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Review
, 8 (10), 2304-14

Nanoelectronics Meets Biology: From New Nanoscale Devices for Live-Cell Recording to 3D Innervated Tissues

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Review

Nanoelectronics Meets Biology: From New Nanoscale Devices for Live-Cell Recording to 3D Innervated Tissues

Xiaojie Duan et al. Chem Asian J.

Abstract

High spatiotemporal resolution interfaces between electrical sensors and biological systems, from single live cells to tissues, is crucial for many areas, including fundamental biophysical studies as well as medical monitoring and intervention. Herein, we summarize recent progress in the development and application of novel nanoscale devices for intracellular electrical recording of action potentials and the effort of merging electronic and biological systems seamlessly in three dimensions by using macroporous nanoelectronic scaffolds. The uniqueness of these nanoscale devices for minimally invasive, large-scale, high spatial resolution, and three-dimensional neural activity mapping are highlighted.

Keywords: bioelectronics; electrochemistry; field-effect transistors; flexible electronics; nanostructures; neural mapping; synthetic biology.

Figures

Figure 1
Figure 1
Intracellular action potential recording with kinked nanowire FET devices: (a) schematic of kinked nanowire probe with encoded active region (pink) by dopant modulation during synthesis. Blue regions are nanowire source/drain (S/D); (b) SEM image of a doubly kinked nanowire with a cis configuration. Scale bar, 200 nm; (c) A 3D, free-standing kinked nanowire FET bent-up probe. The yellow arrow and pink star mark the nanoscale FET and SU-8, respectively. Scale bar, 5 μm; (d) Schematic of intracellular recording from cells cultured on PDMS substrate using bent-up kinked nanowire nanoprobes; (e) Transition from extracellular to intracellular signals during penetration of a kinked nanowire probe into a beating cardiomyocyte. Green and pink stars denote the positions of intracellular and extracellular peaks, respectively; (f) Steady-state intracellular recording; (g) Zoom-in of an intracellular action potential peak. The red-dashed line corresponds to the intracellular rest potential. Reprinted with permission from Ref. [6b].
Figure 2
Figure 2
Kinked nanowire p-n junction probes: (a) Representative SEM image and schematic (inset) of a kinked p-n junction silicon nanowire with 120° tip angle. Scale bar, 1 μm; (b) Conductance versus water-gate potential recorded from a representative kinked p-n nanowire device in 1× phosphate buffer saline (PBS). Inset: schematic of conductance vs water-gate experiment; (c) Superposition of tmSGM and AFM topographic images of a representative kinked p-n nanowire device under Vtip of +5 V (left) and −5 V (right), respectively. Scale bars, 0.5 μm. The blue/red arrows indicate the p-type and n-type depletion/accumulation regions (left panel), respectively; the same positions show accumulation/depletion in the right panel. Insets: line profiles of the tmSGM signal along the white dashed lines about these p-type and n-type regions. Reprinted with permission from Ref. [6d].
Figure 3
Figure 3
Diverse functional kinked nanowire structures for nanoelectronic bioprobes: (a) SEM image of a 3D probe device fabricated using a 30 nm diameter U-shaped kinked nanowire building blocks. Scale bar, 3 μm. Inset, schematic of a U-shaped kinked nanowire with tip constructed from three 120° cis-linked kinks. The lightly doped n-type nanoFET element (pink) is encoded at the tip and connected by heavily doped n++ S/D arms (blue); (b) Dark-field optical microscopy image of a KOH-etched kinked nanowire with 4 nanoFETs. The dark segments correspond to the four lightly doped nanoFET elements (red arrows). Scale bar, 2 μm. Inset, schematic of the probe design; (c) Dark-field optical microscopy image of KOH etched W-shaped kinked nanowire. The two dark color segments correspond to the lightly doped nanoFET elements (red arrows) near the two tips. Scale bar, 2 μm. Inset, schematic of the probe design; (d) SEM image of W-shaped parallel-nanoFET kinked nanowire bend-up probe. Scale bar, 20 μm; (e) W-shaped kinked nanowire with multiple nanoFETs (red) illustrated as a bioprobe for simultaneous intracellular/extracellular recording. Green indicates heavily doped (n++) S/D nanowire nanoelectrode arms, red highlights the pointlike active nanoFET elements, and gold indicates the fabricated metal interconnects. Reprinted with permission from Ref. [15].
Figure 4
Figure 4
BIT-FET nanoprobes for intracellular action potential recording: (a) Schematic illustrating the working principle of the BIT-FET; (b) Calculated bandwidth of the BIT-FET device versus the inner diameter of the nanotube for fixed nanotube length of 1.5 μm. Inset, SEM image of a BIT-FET device. Scale bar, 200 nm; (c) Representative trace (conductance versus time) reflecting the transition from extracellular to intracellular recording; (d) Trace corresponding to the second entry of the BIT-FET nanotube at approximately the same position on the cell as in (c). Reprinted with permission from Ref. [6c].
Figure 5
Figure 5
Intracellular recording with the ANTT probe: (a) Schematic illustration of the working principle of the ANTT probe; (b) SEM image of an ANTT probe. Scale bar, 10 μm. Inset, zoom of the probe tip from the dashed red box. Scale bar, 100 nm; (c) Representative intracellular action potential peak recorded with an ANTT probe; (d) Schematic of chip-based vertical ANTT probe arrays fabricated from epitaxial Ge/Si nanowires for enhanced integration. Reprinted with permission from Ref. [6e].
Figure 6
Figure 6
Multiplexed intracellular action potential recording: (a) Optical image of two BIT-FET devices (yellow dots) coupled to a single cardiomyocyte cell. Cell boundary is marked by the yellow dashed line. Scale bar, 10 μm; (b) Simultaneously recorded traces from the two devices in a, corresponding to the transition from extracellular to intracellular recording; (c) Design and SEM image of a probe with two independent ANTT devices. Scale bar, 5 μm; (d) Intracellular recording from a single cardiomyocyte using a probe with two independent ANTT devices. The interval between tick marks is 1 s; (e) Optical image of three BIT-FET devices coupled to a beating cardiomyocyte cell network. Scale bar, 30 μm; (f) Representative intracellular signals recorded simultaneously from the devices shown in e. Reprinted with permission from Ref. [6c, e].
Figure 7
Figure 7
Merging nanoelectronics with artificial tissues seamlessly in three dimension. Reprinted with permission from Ref. [8a].
Figure 8
Figure 8
Reticular nanoES: (a) Device fabrication schematics for reticular nanoES. Light blue: silicon oxide substrates; blue: nickel sacrificial layers; green: nanoES; yellow dots: individual nanowire FETs; (b) 3D reconstructed confocal fluorescence micrographs of reticular nanoES viewed along the y (I) and x (II) axes. Solid and dashed open magenta squares indicate two nanowire FET devices located on different planes along the x axis. Scale bars, 20 μm; (c) SEM image of a single kinked nanowire FET within a reticular scaffold, showing (1) the kinked nanowire, (2) metallic interconnects (dashed magenta lines) and (3) the SU-8 backbone. Scale bar, 2 μm. Reprinted with permission from Ref. [8a].
Figure 9
Figure 9
Mesh nanoES: (a) Device fabrication schematics for mesh nanoES. The color designation is same as Figure 8a; (b) SEM image of a 2D macroporous nanoelectronic network before release from the substrate. (Inset) Zoom-in of the region enclosed by the small red dashed box containing a single nanowire device; (c) Photograph of a manually scrolled-up 3D macroporous nanoelectronic network. (d) 3D reconstructed confocal fluorescence image of self-organized 3D macroporous nanoelectronic network viewed along the x-axis; (e) Strategy for preparing 3D macroporous nanoelectronic networks using nanowires with variations in composition, morphology, and doping for diverse device functionality. Reprinted with permission from Ref. [8].
Figure 10
Figure 10
3D nanoelectronics/tissue hybrids: (a, b) 3D reconstructed confocal images of rat hippocampal neurons after a two-week culture on a reticular nanoES. The white arrow highlights a neurite passing through a ring-like structure supporting a nanowire FET. Dimensions in a, x: 317 μm; y: 317 μm; z: 100 μm; in b, x: 127 μm; y: 127 μm; z: 68 μm; (c) Confocal fluorescence micrographs of a synthetic cardiac patch. (II and III), Zoomed-in view of the upper and lower dashed regions in I, Scale bar, 40 μm; (d) Epifluorescence micrograph of the surface of the cardiac patch. Green: α-actin; blue: cell nuclei. The dashed lines outline the position of the S/D electrodes. Scale bar, 40 μm; (e) Conductance versus time traces recorded from a single nanowire FET before (black) and after (blue) applying noradrenaline; (f) Multiplexed electrical recording of extracellular field potentials from four nanowire FETs at different depth in a nanoES/cardiac hybrid. Reprinted with permission from Ref. [8a].
Figure 11
Figure 11
Synthetic vascular construct for 3D sensing: (a) Schematic of the smooth muscle nanoES. The upper panels are the side view, and the lower one is a zoom-in view. Grey: mesh nanoES; blue fibers: collagenous matrix secreted by HASMCs; yellow dots: nanowire FETs; pink: HASMCs; (b) (I) Photograph of a single HASMC sheet cultured with sodium L-ascorbate on a nanoES. (II) Zoomed-in view of the dashed area in I. Scale bar, 5 mm; (c) Photograph of the vascular construct after rolling into a tube and maturation in a culture chamber for three weeks. Scale bar, 5 mm; (d) Changes in conductance over time for nanowire FET devices located in the outermost (red) and innermost (blue) layers. The inset shows a schematic of the experimental set-up. Outer tubing delivered bathing solutions with varying pH (red dashed lines and arrows); inner tubing delivered solutions with fixed pH (blue dashed lines and arrows). Reprinted with permission from Ref. [8a].
Figure 12
Figure 12
3D macroporous nanoelectronic photodetectors and device localization: (a) Schematics of the nanowire photodetector characterization. Green ellipse is the scanned laser spot; blue cylinder, nanowire; orange, SU-8 mesh network (I). Changes in the conductance of the nanowire during scanning (II) can be correlated with position. Green spots in II represents the laser spots in I; (b) 3D reconstructed photocurrent image overlapped with confocal microscopy imaging shows the spatial correlation between nanowire photodetectors and the SU-8 framework in 3D. Green, false color of the photocurrent signal; orange (rhodamine 6G), SU-8 mesh network. Dimensions in I, x: 317 μm; y: 317 μm; z: 53 μm; II, x: 127 μm; y: 127 μm; z: 65 μm. The white numbers in II indicate the heights of the nanowire photodetectors. Reprinted with permission from Ref. [8b].
Figure 13
Figure 13
The 3D macroporous nanoelectronic strain sensors and strain field mapping: (a) Micro-CT 3D reconstruction of the mesh network embedded in a piece of elastomer; (b) Dark-field microscopy image of a typical nanowire device indicated by red dash circle in a. The white arrow points to a nanowire; (c, d) The 3D mapping of the strain field applied in the deformed elastomer recorded with the nanowire strain sensors. The detected strains are marked at the device positions in the cylinder image. Reprinted with permission from Ref. [8b].
Figure 14
Figure 14
Overview of the new fundamental studies and novel directions in biomedical research and applications enabled by the progress at nanoelectronics-biology interface. These new studies benefit from unique features of the nanoelectronics.

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