Abstract. Direct electrical recording and stimulation of neural activity using microfabricated 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 3D 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 (LFPs) 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.Currently, there is intense interest in the development of materials and electronic devices that can extend and/or provide new capabilities for probing neural circuitry and afford long-term minimally-invasive brain-electronics interfaces 1,2,3,4 . Conventional brain probes have contributed extensively to basic neuroscience 5,6 and therapeutic applications 7,8,9,10 , although they suffer from chronic stability and poor neuron-device contacts 4,11,12,13 . Recent studies of smaller 14,15 and more flexible 16,17 probes suggest that addressing size and mechanical factors could help overcome current limitations. 3The most common neural electrical probes are fabricated from metal 18 and silicon 19,20 , materials that have very different structural and mechanical properties compared to brain tissue 21 .Evidence suggests that mechanical mismatch is an important reason leading to abrupt and chronically unstable interfaces within the brain 4,22 . For example, motion of skull-affixed rigid probes in chronic experiments can induce shear stresses and lead to tissue scarring 13,23 , and thereby compromise the stability of recorded signals on the time scale of weeks to months 4,24, 25 .More recent work has shown that flexible probes fabricated on polymer substrates 12,17 and smaller-sized probes 11,14 can reduce deleterious tissue response. More generally, there has also been effort developing flexible bioelectronics 26, 27, 28 and nanoscale devices for single cell recording 29, 30 . We have also shown that 3D macroporous electronic device arrays can function as a scaffold for and allow for 3D interpenetration of cultured neuron cell networks without an adverse effect on cell viability 31 , and such networks can be injected by syringe through needles into materials, including brain tissue 32 . In the latter case, it remains challenging to make electrical in...

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 biomoleculepermeable 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.field-effect transistor | Debye screening | surface modification | DNA aptamer receptor | polyethylene glycol N anoelectronic biosensors offer broad capabilities for label-free high-sensitivity real-time detection of biological species that are important to both fundamental research and biomedical applications (1-6). In particular, field-effect transistor (FET) biosensors configured from semiconducting nanowires (1, 2), single-walled carbon nanotubes (1, 3, 4), and graphene (1, 5, 6) have been extensively investigated since the first report of real-time protein detection using silicon nanowire devices (7). Subsequent studies have demonstrated highly sensitive and in some cases multiplexed detection of key analytes, including protein disease markers (8-10), nucleic acids (11-13), and viruses (14), as well as detection of protein-protein interactions (8,(15)(16)(17) and enzymatic activity (8).The success achieved with nanomaterial-based FET biosensors has been limited primarily to measurements in relatively low-ionicstrength nonphysiological solutions due to the Debye screening length (18,19). In short, the screening length in physiological solutions, <1 nm, reduces the field produced by charged macromolecules at the FET surface and thus makes real-time label-free detection difficult. The first method reported to overcome this ...

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.

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 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 2D nanowire nanoelectronic precursors, which are fabricated by conventional lithography. The 3D networks have porosities larger than 99%, contain approximately hundreds of addressable nanowire devices, and have feature sizes from the 10-μm scale (for electrical and structural interconnections) to the 10-nm 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 showed a >90% yield of active devices in the hybrid materials. The positions of the nanowire devices were located within 3D hybrid materials with ∼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 reveals a powerful approach to smart materials in which the capabilities of multifunctional nanoelectronics allow for active monitoring and control of host systems.smart systems | field-effect transistor | sensor S eamlessly merging functional electronic circuits in a minimally invasive manner with host materials in 3D could serve as a pathway for creating "very smart" systems, because this would transform conventional inactive materials into active systems. For example, embedded electronic sensor circuitry could monitor chemical, mechanical, or other changes throughout a host material, thus providing detailed information about the host material's response to external environments as well as desired feedback to the host and external environment (1, 2). Seamless and minimally invasive integration of electronics in 3D has not been achieved, except for our recent example of synthetic tissues (2). Though focused on biological systems, this previous work provides key constraints for achieving our goal of a general strategy for integration electronic networks with host materials, as follows. First, the addressable electronic networks must be macroporous, not planar, to enable 3D interpenetration with the host materials. Second, to minimize invasiveness of the macroporous electronic network it must have (i) microscale-to-nanoscale feature sizes, (ii) a small filling fraction with respect to the host (e.g., ≤1%), (iii) comparable or sof...