Microsystems & Nanoengineering最新文献

Patient-derived tumor organoids have emerged as promising models for predicting personalized drug responses in cancer therapy, but they typically lack immune components. Preserving the in vivo association between tumor cells and endogenous immune cells is critical for accurate testing of cancer immunotherapies. Mechanical dissection of tumor specimens into tumor fragments, as opposed to enzymatic digestion into single cells, is essential for maintaining these native tumor-immune cell spatial relationships. However, conventional mechanical dissection relying on manual mincing is time-consuming and irreproducible. This study describes two microdissection devices, the µDicer and µGrater, to facilitate the generation of intact tumor fragments from mouse B16 melanoma, a common model of human melanoma. The µDicer- and µGrater-cut tumor fragments were used to generate air‒liquid interface (ALI) organoids that copreserve tumor cells with infiltrating immune subsets without artificial reconstitution. The µDicer, consisting of a hexagonal array of silicon microblades, was employed to investigate the effect of organoid size. The viability of ALI organoid immune cells appeared insensitive to organoid sizes exceeding ~400 µm but diminished in organoids ~200 µm in size. The µGrater, consisting of an array of submillimeter holes in stainless steel, was employed to accelerate dissection. For the samples studied, the µGrater was 4.5 times faster than manual mincing. Compared with those generated by manual mincing, ALI organoids generated by the µGrater demonstrated similar viability, immune cell composition, and responses to anti-PD-1 immunotherapy. With further optimization, the µGrater holds potential for integration into clinical workflows to support the advancement of personalized cancer immunotherapy.

Over the last two decades, platinum group metals (PGMs) and their alloys have dominated as the materials of choice for electrodes in long-term implantable neurostimulation and cardiac rhythm management devices due to their superior conductivity, mechanical and chemical stability, biocompatibility, corrosion resistance, radiopacity, and electrochemical performance. Despite these benefits, PGM manufacturing processes are extremely costly, complex, and challenging with potential health hazards. Additionally, the volatility in PGM prices and their high supply risk, combined with their scarce concentration of approximately 0.01 ppm in the earth’s upper crust and limited mining geographical areas, underscores their classification as critical raw materials, thus, their effective recovery or substitution worldwide is of paramount importance. Since postmortem recovery from deceased patients and/or refining of PGMs that are used in the manufacturing of the electrodes and microelectrode arrays is extremely rare, challenging, and highly costly, therefore, substitution of PGM-based electrodes with other biocompatible materials that can yield electrochemical performance values equal or greater than PGMs is the only viable and sustainable solution to reduce and ultimately substitute the use of PGMs in long-term implantable neurostimulation and cardiac rhythm management devices. In this article, we demonstrate for the first time how the novel technique of “reactive hierarchical surface restructuring” can be utilized on titanium—that is widely used in many non-stimulation medical device and implant applications—to manufacture biocompatible, low-cost, sustainable, and high-performing neurostimulation and cardiac rhythm management electrodes. We have shown how the surface of titanium electrodes with extremely poor electrochemical performance undergoes compositional and topographical transformations that result in electrodes with outstanding electrochemical performance.

The demand for high-performance electromechanical resonators is ever-growing across diverse applications, ranging from sensing and time-keeping to advanced communication devices. Among the electromechanical materials being explored, thin-film lithium niobate stands out due to its strong piezoelectric properties and low acoustic loss. However, in nearly all existing lithium niobate electromechanical devices, the configuration is such that the electrodes are in direct contact with the mechanical resonator. This configuration introduces an undesirable mass-loading effect, producing spurious modes and additional damping. Here, we present an electromechanical platform that mitigates this challenge by leveraging a flip-chip bonding technique to separate the electrodes from the mechanical resonator. By offloading the electrodes from the resonator, our approach yields a substantial increase in the quality factor of these resonators, paving the way for enhanced performance and reliability for their device applications.

Field-controlled micromanipulation represents a pivotal technique for handling microparticles, yet conventional methods often risk physical damage to targets. Here, we discovered a completely new mechanism for true noncontact manipulation through photothermal effects, called thermal-optical tweezers. We employ a laser self-assembly photothermal waveguide (PTW) for dynamic microparticle manipulation. This waveguide demonstrates superior photothermal conversion and precision control, generating a nonisothermal temperature field. The interaction of thermal convection and thermophoresis within this field creates a microfluidic potential well, enabling noncontact and nondestructive particle manipulation. By varying the path of PTWs in lithography and manipulating laser loading modes, diverse manipulation strategies, such as Z-shaped migration, periodic oscillation, and directional transport, are achievable. Our innovative noninvasive micromanipulation technology minimizes not only physical damage to target objects but also enables precise and diverse manipulation of micro entities, opening up new avenues for the photothermal control of cells and biomolecules.

The chip-scale hybrid optical pumping spin-exchange relaxation-free (SERF) atomic magnetometer with a single-beam arrangement has prominent applications in biomagnetic measurements because of its outstanding features, including ultrahigh sensitivity, an enhanced signal-to-noise ratio, homogeneous spin polarization and a much simpler optical configuration than other devices. In this work, a miniaturized single-beam hybrid optical pumping SERF atomic magnetometer based on a microfabricated atomic vapor cell is demonstrated. Although the optically thin Cs atoms are spin-polarized, the dense Rb atoms determine the experimental results. The enhanced signal strength and narrowed resonance linewidth are experimentally proven, which shows the superiority of the proposed magnetometer scheme. By using a differential detection scheme, we effectively suppress optical noise with an approximate five-fold improvement. Moreover, the cell temperature markedly affects the performance of the magnetometer. We systematically investigate the effects of temperature on the magnetometer parameters. The theoretical basis for these effects is explained in detail. The developed miniaturized magnetometer has an optimal magnetic sensitivity of 20 fT/Hz^1/2. The presented work provides a foundation for the chip-scale integration of ultrahighly sensitive quantum magnetometers that can be used for forward-looking magnetocardiography (MCG) and magnetoencephalography (MEG) applications.

Functionalized monodisperse microbubbles have the potential to boost the sensitivity and efficacy of molecular ultrasound imaging and targeted drug delivery using bubbles and ultrasound. Monodisperse bubbles can be produced in a microfluidic flow focusing device. However, their functionalization and sequential use require removal of the excess lipids from the bubble suspension to minimize the use of expensive ligands and to avoid competitive binding and blocking of the receptor molecules. To date, excess lipid removal is performed by centrifugation, which is labor intensive and challenging to automate. More importantly, as we show, the increased hydrostatic pressure during centrifugation can reduce bubble monodispersity. Here, we introduce a novel automated microfluidic 'washing' method. First, bubbles are injected in a microfluidic chamber 1 mm in height where they are left to float against the top wall. Second, lipid-free medium is pumped through the chamber to remove excess lipids while the bubbles remain located at the top wall. Third, the washed bubbles are resuspended and removed from the device into a collection vial. We demonstrate that the present method can (i) reduce the excess lipid concentration by 4 orders of magnitude, (ii) be fully automated, and (iii) be performed in minutes while the size distribution, functionality, and acoustic response of the bubbles remain unaffected. Thus, the presented method is a gateway to the fully automated production of functionalized monodisperse microbubbles.

The Fabry-Pérot interferometer, a fundamental component in optoelectronic systems, offers interesting applications such as sensors, lasers, and filters. In this work, we show a tunable Fabry-Pérot cavity consisting of tunable Sagnac loop reflectors (SLRs) and phase shifters based on electrostatic microelectromechanical (MEMS) actuator. The fabrication process of the device is compatible with the standard wafer-level silicon photonics fabrication processes. This electrostatic actuation mechanism provides well-balanced, scalable pathways for efficient tuning methodologies. The extinction ratio of the continuously tunable SLRs' reflectivity is larger than 20 dB. Full 2π phase shifting is achieved, and response times of all the components are less than 25 μs. Both actuators have extremely low static power, measuring under 20 fW and the energy needed for tuning is both below 20 pJ.

Acoustic gravimetric biosensors attract attention due to their simplicity, robustness, and low cost. However, a prevailing challenge in these sensors is dissipation which manifests in a low quality factor (Q-factor), which limits their sensitivity and accuracy. To mitigate dissipation of acoustic sensors in liquid environments we introduce an innovative approach in which we combine microfluidic channels with gravimetric sensors. To implement this novel paradigm we chose the quartz crystal microbalance (QCM) as our model system, owing to its wide applicability in biosensing and the relevance of its operating principles to other types of acoustic sensors. We postulate that the crucial determinant for enhancing performance lies in the ratio between the width of the microfluidic channels and the wavelength of the pressure wave generated by the oscillating channel side walls driven by the QCM. Our hypothesis is supported by finite element analysis (FEA) and dimensional studies, which revealed two key factors that affect device performance: (1) the ratio of the channel width to the pressure wavelength ( $W/{\lambda }_p$ ) and (2) the ratio of the channel height to the shear evanescent wavelength ( $H/{\lambda }_s$ ). To validate our hypothesis, we fabricated a microfluidic QCM (µ-QCM) and demonstrated a remarkable 10-fold improvement in its dissipation when compared to conventional QCM. The novel microfluidic approach offers several additional advantages, such as direct data interpretation, reduced volume requirement for sample liquids, and simplified temperature control, augmenting the sensor's overall performance. By fostering increased sensitivity, accuracy, and ease of operation, our novel paradigm unlocks new possibilities for advancing gravimetric technologies, potentially for biosensing applications.

Bioanalysis at a single-cell level has yielded unparalleled insight into the heterogeneity of complex biological samples. Combined with Lab-on-a-Chip concepts, various simultaneous and high-frequency techniques and microfluidic platforms have led to the development of high-throughput platforms for single-cell analysis. Dielectrophoresis (DEP), an electrical approach based on the dielectric property of target cells, makes it possible to efficiently manipulate individual cells without labeling. This review focusses on the engineering designs of recent advanced microfluidic designs that utilize DEP techniques for multiple single-cell analyses. On-chip DEP is primarily effectuated by the induced dipole of dielectric particles, (i.e., cells) in a non-uniform electric field. In addition to simply capturing and releasing particles, DEP can also aid in more complex manipulations, such as rotation and moving along arbitrary predefined routes for numerous applications. Correspondingly, DEP electrodes can be designed with different patterns to achieve different geometric boundaries of the electric fields. Since many single-cell analyses require isolation and compartmentalization of individual cells, specific microstructures can also be incorporated into DEP devices. This article discusses common electrical and physical designs of single-cell DEP microfluidic devices as well as different categories of electrodes and microstructures. In addition, an up-to-date summary of achievements and challenges in current designs, together with prospects for future design direction, is provided.

The projected speckle-based three-dimensional digital image correlation method (3D-DIC) is being increasingly used in the reliability measurement of microelectronic packaging structures because of its noninvasive nature, high precision, and low cost. However, during the measurement of the thermal reliability of packaging structures, the thermal airflow generated by heating introduces distortions in the images captured by the DIC measurement system, impacting the accuracy and reliability of noncontact measurements. To address this challenge, a thermal airflow distortion correction model based on the transformer attention mechanism is proposed specifically for the measurement of thermal warpage in microelectronic packaging structures. This model avoids the oversmoothing issue associated with convolutional neural networks and the lack of physical constraints in generative adversarial networks, ensuring the precision of grayscale gradient changes in speckle patterns and minimizing adverse effects on DIC calculation accuracy. By inputting the distorted images captured by the DIC measurement system into the network, corrected images are obtained for 3D-DIC calculations, thus allowing the thermal warpage measurement results of the sample to be acquired. Through experiments measuring topography with customized step block specimens, the effectiveness of the proposed method in improving warpage measurement accuracy is confirmed; this is particularly true when captured images are affected by thermal airflow at 140 °C and 160 °C, temperatures commonly encountered in thermal reliability testing of packaging structures. The method successfully reduces the standard deviation from 9.829 to 5.943 µm and from 12.318 to 6.418 µm, respectively. The results demonstrate the substantial practical value of this method for measuring thermal warpage in microelectronic packaging structures.