Talking to cells: semiconductor nanomaterials at the cellular interface

Abstract

The interface of biological components with semiconductors is a growing field with numerous applications. For example, the interfaces can be used to sense and modulate the electrical activity of single cells and tissues. From the materials point of view, silicon is the ideal option for such studies due to its controlled chemical synthesis, scalable lithography for functional devices, excellent electronic and optical properties, biocompatibility and biodegradability. Recent advances in this area are pushing the bio-interfaces from the tissue and organ level to the single cell and sub-cellular regimes. In this progress report, we will describe some fundamental studies focusing on miniaturizing the bioelectric and biomechanical interfaces. Additionally, many of our highlighted examples involve freestanding silicon-based nanoscale systems, in addition to substrate-bound structures or devices; the former offers new promise for basic research and clinical application. In this report, we will describe recent developments in the interfacing of neuronal and cardiac cells and their networks. Moreover, we will briefly discuss the incorporation of semiconductor nanostructures for interfacing non-excitable cells in applications such as probing intracellular force dynamics and drug delivery. Finally, we will suggest several directions for future exploration.

Keywords: bioelectronics; mechanical; nanowires; optical; silicon.

Figure 1.. Semiconductor-enabled advances in traditional electrophysiology tools.

(A) The Neuropixels probe, showing checkerboard site layout (left), a Scanning electron microscopy (SEM) of a probe tip (upper right), and one approximate probe location overlaid on the Allen Mouse Brain Atlas (lower right). (B) Quantum dot-assisted dendritic patching. A QD 625–coated pipette was used to record the electrical activities from the apical trunk of an in vitro CA1 pyramidal cell (labeled with Alexa Fluor 488). Sequential images i–iii (upper right) showed the patch formation. With this approach, uncaging-evoked excitatory postsynaptic potentials can be recorded from a dendrite (lower right). (A) Reproduced with permission.^[24] Copyright 2017, Springer Nature. (B) Reproduced with permission.⁴⁴ Copyright 2014, Springer Nature.

Figure 2.. Microelectrode arrays for electrical recording from neurons.

(A) SEM image of Au mushroom-shaped microelectrode, and (B) Transmission electron microscopy image of Au mushroom-shaped microelectrode engulfed by a cell. The engulfment of the electrode dramatically improves the cellular-electrode electrical coupling. (C) False-colored SEM image of a nanowire array, showing metal tip (gray) and the insulating silicon dioxide stem (blue). The array was used for intracellular recording from neurons. (D) The nanowires penetrated the rat cortical cell (false-colored yellow), while the insolation layer of silicon dioxide allows the electrode to record electrical activity from the intracellular region alone, maximizing the signal-to-noise ratio. (A) Reproduced under the terms of the Creative Commons Attribution 4.0 International License. Copyright 2015, Springer Nature. Reproduced with permission.^[43] Copyright 2012, Springer Nature.

Figure 3.. Mesostructured and deformable Si particles for optically controlled neuromodulation.

(A) SEM image of the nanoporous Si, showing periodic arrangement of Si nanowire assembly. (B) Schematic diagram of the experimental setup (left) for neuromodulation. AMP, amplifier; LPF, low-pass filter; ADC, analog-to-digital converter; AOM, acousto-optic modulator; ND, neutral density filters; DIC, dichroic mirror; OBJ, microscope objective. Patch clamp recordings (right) of a DRG neuron that was subjected to stimulation at different frequencies (5.32 μJ for each pulse), with corresponding FFTs (right). f₀ and f are input and output frequencies, respectively. Green bars show the laser pulse locations. (C) A Box-and-whisker plot of the Young’s moduli of nanoporous Si. The boxes include half of the data points, while the whiskers contain 80% of the points. Solid and dashed lines denote the medians and means, respectively. The dots are the maximum and minimum values. The p-value (the number above the bar) is from the Mann-Whitney test. (D) A schematic diagram for the single-cell calcium assay (upper left), with (∆F/F₀) and ((dF/dt)/F₀) defined below. A scattered plot (right) for the amplitude and slope values of the calcium dynamics shows that porous Si is mechanically less invasive. Insets show the 2D distribution histograms. See original paper for details. Reproduced with permission.^[51] Copyright 2016, Springer Nature.

Figure 4.. Photodiode devices for optically-controlled neuromodulation.

(A) SEM image of a hexagonal array of three-diode pixels used for subretinal implant. (B) Zoom-in view of one of the pixels. (C and D) SEM images of coaxial p-type/intrinsic/n-type Si nanowires, used for nanoscale photovoltaic studies. The cross-sectional image (D) shows the coaxial structure with dopant modulation. This structure has the potential for subcellular-level neuromodulation. (A and B) Reproduced with permission.⁹¹ Copyright 2012, Springer Nature. (C and D) Reproduced with permission.^[62] Copyright 2007, Springer Nature.

Figure 5.. 3D Si nanowire FETs for cardiac recording.

(A) Kinked nanowire probe for intracellular recording, showing an SEM image of a device (upper left), schematic diagrams of the material design (lower left), and representative electrical recordings (right). During the experiment, extracellular recording (I) was obtained, followed by the transitions (II) into internal recording until it maintained steady-state intracellular recording (III). Scale bar, 5 µm. (B) Multiplexed recording is possible by using two independent nanoFETs mounted over micromanipulators (upper). Two probes, P1 and P2, were positioned at two adjacent cardiomyocytes (lower left). Alternatively, they were placed in two different subcellular locations of the same cardiomyocyte (lower right). Scale bars, 1 cm (upper) and 10 µm (lower). (C) A schematic illustration (upper) and an SEM image (lower) of a branched nanotube-enabled nanoFET intracellular recording device, where the intracellular fluid can be introduced to the nanoFET by a silicon dioxide nanotube. (A) Reproduced with permission.^[11] Copyright 2010, AAAS. (B) Reproduced with permission.^[12] Copyright 2014, Springer Nature. (C) Reproduced with permission.^[13] Copyright 2012, Springer Nature.

Figure 6.. Nanoelectronic scaffold for cardiac mapping.

(A) Schematic diagrams of a folded free-standing nanoelectronics scaffold, showing addressable FET sensors distributed over four different layers and engineered cardiac tissue. The inset highlights the individual FETs (blue circles). (B) Electrical recording traces from 16 FETs in the top layer (L1) of the hybrid construct. The (x, y) coordinates of each FET are shown. (C) Zoom-in view of single AP spikes. Reproduced with permission. ^[14] Copyright 2016, Springer Nature.

Figure 7.. Si nanostructures for mechanical measurements.

(A-B), Si nanowires can be internalized into cells (A), while their nanoscale 1D geometry promotes their flexibility, force applied by cells (C) can be monitored by the mechanical deformation of the nanowires. (C-D), Skeleton-like Si spicules can be synthesized using 3D lithography by controlling atomic Au diffusion during a nanowire growth. These structures can be mounted on an AFM cantilever and used to probe the force applied to them by poking in and out collagen hydrogel, and generating F-D curves (C). Statistical analysis shows that anisotropy at the mesoscale can enhance Si’s interaction with collagen (D). (A and B) Reproduced with permission.¹³² Copyright 2015, ACS Publications‏. (C and D) Reproduced (Adapted) with permission.^[92] Copyright 2015, AAAS.