Person:

Dai, Xiaochuan

The miniaturization of bioelectronic intracellular probes with a wide dynamic frequency range can open up opportunities to study biological structures inaccessible by existing methods in a minimally invasive manner. Here, we report the design, fabrication, and demonstration of intracellular bioelectronic devices with probe sizes less than 10 nm. The devices are based on a nanowire–nanotube heterostructure in which a nanowire field-effect transistor detector is synthetically integrated with a nanotube cellular probe. Sub-10-nm nanotube probes were realized by a two-step selective etching approach that reduces the diameter of the nanotube free-end while maintaining a larger diameter at the nanowire detector necessary for mechanical strength and electrical sensitivity. Quasi-static water-gate measurements demonstrated selective device response to solution inside the nanotube, and pulsed measurements together with numerical simulations confirmed the capability to record fast electrophysiological signals. Systematic studies of the probe bandwidth in different ionic concentration solutions revealed the underlying mechanism governing the time response. In addition, the bandwidth effect of phospholipid coatings, which are important for intracellular recording, was investigated and modeled. The robustness of these sub-10-nm bioelectronics probes for intracellular interrogation was verified by optical imaging and recording the transmembrane resting potential of HL-1 cells. These ultrasmall bioelectronic probes enable direct detection of cellular electrical activity with highest spatial resolution achieved to date, and with further integration into larger chip arrays could provide a unique platform for ultra-high-resolution mapping of activity in neural networks and other systems.

Nanowire nanoelectronic devices have been exploited as highly sensitive subcellular resolution detectors for recording extracellular and intracellular signals from cells, as well as from natural and engineered/cyborg tissues, and in this capacity open many opportunities for fundamental biological research and biomedical applications. Here we demonstrate the capability to take full advantage of the attractive capabilities of nanowire nanoelectronic devices for long term physiological studies by passivating the nanowire elements with ultrathin metal oxide shells. Studies of Si and Si/aluminum oxide (Al2O3) core/shell nanowires in physiological solutions at 37 °C demonstrate long-term stability extending for at least 100 days in samples coated with 10 nm thick Al2O3 shells. In addition, investigations of nanowires configured as field-effect transistors (FETs) demonstrate that the Si/Al2O3 core/shell nanowire FETs exhibit good device performance for at least 4 months in physiological model solutions at 37 °C. The generality of this approach was also tested with in studies of Ge/Si and InAs nanowires, where Ge/Si/Al2O3 and InAs/Al2O3 core/shell materials exhibited stability for at least 100 days in physiological model solutions at 37 °C. In addition, investigations of hafnium oxide-Al2O3 nanolaminated shells indicate the potential to extend nanowire stability well beyond 1 year time scale in vivo. These studies demonstrate that straightforward core/shell nanowire nanoelectronic devices can exhibit the long term stability needed for a range of chronic in vivo studies in animals as well as powerful biomedical implants that could improve monitoring and treatment of disease.

Seamless and minimally-invasive integration of three-dimensional (3D) electronic circuitry within host materials could enable the development of materials systems that are self- monitoring and allow for communication with external environments. Here, we report a general strategy for preparing ordered 3D interconnected and addressable macroporous nanoelectronic networks from ordered two-dimensional (2D) nanowire nanoelectronic “precursors”, which are fabricated by conventional lithography. The 3D networks have porosities larger than 99%, contain ca. 100’s of addressable nanowire devices, and have feature sizes from the 10 micron scale (for electrical and structural interconnections) to the 10 nanometer scale (for device elements). The macroporous nanoelectronic networks were merged with organic gels and polymers to form hybrid materials in which the basic physical and chemical properties of the host were not substantially altered, and electrical measurements further show a > 90% yield of active devices in the hybrid materials. The positions of the nanowire devices were located within 3D hybrid materials with ca. 14 nm resolution through simultaneous nanowire device photocurrent/confocal microscopy imaging measurements. In addition, we explored functional properties of these hybrid materials, including (i) mapping time-dependent pH changes throughout a nanowire network/agarose gel sample during external solution pH changes, and (ii) characterizing the strain field in a hybrid nanoelectronic elastomer structures subject to uniaxial and bending forces. The seamless incorporation of active nanoelectronic networks within 3D materials opens up a powerful approach to smart materials in which the capabilities of multi- functional nanoelectronics allow for active monitoring and control of host systems.

Nanomaterials provide unique opportunities at the interface between nanoelectronics and biology. “Bottom-up” synthesized nanowire(NW) with defined functionality can be assembled and enabled into three-dimensional(3D) flexible nanoelectronic networks. The micro- to nanoscale electronic units blur the distinction between electronics and cells/tissue in terms of length scale and mechanical stiffness. These unconventional 3D nanoelectronic networks can thus provide a path towards truly seamless integration of non-living electronics and living systems. In this thesis, I will introduce a general method for fabricating 3D macroporous NW nanoelectronic networks and their integration with hydrogel, elastomer and living tissues, with an emphasis on the realization of two-way communication between active nanoelectronics and the passive or living systems in which they are embedded. First, fabrication of 3D macroporous NW nanoelectronic networks will be described. Examples showing hundreds of individually addressable, multifunctional nanodevices fully distributed and interconnected throughout 3D networks will be illustrated. Proof-of-concept studies of macroporous nanoelectronic networks embedded through hydrogels and polymers demonstrate the ability for dynamically mapping pH gradients and strain fields. Second, a universal method to improve the long-term stability of semiconductor NWs in physiological environments using atomic layer deposition(ALD) of dielectric metal oxides shells on NW cores will be introduced. Long-term stability improvement by ALD of Al2O3 shells with different shell thickness and annealing conditions will be described and discussed. In addition, studies of semiconductor NW nanodevices with multilayer Al2O3/HfO2 shells indicates stability for up to two years in physiological solutions at 37◦C. Third, 3D macroporous nanoelectronic networks were integrated with synthetic cardiac tissues to build “cyborg” cardiac tissues. Spatiotemporal mapping of action potential(AP) propagating throughout 3D cardiac tissue was carried out with sub-millisecond time resolution, allowing investigation of cardiac tissue development and responses to pharmacological agents. These results have promised the applications of cyborg tissues in the fields ranging from fundamental electrophysiology and regenerative medicine to pharmacological studies. Finally, multifunctionallities of nanoelectronic devices for applications at the bio/nano interface will be discussed. Incorporation of NW field-effect-transistor(FET) and electrical stimulators in macroporous nanoelectronic networks demonstrates simultaneous recording and regulation of AP propagation in cyborg cardiac tissues. In addition, a convexed-NW FET bioprobe has been developed for simultaneous detection of AP and contraction force from individual cardiomyocyte. These explorations on the nanoelectronics functionalities highlight the capability to enable new communication modes between electronics and living tissues.

Direct electrical recording and stimulation of neural activity using micro-fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron–device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron–probe interactions, consistent with long-term biocompatibility of the device.

Real-time mapping and manipulation of electrophysiology in three-dimensional (3D) tissues could impact broadly fundamental scientific and clinical studies, yet realization lacks effective methods. Here we introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and sub-millisecond time-resolution. Real-time extracellular action potential (AP) recordings reveal quantitative maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topology of 3D conducting pathways in developing cardiac tissues, and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. We further demonstrate simultaneous multi-site stimulation and mapping to manipulate actively the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacology and electronic therapeutics.

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.