Structural maturation of myofilaments in engineered 3D cardiac microtissues characterized using small angle x-ray scattering.

Understanding the structural and functional development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) is essential to engineering cardiac tissue that enables pharmaceutical testing, modeling diseases, and designing therapies. Here we use a method not commonly applied to biological materials, small angle x-ray scattering, to characterize the structural development of hiPSC-CMs within three-dimensional engineered tissues during their preliminary stages of maturation. An x-ray scattering experimental method enables the reliable characterization of the cardiomyocyte myofilament spacing with maturation time. The myofilament lattice spacing monotonically decreases as the tissue matures from its initial post-seeding state over the span of 10 days. Visualization of the spacing at a grid of positions in the tissue provides an approach to characterizing the maturation and organization of cardiomyocyte myofilaments and has the potential to help elucidate mechanisms of pathophysiology, and disease progression, thereby stimulating new biological hypotheses in stem cell engineering.

Zeptonewton and attotesla per centimeter metrology with coupled oscillators.

We present the coupled oscillator: A new mechanism for signal amplification with widespread application in metrology. We introduce the mechanical theory of this framework and support it by way of simulations. We present a particular implementation of coupled oscillators: A microelectromechanical system (MEMS) that uses one large (∼100mm) N52 magnet coupled magnetically to a small (∼0.25mm), oscillating N52 magnet, providing a force resolution of 200zN measured over 1s in a noiseless environment. We show that the same system is able to resolve magnetic gradients of 130aT/cm at a single point (within 500µm). This technology, therefore, has the potential to revolutionize force and magnetic gradient sensing, including high-impact areas such cardiac and brain imaging.

Modal engineering of electromagnetic circuits to achieve rapid settling times.

Inductive circuits and devices are ubiquitous and important design elements in many applications, such as magnetic drives, galvanometers, magnetic scanners, applying direct current (DC) magnetic fields to systems, radio frequency coils in nuclear magnetic resonance (NMR) systems, and a vast array of other applications. They are widely used to generate both DC and alternating current (AC) magnetic fields. Many of these applications require a rapid step and settling time, turning the DC or AC magnetic field on and off quickly. The inductive response normally makes this a challenging thing to do. In this article, we discuss open loop control algorithms for achieving rapid step and settling times in four general categories of applications: DC and AC systems where the system is either under- or over-damped. Each of these four categories requires a different algorithm, which we describe here. We show the operation of these drive methods using Simulink and Simscape modeling tools, analytical solutions to the underlying differential equations, and experimental results using an inductive magnetic coil and a Hall sensor. Finally, we demonstrate the application of these techniques to significantly reduce ringing in a standard NMR circuit. We intend this article to be practical, with useful, easy-to-apply algorithms and helpful tuning tricks.

The Integration of Optical Stimulation in a Mechanically Dynamic Cell Culture Substrate.

A cell culture well with integrated mechanical and optical stimulation is presented. This is achieved by combining dielectric elastomer soft actuators, also known as artificial muscles, and a varifocal micro-electromechanical mirror that couples light from an optical fiber and focuses it onto the transparent cell substrate. The device enables unprecedented control of in vitro cell cultures by allowing the experimenter to tune and synchronize mechanical and optical stimuli, thereby enabling new experimental assays in optogenetics, fluorescent microscopy, or laser stimulation that include dynamic mechanical strain as a controlled input parameter.

Analysis of a Casimir-driven parametric amplifier with resilience to Casimir pull-in for MEMS single-point magnetic gradiometry.

The Casimir force, a quantum mechanical effect, has been observed in several microelectromechanical system (MEMS) platforms. Due to its extreme sensitivity to the separation of two objects, the Casimir force has been proposed as an excellent avenue for quantum metrology. Practical application, however, is challenging due to attractive forces leading to stiction and device failure, called Casimir pull-in. In this work, we design and simulate a Casimir-driven metrology platform, where a time-delay-based parametric amplification technique is developed to achieve a steady-state and avoid pull-in. We apply the design to the detection of weak, low-frequency, gradient magnetic fields similar to those emanating from ionic currents in the heart and brain. Simulation parameters are selected from recent experimental platforms developed for Casimir metrology and magnetic gradiometry, both on MEMS platforms. While a MEMS offers many advantages to such an application, the detected signal must typically be at the resonant frequency of the device, with diminished sensitivity in the low frequency regime of biomagnetic fields. Using a Casimir-driven parametric amplifier, we report a 10,000-fold improvement in the best-case resolution of MEMS single-point gradiometers, with a maximum sensitivity of 6 Hz/(pT/cm) at 1 Hz. Further development of the proposed design has the potential to revolutionize metrology and may specifically enable the unshielded monitoring of biomagnetic fields in ambient conditions.

Probing the subcellular nanostructure of engineered human cardiomyocytes in 3D tissue.

The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for pharmaceutical testing, disease modeling, and ultimately therapeutic use. Multicellular 3D-tissue platforms have improved the functional maturation of hiPSC-CMs, but probing cardiac contractile properties in a 3D environment remains challenging, especially at depth and in live tissues. Using small-angle X-ray scattering (SAXS) imaging, we show that hiPSC-CMs matured and examined in a 3D environment exhibit a periodic spatial arrangement of the myofilament lattice, which has not been previously detected in hiPSC-CMs. The contractile force is found to correlate with both the scattering intensity (R 2 = 0.44) and lattice spacing (R 2 = 0.46). The scattering intensity also correlates with lattice spacing (R 2 = 0.81), suggestive of lower noise in our structural measurement than in the functional measurement. Notably, we observed decreased myofilament ordering in tissues with a myofilament mutation known to lead to hypertrophic cardiomyopathy (HCM). Our results highlight the progress of human cardiac tissue engineering and enable unprecedented study of structural maturation in hiPSC-CMs.

100 pT/cm single-point MEMS magnetic gradiometer from a commercial accelerometer.

Magnetic sensing is present in our everyday interactions with consumer electronics and demonstrates the potential for the measurement of extremely weak biomagnetic fields, such as those of the heart and brain. In this work, we leverage the many benefits of microelectromechanical system (MEMS) devices to fabricate a small, low-power, and inexpensive sensor whose resolution is in the range of biomagnetic fields. At present, biomagnetic fields are measured only by expensive mechanisms such as optical pumping and superconducting quantum interference devices (SQUIDs), suggesting a large opportunity for MEMS technology in this work. The prototype fabrication is achieved by assembling micro-objects, including a permanent micromagnet, onto a postrelease commercial MEMS accelerometer using a pick-and-place technique. With this system, we demonstrate a room-temperature MEMS magnetic gradiometer. In air, the sensor's response is linear, with a resolution of 1.1 nT cm-1, spans over 3 decades of dynamic range to 4.6 µT cm-1, and is capable of off-resonance measurements at low frequencies. In a 1 mTorr vacuum with 20 dB magnetic shielding, the sensor achieves a 100 pT cm-1 resolution at resonance. This resolution represents a 30-fold improvement compared with that of MEMS magnetometer technology and a 1000-fold improvement compared with that of MEMS gradiometer technology. The sensor is capable of a small spatial resolution with a magnetic sensing element of 0.25 mm along its sensitive axis, a >4-fold improvement compared with that of MEMS gradiometer technology. The calculated noise floor of this platform is 110 fT cm-1 Hz-1/2, and thus, these devices hold promise for both magnetocardiography (MCG) and magnetoencephalography (MEG) applications.

Building a Casimir metrology platform with a commercial MEMS sensor.

The Casimir Effect is a physical manifestation of quantum fluctuations of the electromagnetic vacuum. When two metal plates are placed close together, typically much less than a micron, the long wavelength modes between them are frozen out, giving rise to a net attractive force between the plates, scaling as d -4 (or d -3 for a spherical-planar geometry) even when they are not electrically charged. In this paper, we observe the Casimir Effect in ambient conditions using a modified capacitive micro-electromechanical system (MEMS) sensor. Using a feedback-assisted pick-and-place assembly process, we are able to attach various microstructures onto the post-release MEMS, converting it from an inertial force sensor to a direct force measurement platform with pN (piconewton) resolution. With this system we are able to directly measure the Casimir force between a silver-coated microsphere and gold-coated silicon plate. This device is a step towards leveraging the Casimir Effect for cheap, sensitive, room temperature quantum metrology.