Qianru Yang

All Publications

• Color-neutral and reversible tissue transparency enables longitudinal deep-tissue imaging in live mice. Proceedings of the National Academy of Sciences of the United States of America Keck, C. H., Schmidt, E. L., Roth, R. H., Floyd, B. M., Tsai, A. P., Garcia, H. B., Cui, M., Chen, X., Wang, C., Park, A., Zhao, S., Liao, P. A., Casey, K. M., Reineking, W., Cai, S., Zhang, L. Y., Yang, Q., Yuan, L., Baghdasaryan, A., Lopez, E. R., Cooper, L., Cui, H., Esquivel, D., Brinson, K., Chen, X., Wyss-Coray, T., Coleman, T. P., Brongersma, M. L., Bertozzi, C. R., Wang, G. X., Ding, J. B., Hong, G. 2025; 122 (35): e2504264122

  Abstract

  Light scattering in biological tissue presents a significant challenge for deep in vivo imaging. Our previous work demonstrated the ability to achieve optical transparency in live mice using intensely absorbing dye molecules, which created transparency in the red spectrum while blocking shorter-wavelength photons. In this paper, we extend this capability to achieve optical transparency across the entire visible spectrum by employing molecules with strong absorption in the ultraviolet spectrum and sharp absorption edges that rapidly decline upon entering the visible spectrum. This color-neutral and reversible tissue transparency method enables optical transparency for imaging commonly used fluorophores in the green and yellow spectra. Notably, this approach facilitates tissue transparency for structural and functional imaging of the live mouse brain labeled with yellow fluorescent protein and GCaMP through the scalp and skull. We show that this method enables longitudinal imaging of the same brain regions in awake mice over multiple days during development. Histological analyses of the skin and systemic toxicology studies indicate minimal acute or chronic damage to the skin or body using this approach. This color-neutral and reversible tissue transparency technique opens opportunities for noninvasive deep-tissue optical imaging, enabling long-term visualization of cellular structures and dynamic activity with high spatiotemporal resolution and chronic tracking capabilities.

  View details for DOI 10.1073/pnas.2504264122

  View details for PubMedID 40857313

• Color-neutral and reversible tissue transparency enables longitudinal deep-tissue imaging in live mice. bioRxiv : the preprint server for biology Keck, C. H., Schmidt, E. L., Roth, R. H., Floyd, B. M., Tsai, A. P., Garcia, H. B., Cui, M., Chen, X., Wang, C., Park, A., Zhao, S., Liao, P. A., Casey, K. M., Reineking, W., Cai, S., Zhang, L., Yang, Q., Yuan, L., Baghdasaryan, A., Lopez, E. R., Cooper, L., Cui, H., Esquivel, D., Brinson, K., Chen, X., Wyss-Coray, T., Coleman, T. P., Brongersma, M. L., Bertozzi, C. R., Wang, G. X., Ding, J. B., Hong, G. 2025

  Abstract

  Light scattering in biological tissue presents a significant challenge for deep in vivo imaging. Our previous work demonstrated the ability to achieve optical transparency in live mice using intensely absorbing dye molecules, which created transparency in the red spectrum while blocking shorter-wavelength photons. In this paper, we extend this capability to achieve optical transparency across the entire visible spectrum by employing molecules with strong absorption in the ultraviolet spectrum and sharp absorption edges that rapidly decline upon entering the visible spectrum. This new color-neutral and reversible tissue transparency method enables optical transparency for imaging commonly used fluorophores in the green and yellow spectra. Notably, this approach facilitates tissue transparency for structural and functional imaging of the live mouse brain labeled with yellow fluorescent protein and GCaMP through the scalp and skull. We show that this method enables longitudinal imaging of the same brain regions in awake mice over multiple days during development. Histological analyses of the skin and systemic toxicology studies indicate minimal acute or chronic damage to the skin or body using this approach. This color-neutral and reversible tissue transparency technique opens new opportunities for noninvasive deep-tissue optical imaging, enabling long-term visualization of cellular structures and dynamic activity with high spatiotemporal resolution and chronic tracking capabilities.

  View details for DOI 10.1101/2025.02.20.639185

  View details for PubMedID 40060493

• Revealing in vivo cellular mechanisms of cerebral microbleeds on neurons and microglia across cortical layers. iScience Yang, Q., Vazquez, A. L., Cui, X. T. 2024; 27 (4): 109371

  Abstract

  Cerebral microbleeds (CMBs) are associated with higher risk for various neurological diseases including stroke, dementia, and Alzheimer's disease. However, the understanding of cellular pathology of CMBs, particularly in deep brain regions, remains limited. Utilizing two-photon microscopy and microprism implantation, we longitudinally imaged the impact of CMBs on neuronal and microglial activities across cortical depths in awake mice. A temporary decline in spontaneous neuronal activity occurred throughout cortical layers, followed by recovery within a week. However, significant changes of neuron-neuron activity correlations persisted for weeks. Moreover, microglial contact with neuron soma significantly increased post-microbleeds, indicating an important modulatory role of microglia. Notably, microglial contact, negatively correlated with neuronal firing rate in normal conditions, became uncorrelated after microbleeds, suggesting a decreased neuron-microglia inhibition. These findings reveal chronic alterations in cortical neuronal networks and microglial-neuronal interactions across cortical depths, shedding light on the pathology of CMBs.

  View details for DOI 10.1016/j.isci.2024.109371

  View details for PubMedID 38510113

  View details for PubMedCentralID PMC10951986

• Integrated Microprism and Microelectrode Array for Simultaneous Electrophysiology and Two-Photon Imaging across All Cortical Layers. Advanced healthcare materials Yang, Q., Wu, B., Castagnola, E., Pwint, M. Y., Williams, N. P., Vazquez, A. L., Cui, X. T. 2024: e2302362

  Abstract

  Cerebral neural electronics play a crucial role in neuroscience research with increasing translational applications such as brain-computer interfaces for sensory input and motor output restoration. While widely utilized for decades, the understanding of the cellular mechanisms underlying this technology remains limited. Although two-photon microscopy (TPM) has shown great promise in imaging superficial neural electrodes, its application to deep-penetrating electrodes is technically difficult. Here, a novel device integrating transparent microelectrode arrays with glass microprisms, enabling electrophysiology recording and stimulation alongside TPM imaging across all cortical layers in a vertical plane, is introduced. Tested in Thy1-GCaMP6 mice for over 4 months, the integrated device demonstrates the capability for multisite electrophysiological recording/stimulation and simultaneous TPM calcium imaging. As a proof of concept, the impact of microstimulation amplitude, frequency, and depth on neural activation patterns is investigated using the setup. With future improvements in material stability and single unit yield, this multimodal tool greatly expands integrated electrophysiology and optical imaging from the superficial brain to the entire cortical column, opening new avenues for neuroscience research and neurotechnology development.

  View details for DOI 10.1002/adhm.202302362

  View details for PubMedID 38563704

• Advanced <i>in vivo</i> fluorescence microscopy of neural electronic interface MRS BULLETIN Yang, Q., Cui, X. 2023; 48 (5): 506-517

  View details for DOI 10.1557/s43577-023-00530-7

  View details for Web of Science ID 000982960100002

• Melatonin Decreases Acute Inflammatory Response to Neural Probe Insertion ANTIOXIDANTS Krahe, D. D., Woeppel, K. M., Yang, Q., Kushwah, N., Cui, X. 2022; 11 (8)

  Abstract

  Neural electrode insertion trauma impedes the recording and stimulation capabilities of numerous diagnostic and treatment avenues. Implantation leads to the activation of inflammatory markers and cell types, which is detrimental to neural tissue health and recording capabilities. Oxidative stress and inflammation at the implant site have been shown to decrease with chronic administration of antioxidant melatonin at week 16, but its effects on the acute landscape have not been studied. To assess the effect of melatonin administration in the acute phase, specifically the first week post-implantation, we utilized histological and q-PCR methods to quantify cellular and molecular indicators of inflammation and oxidative stress in the tissue surrounding implanted probes in C57BL/6 mice as well as two-photon microscopy to track the microglial responses to the probes in real-time in transgenic mice expressing GFP with CX3CR1 promotor. Histological results indicate that melatonin effectively maintained neuron density surrounding the electrode, inhibited accumulation and activation of microglia and astrocytes, and reduced oxidative tissue damage. The expression of the pro-inflammatory cytokines, TNF-α and IL-6, were significantly reduced in melatonin-treated animals. Additionally, microglial encapsulation of the implant surface was inhibited by melatonin as compared to control animals following implantation. Our results combined with previous research suggest that melatonin is a particularly suitable drug for modulating inflammatory activity around neural electrode implants both acutely and chronically, translating to more stable and reliable interfaces.

  View details for DOI 10.3390/antiox11081628

  View details for Web of Science ID 000846294400001

  View details for PubMedID 36009346

  View details for PubMedCentralID PMC9405074

• Imaging the stability of chronic electrical microstimulation using electrodes coated with PEDOT/CNT and iridium oxide ISCIENCE Zheng, X., Yang, Q., Vazquez, A., Cui, X. 2022; 25 (7): 104539

  Abstract

  Chronic microstimulation is faced with challenges that require an additional understanding of stability and safety. We implanted silicon arrays coated with poly(3,4-ethylenedioxythiophene) (PEDOT)/Carbon Nanotubes (CNT), or PCand IrOx into the cortex of GCaMP6s mice and electrically stimulated them for up to 12 weeks. We quantified neuronal responses to stimulation using two-photon imaging and mesoscale fluorescence microscopy and characterized electrode performance over time. We observed dynamic changes in stimulation stability over time and a significant advantage in energy efficiency using PC coated electrodes over IrOx coated electrodes. In a subset of mice, we observed abnormal ictal cortical responses or cortical spreading depression using stimulation parameters commonly used in intracortical stimulation applications, suggesting the need to investigate the potential neuronal damage and redefine the stimulation safety limit. This study not only revealed the dynamic changes in stimulation efficiency after implantation but also reiterates the potential for PC as a high-efficiency material in chronic neuromodulation.

  View details for DOI 10.1016/j.isci.2022.104539

  View details for Web of Science ID 000828607200005

  View details for PubMedID 35769881

  View details for PubMedCentralID PMC9234710

• Long-term in vivo two-photon imaging of the neuroinflammatory response to intracortical implants and micro-vessel disruptions in awake mice. Biomaterials Yang, Q., Vazquez, A. L., Cui, X. T. 2021; 276: 121060

  Abstract

  Our understanding of biomaterials in the brain have been greatly enhanced by advancements in in vivo imaging technologies such as two-photon microscopy. However, when applied to chronic studies, two-photon microscopy enables high-resolution imaging only in superficial regions due to inflammatory responses introduced by the craniotomy and insertion of foreign biomaterials. Microprisms provide a unique vertical view from brain surface to ~1 mm deep or more (depending on the size of the microprisms) which may break through this limitation on imaging depth. Although microprism has been used in the field of neuroscience, the in vivo foreign body responses to the microprism implant have yet to be fully elucidated. This is of important concern in broader applications of this approach, especially for neuroinflammation-sensitive studies. In this work, we first assessed the activation of microglia/macrophages for 16 weeks after microprism implantation using two-photon microscopy in awake CX3CR1-GFP mice. The imaging window became clear from bleedings after ~2 weeks and the maximum imaging distance (in the horizontal direction) stabilized at around 500 μm after ~5 weeks. We also quantified the microglial morphology from week 3 to week 16 post-implantation. Compared to non-implant controls, microglia near the microprism showed higher cell density, smaller soma, and shorter and less branched processes in the early-chronic phase. After week 5, microglial morphology further than 100 μm from the microprism was generally similar to microglia in the control group. In addition, time-lapse imaging confirmed that microglial processes were surveying normally from week 3, even for microglia as close as 50 μm away. These morphological analyses and dynamic imaging results suggest that microglia around chronically implanted microprism eventually exhibit inactive phenotypes. Next, we examined microglial/macrophage responses following laser induced micro-vessel disruptions as an example application of microprism implantation for neuroinflammation related studies. Through the microprism, we captured microglial/macrophage polarization and migration, as well as blood flow changes after the insult for additional 16 weeks. To our surprise, microglia/macrophage aggregation around the insult site was sustained over the 16-week observation period. This work demonstrates the feasibility of using microprisms for long-term characterizations of inflammatory responses to other injuries including implantable devices at deeper depths than that achievable by conventional two-photon microscopy.

  View details for DOI 10.1016/j.biomaterials.2021.121060

  View details for PubMedID 34419839

  View details for PubMedCentralID PMC8409342

• Imaging the Efficiency of Poly(3,4-ethylenedioxythiophene) Doped with Acid-Functionalized Carbon Nanotube and Iridium Oxide Electrode Coatings for Microstimulation ADVANCED NANOBIOMED RESEARCH Zheng, X. S., Yang, Q., Vazquez, A. L., Cui, X. 2021; 1 (7): 2000092

  Abstract

  Electrical microstimulation has shown promise in restoring neural deficits in humans. Electrodes coated with materials like the conducting polymer poly(3,4-ethylenedioxythiophene) doped with acid-functionalized carbon nanotubes (PEDOT/CNTs, or PC) exhibit superior charge injection than traditional metals like platinum. However, the stimulation performance of PC remains to be fully characterized. Advanced imaging techniques and transgenic tools allow for real-time observations of neural activity in vivo. Herein, microelectrodes coated with PC and iridium oxide (IrOx) (a commonly used high-charge-injection material) are implanted in GCaMP6s mice and electrical stimulation is applied while imaging neuronal calcium responses. Results show that PC-coated electrodes stimulate more intense and broader GCaMP responses than IrOx. Two-photon microscopy reveals that PC-coated electrodes activate significantly more neuronal soma and neuropil than IrOx-coated electrodes in constant-voltage stimulation and significantly more neuronal soma in constant-current stimulation. Furthermore, with the same injected charge, both materials activate more spatially confined neural elements with shorter pulses than longer pulses, providing a means to tune stimulation selectivity. Finite element analyses reveal that the PC coating creates a denser and nonuniform electric field, increasing the likelihood of activating nearby neural elements. PC coating can significantly improve energy efficiency for electrical stimulation applications.

  View details for DOI 10.1002/anbr.202000092

  View details for Web of Science ID 000782092000003

  View details for PubMedID 34746928

  View details for PubMedCentralID PMC8552016

• Zwitterionic Polymer Coating Suppresses Microglial Encapsulation to Neural Implants In Vitro and In Vivo. Advanced biosystems Yang, Q., Wu, B., Eles, J. R., Vazquez, A. L., Kozai, T. D., Cui, X. T. 2020; 4 (6): e1900287

  Abstract

  For brain computer interfaces (BCI), the immune response to implanted electrodes is a major biological cause of device failure. Bioactive coatings such as neural adhesion molecule L1 have been shown to improve the biocompatibility, but are difficult to handle or produce in batches. Here, a synthetic zwitterionic polymer coating, poly(sulfobetaine methacrylate) (PSBMA) is developed for neural implants with the goal of reducing the inflammatory host response. In tests in vitro, the zwitterionic coating inhibits protein adsorption and the attachment of fibroblasts and microglia, and remains stable for at least 4 weeks. In vivo two-photon microscopy on CX3CR1-GFP mice shows that the zwitterionic coating significantly suppresses the microglial encapsulation of neural microelectrodes over a 6 h observation period. Furthermore, the lower microglial encapsulation on zwitterionic polymer-coated microelectrodes is revealed to originate from a reduction in the size but not the number of microglial end feet. This work provides a facile method for coating neural implants with zwitterionic polymers and illustrates the initial interaction between microglia and coated surface at high temporal and spatial resolution.

  View details for DOI 10.1002/adbi.201900287

  View details for PubMedID 32363792

  View details for PubMedCentralID PMC7686959

• Recent advances in neural electrode-tissue interfaces CURRENT OPINION IN BIOMEDICAL ENGINEERING Woeppel, K., Yang, Q., Cui, X. 2017; 4: 21-31

  Abstract

  Neurotechnology is facing an exponential growth in the recent decades. Neural electrode-tissue interface research has been well recognized as an instrumental component of neurotechnology development. While satisfactory long-term performance was demonstrated in some applications, such as cochlear implants and deep brain stimulators, more advanced neural electrode devices requiring higher resolution for single unit recording or microstimulation still face significant challenges in reliability and longevity. In this article, we review the most recent findings that contribute to our current understanding of the sources of poor reliability and longevity in neural recording or stimulation, including the material failure, biological tissue response and the interplay between the two. The newly developed characterization tools are introduced from electrophysiology models, molecular and biochemical analysis, material characterization to live imaging. The effective strategies that have been applied to improve the interface are also highlighted. Finally, we discuss the challenges and opportunities in improving the interface and achieving seamless integration between the implanted electrodes and neural tissue both anatomically and functionally.

  View details for DOI 10.1016/j.cobme.2017.09.003

  View details for Web of Science ID 000655211300005

  View details for PubMedID 29423457

  View details for PubMedCentralID PMC5798641