new class of oxygen carriers. Lipid-coated GVs were found to be stable in solution and effective O2 carriers. This will overcome the limitations of coalescence, short circulation time of synthetic bubbles during application. Our surface-modified GVs demonstrated low toxicity in vitro cell in vivo, while also being able to overcome hypoxia-associated therapy resistance when combined with photodynamic therapy.
View details for DOI 10.1016/j.actbio.2020.03.034
View details for PubMedID 32268236
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Surface-modified GVs as nanosized contrast agents for molecular ultrasound imaging of tumor
BIOMATERIALS
2020; 236: 119803
Abstract
Nanobubbles, as a kind of new ultrasound contrast agent (UCAs), have shown promise to penetrate tumor vasculature to allow for targeted imaging. However, their inherent physical instability is an ongoing concern that could weaken their imaging ability with ultrasound. Gas vesicles (GVs), which are genetically encoded, naturally stable nanostructures, have been developed as the first ultrasonic biomolecular reporters which showed strong contrast enhancement. However, further development of tumor imaging with GVs is limited by the quick clearance of GVs by the reticuloendothelial system (RES). Here, we developed PEGylated HA-GVs (PH-GVs) for in-tumor molecular ultrasound imaging by integrating polyethylene glycol (PEG) and hyaluronic acid (HA) in GV shells. PH-GVs were observed to accumulate around CD44-positive cells (SCC7) but not be internalized by macrophage cell line RAW 264.7. Green fluorescence from PH-GVs was found around cell nuclei in the tumor site after 6 h and the signal was sustained over 48 h following tail injection, demonstrating PH-GVs' ability to escape the clearance from the RES and to penetrate tumor vasculature through enhanced permeability and retention (EPR) effects. Further, PH-GVs produced strong ultrasound contrast in the tumor site in vivo, with no obvious side-effects detected following intravenous injection. Thus, we demonstrate the potential of PH-GVs as novel, nanosized and targeted UCAs for efficient and specific molecular tumor imaging, paving the way for the application of GVs in precise and personalized medicine.
View details for DOI 10.1016/j.biomaterials.2020.119803
View details for Web of Science ID 000517849800005
View details for PubMedID 32028170
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Fluorescent magnetic PEI-PLGA nanoparticles loaded with paclitaxel for concurrent cell imaging, enhanced apoptosis and autophagy in human brain cancer
COLLOIDS AND SURFACES B-BIOINTERFACES
2018; 172: 708-717
Abstract
Magnetic nanoparticles are regarded as a promising drug delivery vehicle with the improved efficacy and lowered side effects for antitumor therapy. Herein, the poly lactic-co-glycolic acid (PLGA) modified magnetic nanoplatform was synthesized using superparamagnetic γ-Fe2O3 nanoparticles (MNPs) as a core, and then labelled with polyethylenimine (PEI)-conjugated fluorescein isothiocyanate (FITC), and simultaneously loaded with antitumor drug paclitaxel (PTX) for theranostic analysis of antitumor effects investigated in human brain glioblastoma U251 cells. As a result, the prepared PEI-PLGA-MNPs showed a relatively round sphere with an average size of 80 nm approximately, and the FITC-labeling PEI-PLGA-MNPs were efficiently endocytosed by the U251 cells for cellular imaging. Moreover, the fabricated PEI-PLGA-PTX-MNPs also demonstrated an inhibition of the targeted cell proliferation and migration, and a programmed cell death, via both apoptosis modulating by a burst of reactive oxygen species (ROS) and autophagy with accumulation of autophagosomes and LC3-II signals detected in the treated glioblastoma U251 cells after uptaking. Therefore, the constructed nanoplatform could be effectively applied for simultaneous cellular imaging and drug delivery in human brain glioblastoma treatment in future.
View details for DOI 10.1016/j.colsurfb.2018.09.033
View details for Web of Science ID 000455858500084
View details for PubMedID 30245296
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PINK1/Parkin-Mediated Mitophagy Promotes Resistance to Sonodynamic Therapy.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
2018; 49 (5): 1825-1839
Abstract
Sonodynamic therapy (SDT), based on the synergistic effect of low-intensity ultrasound and sonosensitizer, is a potential approach for non-invasive treatment of cancers. In SDT, mitochondria played a crucial role in cell fate determination. However, mitochondrial activities and their response to SDT remain elusive. The purpose of this study was to examine the response of mitochondria to SDT in tumor cells.A human breast adenocarcinoma cell line - MCF-7 cells were subjected to 5-aminolevulinic acid (ALA)-SDT, with an average ultrasonic intensity of 0.25W/cm2. Mitochondrial dynamics and redox balance were examined by confocal immunofluorescence microscopy and western blot. The occurrence of mitophagy was determined by confocal immunofluorescence microscopy.Our results showed that ALA-SDT could induce mitochondrial dysfunction through mitochondrial depolarization and fragmentation and lead to mitophagy. The Parkin-dependent signaling pathway was involved and promoted resistance to ALA-SDT induced cell death. Finally, excessive production of ROS was found to be necessary for the initiation of mitophagy.Taken together, we conclude that ROS produced by 5-ALA-SDT could initiate PINK1/Parkin-mediated mitophagy which may exert a protective effect against 5-ALA-SDT-induced cell death in MCF-7 cells.
View details for DOI 10.1159/000493629
View details for PubMedID 30231241
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Ultrasonic Characteristics and Cellular Properties of Anabaena Gas Vesicles.
Ultrasound in medicine & biology
2017; 43 (12): 2862-2870
Abstract
Ultrasound imaging is a common modality in clinical examination and biomedical research, but has not played a significant role in molecular imaging for lack of an appropriate contrast agent. Recently, biogenic gas vesicles (GVs), naturally formed by cyanobacteria and haloarchaea, have exhibited great potential as an ultrasound molecular imaging probe with a much smaller size (∼100 nm) and improved imaging contrast. However, the basic acoustic and biological properties of GVs remain unclear, which hinders future application. Here, we studied the fundamental acoustic properties of a rod-shaped gas vesicle from Anabaena, a kind of cyanobacterium, including attenuation, oscillation resonance, and scattering, as well as biological behaviors (cellular internalization and cytotoxicity). We found that GVs have two resonance peaks (85 and 120 MHz). We also observed a significant non-linear effect and its pressure dependence as well. Ultrasound B-mode imaging reveals sufficient echogenicity of GVs for ultrasound imaging enhancement at high frequencies. Biological characterization also reveals endocytosis and non-toxicity.
View details for DOI 10.1016/j.ultrasmedbio.2017.08.004
View details for PubMedID 28889941
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Polyethylenimine mediated magnetic nanoparticles for combined intracellular imaging, siRNA delivery and anti-tumor therapy
RSC ADVANCES
2015; 5 (123): 101569-101581
View details for DOI 10.1039/c5ra18464a
View details for Web of Science ID 000365952200042
https://orcid.org/0000-0002-9718-6539