Implantable microfluidics: methods and applications.

Implantable microfluidics involves integrating microfluidic functionalities into implantable devices, such as medical implants or bioelectronic devices, revolutionizing healthcare by enabling personalized and precise diagnostics, targeted drug delivery, and regeneration of targeted tissues or organs. The impact of implantable microfluidics depends heavily on advancements in both methods and applications. Despite significant progress in the past two decades, continuous advancements are still required in fluidic control and manipulation, device miniaturization and integration, biosafety considerations, as well as the development of various application scenarios to address a wide range of healthcare issues. In this review, we discuss advancements in implantable microfluidics, focusing on methods and applications. Regarding methods, we discuss progress made in fluid manipulation, device fabrication, and biosafety considerations in implantable microfluidics. In terms of applications, we review advancements in using implantable microfluidics for drug delivery, diagnostics, tissue engineering, and energy harvesting. The purpose of this review is to expand research ideas for the development of novel implantable microfluidic devices for various healthcare applications.

A strategy for Cas13 miniaturization based on the structure and AlphaFold.

The small size of the Cas nuclease fused with various effector domains enables a broad range of function. Although there are several ways of reducing the size of the Cas nuclease complex, no efficient or generalizable method has been demonstrated to achieve protein miniaturization. In this study, we establish an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturization and generate five compact variants of Cas13 with full RNA binding and cleavage activity comparable the wild-type enzymes based on a combination of IDC strategy and AlphaFold2. In addition, we construct an RNA base editor, mini-Vx, and a single AAV (adeno-associated virus) carrying a mini-RfxCas13d and crRNA expression cassette, which individually shows efficient conversion rate and RNA-knockdown activity. In summary, these findings highlight a feasible strategy for generating downsized CRISPR/Cas13 systems based on structure predicted by AlphaFold2, enabling targeted degradation of RNAs and RNA editing for basic research and therapeutic applications.

Miniaturization and Automation Protocol of a Urinary Organic Acid Liquid-Liquid Extraction Method on GC-MS.

The aim of this study was to improve the extraction method for urinary organic acids by miniaturizing and automating the process. Currently, manual extraction methods are commonly used, which can be time-consuming and lead to variations in test results. To address these issues, we reassessed and miniaturized the in-house extraction method, reducing the number of steps and the sample-to-solvent volumes required. The evaluated miniaturized method was translated into an automated extraction procedure on a MicroLab (ML) Star (Hamilton Technologies) liquid handler. This was then validated using samples obtained from the ERNDIM External Quality Assurance program. The organic acid extraction method was successfully miniaturized and automated using the Autosampler robot. The linear range for most of the thirteen standard analytes fell between 0 to 300 mg/L in spiked synthetic urine, with low (50 mg/L), medium (100 mg/L), and high (500 mg/L) levels. The correlation coefficient (r) for most analytes was >0.99, indicating a strong relationship between the measured values. Furthermore, the automated extraction method demonstrated acceptable precision, as most organic acids had coefficients of variation (CVs) below 20%. In conclusion, the automated extraction method provided comparable or even superior results compared to the current in-house method. It has the potential to reduce solvent volumes used during extraction, increase sample throughput, and minimize variability and random errors in routine diagnostic settings.

Expansion of the Analytical Modeling of Capacitance for 1-N-1 Multilayered CID Structures with Monotonically Increasing/Decreasing Permittivity.

Capacitive sensors that utilize the Coplanar Interdigitated (CID) electrode structure are widely employed in various technical and analytical domains, such as healthcare, infectious disease management, pharmaceuticals, metrology, and environmental monitoring. The present exigency for lab-on-a-chip contrivances and the requisite for the miniaturization of sensors have led to the widespread adoption of CID sensors featuring multiple dielectric layers (DLs), either in the form of substrates or superstrates. Previously, we derived an analytical model for the capacitance of CID capacitive sensors with four distinct 1-N-1 patterns (namely, 1-1-1, 1-3-1, 1-5-1, and 1-11-1) using partial capacitance (PC) and conformal mapping (CM) techniques. The aforementioned model has been employed in various applications wherein the permittivity of successive layers exhibits a monotonic decrease as one moves away from the electrode plane, resulting in highly satisfactory outcomes. Nevertheless, the PC technique is inadequate for structures with multiple layers where the permittivity exhibits a monotonic increase as the distance from the electrodes increases. Given these circumstances, it is necessary to adapt the initial PC method to incorporate these novel configurations. In this work, we have discussed a new approach, splitting the concept of PC into partial parallel capacitance (PPC) and partial serial capacitance (PSC), where new CM transformations are proposed for the latter case. Thus, the present study proposes a novel methodology to expand upon our prior analytical framework, which aims to incorporate scenarios where the permittivity experiences a reduction across successive layers. The outcomes are juxtaposed with the finite element simulation and analytical findings.

Evolutionary traces of miniaturization in a giant-Comparative anatomy of brain and brain nerves in Bathochordaeus stygius (Tunicata, Appendicularia).

Appendicularia comprises 70 marine, invertebrate, chordate species. Appendicularians play important ecological and evolutionary roles, yet their morphological disparity remains understudied. Most appendicularians are small, develop rapidly, and with a stereotyped cell lineage, leading to the hypothesis that Appendicularia derived progenetically from an ascidian-like ancestor. Here, we describe the detailed anatomy of the central nervous system of Bathochordaeus stygius, a giant appendicularian from the mesopelagic. We show that the brain consists of a forebrain with on average smaller and more uniform cells and a hindbrain, in which cell shapes and sizes vary to a greater extent. Cell count for the brain was 102. We demonstrate the presence of three paired brain nerves. Brain nerve 1 traces into the epidermis of the upper lip region and consists of several fibers with some supportive bulb cells in its course. Brain nerve 2 innervates oral sensory organs and brain nerve 3 innervates the ciliary ring of the gill slits and lateral epidermis. Brain nerve 3 is asymmetric, with the right nerve consisting of two neurites originating posterior to the left one that contains three neurites. Similarities and differences to the anatomy of the brain of the model species Oikopleura dioica are discussed. We interpret the small number of cells in the brain of B. stygius as an evolutionary trace of miniaturization and conclude that giant appendicularians evolved from a small, progenetic ancestor that secondarily increased in size within Appendicularia.

Plasmonic-enhanced efficiency of AlGaN-based deep ultraviolet LED by graphene/Al nanoparticles/graphene hybrid structure.

The AlGaN-based deep ultraviolet light-emitting diode (DUV LED) has advantages of environmentally friendly materials, tunable emission wavelength, and easy miniaturization. However, the light extraction efficiency (LEE) of an AlGaN-based DUV LED is low, which hinders its applications. Here, we design a graphene/Al nanoparticles/graphene (Gra/Al NPs/Gra) hybrid plasmonic structure, where the strong resonant coupling of local surface plasmons (LSPs) induces a 2.9-times enhancement for the LEE of the DUV LED according to the photoluminescence (PL). The dewetting of Al NPs on a graphene layer by annealing is optimized, resulting in better formation and uniform distribution. The near-field coupling of Gra/Al NPs/Gra is enhanced via charge transfer among graphene and Al NPs. In addition, the skin depth increment results in more excitons being coupled out of multiple quantum wells (MQWs). An enhanced mechanism is proposed, revealing that the Gra/metal NPs/Gra offers a reliable strategy for improving the optoelectronic device performance, which might trigger the advances of LEDs and lasers with high brightness and power density.

MIMO 5G Smartphone Antenna with Tri-Band and Decoupled Elements.

In this article, a miniaturized antenna is proposed for 4G/5G multiple input, multiple output (MIMO) applications for smartphones. The proposed antenna is composed of an inverted L-shaped antenna with decoupled elements to cover 4G (2000-2600 MHz), and a planar inverted-F antenna (PIFA) with a J-slot to cover 5G (3400-3600 MHz and 4800-5000 MHz). Furthermore, to achieve the purposes of miniaturization and decoupling, the structure adopts a feeding stub, shorting stub, and outstanding floor, additionally adding the slot to the PIFA, to generate additional frequency bands. Due to the advantages such as multiband operation, MIMO configuration for 5G communications, high isolation, and a compact structure, the proposed antenna design is attractive for 4G/5G smartphones. The antenna array is printed on an FR4 dielectric board, measuring 140 × 70 × 0.8 mm3, with the 4G antenna located on a top 15 mm-long headroom.

Characterization of the electrocardiogram of microminipig in comparison with that of Clawn miniature swine: impacts of miniaturization of body size on electrocardiographic indices.

Effects of body size reduction on electrocardiographic indices were examined using microminipigs in comparison with Clawn miniature swine (Clawn). Electrocardiogram was recorded using Holter electrocardiograph in conscious state for 24 hr for microminipigs (male: 11.6 ± 0.1 kg, 12-17 months, n=5; and female: 9.9 ± 0.4 kg, 6 months, n=5) and Clawn (female: 20.3 ± 0.4 kg, 8-9 months, n=8). Microminipig had shorter PR interval and QRS width than Clawn, whereas no significant difference was detected in JTcF/QTcF between them. Ratios of PR interval, QRS width, and body weight cubic root for microminipigs to Clawn ranged between 0.713 and 0.830. These findings indicate that PR interval and QRS width will depend on distance for excitatory current propagation, whereas JTcF/QTcF may be governed by local electrical activities.

Enhanced magnetic modulation of surface plasmon polaritons on hyperbolic metasurfaces.

In this Letter we demonstrate a fundamentally new, to the best of our knowledge, concept to enhance the magnetic modulation of the surface plasmon polaritons (SPPs) by using hybrid magneto-plasmonic structures consisting of hyperbolic plasmonic metasurfaces and magnetic dielectric substrates. Our results show that the magnetic modulation of SPPs in the proposed structures can be an order of magnitude stronger than in the hybrid metal-ferromagnet multilayer structures conventionally used in active magneto-plasmonics. We believe that this effect will allow for the further miniaturization of magneto-plasmonic devices.

Innovative Quantification of Critical Quality Attributes.

Potency testing is an important part of the evaluation of cellular therapy products. In vitro quantification of identified quality-related biomarkers is a technique often used at the laboratory. Nonetheless, the limited stability of most cellular therapy products, the lot variability and the limited time within which to perform testing are currently hindering their widespread use. Fortunately, within the last two decades, the evolution of material technology and miniaturisation processes has enabled the research community to shift the spotlight of attention towards the Lab-on-Chip concept for diagnostic applications. Such devices enable portable, rapid, sensitive, automated and affordable biochemical analyses aiming to advance the healthcare services across a broad application spectrum. However, it could be argued that the aspirations on their affordability are far from being exceeded, mainly due to the lack of a practical manufacturing technology. The Lab-on-Printed Circuit Board (Lab-on-PCB) approach has demonstrated enormous potential for developing economical diagnostic platforms leveraging the advantage provided by economy of scale manufacturing of the long-standing PCB industry. The integration capabilities that the PCB platform introduces to the Lab-on-Chip concept concerning the electronics and microfluidics seem to be unique. In this chapter, we will be reviewing the progress of Lab-on-PCB prototypes quantifying within miniaturised microchips a range of critical quality attributes with potential in potency testing. We will focus on their technology and applications whilst addressing the potential of this approach in practical use and commercialisation.

Miniaturization of an Osmotic Pressure-Based Glucose Sensor for Continuous Intraperitoneal and Subcutaneous Glucose Monitoring by Means of Nanotechnology.

The Sencell sensor uses glucose-induced changes in an osmotic pressure chamber for continuous glucose measurement. A final device shall have the size of a grain of rice. The size limiting factor is the piezo-resistive pressure transducers inside the core sensor technology (resulting chamber volume: 70 µL. To achieve the necessary miniaturization, these pressure transducers were replaced by small (4000 × 400 × 150 nm³) nano-granular tunneling resistive (NTR) pressure sensors (chamber volume: 750 nL). For benchmark testing, we filled the miniaturized chamber with bovine serum albumin (BSA, 1 mM) and exposed it repeatedly to distilled water followed by 1 mM BSA solution. Thereafter, we manufactured sensors with glucose testing chemistry (ConcanavalinA/dextran) and investigated sensor performance with dynamic glucose changes between 0 and 300 mg/dL. Evaluation of the miniaturized sensors resulted in reliable pressure changes, both in the BSA benchmark experiment (30-35 mBar) and in the dynamic in vitro continuous glucose test (40-50 mBar). These pressure results were comparable to similar experiments with the previous larger in vitro sensors (30-50 mBar). In conclusion, the NTR pressure sensor technology was successfully employed to reduce the size of the core osmotic pressure chamber by more than 95% without loss in the osmotic pressure signal.

Toughening Thermoelectric Materials: From Mechanisms to Applications.

With the tendency of thermoelectric semiconductor devices towards miniaturization, integration, and flexibility, there is an urgent need to develop high-performance thermoelectric materials. Compared with the continuously enhanced thermoelectric properties of thermoelectric materials, the understanding of toughening mechanisms lags behind. Recent advances in thermoelectric materials with novel crystal structures show intrinsic ductility. In addition, some promising toughening strategies provide new opportunities for further improving the mechanical strength and ductility of thermoelectric materials. The synergistic mechanisms between microstructure-mechanical performances are expected to show a large set of potential applications in flexible thermoelectric devices. This review explores enlightening research into recent intrinsically ductile thermoelectric materials and promising toughening strategies of thermoelectric materials to elucidate their applications in the field of flexible thermoelectric devices.

Flexible Needle Steering with Tethered and Untethered Actuation: Current States, Targeting Errors, Challenges and Opportunities.

Accurate needle targeting is critical for many clinical procedures, such as transcutaneous biopsy or radiofrequency ablation of tumors. However, targeting errors may arise, limiting the widespread adoption of these procedures. Advances in flexible needle (FN) steering are emerging to mitigate these errors. This review summarizes the state-of-the-art developments of FNs and addresses possible targeting errors that can be overcome with steering actuation techniques. FN steering techniques can be classified as passive and active. Passive steering directly results from the needle-tissue interaction forces, whereas active steering requires additional forces to be applied at the needle tip, which enhances needle steerability. Therefore, the corresponding targeting errors of most passive FNs and active FNs are between 1 and 2 mm, and less than 1 mm, respectively. However, the diameters of active FNs range from 1.42 to 12 mm, which is larger than the passive steering needle varying from 0.5 to 1.4 mm. Therefore, the development of active FNs is an area of active research. These active FNs can be steered using tethered internal direct actuation or untethered external actuation. Examples of tethered internal direct actuation include tendon-driven, longitudinal segment transmission and concentric tube transmission. Tendon-driven FNs have various structures, and longitudinal segment transmission needles could be adapted to reduce tissue damage. Additionally, concentric tube needles have immediate advantages and clinical applications in natural orifice surgery. Magnetic actuation enables active FN steering with untethered external actuation and facilitates miniaturization. The challenges faced in the fabrication, sensing, and actuation methods of FN are analyzed. Finally, bio-inspired FNs may offer solutions to address the challenges faced in FN active steering mechanisms.

Mass-Fabrication Scheme of Highly Sensitive Wireless Electrodeless MEMS QCM Biosensor with Antennas on Inner Walls of Microchannel.

Quartz-crystal-microbalance (QCM) biosensor is a typical label-free biosensor, and its sensitivity can be greatly improved by removing electrodes and wires that would be otherwise attached to the surfaces of the quartz resonator. The wireless-electrodeless QCM biosensor was then developed using a microelectro-mechanical systems (MEMS) process, although challenges remain in the sensitivity, the coupling efficiency, and the miniaturization (or mass production). In this study, we establish a MEMS process to obtain a large number of identical ultrasensitive and highly efficient sensor chips with dimensions of 6 mm square. The fundamental shear resonance frequency of the thinned AT-cut quartz resonator packaged in the microchannel exceeds 160 MHz, which is excited by antennas deposited on inner walls of the microchannel, significantly improving the electro-mechanical coupling efficiency in the wireless operation. The high sensitivity of the developed MEMS QCM biosensors is confirmed by the immunoglobulin G (IgG) detection using protein A and ZZ-tag displaying a bionanocapsule (ZZ-BNC), where we find that the ZZ-BNC can provide more effective binding sites and higher affinity to the target molecules, indicating a further enhancement in the sensitivity of the MEMS QCM biosensor. We then perform the label-free C-reactive protein (CRP) detection using the ZZ-BNC-functionalized MEMS QCM biosensor, which achieves a detection limit of 1 ng mL-1 or less even with direct detection.

Trends in monoliths: Packings, stationary phases and nanoparticles.

Monoliths media are gaining interest as excellent substitutes to conventional particle-packed columns. Monolithic columns show higher permeability and lower flow resistance than conventional liquid chromatography columns, providing high-throughput performance, resolution and separation in short run times. Monolithic columns with longer length, smaller inner diameter and specific selectivity to peptides or enantiomers have been played important role in hyphenated system. Monolithic stationary phases possess great efficiency, resolution, selectivity and sensitivity in the separation of complex biological samples, such as the complex mixtures of peptides for proteome analysis. The development of monolithic stationary phases has opened the new avenue in chromatographic separation science and is in turn playing much more important roles in the wide application area. Monolithic stationary phases have been widely used in fast and high efficiency one- and multi-dimensional separation systems, miniaturized devices, and hyphenated system coupled with mass spectrometers. The developing technology for preparation of monolithic stationary phases is revolutionizing the column technology for the separation of complex biological samples. These techniques using porous monoliths offer several advantages, including miniaturization and on-line coupling with analytical instruments. Additionally, monoliths are ideal support media for imprinting template-specific sites, resulting in the so-called molecularly-imprinted monoliths, with ultra-high selectivity. In this review, the origin of the concept, the differences between their characteristics and those of traditional packings, their advantages and drawbacks, theory of separations, the methods for the monoliths preparation of different forms, nanoparticle monoliths and metal-organic framework are discussed. Two application areas of monolithic metal-organic framework and nanoparticle monoliths are provided. The review article discusses the results reported in a total of 218 references. Other older references were included to illustrate the historical development of monoliths, both in preparation and types, as well as separation mechanism.

Gyrolab Immunoassays: Miniaturization, Automation, and Integration into a Rapid Workflow.

Gyrolab® is an open immunoassay platform that automates the complete immunoassay protocol in a microfluidic disc. The column profiles generated with Gyrolab immunoassays are used to gain more information about biomolecular interactions that can be useful in assay development or quantify analytes in samples. Gyrolab immunoassays can be used to cover a broad concentration range and diversity of matrices in applications ranging from biomarker monitoring, pharmacodynamics and pharmacokinetics studies, to bioprocess development in many areas, including therapeutic antibodies, vaccines, and cell and gene therapy.This chapter is an overview of Gyrolab technology, including system components and the assay development workflow, including the process of selecting affinity reagents, Gyrolab Bioaffy CDs, and assay conditions to optimize immunoassays. Two case studies are included. The first involves an assay for the humanized antibody pembrolizumab used in cancer immunotherapy that can generate data for pharmacokinetics studies. The second case study involves quantification of the biomarker and biotherapeutic interleukin-2 (IL-2) in human serum and buffer. IL-2 has been implicated in the cytokine storm associated with COVID-19, and cytokine release syndrome (CRS), which can occur during chimeric antigen receptor T cell (CART) therapy used in treating cancer. These molecules also have therapeutic relevance in combination.

Review of pMUTs for medical imaging: towards high frequency arrays.

pMUT (piezoelectric Micromachined Ultrasound Transducer) devices are an alternative that can overcome the limitations associated with conventional ultrasound transducers. pMUT's are reported for many applications such as range-finding, biometrics, and ultrasound imaging. However, pulse-echo measurements from fabricated pMUT devices/arrays are not commonly reported in literature, a reason being lack of desirable performance either in transmit or receive mode of operation. There is also limited information about the design, fabrication and characterization of 2D-pMUT-arrays operating at high frequencies (>15 MHz) in water medium. In this paper we review 'state-of-the-art' for pMUT-array based medical ultrasound imaging, with a focus on their pulse-echo imaging capability. Over the next 3-5 years, we expect further improvement in piezoelectric thin film deposition techniques, on-chip integration of pre-amplification circuits and further miniaturization of pMUT devices, thus paving the way for development of pMUT-array based high frequency medical imaging systems.

Robotic probes at the cell scale.

The miniaturization of robotic tools and probes enables the fundamental study of mechanical properties of cells and tissues.

Split Ring Antennas and Their Application for Antenna Miniaturization.

This paper investigates the miniaturization capability of split ring array antennas embedded in a low-permittivity dielectric substrate, in comparison with the same-sized high-permittivity dielectric resonator antennas (DRAs). In order to understand the miniaturization performance, a size-fixed dielectric substrate with different split ring arrays is studied. The simulation results show that the miniaturization capability increases with decreased unit cell resonant frequency and/or increased unit cell induced permeability. Miniaturizations as high as 25.54 times that of a high-permittivity DRA are obtained with split rings, etched on a dielectric substrate having a low permittivity of 2.2. Furthermore, this excessive miniaturization does not come at the expense of excessive deterioration of the antenna impedance bandwidth, gain, and radiation efficiency. Consequently, the miniaturized split ring arrays still provide high gains over wider bandwidths. This inference is further verified by comparing the miniaturization and other antenna performance parameters with three other modified split ring configurations. To experimentally verify this work, a split ring antenna was fabricated and tested, and good agreement between the simulated and measured results was observed. The results of this study indicate that adding resonant metallic inclusions into low- permittivity DRAs significantly increases their miniaturization capability, without overly deteriorating the performance.

Design of Miniaturized Wideband Beam Deflection Conformal Array Antenna.

Antenna beam deflection, along with miniaturization and wideband of the antenna is in demand for practical applications. In this paper, a cylindrical conformal array antenna with a small-tilt forward beam was designed. The microstrip antenna unit was loaded with the artificial electromagnetic structure, which reduced the size of the antenna unit. As a result, the center spacing of the array elements can be shortened with the same array element spacing. The beam deflection angle can be increased in this way without increasing the coupling effect between the parts. Changing the number of line array elements and the number of line arrays can regulate the beam width of E-field and H-field, respectively. The bandwidth of the antenna can be significantly extended by slotting the ground plane. This work implemented a cylindrical conformal array of the antenna's forward beam with a small dip angle using a cylindrical carrier as an example. The measurement results showed that the angle between the main beam and the carrier axis of the conformal antenna was less than 30°, the bandwidth was more than 30%, and the antenna volume decreased by 40.4%.