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Introduction Doxorubicin (DOX), an anticancer drug used in chemotherapy, causes significant cardiotoxicity. This study aimed to investigate the effects of DOX on mouse cardiac electrophysiology, in conscious versus anesthetized state. Methods Male and female C57BL/6 mice were injected with saline, 20 or 30 mg/kg DOX. ECGs were recorded 5 days post‐injection in conscious and isoflurane anesthetized states. ECGs were analyzed using a custom MATLAB software to determine P, PR, QRS, QTc, and RR intervals as well as heart rate variability (HRV). Results ECGs from the same mouse demonstrated P wave and QTc shortening as well as PR and RR interval prolongation in anesthetized versus conscious saline‐treated mice. ECG response to DOX was also modulated by anesthesia. DOX treatment induced significant ECG modulation in female mice alone. While DOX20 treatment caused decrease in P and QRS durations, DOX30 treatment‐induced QTc and RR interval prolongation in anesthetized but not in conscious female mice. These data suggest significant sex differences and anesthesia‐induced differences in ECG response to DOX. HRV measured in time and frequency domains, a metric of arrhythmia susceptibility, was increased in DOX20‐treated mice compared to saline. Conclusions This study for the first time identifies that the ECG response to DOX is modulated by anesthesia. Furthermore, this response demonstrated stark sex differences. These findings could have significant implications in clinical diagnosis of DOX cardiotoxicity. Doxorubicin treatment in mice produces acute cardiotoxic ECG response. Female sex and isoflurane anesthesia are associated with greater cardiotoxicity.

Recently developed optically transparent microelectrode technology provides a promising approach for simultaneous high-resolution electrical and optical biointerfacing with tissues in vivo and in vitro. A critically unmet need is designing high-performance stretchable platforms for conformal biointerfacing with mechanically active organs. Here, we report silver nanowire (Ag NW) stretchable transparent microelectrodes and interconnects that exhibit excellent electrical and electrochemical performance, high optical transparency, superior mechanical robustness and durability by a simple selective-patterning process. The fabrication method allows the direct integration of Ag NW networks on elastomeric substrates. The resulting Ag NW interface exhibits a low sheet resistance (Rsh) of 1.52–4.35 Ω sq−1, an advantageous normalized electrochemical impedance of 3.78–6.04 Ω cm2, a high optical transparency of 61.3–80.5% at 550 nm and a stretchability of 40%. The microelectrode arrays (MEAs) fabricated with this approach exhibit uniform electrochemical performance across all channels. Studies on mice demonstrate that both pristine and stretched Ag NW microelectrodes can achieve high-fidelity electrophysiological monitoring of cardiac activity with/without co-localized optogenetic pacing. Together, these results pave the way for developing stretchable and transparent metal nanowire networks for high-resolution opto-electric biointerfacing with mechanically active organs, such as the heart.

Recording cell-specific neuronal activity while monitoring behaviors of freely moving subjects can provide some of the most significant insights into brain function. Current means for monitoring calcium dynamics in genetically targeted populations of neurons rely on delivery of light and recording of fluorescent signals through optical fibers that can reduce subject mobility, induce motion artifacts, and limit experimental paradigms to isolated subjects in open, two-dimensional (2D) spaces. Wireless alternatives eliminate constraints associated with optical fibers, but their use of head stages with batteries adds bulk and weight that can affect behaviors, with limited operational lifetimes. The systems introduced here avoid drawbacks of both types of technologies, by combining highly miniaturized electronics and energy harvesters with injectable photometric modules in a class of fully wireless, battery-free photometer that is fully implantable subdermally to allow for the interrogation of neural dynamics in freely behaving subjects, without limitations set by fiber optic tethers or operational lifetimes constrained by traditional power supplies. The unique capabilities of these systems, their compatibility with magnetic resonant imaging and computed tomography and the ability to manufacture them with techniques in widespread use for consumer electronics, suggest a potential for broad adoption in neuroscience research.

Optical fluorescence and electrical monitoring of cell activity are two powerful approaches to study organ functions. Simultaneous recording of optical and electrical data types will provide complementary information from and take advantage of each approach. However, devices that can concurrently record optical signals from the same cell population underneath the microelectrodes have not been widely explored and remain a grand technical challenge. This work presents an innovative flexible opto-electric device that monolithically integrates transparent gold nanogrid microelectrodes directly above microscale light-emitting diodes, photodetectors, and optical filters to achieve co-localized crosstalk-free optical fluorescence and electrical recording. The optimized gold nanogrid microelectrodes show excellent optical transparency (>81%) and low normalized 1 kHz electrochemical impedance (6.3 Ω cm2). The optical recording subsystem offers high wavelength selectivity (>1,300) and linearity (R2 >0.99) for exciting and capturing green fluorescence from various fluorescent reporters in measurement ranges relevant to in vivo applications with minimal thermal effects. The opto-electric device exhibits remarkable durability under soaking for 40 days and repetitive mechanical bending for 5,000 cycles. The work may provide a versatile approach for constructing mechanically compliant biointerfaces containing crosstalk-free optical and electrical modalities with widespread application potentials in basic and clinical research.Competing Interest StatementThe authors have declared no competing interest.

Bioelectronic devices that allow simultaneous accurate monitoring and control of the spatiotemporal patterns of cardiac activity provide an effective means to understand the mechanisms and optimize therapeutic strategies for heart disease. Optogenetics is a promising technology for cardiac research due to its advantages such as cell-type selectivity and high space-time resolution, but its efficacy is limited by the insufficient number of modulation channels and lack of simultaneous spatiotemporal mapping capabilities in current cardiac optogenetics tools. Here we present soft implantable electro-optical cardiac devices integrating multilayered highly uniform arrays of transparent microelectrodes and multicolor micro-light-emitting-diodes in thin, flexible platforms for mechanically compliant high-content electrical mapping and single-/multi-site optogenetics and electrical stimulation without light-induced artifacts. Systematic benchtop characterizations, together with ex vivo and in vivo evaluations on healthy and diseased small animal and human hearts demonstrate their functionalities in real-time spatiotemporal mapping and control of cardiac rhythm and function, with broad applications in basic and ultimately clinical cardiology. Competing Interest Statement The authors have declared no competing interest.

Abstract Transparent microelectrodes have recently emerged as a promising approach to combine electrophysiology with optophysiology for multifunctional biointerfacing. High-performance flexible platforms that allow seamless integration with soft tissue systems for such applications are urgently needed. Here, silver nanowires (Ag NWs)-based transparent microelectrodes and interconnects are designed to meet this demand. The Ag NWs percolating networks are patterned on flexible polymer substrates using an innovative photolithography-based solution-processing technique. The resulting nanowire networks exhibit a high average optical transparency of 76.1-90.0% over the visible spectrum, low normalized electrochemical impedance of 3.4-15 Ω cm2 at 1 kHz which is even better than those of opaque solid Ag films, superior sheet resistance of 11-25 Ω sq−1, excellent mechanical stability up to 10,000 bending cycles, good biocompatibility and chemical stability. Studies on Langendorff-perfused mouse and rat hearts demonstrate that the Ag NWs microelectrodes enable high-fidelity real-time monitoring of heart rhythm during co-localized optogenetic pacing and optical mapping with negligible light-induced electrical artifacts. This proof-of-concept work illustrates that the solution-processed, transparent, and flexible Ag NWs networks are a promising candidate for the next-generation of large-area multifunctional biointerfaces for interrogating complex biological systems in basic and translational research. Competing Interest Statement The authors have declared no competing interest.

The human heart is an efficient electromechanical pump which provides oxygen and nutrients to all human organs. Each heartbeat is ignited and synchronized by an electrical action potential initiating and rapidly propagating through the heart's electrical system. Cardiovascular diseases, a leading cause of death in humans, disrupt this synchronous excitation. Heart rhythm disorders, known as arrhythmias, are particularly deadly. Cardiac arrhythmias are primarily treated by implantable pacemakers and defibrillators because pharmacological treatments are mostly ineffective. In this work, we report on graphene-only cardiac pacemakers as advanced cardiac biointerfaces. Leveraging sub-micrometer thick tissue-conformable graphene arrays, we are able to sense from and stimulate the heart, altering its functions, suggesting that the devices can be used for high-density functional interfacing with the heart. The arrays show effective electrochemical properties, namely interface impedance down to 40 Ohm x cm2, charge storage capacity up to 63.7 mC/cm2, and charge injection capacity up to 704 uC/cm2. Transparency of the structures allows for simultaneous optical mapping of cardiac action potentials and calcium transients while performing electrical measurements. Upon validating the graphene-based cardiac pacing in ex vivo mouse hearts, we performed in vivo cardiac pacing in a rat model with clinically induced arrhythmia. The condition was successfully diagnosed and treated using graphene biointerfaces. Competing Interest Statement The authors have declared no competing interest.

BACKGROUND: The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38gamma and p38delta, remain uncharacterized. OBJECTIVES: To determine the potential cardioprotective effects of p38gamma and p38delta genetic deletion in mice subjected to acute DOX treatment. METHODS: Male and female wild-type (WT), p38gamma-/-, p38delta-/- and p38gamma-/-delta-/- mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: Significantly improved survival was observed in p38delta-/- female mice post-DOX relative to WT females, but not in p38gamma-/- or p38gamma-/-delta-/- male or female mice. The improved survival in DOX-treated p38delta-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38delta-/- females. CONCLUSIONS: p38delta plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38delta targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.

The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized. To determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment. Male and female wild-type (WT), p38γ-/-, p38δ-/- and p38γ-/-δ-/- mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. Significantly improved survival was observed in p38δ-/- female mice post-DOX relative to WT females, but not in p38γ-/- or p38γ-/-δ-/- male or female mice. The improved survival in DOX-treated p38δ-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38δ-/- females. p38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. This study for the first time identifies the roles of the alternative p38γ and p38δ MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38γ systemic deletion did not affect DOX-cardiotoxicity, p38δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ-/- females and autophagy was increased.