Collection of microrobots for gentle cell manipulation.

Optically actuated soft microrobotic tools were designed for cell transportation, manipulation, and cell-to-cell interactions.

Cerenkov free micro-dosimetry in small-field radiation therapy technique.

Objective. Optical fiber-based scintillating dosimetry is a recent promising technique owing to the miniature size dosimeter and quality measurement in modern radiation therapy treatment. Despite several advantages, the major issue of using scintillating dosimeters is the Cerenkov effect and predominantly requires extra measurement corrections. Therefore, this work highlighted a novel micro-dosimetry technique to ensure Cerenkov-free measurement in radiation therapy treatment protocol by investigating several dosimetric characteristics.Approach.A micro-dosimetry technique was proposed with the performance evaluation of a novel infrared inorganic scintillator detector (IR-ISD). The detector essentially consists of a micro-scintillating head based on IR-emitting micro-clusters with a sensitive volume of 1.5 × 10-6mm3. The proposed system was evaluated under the 6 MV LINAC beam used in patient treatment. Overall measurements were performed using IBATMwater tank phantoms by following TRS-398 protocol for radiotherapy. Cerenkov measurements were performed for different small fields from 0.5 × 0.5 cm2to 10 × 10 cm2under LINAC. In addition, several dosimetric parameters such as percentage depth dose (PDD), high lateral resolution beam profiling, dose linearity, dose rate linearity, repeatability, reproducibility, and field output factor were investigated to realize the performance of the novel detector.Main results. This study highlighted a complete removal of the Cerenkov effect using a point-like miniature detector, especially for small field radiation therapy treatment. Measurements demonstrated that IR-ISD has acceptable behavior with dose rate variability (maximum standard deviation ∼0.18%) for the dose rate of 20-1000 cGy s-1. An entire linear response (R2= 1) was obtained for the dose delivered within the range of 4-1000 cGy, using a selected field size of 1 × 1 cm2. Perfect repeatability (max 0.06% variation from average) with day-to-day reproducibility (0.10% average variation) was observed. PDD profiles obtained in the water tank present almost identical behavior to the reference dosimeter with a build-up maximum depth dose at 1.5 cm. The small field of 0.5 × 0.5 cm2profiles have been characterized with a high lateral resolution of 100µm.Significance. Unlike recent plastic scintillation detector systems, the proposed micro-dosimetry system in this study requires no Cerenkov corrections and showed efficient performance for several dosimetric parameters. Therefore, it is expected that considering the detector correction factors, the IR-ISD system can be a suitable dose measurement tool, such as in small-field dose measurements, high and low gradient dose verification, and, by extension, in microbeam radiation and FLASH radiation therapy.

Thin-Film Piezoelectric Micromachined Ultrasound Transducers in Biomedical Applications: A Review.

Thin-film piezoelectric micromachined ultrasound transducers (PMUTs) are an increasingly relevant and well-researched field, and their biomedical importance has been growing as the technology continues to mature. This review article briefly discusses their history in biomedical use, provides a simple explanation of their principles for newer readers, and sheds light on the materials selection for these devices. Primarily, it discusses the significant applications of PMUTs in the biomedical industry and showcases recent progress that has been made in each application. The biomedical applications covered include common historical uses of ultrasound such as ultrasound imaging, ultrasound therapy, and fluid sensing, but additionally new and upcoming applications such as drug delivery, photoacoustic imaging, thermoacoustic imaging, biometrics, and intrabody communication. By including a device comparison chart for different applications, this review aims to assist microelectromechanical systems (MEMS) designers that work with PMUTs by providing a benchmark for recent research works. Furthermore, it puts forth a discussion on the current challenges being faced by PMUTs in the biomedical field, current and likely future research trends, and opportunities for PMUT development areas, as well as sharing the opinions and predictions of the authors on the state of this technology as a whole. The review aims to be a comprehensive introduction to these topics without diving excessively deep into existing literature.

Construction of intelligent moving micro/nanomotors and their applications in biosensing and disease treatment.

Micro/nanomotors are containers that pass through liquid media and carry cargo. Because they are tiny, micro/nanomotors exhibit excellent potential for biosensing and disease treatment applications. However, their size also makes overcoming random Brownian forces very challenging for micro/nanomotors moving on targets. Additionally, to achieve desired practical applications, the expensive materials, short lifetimes, poor biocompatibility, complex preparation methods, and side effects of micro/nanomotors must be addressed, and potential adverse effects must be evaluated both in vivo and in practical applications. This has led to the continuous development of key materials for driving micro/nanomotors. In this work, we review the working principles of micro/nanomotors. Metallic and nonmetallic nanocomplexes, enzymes, and living cells are explored as key materials for driving micro/nanomotors. We also consider the effects of exogenous stimulations and endogenous substance conditions on micro/nanomotor motions. The discussion focuses on micro/nanomotor applications in biosensing, treating cancer and gynecological diseases, and assisted fertilization. By addressing micro/nanomotor shortcomings, we propose directions for further developing and applying micro/nanomotors.

In Situ Manipulation and Micromechanical Characterization of Diatom Frustule Constituents Using Focused Ion Beam Scanning Electron Microscopy.

Biocomposite structures are difficult to characterize by bulk approaches due to their morphological complexity and compositional heterogeneity. Therefore, a versatile method is required to assess, for example, the mechanical properties of geometrically simple parts of biocomposites at the relevant length scales. Here, it is demonstrated how a combination of Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) and micromanipulators can be used to isolate, transfer, and determine the mechanical properties of frustule constituents of diatom Thalassiosira pseudonana (T.p.). Specifically, two parts of the diatom frustule, girdle bands and valves, are separated by FIB milling and manipulated using a sharp tungsten tip without compromising their physical or chemical integrity. In situ mechanical studies on isolated girdle bands combined with Finite Element Method (FEM) simulations, enables the quantitative assessment of the Young's modulus of this biosilica; E = 40.0 GPa. In addition, the mechanical strength of isolated valves could be measured by transferring and mounting them on top of premilled holes in the sample support. This approach may be extended to any hierarchical biocomposite material, regardless of its chemical composition, to isolate, transfer, and investigate the mechanical properties of selected constituents or specific regions.

Fabrication and use of silicon hollow-needle arrays to achieve tissue nanotransfection in mouse tissue in vivo.

Tissue nanotransfection (TNT) is an electromotive gene transfer technology that was developed to achieve tissue reprogramming in vivo. This protocol describes how to fabricate the required hardware, commonly referred to as a TNT chip, and use it for in vivo TNT. Silicon hollow-needle arrays for TNT applications are fabricated in a standardized and reproducible way. In <1 s, these silicon hollow-needle arrays can be used to deliver plasmids to a predetermined specific depth in murine skin in response to pulsed nanoporation. Tissue nanotransfection eliminates the need to use viral vectors, minimizing the risk of genomic integration or cell transformation. The TNT chip fabrication process typically takes 5-6 d, and in vivo TNT takes 30 min. This protocol does not require specific expertise beyond a clean room equipped for basic nanofabrication processes.

Swarming Aqua Sperm Micromotors for Active Bacterial Biofilms Removal in Confined Spaces.

Microscale self-propelled robots show great promise in the biomedical field and are the focus of many researchers. These tiny devices, which move and navigate by themselves, are typically based on inorganic microstructures that are not biodegradable and potentially toxic, often using toxic fuels or elaborate external energy sources, which limits their real-world applications. One potential solution to these issues is to go back to nature. Here, the authors use high-speed Aqua Sperm micromotors obtained from North African catfish (Clarias gariepinus, B. 1822) to destroy bacterial biofilm. These Aqua Sperm micromotors use water-induced dynein ATPase catalyzed adenosine triphosphate (ATP) degradation as biocompatible fuel to trigger their fast speed and snake-like undulatory locomotion that facilitate biofilm destruction in less than one minute. This efficient biofilm destruction is due to the ultra-fast velocity as well as the head size of Aqua Sperm micromotors being similar to bacteria, which facilitates their entry to and navigation within the biofilm matrix. In addition, the authors demonstrate the real-world application of Aqua Sperm micromotors by destroying biofilms that had colonized medical and laboratory tubing. The implemented system extends the biomedical application of Aqua Sperm micromotors to include hybrid robots for fertilization or cargo tasks.

Microfabrication of a Chamber for High-Resolution, In Situ Imaging of the Whole Root for Plant-Microbe Interactions.

Fabricated ecosystems (EcoFABs) offer an innovative approach to in situ examination of microbial establishment patterns around plant roots using nondestructive, high-resolution microscopy. Previously high-resolution imaging was challenging because the roots were not constrained to a fixed distance from the objective. Here, we describe a new 'Imaging EcoFAB' and the use of this device to image the entire root system of growing Brachypodium distachyon at high resolutions (20×, 40×) over a 3-week period. The device is capable of investigating root-microbe interactions of multimember communities. We examined nine strains of Pseudomonas simiae with different fluorescent constructs to B. distachyon and individual cells on root hairs were visible. Succession in the rhizosphere using two different strains of P. simiae was examined, where the second addition was shown to be able to establish in the root tissue. The device was suitable for imaging with different solid media at high magnification, allowing for the imaging of fungal establishment in the rhizosphere. Overall, the Imaging EcoFAB could improve our ability to investigate the spatiotemporal dynamics of the rhizosphere, including studies of fluorescently-tagged, multimember, synthetic communities.

Point-of-care microvolume cytometer measures platelet counts with high accuracy from capillary blood.

BACKGROUND: Point-of-care (PoC) testing of platelet count (PLT) provides real-time data for rapid decision making. The goal of this study is to evaluate the accuracy and precision of platelet counting using a new microvolume (8 µL), absolute counting, 1.5 kg cytometry-based blood analyzer, the rHEALTH ONE (rHEALTH) in comparison with the International Society of Laboratory Hematology (ISLH) platelet method, which uses a cytometer and an impedance analyzer. METHODS: Inclusion eligibility were healthy adults (M/F) ages 18-80 for donation of fingerprick and venous blood samples. Samples were from a random N = 31 volunteers from a single U.S. site. Samples were serially diluted to test thrombocytopenic ranges. Interfering substances and conditions were tested, including RBC fragments, platelet fragments, cholesterol, triglycerides, lipids, anti-platelet antibodies, and temperature. RESULTS: The concordance between the rHEALTH and ISLH methods had a slope = 1.030 and R2 = 0.9684. The rHEALTH method showed a correlation between capillary and venous blood samples (slope = 0.9514 and R2 = 0.9684). Certain interferents changed platelet recovery: RBC fragments and anti-platelet antibodies with the ISLH method; platelet fragments and anti-platelet antibodies on the rHEALTH; and RBC fragments, platelets fragments, triglycerides and LDL on the clinical impedance analyzer. The rHEALTH's precision ranged from 3.1-8.0%, and the ISLH from 1.0-10.5%. CONCLUSIONS: The rHEALTH method provides similar results with the reference method and good correlation between adult capillary and venous blood samples. This demonstrates the ability of the rHEALTH to provide point-of-care assessment of normal and thrombocytopenic platelet counts from fingerprick blood with high precision and limited interferences.

High Aspect Ratio and Light-Sensitive Micropillars Based on a Semiconducting Polymer Optically Regulate Neuronal Growth.

Many nano- and microstructured devices capable of promoting neuronal growth and network formation have been previously investigated. In certain cases, topographical cues have been successfully complemented with external bias, by employing electrically conducting scaffolds. However, the use of optical stimulation with topographical cues was rarely addressed in this context, and the development of light-addressable platforms for modulating and guiding cellular growth and proliferation remains almost completely unexplored. Here, we develop high aspect ratio micropillars based on a prototype semiconducting polymer, regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT), as an optically active, three-dimensional platform for embryonic cortical neurons. P3HT micropillars provide a mechanically compliant environment and allow a close contact with neuronal cells. The combined action of nano/microtopography and visible light excitation leads to effective optical modulation of neuronal growth and orientation. Embryonic neurons cultured on polymer pillars show a clear polarization effect and, upon exposure to optical excitation, a significant increase in both neurite and axon length. The biocompatible, microstructured, and light-sensitive platform developed here opens up the opportunity to optically regulate neuronal growth in a wireless, repeatable, and spatio-temporally controlled manner without genetic modification. This approach may be extended to other cell models, thus uncovering interesting applications of photonic devices in regenerative medicine.

Printable graphene BioFETs for DNA quantification in Lab-on-PCB microsystems.

Lab-on-Chip is a technology that aims to transform the Point-of-Care (PoC) diagnostics field; nonetheless a commercial production compatible technology is yet to be established. Lab-on-Printed Circuit Board (Lab-on-PCB) is currently considered as a promising candidate technology for cost-aware but simultaneously high specification applications, requiring multi-component microsystem implementations, due to its inherent compatibility with electronics and the long-standing industrial manufacturing basis. In this work, we demonstrate the first electrolyte gated field-effect transistor (FET) DNA biosensor implemented on commercially fabricated PCB in a planar layout. Graphene ink was drop-casted to form the transistor channel and PNA probes were immobilized on the graphene channel, enabling label-free DNA detection. It is shown that the sensor can selectively detect the complementary DNA sequence, following a fully inkjet-printing compatible manufacturing process. The results demonstrate the potential for the effortless integration of FET sensors into Lab-on-PCB diagnostic platforms, paving the way for even higher sensitivity quantification than the current Lab-on-PCB state-of-the-art of passive electrode electrochemical sensing. The substitution of such biosensors with our presented FET structures, promises further reduction of the time-to-result in microsystems combining sequential DNA amplification and detection modules to few minutes, since much fewer amplification cycles are required even for low-abundance nucleic acid targets.

Transparent capacitive micromachined ultrasound transducer linear arrays for combined realtime optical and ultrasonic imaging.

Transparent ultrasound transducers could enable many novel applications involving both ultrasonics and optics. Recently, we reported transparent capacitive micromachined ultrasound transducers (CMUTs) and demonstrated through-illumination photoacoustic imaging. This work presents the feasibility of transparent CMUTs for combined ultrasound imaging and through-array white-light imaging with a miniature camera placed behind the array. Transparent CMUT devices are fabricated with an adhesive wafer bonding technique and provide high transparency up to 90% in visible wavelengths. Fabricated linear arrays have a central operating frequency of 9 MHz with 128 active elements. Realtime plane-wave imaging is performed for ultrasound imaging, and lateral and axial resolutions of, respectively, 234 and 338 µm are achieved. Transparent CMUT has demonstrated a high transmit sensitivity of 1.4 kPa/V per channel with a 100 VDC bias voltage. The signal-to-noise ratio for a beamformed image of wire targets is determined to be 28.4 dB. To the best of our knowledge, this is the first report of combined realtime optical and ultrasonic imaging with transparent arrays. This technology may enable one to visually see what is being scanned and scan what one sees without co-registration errors. Future applications could include multi-modality probes for interventional and surgical procedures.

NIR-Responsive Spatiotemporally Controlled Cyanobacteria Micro-Nanodevice for Intensity-Modulated Chemotherapeutics in Rheumatoid Arthritis.

The expression of hypoxia-inducible factor-1α (HIF-1α) is upregulated in hypoxic environments at the lesions of rheumatoid arthritis (RA), which promoted the polarization of proinflammatory M1 macrophages and inhibited the differentiation of anti-inflammatory M2 to deteriorate synovial inflammation. Since oxygen scarcity at the joints causes an imbalance of macrophages M1 and M2, herein, we designed a cyanobacteria micro-nanodevice that can be spatiotemporally controlled in vivo to continuously producing oxygen in the RA joints for the downregulation of the expression of HIF-1α, thereby reducing the amounts of M1 macrophages and inducing the polarization of M2 macrophages for chemically sensitized RA treatment. The forthputting of temperature-sensitive hydrogel guaranteed the safety of cyanobacteria micro-nanodevice in vivo. Furthermore, the oxygen produced by cyanobacteria micro-nanodevice in a sustained manner enhanced the therapeutic effect of the antirheumatic drug methotrexate (MTX) and discouraged inflammation and bone erosion at RA. This study provided a new approach for the RA treatment of spatiotemporal-controlled release of oxygen in vitro.

Bone Material Strength Index as Measured by Impact Microindentation is Low in Patients with Primary Hyperparathyroidism.

CONTEXT: In primary hyperparathyroidism (PHPT) bone mineral density (BMD) is typically decreased in cortical bone and relatively preserved in trabecular bone. An increased fracture rate is observed however not only at peripheral sites but also at the spine, and fractures occur at higher BMD values than expected. We hypothesized that components of bone quality other than BMD are affected in PHPT as well. OBJECTIVE: To evaluate bone material properties using impact microindentation (IMI) in PHPT patients. METHODS: In this cross-sectional study, the Bone Material Strength index (BMSi) was measured by IMI at the midshaft of the tibia in 37 patients with PHPT (28 women), 11 of whom had prevalent fragility fractures, and 37 euparathyroid controls (28 women) matched for age, gender, and fragility fracture status. RESULTS: Mean age of PHPT patients and controls was 61.8 ±â€…13.3 and 61.0 ±â€…11.8 years, respectively, P = .77. Calcium and PTH levels were significantly higher in PHPT patients but BMD at the lumbar spine (0.92 ±â€…0.15 vs 0.89 ±â€…0.11, P = .37) and the femoral neck (0.70 ±â€…0.11 vs 0.67 ±â€…0.07, P = .15) were comparable between groups. BMSi however was significantly lower in PHPT patients than in controls (78.2 ±â€…5.7 vs 82.8 ±â€…4.5, P < .001). In addition, BMSi was significantly lower in 11 PHPT patients with fragility fractures than in the 26 PHPT patients without fragility fractures (74.7 ±â€…6.0 vs 79.6 ±â€…5.0, P = .015). CONCLUSION: Our data indicate that bone material properties are altered in PHPT patients and most affected in those with prevalent fractures. IMI might be a valuable additional tool in the evaluation of bone fragility in patients with PHPT.

Optimizing the design of a contraceptive microarray patch: a discrete choice experiment on women's preferences in India and Nigeria.

BACKGROUND: Efforts are underway to develop an easy-to-use contraceptive microarray patch (MAP) that could expand the range of self-administrable methods. This paper presents results from a discrete choice experiment (DCE) designed to support optimal product design. METHODS: We conducted a DCE survey of users and non-users of contraception in New Delhi, India (496 women) and Ibadan, Nigeria (two versions with 530 and 416 women, respectively) to assess stated preferences for up to six potential product attributes: effect on menstruation, duration of effectiveness, application pain, location, rash after application, and patch size. We estimated Hierarchical Bayes coefficients (utilities) for each attribute level and ran simulations comparing women's preferences for hypothetical MAPs with varying attribute combinations. RESULTS: The most important attributes of the MAP were potential for menstrual side effects (55% of preferences in India and 42% in Nigeria) and duration (13% of preferences in India and 24% in Nigeria). Women preferred a regular period over an irregular or no period, and a six-month duration to three or one month. Simulations show that the most ideal design would be a small patch, providing 6 months of protection, that would involve no pain on administration, result in a one-day rash, and be applied to the foot. CONCLUSIONS: To the extent possible, MAP developers should consider method designs and formulations that limit menstrual side effects and provide more than one month of protection.

Combinatorial microneedle patch with tunable release kinetics and dual fast-deep/sustained release capabilities.

Transdermal microneedle (MN) drug delivery patches, comprising water-soluble polymers, have played an essential role in diverse biomedical applications, but with limited development towards fast deep release or sustained delivery applications. The effectiveness of such MN delivery patches strongly depends on the materials from which they are constructed. Herein, we present a dual-action combinatorial programmable MN patch, comprising of fast and sustained-release MN zones, with tunable release kinetics towards delivering a wide range of therapeutics over different timeframes in single application. We demonstrate the fine tuning of MN materials; the patches can be tailored to deliver a first payload faster and deeper within minutes, while simultaneously delivering a second payload over long times ranging from weeks to months. The active and rapid burst release relies on embedding biodegradable Mg microparticle 'engines' in dissolvable MNs while the sustained release is attributed to biocompatible polymers that allow prolonged release in a controllable tunable manner. In addition, the patches are characterized and optimized for their design, materials and mechanical properties. These studies indicate that such programmable dual-action versatile MN platform is expected to improve therapeutic efficacy and patient compliance, achieving powerful benefits by single patch application at low manufacturing cost.

Trends in Micro-/Nanorobotics: Materials Development, Actuation, Localization, and System Integration for Biomedical Applications.

Micro-/nanorobots (m-bots) have attracted significant interest due to their suitability for applications in biomedical engineering and environmental remediation. Particularly, their applications in in vivo diagnosis and intervention have been the focus of extensive research in recent years with various clinical imaging techniques being applied for localization and tracking. The successful integration of well-designed m-bots with surface functionalization, remote actuation systems, and imaging techniques becomes the crucial step toward biomedical applications, especially for the in vivo uses. This review thus addresses four different aspects of biomedical m-bots: design/fabrication, functionalization, actuation, and localization. The biomedical applications of the m-bots in diagnosis, sensing, microsurgery, targeted drug/cell delivery, thrombus ablation, and wound healing are reviewed from these viewpoints. The developed biomedical m-bot systems are comprehensively compared and evaluated based on their characteristics. The current challenges and the directions of future research in this field are summarized.

Three-Dimensional Stretchable Microelectronics by Projection Microstereolithography (PµSL).

Stretchable and flexible electronics conformal to human skin or implanted into biological tissues has attracted considerable interest for emerging applications in health monitoring and medical treatment. Although various stretchable materials and structures have been designed and manufactured, most are limited to two-dimensional (2D) layouts for interconnects and active components. Here, by using projection microstereolithography (PµSL)-based three-dimensional (3D) printing, we introduce a versatile microfabrication process to push the manufacturing limit and achieve previously inaccessible 3D geometries at a high resolution of 2 µm. After coating the printed microstructures with thin Au films, the 3D conductive structures offer exceptional stretchability (∼130%), conformability, and stable electrical conductivity (<5% resistance change at 100% tensile strain). This fabrication process can be further applied to directly create complicated 3D interconnect networks of sophisticated active components, as demonstrated with a stretchable capacitive pressure sensor array here. The proposed scheme allows a simple, facile, and scalable manufacturing route for complex, integrated 3D flexible electronic systems.

Strain-Engineering Induced Anisotropic Crystallite Orientation and Maximized Carrier Mobility for High-Performance Microfiber-Based Organic Bioelectronic Devices.

Despite the importance of carrier mobility, recent research efforts have been mainly focused on the improvement of volumetric capacitance in order to maximize the figure-of-merit, µC* (product of carrier mobility and volumetric capacitance), for high-performance organic electrochemical transistors. Herein, high-performance microfiber-based organic electrochemical transistors with unprecedentedly large µC* using highly ordered crystalline poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) microfibers with very high carrier mobilities are reported. The strain engineering via uniaxial tension is employed in combination with solvent-mediated crystallization in the course of drying coagulated fibers, resulting in the permanent preferential alignment of crystalline PEDOT:PSS domains along the fiber direction, which is verified by atomic force microscopy and transmission wide-angle X-ray scattering. The resultant strain-engineered microfibers exhibit very high carrier mobility (12.9 cm2 V-1 s-1 ) without the trade-off in volumetric capacitance (122 F cm-3 ) and hole density (5.8 × 1020  cm-3 ). Such advantageous electrical and electrochemical characteristics offer the benchmark parameter of µC* over ≈1500 F cm-1  V-1  s-1 , which is the highest metric ever reported in the literature and can be beneficial for realizing a new class of substrate-free fibrillar and/or textile bioelectronics in the configuration of electrochemical transistors and/or electrochemical ion pumps.

Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid.

The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and analysis. Here we report the use of a microneedle patch for fast in vivo sampling and on-needle quantification of target protein biomarkers in interstitial fluid. We used plasmonic fluor-an ultrabright fluorescent label-to improve the limit of detection of various interstitial fluid protein biomarkers by nearly 800-fold compared with conventional fluorophores, and a magnetic backing layer to implement conventional immunoassay procedures on the patch and thus improve measurement consistency. We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum-a challenging site for biomarker detection-and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids. Microneedle patches for the minimally invasive collection and analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.