Understanding biological systems and mimicking their functions require electronic tools that can interact with biological tissues with matched softness. These tools involve biointerfacing materials ...that should concurrently match the softness of biological tissue and exhibit suitable electrical conductivities for recording and reading bioelectronic signals. However, commonly employed intrinsically soft and stretchable materials usually contain solvents that limit stability for long-term use or possess low electronic conductivity. To date, an ultrasoft (i.e., Young's modulus <30 kPa), conductive, and solvent-free elastomer does not exist. Additionally, integrating such ultrasoft and conductive materials into electronic devices is poorly explored. This article reports a solvent-free, ultrasoft and conductive PDMS bottlebrush elastomer (BBE) composite with single-wall carbon nanotubes (SWCNTs) as conductive fillers. The conductive SWCNT/BBE with a filler concentration of 0.4 - 0.6 wt% reveals an ultralow Young's modulus (<11 kPa) and satisfactory conductivity (>2 S/m) as well as adhesion property. Furthermore, we fabricate ultrasoft electronics based on laser cutting and 3D printing of conductive and non-conductive BBEs and demonstrate their potential applications in wearable sensing, soft robotics, and electrophysiological recording.
Emerging heart-on-a-chip platforms are promising approaches to establish cardiac cell/tissue models in vitro for research on cardiac physiology, disease modeling and drug cardiotoxicity as well as ...for therapeutic discovery. Challenges still exist in obtaining the complete capability of in situ sensing to fully evaluate the complex functional properties of cardiac cell/tissue models. Changes to contractile strength (contractility) and beating regularity (rhythm) are particularly important to generate accurate, predictive models. Developing new platforms and technologies to assess the contractile functions of in vitro cardiac models is essential to provide information on cell/tissue physiologies, drug-induced inotropic responses, and the mechanisms of cardiac diseases. In this review, we discuss recent advances in biosensing platforms for the measurement of contractile functions of in vitro cardiac models, including single cardiomyocytes, 2D monolayers of cardiomyocytes, and 3D cardiac tissues. The characteristics and performance of current platforms are reviewed in terms of sensing principles, measured parameters, performance, cell sources, cell/tissue model configurations, advantages, and limitations. In addition, we highlight applications of these platforms and relevant discoveries in fundamental investigations, drug testing, and disease modeling. Furthermore, challenges and future outlooks of heart-on-a-chip platforms for in vitro measurement of cardiac functional properties are discussed.
Alteration of tissue mechanical properties is a physical hallmark of solid tumors including gliomas. How tumor cells sense and regulate tissue mechanics is largely unknown. Here, we show that ...mechanosensitive ion channel Piezo regulates mitosis and tissue stiffness of Drosophila gliomas, but not non-transformed brains. PIEZO1 is overexpressed in aggressive human gliomas and its expression inversely correlates with patient survival. Deleting PIEZO1 suppresses the growth of glioblastoma stem cells, inhibits tumor development, and prolongs mouse survival. Focal mechanical force activates prominent PIEZO1-dependent currents from glioma cell processes, but not soma. PIEZO1 localizes at focal adhesions to activate integrin-FAK signaling, regulate extracellular matrix, and reinforce tissue stiffening. In turn, a stiffer mechanical microenvironment elevates PIEZO1 expression to promote glioma aggression. Therefore, glioma cells are mechanosensory in a PIEZO1-dependent manner, and targeting PIEZO1 represents a strategy to break the reciprocal, disease-aggravating feedforward circuit between tumor cell mechanotransduction and the aberrant tissue mechanics.
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•Drosophila Piezo regulates cell proliferation and tissue stiffening of gliomas•Human PIEZO1 is overexpressed in aggressive gliomas and predicts poor survival•Piezo/PIEZO1 interacts with integrin-FAK signaling to regulate tumor stiffness•PIEZO1 co-opts aberrant tissue mechanics to promote glioma aggression
PIEZO1 is an ion channel that converts mechanical stimuli into cellular signaling. Here, Chen et al. perform multi-species studies to define a feedforward circuit mediated by PIEZO1 and tumor tissue mechanics to promote glioma growth.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Measuring the 3D morphology of spherical cell aggregates is required in both biology and medicine. Traditional methods either use fluorescent labeling, which cause cell toxicity and are unsuitable ...for clinical treatment, or use 2D images to roughly estimate 3D morphology. To overcome these limitations, this paper presents a quantitative label-free 3D morphology measurement technique using multi-view images. This technique, for the first time, enables the morphological evaluation of a blastocyst (Day 5 embryo) from "all angles" for IVF treatment. In this technique, a spherical rotation scale invariant feature transform (SR-SIFT) is proposed to address feature distortions for the rotation matrix calculation of the multi-view images. U-Net with generalized Dice loss is used to segment individual trophectoderm (TE) cells and the inner cell mass (ICM) of the blastocyst. Based on the rotation matrices and the segmentation results, the 3D morphological parameters of the entire blastocyst were quantified. Experimental results showed that the error of rotation angle was less than 1<inline-formula><tex-math notation="LaTeX">^\circ</tex-math></inline-formula>, the Dice was 95.6% for TE segmentation and 92.3% for ICM segmentation, and the overall measurement error of clinically defined blastocyst parameters was less than 6.7%.
Soft tissue cutting is used for incision, separation and removal of tissues or cells. Due to the high deformation of soft tissues resulting from their viscoelasticity, it is challenging to accurately ...cut the tissue along a desired path and control the force applied to the tissue for reducing invasiveness, especially at the microscale. This paper presents a robotic biopsy system for cutting and collecting trophectoderm (TE) cells from a blastocyst (Day 5 embryo). The system, for the first time, enables TE cell junction detection for laser ablation throughout the blastocyst biopsy process by using U-Net with a modified Dice loss. A dynamics model taking into account cell mechanical properties was established to describe the motion of the TE cells inside a biopsy micropipette. Based on the model, an integral-based adaptive control method was developed for TE cell aspiration and positioning inside the biopsy micropipette. Experimental results revealed that the controller was capable of effectively compensating for the cell positioning error by updating the varying system parameters according to the update law. The biopsy success rate was 100% and the average biopsy time is 25 s. Compared to manual blastocyst biopsy, the robotic biopsy system reduced the necessary number of laser pulses (<inline-formula><tex-math notation="LaTeX">\sim</tex-math></inline-formula>5 vs. <inline-formula><tex-math notation="LaTeX">\sim</tex-math></inline-formula>7), reduced the number of lost nuclei in the collected TE cells (8% vs. 36%), and shortened the blastocyst.s recovery time (35 min vs. 50 min), indicating lower invasiveness to both the blastocyst and the collected TE cells.
Electrochemiluminescence (ECL) detection is one of the most prevailing electrochromism approaches to test biotin and chemicals. As thorny ECL signals by impurities are devastative in judging the ...right substance and its concentration precisely, it is crucial to dispose the noise and process it into smooth curves without filtering essential biochemical information conveyed in the signal. This contribution investigates Singular Value Ratio (SVR) spectrum to extract periodic signals from every noise ECL signal. A novel improved method of rearranging periodic compositions from complex signals is proposed. Finally, actual ECL signal generated by Ru(bpy)32+ is analyzed and optimized to demonstrate that the improved technique is efficacious and feasible. Keywords: Electrochemiluminescence (ECL), Periodic signal extraction, Singular value decomposition (SVD), Singular value ratio (SVR)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heart failure fundamentally results from loss of cardio myocyte contractility. Developing new methods that quantify the contractile stress of the human cardiomyocyte would facilitate the study of the ...molecular mechanism of heart failure and advance therapy development, to improve the current five year survival for these patients. The measurement of cellular electrical impedance measurement was recently applied to monitor cardiomyocyte beating rate and rhythm, for the study at cellular maturation, and for drug screening. However, due to the lack of a quantified relationship between the impedance signal and contractile stress, change of cardiomyocyte contractile stress cannot genuinely be quantified from impedance measurements. Here, we report the first quantitative relationship between contractile stress and impedance, which enables the accurate prediction of cardiomyocyte contractility using impedance signals. Through simultaneous measurement of beating human iPSC-cardiomyocytes using impedance spectroscopy and atomic force microscopy, a power-law relationship between impedance and contractile stress was established with a confidence level of 95%. The quantitative relationship was validated using pharmacology known to alter cardiomyocyte contractility and beating (verapamil, using clinically relevant concentrations of 0.05 μM, 0.10 μM, and 0.15 μM). The contractile stress values as measured by AFM were 9.04 ± 0.14 kPa (0.05 μM), 7.72 ± 0.11 kPa (0.10 μM) and 6.23 ± 0.17 kPa (0.15 μM), and as predicted by impedance using the derived power-law relationship were 9.39 kPa, 7.76 kPa, and 6.05 kPa with a relative error of 3.73%. Our power-law relationship is the first to describe a quantitative correlation between contractile stress and impedance, broadening the application of electrical impedance measurement for characterizing complex cardiac functions (beating rate, beating rhythm and contractile stress).
•We report a quantitative power-law relationship between contractile stress generated by cardiomyocytes and impedance.•The established relationship was validated by treating the cardiomyocytes with different concentrations of medication.•The impedance-predicted contractile stress values were compared with those measured by AFM.•The quantitative relationship between contractile stress and impedance broadens the impedance measurement applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Emerging heart-on-a-chip technology is a promising tool to establish in vitro cardiac models for therapeutic testing and disease modeling. However, due to the technical complexity of integrating cell ...culture chambers, biosensors, and bioreactors into a single entity, a microphysiological system capable of reproducing controlled microenvironmental cues to regulate cell phenotypes, promote iPS-cardiomyocyte maturity, and simultaneously measure the dynamic changes of cardiomyocyte function in situ is not available. This paper reports an ultrathin and flexible bioelectronic array platform in 24-well format for higher-throughput contractility measurement under candidate drug administration or defined microenvironmental conditions. In the array, carbon black (CB)-PDMS flexible strain sensors were embedded for detecting iPSC-CM contractility signals. Carbon fiber electrodes and pneumatic air channels were integrated to provide electrical and mechanical stimulation to improve iPSC-CM maturation. Performed experiments validate that the bioelectronic array accurately reveals the effects of cardiotropic drugs and identifies mechanical/electrical stimulation strategies for promoting iPSC-CM maturation.
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Cardiac conduction is an important function of the heart. To date, accurate measurement of conduction velocity (CV) in vitro is hindered by the low spatial resolution and poor signal-to-noise ratio ...of microelectrode arrays (MEAs), or the cytotoxicity and end-point analysis of fluorescence optical imaging. Here, we have developed a new label-free method based on defocused brightfield imaging to quantify CV by analyzing centroid displacements and contraction trajectories of each cardiomyocyte in a monolayer of human stem cell-derived cardiomyocytes (iPSC-CMs). Our data revealed that the time delay between intracellular calcium release and the initiation of cell contraction is highly consistent across cardiomyocytes; however, the duration a cell takes to reach its maximum beating magnitude varies significantly, proving that the time delay in excitation-contraction coupling is largely constant in iPSC-CMs. Standard calcium imaging of the same iPSC-CM populations (~106 cells) was conducted for comparison with our label-free method. The results confirmed that our label-free method was capable of achieving highly accurate CV mapping (17.64 ± 0.89 cm/s vs. 17.95 ± 2.29 cm/s, p-value>0.1). Additionally, our method effectively revealed various shapes in cell beating pattern. We also performed label-free CV mapping on disease-specific iPSC-CM monolayers with plakophilin-2 (PKP2) knockdown, which effectively quantified their low CV values and further validated the arrhythmogenic role of PKP2 mutation in arrhythmogenic right ventricular cardiomyopathy (ARVC) through the disruption of cardiac conduction. The label-free method offers a cytotoxic-free technique for long-term measurement of dynamic beating trajectories, beating propagation and conduction velocities of cardiomyocyte monolayers.
•The label-free method effectively maps conduction velocity (CV) of iPSC-cardiomyocyte monolayers.•Long-term and cytotoxicity-free measurement of cell beating trajectories and beating propagation waveforms.•This technique accurately quantified the low CV values and arrhythmic beatings of iPSC-CM monolayers with PKP2 knockdown.•The results confirmed the arrhythmogenic role of PKP2 mutation in arrhythmogenic right ventricular cardiomyopathy (ARVC).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heart beating is triggered by the generation and propagation of action potentials through the myocardium, resulting in the synchronous contraction of cardiomyocytes. This process highlights the ...importance of electrical and mechanical coordination in organ function. Investigating the pathogenesis of heart diseases and potential therapeutic actions in vitro requires biosensing technologies which allow for long-term and simultaneous measurement of the contractility and electrophysiology of cardiomyocytes. However, the adoption of current biosensing approaches for functional measurement of in vitro cardiac models is hampered by low sensitivity, difficulties in achieving multifunctional detection, and costly manufacturing processes. Leveraging carbon-based nanomaterials, we developed a biosensing platform that is capable of performing on-chip and simultaneous measurement of contractility and electrophysiology of human induced pluripotent stem-cell-derived cardiomyocyte (iPSC-CM) monolayers. This platform integrates with a flexible thin-film cantilever embedded with a carbon black (CB)-PDMS strain sensor for high-sensitivity contraction measurement and four pure carbon nanotube (CNT) electrodes for the detection of extracellular field potentials with low electrode impedance. Cardiac functional properties including contractile stress, beating rate, beating rhythm, and extracellular field potential were evaluated to quantify iPSC-CM responses to common cardiotropic agents. In addition, an in vitro model of drug-induced cardiac arrhythmia was established to further validate the platform for disease modeling and drug testing.
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