Ultrasound-Induced Cascade Amplification in a Mechanoluminescent Nanotransducer for Enhanced Sono-Optogenetic Deep Brain Stimulation.

Remote and genetically targeted neuromodulation in the deep brain is important for understanding and treatment of neurological diseases. Ultrasound-triggered mechanoluminescent technology offers a promising approach for achieving remote and genetically targeted brain modulation. However, its application has thus far been limited to shallow brain depths due to challenges related to low sonochemical reaction efficiency and restricted photon yields. Here we report a cascaded mechanoluminescent nanotransducer to achieve efficient light emission upon ultrasound stimulation. As a result, blue light was generated under ultrasound stimulation with a subsecond response latency. Leveraging the high energy transfer efficiency of focused ultrasound in brain tissue and the high sensitivity to ultrasound of these mechanoluminescent nanotransducers, we are able to show efficient photon delivery and activation of ChR2-expressing neurons in both the superficial motor cortex and deep ventral tegmental area after intracranial injection. Our liposome nanotransducers enable minimally invasive deep brain stimulation for behavioral control in animals via a flexible, mechanoluminescent sono-optogenetic system.

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.

Reversible, Covalent DNA Condensation Approach Using Chemical Linkers for Enhanced Gene Delivery.

Nonviral gene delivery has emerged as a promising technology for gene therapy. Nonetheless, these approaches often face challenges, primarily associated with lower efficiency, which can be attributed to the inefficient transportation of DNA into the nucleus. Here, we report a two-stage condensation approach to achieve efficient nuclear transport of DNA. First, we utilize chemical linkers to cross-link DNA plasmids via a reversible covalent bond to form smaller-sized bundled DNA (b-DNA). Then, we package the b-DNA into cationic vectors to further condense b-DNA and enable efficient gene delivery to the nucleus. We demonstrate clear improvements in the gene transfection efficiency in vitro, including with 11.6 kbp plasmids and in primary cultured neurons. Moreover, we also observed a remarkable improvement in lung-selective gene transfection efficiency in vivo by this two-stage condensation approach following intravenous administration. This reversible covalent assembly strategy demonstrates substantial value of nonviral gene delivery for clinical therapeutic applications.

Ultrasound-Triggered In Situ Photon Emission for Noninvasive Optogenetics.

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.

A highly stable electrode with low electrode-skin impedance for wearable brain-computer interface.

To date, brain-computer interfaces (BCIs) have proved to play a key role in many medical applications, for example, the rehabilitation of stroke patients. For post-stroke rehabilitation, the BCIs require the EEG electrodes to precisely translate the brain signals of patients into intended movements of the paralyzed limb for months. However, the gold standard silver/silver-chloride electrodes cannot satisfy the requirements for long-term stability and preparation-free recording capability in wearable EEG devices, thus limiting the versatility of EEG in wearable BCI applications over time outside the rehabilitation center. Here, we design a long-term stable and low electrode-skin interfacial impedance conductive polymer-hydrogel EEG electrode that maintains a lower impedance value than gel-based electrodes for 29 days. With this technology, EEG-based long-term and wearable BCIs could be realized in the near future. To demonstrate this, our designed electrode is applied for a wireless single-channel EEG device that detects changes in alpha rhythms in eye-open/eye-close conditions. In addition, we validate that the designed electrodes could capture oscillatory rhythms in motor imagery protocols as well as low-frequency time-locked event-related potentials from healthy subjects, with similar or better performance than gel-based electrodes. Finally, we demonstrate the use of the designed electrode in online BCI-based functional electrical stimulation, which could be used for post-stroke rehabilitation.

Design of hydrogel-based wearable EEG electrodes for medical applications.

The electroencephalogram (EEG) is considered to be a promising method for studying brain disorders. Because of its non-invasive nature, subjects take a lower risk compared to some other invasive methods, while the systems record the brain signal. With the technological advancement of neural and material engineering, we are in the process of achieving continuous monitoring of neural activity through wearable EEG. In this article, we first give a brief introduction to EEG bands, circuits, wired/wireless EEG systems, and analysis algorithms. Then, we review the most recent advances in the interfaces used for EEG recordings, focusing on hydrogel-based EEG electrodes. Specifically, the advances for important figures of merit for EEG electrodes are reviewed. Finally, we summarize the potential medical application of wearable EEG systems.

Ultrasound triggered organic mechanoluminescence materials.

Ultrasound induced organic mechanoluminescence materials have become one of the focal topics in wireless light sources since they exhibit high spatiotemporal resolution, biocompatibility and excellent tissue penetration depth. These properties promote great potential in ultrahigh sensitive bioimaging with no background noise and noninvasive nanodevices. Recent advances in chemistry, nanotechnology and biomedical research are revolutionizing ultrasound induced organic mechanoluminescence. Herein, we try to summarize some recent researches in ultrasound induced mechanoluminescence that use various materials design strategies based on the molecular conformational changes and cycloreversion reaction. Practical applications, like noninvasive bioimaging and noninvasive optogenetics, are also presented and prospected.

Overcoming barriers in non-viral gene delivery for neurological applications.

Gene therapy for neurological disorders has attracted significant interest as a way to reverse or stop various disease pathologies. Typical gene therapies involving the central and peripheral nervous system make use of adeno-associated viral vectors whose questionable safety and limitations in manufacturing has given rise to extensive research into non-viral vectors. While early research studies have demonstrated limited efficacy with these non-viral vectors, investigation into various vector materials and functionalization methods has provided insight into ways to optimize these non-viral vectors to improve desired characteristics such as improved blood-brain barrier transcytosis, improved perfusion in brain region, enhanced cellular uptake and endosomal escape in neural cells, and nuclear transport of genetic material post- intracellular delivery. Using a combination of various strategies to enhance non-viral vectors, research groups have designed multi-functional vectors that have been successfully used in a variety of pre-clinical applications for the treatment of Parkinson's disease, brain cancers, and cellular reprogramming for neuron replacement. While more work is needed in the design of these multi-functional non-viral vectors for neural applications, much of the groundwork has been done and is reviewed here.

The Relationship between Bone Remodeling and the Clockwise Rotation of the Facial Skeleton: A Computed Tomographic Imaging-Based Evaluation.

BACKGROUND: Information on the onset and gender differences of midfacial skeletal changes, including the complete understanding of the theory behind the clockwise rotational theory, remains elusive. METHODS: One hundred fifty-seven Caucasian individuals (10 men and 10 women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 79 years, and 80 to 89 years, and eight men and nine women aged 90 to 98 years) were investigated. Multiplanar computed tomographic scans with standardized angle and distance measurements in all three anatomical axes and in alignment to the sella-nasion (horizontal) line were conducted. RESULTS: Both men and women displayed an increase in orbital floor angle (p < 0.001, maximum at 60 to 69 years), decrease in maxillary angle (p = 0.035, 40 to 49 years), increase in palate angle (p < 0.001, 50 to 59 years), increase in vomer angle (p = 0.022, 30 to 39 years), but a decrease in the pterygoid angle (p = 0.002, 80 to 89 years). Orbital width decreased (p < 0.001, 60 to 69 years), pyriform aperture width increased (p = 0.015, 60 to 69 years), and midfacial height decreased with aging (p < 0.001, 60 to 69 years). CONCLUSIONS: Age-related changes of the midfacial skeleton occurred independently of gender, but at various time points in different locations. The observed changes seem to be driven by a bone resorption center located in the posterior maxilla, rather than by a rotational movement of the facial skeleton.