Mesh Nanoelectronics: Seamless Integration of Electronics with Tissues

Abstract

Nanobioelectronics represents a rapidly developing field with broad-ranging opportunities in fundamental biological sciences, biotechnology, and medicine. Despite this potential, seamless integration of electronics has been difficult due to fundamental mismatches, including size and mechanical properties, between the elements of the electronic and living biological systems. In this Account, we discuss the concept, development, key demonstrations, and future opportunities of mesh nanoelectronics as a general paradigm for seamless integration of electronics within synthetic tissues and live animals. We first describe the design and realization of hybrid synthetic tissues that are innervated in three dimensions (3D) with mesh nanoelectronics where the mesh serves as both as a tissue scaffold and as a platform of addressable electronic devices for monitoring and manipulating tissue behavior. Specific examples of tissue/nanoelectronic mesh hybrids highlighted include 3D neural tissue, cardiac patches, and vascular constructs, where the nanoelectronic devices have been used to carry out real-time 3D recording of electrophysiological and chemical signals in the tissues. This novel platform was also exploited for time-dependent 3D spatiotemporal mapping of cardiac tissue action potentials during cell culture and tissue maturation as well as in response to injection of pharmacological agents. The extension to simultaneous real-time monitoring and active control of tissue behavior is further discussed for multifunctional mesh nanoelectronics incorporating both recording and stimulation devices, providing the unique capability of bidirectional interfaces to cardiac tissue. In the case of live animals, new challenges must be addressed, including minimally invasive implantation, absence of deleterious chronic tissue response, and long-term capability for monitoring and modulating tissue activity. We discuss each of these topics in the context of implantation of mesh nanoelectronics into rodent brains. First, we describe the design of ultraflexible mesh nanoelectronics with size features and mechanical properties similar to brain tissue and a novel syringe-injection methodology that allows the mesh nanoelectronics to be precisely delivered to targeted brain regions in a minimally invasive manner. Next, we discuss time-dependent histology studies showing seamless and stable integration of mesh nanoelectronics within brain tissue on at least one year scales without evidence of chronic immune response or glial scarring characteristic of conventional implants. Third, armed with facile input/output interfaces, we describe multiplexed single-unit recordings that demonstrate stable tracking of the same individual neurons and local neural circuits for at least 8 months, long-term monitoring and stimulation of the same groups of neurons, and following changes in individual neuron activity during brain aging. Moving forward, we foresee substantial opportunities for (1) continued development of mesh nanoelectronics through, for example, broadening nanodevice signal detection modalities and taking advantage of tissue-like properties for selective cell targeting and (2) exploiting the unique capabilities of mesh nanoelectronics for tackling critical scientific and medical challenges such as understanding and potentially ameliorating cell and circuit level changes associated with natural and pathological aging, as well as using mesh nanoelectronics as active tissue scaffolds for regenerative medicine and as neuroprosthetics for monitoring and treating neurological diseases.

Figure 1

Seamless integration of mesh nanoelectronics with synthetic tissues and live animals. Mesh nanoelectronics with devices (top) can serve as active scaffolds for synthetic tissues (bottom left) or be delivered into live animals for integration and interrogation of neural tissue (bottom right).

Figure 2

Mesh nanoelectronics-innervated synthetic tissues. (A) Schematic of 2D mesh nanoelectronics (as fabricated) that is rolled up into 3D scaffolds; red dots indicate positions of addressable devices. (B) 3D reconstructed confocal fluorescence image of rat hippocampal neurons (red) cultured for two weeks in mesh nanoelectronics (yellow). Dimensions, x: 127 μm; y: 127 μm; z: 68 μm. (C) Multiplexed electrical recording of local field potential following glutamate addition (orange segments) without (top) and with (bottom) synaptic blockers. (D) Schematics of mesh nanoelectronics scaffold seeded with HASMCs (i), rolled into tubular structure (ii), and connected to tubing and PDMS chamber for endovascular and extravascular perfusion (iii). (E) Photographs of a single HASMC sheet cultured on mesh nanoelectronics scaffold (left) and zoom-in view (right) of dashed region. Scale bar, 5 mm. (F) Hematoxylin and eosin stained section cut perpendicular to the tube axis. Small black arrows mark positions of two mesh elements. Scale bar, 50 μm. (G) Changes in conductance over time from two nanowire FETs located in the outermost (red) and innermost (blue) layers of a mesh nanoelectronics-innervated blood vessel, where pH is varied in the outer tubing and fixed in the inner tubing. Reproduced with permission from ref . Copyright 2012 Nature Publishing Group.

Figure 3

3D mapping of APs in mesh nanoelectronics-innervated cardiac tissue. (A) Schematic illustrating the hybrid synthetic tissue formed by culturing cardiomyocytes in a folded 3D mesh nanoelectronics with red dots indicating silicon nanowire FETs. (B) Reconstructed 3D confocal fluorescence image of a mesh nanoelectronics-innervated cardiac tissue. Scale bars, 25 μm. (C) Simultaneous traces recorded from 16 sensors in the top layer (L1). (D) Isochronal map of time latency in L1. Mapping area, ~25 mm². (E) 3D isochronal latency maps from L1 – L4 for the 3D cardiac tissue. Mapping area, ~25 mm × 25 mm × 200 μm. (F) Schematic of the focal injection of norepinephrine. (G) Time-dependent traces from three sensors in L1, L2 and L3 with synchronized and periodic APs. The blue arrow indicates the injection of ~25 μL norepinephrine at a concentration of 100 μM. (H) Zoom-in of the four dashed boxes in (G), highlighting the time latency variation at different times relative to addition of norepinephrine. Reproduced with permission from ref . Copyright 2016 Nature Publishing Group.

Figure 4

Simultaneous recording and modulation of APs in mesh nanoelectronics-innervated cardiac tissue. (A) Schematic illustrating the positions of individually addressable stimulators (purple dots) in the 3D mesh nanoelectronics. (B) Time-dependent traces recorded from nanowire FETs in layers L1, L2 and L3 under a periodic biphasic stimulation spike train in L4. Blue asterisks highlight APs (downward spikes) versus capacitive coupling peaks (red dashed lines). (C–F) 3D isochronal time latency maps showing the original pacemaker foci location (blue arrow), and sequential 90° clockwise rotations of the AP propagation direction induced by the indicated simulators (purple dots in lower corners). Reproduced with permission from ref . Copyright 2016 Nature Publishing Group.

Figure 5

Syringe-injection of mesh nanoelectronics into live animals. (A) Schematic of syringe-injectable mesh nanoelectronics. Orange and red lines represent polymer-encapsulated metal interconnects and supporting polymer elements, respectively. The dashed boxes (bottom) highlights the regions of devices (red), metal interconnect lines (green) and metal I/O pads (black). (B) Bright-field image of mesh nanoelectronics loaded into a glass needle (inner diameter = 95 μm). (C) Bright-field image showing partially ejected mesh nanoelectronics through a glass needle, exhibiting significant expansion and unfolding of the mesh. (D) Semi-automated instrumentation for controlled injection of mesh nanoelectronics, highlighting the motorized translation stage for needle withdrawal (upper orange) and the camera for visualizing the mesh during injection (lower orange). (E) Micro-CT image showing two fully extended mesh nanoelectronics structures (green arrows) inside a mouse brain following controlled injection. Reproduced with permission from ref ,18. Copyright 2015 American Chemical Society and 2015 Nature Publishing Group.

Figure 6

Chronic tissue response of implanted mesh and conventional flexible electronics. Time-dependent immuno-histology images of horizontal brain slices containing flexible thin-film probes (A) and mesh nanoelectronics (B) at 2 weeks to 1 year post implantation. Plots at right of each image display fluorescence intensities versus distance from the probe/brain tissue interface and are normalized against background (black dashed horizontal lines). The pink shaded regions indicate the interior of mesh nanoelectronics. Reproduced with permission from ref ,19. Copyright 2016 Nature Publishing Group and 2017 National Academy of Sciences.

Figure 7

Long-term stable recording and stimulation of brain activity at the single-neuron level with mesh nanoelectronics. (A) Plug-and-play mesh nanoelectronics showing full view (top), zoom-in images (bottom, i–iii) and the insertion process (bottom, iv). (B) Photograph of the interface board cemented on the mouse skull forming a compact head-stage for recording from freely behaving animals. Inset: schematic showing electrical connection of 32-channel mesh nanoelectronics to a ZIF connector (red arrow) and a standard Omnetics connector (yellow arrow). (C) 16-channel multiplexed recording of LFP (background heat map) and single-unit firing (foreground black traces) from the same mouse brain at 2 and 4 months post injection. Leftmost panel, relative positions of the 16 recording electrodes. (D–G) Week 3 to 34 chronic tracking of the same three neurons by time-dependent PCA (D), averaged spike waveforms (E), ISI histogram (F) and phase locking spike firing rates to theta oscillation (G). (H) Peristimulus raster plot showing spike events (black ticks) of 150 stimulation trials (red solid line, stimulation pulse). (I) First spike latency histograms of stimulus-evoked firings at 4, 6 and 14 weeks post injection, with insets showing spike sorting (left) and PCA clustering results (right). Reproduced with permission from ref ,20. Copyright 2017 American Chemical Society and 2016 Nature Publishing Group.

Figure 8

Outlook of mesh nanoelectronics as synthetic tissue scaffolds and in vivo probes in nanotechnology, biological sciences and medicine.