Biology subjects

Hsieh, J.-C.

Publications and source records attributed to Hsieh, J.-C..

8 recordsLinked to original sources

bioRxiv2026

Stabilizing gas in aqueous liquids with metal-organic frameworks for persistent acoustic transduction

Gas is the most efficient mediator of acoustic energy owing to its high compressibility, yet its thermodynamic instability in aqueous environments makes it inherently transient, limiting sustained ultrasound-biological interfacing. Here, we show that gas can be stabilized, confined, and manipulated in the liquid phase to function as a persistent acoustic transducer. By trapping gas within designed microporous metal-organic framework (MOF) nanocrystals, interfacial forces establish a stable ternary-phase equilibrium that suppresses water intrusion and prevents gas collapse, enabling reversible, non-destructive oscillations under ultrasound stimulation and providing design principles for stabilizing gas in liquid environments. By leveraging high-resolution ultra-high-speed digital image correlation (DIC), we unveil the previously inaccessible spatiotemporal dynamics of confined gas oscillations within these nanotransducers under ultrasound stimulation, revealing localized amplification of the surrounding acoustic field and establishing a quantitative structure-function relationship for programmable acoustic transduction. These aqueous-phase gas nanotransducers exhibit sustained acoustic amplification over millions of excitation cycles and remain functional after prolonged storage (>2 years) under physiological conditions. In vitro and in vivo, this platform enables long-term ultrasound imaging and sustained, non-invasive neuromodulation by converting confined gas oscillations into persistent and amplified mechanical actuation. Our findings establish a generalizable design framework for stabilizing gas in liquid environments to achieve persistent and programmable acoustic transduction, thereby enabling sustained ultrasound-biological interfacing and opening opportunities for gas-based therapeutics.

bioengineering↗

bioRxiv2026

Simultaneous brain-wide single-cell recording resolves spatiotemporal memory architecture

Many fundamental mammalian brain functions emerge from the coordinated activity of cells distributed across large, brain-wide networks. To understand these processes in healthy and diseased states, ideally one would simultaneously measure and analyze single-cell activity at the brain-wide scale, an enduring challenge for live-measurement approaches that often face an inherent tradeoff between spatial resolution and scale. Here, we present GLOBE (sinGle-cell spatiotemporaL recOrding Brain-widE), a technology for brain-wide single-cell recording of cellular activity in vivo with spatiotemporal resolution, physiological sensitivity, and parallelization-accelerated readout. GLOBE leverages genetically encoded intracellular protein tape recorders and a high-throughput computational platform for integrated image and signal analysis. GLOBE records analog signal amplitudes across a continuous time axis, requires only standard light microscopy for in situ readout, and is compatible with expansion microscopy and RNA readouts. We applied GLOBE to simultaneously record transcriptional activity of the immediate early gene Fos in up to 219,703 neurons simultaneously across a single mouse brain over 5.5 continuous days, with a timestamp precision of 3.1-6.7 hours (median absolute error), a local recording density of 69-90% of neurons per imaging field of view, and a post-mortem imaging readout speed of 2.9 seconds per neuron on average. GLOBE resolves the brain-wide spatiotemporal structure of single-cell activity, revealing that Fos transcriptional dynamics associated with fear learning and memory retrieval are distributed across the brain with region-specific temporal heterogeneity, and that the variance of this structure scales down as the number of sampled cells increases. We envision GLOBE to have broad applications for dissecting and decoding physiological and pathological processes at the brain-wide scale.

neuroscience↗

bioRxiv2025

Wearable Focused Ultrasound Neuromodulation and Electrophysiological Recording Patch for REM Sleep Enhancement

The rise in sleep disease affecting the general population globally in the past decade has been detrimental to individually and socioeconomically. As of now, approaches often are temporary through medication, permanently using invasive implants with surgical complications or neuromodulation therapy. However, non-invasive, state-dependent neuromodulation during sleep is technically challenging, especially with the lack of flexibility, comfortability and robustness for sleep conditions. Here, we introduce a Non-invasive Electrophysiological Recording and Ultrasound Neuromodulation Sleep Patch (NEUSLeeP) in delivering focused ultrasound stimulation to the subthalamic nucleus (STN) overnight with simultaneous stable polysomnography recording. Our sleep patch integrates a custom eight-channel concentric ring transducer array with real-time electroencephalography (EEG), electrooculography (EOG), electromyography (EMG) recording, and individualized line-of-sight targeting to sonicate deep brain areas while preserving mobility. Our platform operated safely and comfortably across the two-nights sleep study. Stimulation of the left STN was delivered every 90 minutes throughout the night and was associated with a 25% increase in REM (Rapid Eye Movement) sleep duration and a 43 minutes reduction in REM sleep latency compared to a sham night in a study of 26 subjects. Blood Oxygen Level Dependent (BOLD) signal attenuation in functional Magnetic Resonance Imaging (fMRI) was localized primarily to a left ipsilateral basal-ganglia-midbrain-temporal circuit, consistent with selective network modulation rather than global arousal changes. Overall, NEUSLeeP demonstrates feasibility by (i) a light weight and wearable ultrasound neuromodulation and sleep recording during natural sleep; (ii) establishing a potential mechanism relating targeted ultrasound stimulation of STN/sleep networks to REM enhancement.

bioengineering↗

bioRxiv2025

A parallelly distributed microscope and software system for scalable high-throughput multispectral 3D imaging

Recent advances in high throughput optical microscopy have achieved whole-organism scale imaging at diffraction-limited resolutions. Current microscopes, however, require making compromises between achieving the optimal resolution, imaging depth, multispectral capability, and data throughput due to limitations in optical design and data stream handling. We have created a parallel-line scanning confocal microscope (plSCM) which provides 1.1 Gigavoxels/second high speed imaging while achieving an optical resolution of [~]180 x 220 x 650 nm with 2 millimeters of imaging depth in 3 simultaneous spectral channels. To handle such a massive imaging data stream, we have engineered a scalable network-distributed image acquisition/processing framework (SNDiF), which allows continuous capture, real-time processing, and cluster storage of petabyte-scale single image datasets in days. Together, our parallelly distributed microscope and software system presents a general solution for large-scale high-throughput and high-resolution multicolor imaging which can operate for days at a time.

bioengineering↗

bioRxiv2025

Stretchable, hair-compatible, and long-term stable wearable EEG system

Electroencephalography (EEG) is a cornerstone in both neuroscience research and clinical diagnostics. However, conventional EEG monitoring faces hardware limitations, particularly its adaptability and stability. Headsets either require complicated wiring or do not have enough stretchability and wearability to comply with the diverse head anthropometry and hair conditions of the user population. Additionally, there is an inherent tradeoff between wet and dry electrodes in capturing high-fidelity signals from hair-covered scalp regions while ensuring continuous and long-term recording quality. Here, we present a Mesh-integrated, Stretchable, and Hair-compatible EEG system engineered to overcome these limitations. By incorporating a kirigami-inspired mesh design and stretchable eutectic Gallium-Indium interconnects, MindStretcH adapts to various head sizes and allows for easy wearing and removal. Moreover, its uniquely designed porous, conical, soft 3D-printed mold, embedded with hydrogel electrodes, effectively penetrates hair layers to deliver low impedance and sustained signal integrity with minimal discomfort. We validate MindStretcH through offline and online EEG-based brain-computer interface tasks over a month, demonstrating its exceptional stability in continuous monitoring and dynamic applications. These results mark a promising advance toward non-invasive neural interfaces in both clinical and everyday use.

bioengineering↗

bioRxiv2025

Hydrogen-bonded organic framework nanotransducers enabled sono-optogenetics for Parkinsonian rats

Cell-type-specific activation of parvalbumin (PV)-expressing neurons in the external globus pallidus (GPe) through optogenetics has shown promise in facilitating long-lasting movement dysfunction recovery in mice with Parkinsons disease. However, its translational potential is hindered by adverse effects stemming from the invasive implantation of optical fibers into the brain. In this study, we have developed a non-invasive optogenetics approach, utilizing focused ultrasound-triggered mechanoluminescent nanotransducers to enable remote photon delivery deep in the brain for genetically targeted neuromodulation. These mechanoluminescent nanotransducers consist of sonosensitized hydrogen-bonded frameworks and chemiluminescent L012, serving as a nanoscale light source through ultrasound-induced cascade reactions. This system offers high ultrasound-triggered brightness and long-lasting light emission, facilitating repeatable deep brain stimulation. Our sono-optogenetics technology demonstrated effective modulation in the mouse motor cortex for limb motion control and activation of PV-GPe neurons for rescuing movement dysfunction over time in dopamine-depleted Parkinsons disease rats. This approach demonstrates the pathway for achieving genetically targeted and non-invasive neuromodulation for long-lasting treatment of Parkinsons disease, towards non-human primate models and clinical applications.

bioengineering↗

bioRxiv2023

Ultrasound programmable hydrogen-bonded organic frameworks for sono-chemogenetics

The precise control of mechanochemical activation within deep tissues via non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials at the molecular level to achieve programmable and spatiotemporal activation control. To demonstrate the practicality of this approach, we encapsulate designer drug clozapine N-oxide (CNO) into the optimal HOF nanoparticles for FUS gated release to activate engineered G-protein-coupled receptors in the mice and rat ventral tegmental area (VTA), and hence achieved targeted neural circuits modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interaction and develops ultrasound programmable HOFs to minimally invasive and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities. We anticipate that this research could serve as a source of inspiration for precise and non-invasive molecular manipulation techniques, potentially applicable in programming molecular robots to achieve sophisticated control over cellular events in deep tissues.

bioengineering↗

bioRxiv2022

Profiling neurons surrounding subcellular-scale carbon fiber electrode tracts enables modeling recorded signals

Characterizing the relationship between neuron spiking and the signals electrodes record is vital to defining the neural circuits driving brain function and informing computational modeling. However, electrode biocompatibility and precisely localizing neurons around the electrodes are critical to defining this relationship. Here, we show the ability to localize post-explant recording tips of subcellular-scale carbon fiber electrodes and surrounding neurons. Immunostaining of astrocyte, microglia, and neuron markers confirmed improved tissue health. While neurons near implants were stretched, their number and distribution were similar to control, suggesting that these minimally invasive electrodes demonstrate the potential to sample naturalistic neural populations. This motivated prediction of the spikes produced by neurons nearest to the electrodes using a model fit with recorded electrophysiology. These simulations show the first direct evidence that neuron placement in the immediate vicinity of the recording site influences how many spike clusters can be reliably identified by spike sorting.

neuroscience↗