The peak amplitude, shape, and width are consistent with extracellular recordings
from cardiomyocytes [ 20 ]. We investigate the potential of the nanoES based 3D
cardiac culture for monitoring appropriate pharmacological response by dosing the
3D cardiomyocyte mesh construct with norepinephrine, a drug that stimulates
cardiac contraction viab 1 -adrenergic receptors [ 44 ]. Measurements from the same
nanowire FET device showed a twofold increase in contraction frequency following
drug application. Interestingly, recording from two nanowire FETs from the cardiac
patch upon norepinephrine application showed sub-millisecond and millisecond
level, heterogeneous cellular responses to the drug (Fig.4.16a–c). Additionally,
simultaneous recordings from 4 nanowire FETs with separations up to 6.8 mm in a
nanoES/cardiac construct (Fig.4.16d) demonstrated multiplexed sensing of a
coherently beating cardiac patch, with sub-millisecond time resolution. Our current
device design yields relatively sparse device distribution with 60 devices over a ca.
3.51.5 cm^2 area. Increases in nanowire FET density, the use of cross-bar circuits
and implementing multiplexing/demultiplexing for addressing [ 40 ], could allow the
nanoES scaffolds to map cardiac and other synthetic tissue electrical activities over
the entire constructs at high-density in 3D.
Last, we demonstrate multiplexing measurement of 3D response to chemical
activation from nanoES/neural construct (Fig.4.17). We stimulate the hybrid
construct by applying glutamate to the culture medium. Recording from three
devices in 3D self-organized that distributed from surface to the bottom of con-
struct, we can observe sequential localfield potential changes due to the diffusion of
glutamate from surface into construct. Importantly, the slow diffusion of glutamate
molecule into the construct demonstrates a seamless integration between nanoES
and neural construct in 3D. Together these experiments suggest nanoES constructs
can monitor in vitro the response to drugs from 3D tissue models, and thus have
potential as a platform for in vitro pharmacological studies [ 9 , 10 ].
We have also extended our approach towards development of artificial tissue
with nanoES. Specifically, vascular nanoES constructs were prepared by processes
analogous to those used for tissue engineered autologous blood vessels [ 31 , 45 ]
except the addition of the nanoES (Fig.4.18). HASMCs were cultured on 2D mesh
nanoES with sodium ascorbate to promote deposition of natural ECM. The hybridJFig. 4.16 Multiplexed electrical recording from nanoES innervated synthetic cardiac patch.
aElectrical recording traces from two devices in a cardiac patch, before (left), during (middle) and
after (right) Norepinephrine application. We callDtNas the temporal difference between a pair of
spikes from two devices,tN−tN−1 as the interval between consecutive spikes from a single
device,Nas the spike index.bThe time (t) versus spike index (N) plot. The color coding for
devices is the same as in (a). The data show that the cells exhibit overall coherent beating and
response to the drug. The right panel is the zoom-in view of the transition, where the middle point
(N = 23) shows a decreasedDtNcompared to earlier and later spikes.cTheDtNversus N plot.
hiDtN and 1 SD (standard deviation) before (−) and after (+) norepinephrine application show that
although the drug has minimum effect onhiDtN, the sub-millisecond and millisecondfluctuations
ofDtN(1 SD) increase by*10 fold following drug addition. Such stochastic variation suggests
millisecond-level, heterogeneous cellular responses to the drug.dMultiplex electrical recording of
extracellularfield potentials from 4 nanowire FETs (a–d) in a mesh nanoES
58 4 Three-Dimensional Macroporous Nanoelectronics...