Xiao Yang

All Publications

• Kirigami electronics for long-term electrophysiological recording of human neural organoids and assembloids. Nature biotechnology Yang, X., Forro, C., Li, T. L., Miura, Y., Zaluska, T. J., Tsai, C., Kanton, S., McQueen, J. P., Chen, X., Mollo, V., Santoro, F., Pașca, S. P., Cui, B. 2024

  Abstract

  Realizing the full potential of organoids and assembloids to model neural development and disease will require improved methods for long-term, minimally invasive recording of electrical activity. Current technologies, such as patch clamp, penetrating microelectrodes, planar electrode arrays and substrate-attached flexible electrodes, do not allow chronic recording of organoids in suspension, which is necessary to preserve architecture. Inspired by kirigami art, we developed flexible electronics that transition from a two-dimensional to a three-dimensional basket-like configuration with either spiral or honeycomb patterns to accommodate the long-term culture of organoids in suspension. Here we show that this platform, named kirigami electronics (KiriE), integrates with and enables chronic recording of cortical organoids for up to 120days while preserving their morphology, cytoarchitecture and cell composition. We demonstrate integration of KiriE with optogenetic and pharmacological manipulation and modeling phenotypes related to a genetic disease. Moreover, KiriE can capture corticostriatal connectivity in assembloids following optogenetic stimulation. Thus, KiriE will enable investigation of disease and activity patterns underlying nervous system assembly.

  View details for DOI 10.1038/s41587-023-02081-3

  View details for PubMedID 38253880

• 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

• Kirigami electronics for long-term electrophysiological recording of human neural organoids and assembloids. bioRxiv : the preprint server for biology Yang, X., Forro, C., Li, T. L., Miura, Y., Zaluska, T. J., Tsai, C., Kanton, S., McQueen, J. P., Chen, X., Mollo, V., Santoro, F., Pasca, S. P., Cui, B. 2023

  Abstract

  Organoids and assembloids have emerged as a promising platform to model aspects of nervous system development. Longterm, minimally-invasive recordings in these multi-cellular systems are essential for developing disease models. Current technologies, such as patch-clamp, penetrating microelectrodes, planar electrode arrays and substrate-attached flexible electrodes, do not, however, allow chronic recording of organoids in suspension, which is necessary to preserve their architecture. Inspired by the art of kirigami, we developed flexible electronics that transition from a 2D pattern to a 3D basketlike configuration to accommodate the long-term culture of organoids in suspension. This platform, named kirigami electronics (KiriE), integrates with and enables chronic recording of cortical organoids while preserving morphology, cytoarchitecture, and cell composition. KiriE can be integrated with optogenetic and pharmacological stimulation and model disease. Moreover, KiriE can capture activity in cortico-striatal assembloids. Moving forward, KiriE could reveal disease phenotypes and activity patterns underlying the assembly of the nervous system.

  View details for DOI 10.1101/2023.09.22.559050

  View details for PubMedID 37790529

• Stretchable mesh microelectronics for the biointegration and stimulation of human neural organoids. Biomaterials Li, T. L., Liu, Y., Forro, C., Yang, X., Beker, L., Bao, Z., Cui, B., Pașca, S. P. 2022; 290: 121825

  Abstract

  Advances in tridimensional (3D) culture approaches have led to the generation of organoids that recapitulate cellular and physiological features of domains of the human nervous system. Although microelectrodes have been developed for long-term electrophysiological interfaces with neural tissue, studies of long-term interfaces between microelectrodes and free-floating organoids remain limited. In this study, we report a stretchable, soft mesh electrode system that establishes an intimate in vitro electrical interface with human neurons in 3D organoids. Our mesh is constructed with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) based electrically conductive hydrogel electrode arrays and elastomeric poly(styrene-ethylene-butylene-styrene) (SEBS) as the substrate and encapsulation materials. This mesh electrode can maintain a stable electrochemical impedance in buffer solution under 50% compressive and 50% tensile strain. We have successfully cultured pluripotent stem cell-derived human cortical organoids (hCO) on this polymeric mesh for more than 3 months and demonstrated that organoids readily integrate with the mesh. Using simultaneous stimulation and calcium imaging, we show that electrical stimulation through the mesh can elicit intensity-dependent calcium signals comparable to stimulation from a bipolar stereotrode. This platform may serve as a tool for monitoring and modulating the electrical activity of in vitro models of neuropsychiatric diseases.

  View details for DOI 10.1016/j.biomaterials.2022.121825

  View details for PubMedID 36326509

• Maturation and circuit integration of transplanted human cortical organoids. Nature Revah, O., Gore, F., Kelley, K. W., Andersen, J., Sakai, N., Chen, X., Li, M. Y., Birey, F., Yang, X., Saw, N. L., Baker, S. W., Amin, N. D., Kulkarni, S., Mudipalli, R., Cui, B., Nishino, S., Grant, G. A., Knowles, J. K., Shamloo, M., Huguenard, J. R., Deisseroth, K., Pașca, S. P. 2022; 610 (7931): 319-326

  Abstract

  Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.

  View details for DOI 10.1038/s41586-022-05277-w

  View details for PubMedID 36224417

• Dissecting Biological and Synthetic Soft-Hard Interfaces for Tissue-Like Systems. Chemical reviews Fang, Y., Yang, X., Lin, Y., Shi, J., Prominski, A., Clayton, C., Ostroff, E., Tian, B. 2021

  Abstract

  Soft and hard materials at interfaces exhibit mismatched behaviors, such as mismatched chemical or biochemical reactivity, mechanical response, and environmental adaptability. Leveraging or mitigating these differences can yield interfacial processes difficult to achieve, or inapplicable, in pure soft or pure hard phases. Exploration of interfacial mismatches and their associated (bio)chemical, mechanical, or other physical processes may yield numerous opportunities in both fundamental studies and applications, in a manner similar to that of semiconductor heterojunctions and their contribution to solid-state physics and the semiconductor industry over the past few decades. In this review, we explore the fundamental chemical roles and principles involved in designing these interfaces, such as the (bio)chemical evolution of adaptive or buffer zones. We discuss the spectroscopic, microscopic, (bio)chemical, and computational tools required to uncover the chemical processes in these confined or hidden soft-hard interfaces. We propose a soft-hard interaction framework and use it to discuss soft-hard interfacial processes in multiple systems and across several spatiotemporal scales, focusing on tissue-like materials and devices. We end this review by proposing several new scientific and engineering approaches to leveraging the soft-hard interfacial processes involved in biointerfacing composites and exploring new applications for these composites.

  View details for DOI 10.1021/acs.chemrev.1c00365

  View details for PubMedID 34677943

• Nanotechnology Enables Novel Modalities for Neuromodulation. Advanced materials (Deerfield Beach, Fla.) Yang, X., McGlynn, E., Das, R., Pasca, S. P., Cui, B., Heidari, H. 2021: e2103208

  Abstract

  Neuromodulation is of great importance both as a fundamental neuroscience research tool for analyzing and understanding the brain function, and as a therapeutic avenue for treating brain disorders. Here, an overview of conceptual and technical progress in developing neuromodulation strategies is provided, and it is suggested that recent advances in nanotechnology are enabling novel neuromodulation modalities with less invasiveness, improved biointerfaces, deeper penetration, and higher spatiotemporal precision. The use of nanotechnology and the employment of versatile nanomaterials and nanoscale devices with tailored physical properties have led to considerable research progress. To conclude, an outlook discussing current challenges and future directions for next-generation neuromodulation modalities is presented.

  View details for DOI 10.1002/adma.202103208

  View details for PubMedID 34668249

• Bioinspired neuron-like electronics NATURE MATERIALS Yang, X., Zhou, T., Zwang, T. J., Hong, G., Zhao, Y., Viveros, R. D., Fu, T., Gao, T., Lieber, C. M. 2019; 18 (5): 510-+

  Abstract

  As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes-neuron-like electronics (NeuE)-where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE-brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain-machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine.

  View details for DOI 10.1038/s41563-019-0292-9

  View details for Web of Science ID 000465199900024

  View details for PubMedID 30804509

  View details for PubMedCentralID PMC6474791

• 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

• Out-of-Plane Piezoelectricity and Ferroelectricity in Layered alpha-In2Se3 Nanoflakes NANO LETTERS Zhou, Y., Wu, D., Zhu, Y., Cho, Y., He, Q., Yang, X., Herrera, K., Chu, Z., Han, Y., Downer, M. C., Peng, H., Lai, K. 2017; 17 (9): 5508–13

  Abstract

  Piezoelectric and ferroelectric properties in the two-dimensional (2D) limit are highly desired for nanoelectronic, electromechanical, and optoelectronic applications. Here we report the first experimental evidence of out-of-plane piezoelectricity and ferroelectricity in van der Waals layered α-In2Se3 nanoflakes. The noncentrosymmetric R3m symmetry of the α-In2Se3 samples is confirmed by scanning transmission electron microscopy, second-harmonic generation, and Raman spectroscopy measurements. Domains with opposite polarizations are visualized by piezo-response force microscopy. Single-point poling experiments suggest that the polarization is potentially switchable for α-In2Se3 nanoflakes with thicknesses down to ∼10 nm. The piezotronic effect is demonstrated in two-terminal devices, where the Schottky barrier can be modulated by the strain-induced piezopotential. Our work on polar α-In2Se3, one of the model 2D piezoelectrics and ferroelectrics with simple crystal structures, shows its great potential in electronic and photonic applications.

  View details for DOI 10.1021/acs.nanolett.7b02198

  View details for Web of Science ID 000411043500048

  View details for PubMedID 28841328

• 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

• Specific detection of biomolecules in physiological solutions using graphene transistor biosensors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gao, N., Gao, T., Yang, X., Dai, X., Zhou, W., Zhang, A., Lieber, C. M. 2016; 113 (51): 14633–38

  Abstract

  Nanomaterial-based field-effect transistor (FET) sensors are capable of label-free real-time chemical and biological detection with high sensitivity and spatial resolution, although direct measurements in high-ionic-strength physiological solutions remain challenging due to the Debye screening effect. Recently, we demonstrated a general strategy to overcome this challenge by incorporating a biomolecule-permeable polymer layer on the surface of silicon nanowire FET sensors. The permeable polymer layer can increase the effective screening length immediately adjacent to the device surface and thereby enable real-time detection of biomolecules in high-ionic-strength solutions. Here, we describe studies demonstrating both the generality of this concept and application to specific protein detection using graphene FET sensors. Concentration-dependent measurements made with polyethylene glycol (PEG)-modified graphene devices exhibited real-time reversible detection of prostate specific antigen (PSA) from 1 to 1,000 nM in 100 mM phosphate buffer. In addition, comodification of graphene devices with PEG and DNA aptamers yielded specific irreversible binding and detection of PSA in pH 7.4 1x PBS solutions, whereas control experiments with proteins that do not bind to the aptamer showed smaller reversible signals. In addition, the active aptamer receptor of the modified graphene devices could be regenerated to yield multiuse selective PSA sensing under physiological conditions. The current work presents an important concept toward the application of nanomaterial-based FET sensors for biochemical sensing in physiological environments and thus could lead to powerful tools for basic research and healthcare.

  View details for DOI 10.1073/pnas.1625010114

  View details for Web of Science ID 000390044900045

  View details for PubMedID 27930344

  View details for PubMedCentralID PMC5187689

• Controlled synthesis of single-crystal SnSe nanoplates NANO RESEARCH Zhao, S., Wang, H., Zhou, Y., Liao, L., Jiang, Y., Yang, X., Chen, G., Lin, M., Wang, Y., Peng, H., Liu, Z. 2015; 8 (1): 288–95

  View details for DOI 10.1007/s12274-014-0676-8

  View details for Web of Science ID 000348200300025

• Polyoxometalate-functionalized metal-organic frameworks with improved water retention and uniform proton-conducting pathways in three orthogonal directions CHEMICAL COMMUNICATIONS Liu, Y., Yang, X., Miao, J., Tang, Q., Liu, S., Shi, Z., Liu, S. 2014; 50 (70): 10023–26

  Abstract

  Polyoxometalate-functionalized metal-organic frameworks featuring uniform proton-conducting pathways in three orthogonal directions, good water retention and stability were prepared. The proton conductivity of the hybrid material was observed to increase by 5 orders of magnitude compared to that of the parent material HKUST-1.

  View details for DOI 10.1039/c4cc04009k

  View details for Web of Science ID 000340707600004

  View details for PubMedID 25011438