ABSTRACT
Cilia are hair-like organelles present on cell surfaces. They often exhibit a collective wave-like motion that can enhance fluid or particle transportation function, known as metachronal motion. Inspired by nature, researchers have developed artificial cilia capable of inducing metachronal motion, especially magnetic actuation. However, current methods remain intricate, requiring either control of the magnetic or geometrical properties of individual cilia or the generation of a complex magnetic field. In this paper, we present a novel elegant method that eliminates these complexities and induces metachronal motion of arrays of identical microscopic magnetic artificial cilia by applying a simple rotating uniform magnetic field. The key idea of our method is to place arrays of cilia on surfaces with a specially designed curvature. This results in consecutive cilia experiencing different magnetic field directions at each point in time, inducing a phase lag in their motion, thereby causing collective wave-like motion. Moreover, by tuning the surface curvature profile, we can achieve diverse metachronal patterns analogous to symplectic and antiplectic metachronal motion observed in nature, and we can even devise novel combinations thereof. Furthermore, we characterize the local flow patterns generated by the motion of the cilia, revealing the formation of vortical patterns. Our novel approach simplifies the realization of miniaturized metachronal motion in microfluidic systems and opens the possibility of controlling flow pattern generation and transportation, opening avenues for applications such as lab-on-a-chip technologies, organ-on-a-chip platforms, and microscopic object propulsion.
Subject(s)
Cilia , Magnetic Fields , Surface Properties , MotionABSTRACT
Biological systems interact directly with the environment and learn by receiving multimodal feedback via sensory stimuli that shape the formation of internal neuronal representations. Drawing inspiration from biological concepts such as exploration and sensory processing that eventually lead to behavioral conditioning, we present a robotic system handling objects through multimodal learning. A small-scale organic neuromorphic circuit locally integrates and adaptively processes multimodal sensory stimuli, enabling the robot to interact intelligently with its surroundings. The real-time handling of sensory stimuli via low-voltage organic neuromorphic devices with synaptic functionality forms multimodal associative connections that lead to behavioral conditioning, and thus the robot learns to avoid potentially dangerous objects. This work demonstrates that adaptive neuro-inspired circuitry with multifunctional organic materials, can accommodate locally efficient bio-inspired learning for advancing intelligent robotics.
Subject(s)
Neural Networks, Computer , Robotics , Robotics/instrumentation , Robotics/methods , Electronics/instrumentation , Learning/physiology , HumansABSTRACT
Organ-on-a-chip (OOC) models based on microfluidic technology are increasingly used to obtain mechanistic insight into (patho)physiological processes in humans, and they hold great promise for application in drug development and regenerative medicine. Despite significant progress in OOC development, several limitations of conventional microfluidic devices pose challenges. First, most microfluidic systems have rectangular cross sections and flat walls, and therefore tubular/ curved structures, like blood vessels and nephrons, are not well represented. Second, polymers used as base materials for microfluidic devices are much stiffer than in vivo extracellular matrix (ECM). Finally, in current cell seeding methods, challenges exist regarding precise control over cell seeding location, unreachable spaces due to flow resistances, and restricted dimensions/geometries. To address these limitations, an alternative cell seeding technique and a corresponding workflow is introduced to create circular cross-sectioned tubular OOC models by pre-wrapping cells around sacrificial fiber templates. As a proof of concept, a perfusable renal proximal tubule-on-a-chip is demonstrated with a diameter as small as 50 µm, cellular tubular structures with branches and curvature, and a preliminary vascular-renal tubule interaction model. The cell pre-wrapping seeding technique promises to enable the construction of diverse physiological/pathological models, providing tubular OOC systems for mechanistic investigations and drug development.
Subject(s)
Hydrogels , Lab-On-A-Chip Devices , Hydrogels/chemistry , Humans , Animals , Tissue Engineering/methods , Equipment Design/methods , Rats , Microphysiological SystemsABSTRACT
Cilia are slender, hair-like cell protrusions that are present ubiquitously in the natural world. They perform essential functions, such as generating fluid flow, propulsion, and feeding, in organisms ranging from protozoa to the human body. The coordinated beating of cilia, which results in wavelike motions known as metachrony, has fascinated researchers for decades for its role in functions such as flow generation and mucus transport. Inspired by nature, researchers have explored diverse materials for the fabrication of artificial cilia and developed several methods to mimic the metachronal motion observed in their biological counterparts. In this review, we will introduce the different types of metachronal motion generated by both biological and artificial cilia, the latter including pneumatically, photonically, electrically, and magnetically driven artificial cilia. Furthermore, we review the possible applications of metachronal motion by artificial cilia, focusing on flow generation, transport of mucus, particles, and droplets, and microrobotic locomotion. The overall aim of this review is to offer a comprehensive overview of the metachronal motions exhibited by diverse artificial cilia and the corresponding practical implementations. Additionally, we identify the potential future directions within this field. These insights present an exciting opportunity for further advancements in this domain.
ABSTRACT
4D microstructured actuators are micro-objects made of stimuli-responsive materials capable of induced shape deformations, with applications ranging from microrobotics to smart micropatterned haptic surfaces. The novel technology dual-wavelength volumetric microlithography (DWVML) realizes rapid printing of high-resolution 3D microstructures and so has the potential to pave the way to feasible manufacturing of 4D microdevices. In this work, DWVML is applied for the first time to printing stimuli-responsive materials, namely, liquid crystal networks (LCNs). An LCN photoresist is developed and characterized, and large arrays of up to 5625 LCN micropillars with programmable shape changes are produced by means of DWVML in the time span of seconds, over areas as large as â¼5.4 mm2. The production rate of 0.24 mm3 h-1 is achieved, exceeding speeds previously reported for additive manufacturing of LCNs by 2 orders of magnitude. Finally, a membrane with tunable, micrometer-sized pores is fabricated to illustrate the potential DWVML holds for real-world applications.
ABSTRACT
HYPOTHESIS: Electronic paper displays rely on electrokinetic effects in nonpolar solvents to drive the displacement of colloidal particles within a fluidic cell. While Electrophoresis (EP) is a well-established and frequently employed phenomenon, electro-osmosis (EO), which drives fluid flow along charged solid surfaces, has not been studied as extensively. We hypothesize that by exploiting the interplay between these effects, an enhanced particle transport can be achieved. EXPERIMENTS: In this study, we experimentally investigate the combined effects of EP and EO for colloidal particles in non-polar solvents, driven by an electric field. We use astigmatism micro-particle tracking velocimetry (A-µPTV) to measure the motion of charged particles within model fluidic cells. Using a simple approach that relies on basic fluid flow properties we extract the contributions due to EP and EO, finding that EO contributes significantly to particle transport. The validity of our approach is confirmed by measurements on particles with different magnitudes of charge, and by comparison to numerical simulations. FINDINGS: We find that EO flows can play a dominant role in the transport of particles in electrokinetic display devices. This can be exploited to speed up particle transport, potentially yielding displays with significantly faster switching times.
ABSTRACT
Despite recent advances in artificial cilia technologies, the application of metachrony, which is the collective wavelike motion by cilia moving out-of-phase, has been severely hampered by difficulties in controlling closely packed artificial cilia at micrometer length scales. Moreover, there has been no direct experimental proof yet that a metachronal wave in combination with fully reciprocal ciliary motion can generate significant microfluidic flow on a micrometer scale as theoretically predicted. In this study, using an in-house developed precise micro-molding technique, we have fabricated closely packed magnetic artificial cilia that can generate well-controlled metachronal waves. We studied the effect of pure metachrony on fluid flow by excluding all symmetry-breaking ciliary features. Experimental and simulation results prove that net fluid transport can be generated by metachronal motion alone, and the effectiveness is strongly dependent on cilia spacing. This technique not only offers a biomimetic experimental platform to better understand the mechanisms underlying metachrony, it also opens new pathways towards advanced industrial applications.
Subject(s)
Cilia , Magnetics , Motion , Computer Simulation , Magnetic PhenomenaABSTRACT
Cancer-on-chip (CoC) models, based on microfluidic chips harboring chambers for 3D tumor-cell culture, enable us to create a controlled tumor microenvironment (TME). CoC models are therefore increasingly used to systematically study effects of the TME on the various steps in cancer metastasis. Moreover, CoC models have great potential for developing novel cancer therapies and for predicting patient-specific response to cancer treatments. We review recent developments in CoC models, focusing on three main TME components: (i) the anisotropic extracellular matrix (ECM) architectures, (ii) the vasculature, and (iii) the immune system. We aim to provide guidance to biologists to choose the best CoC approach for addressing questions about the role of the TME in metastasis, and to inspire engineers to develop novel CoC technologies.
Subject(s)
Neoplasms , Tumor Microenvironment , Humans , Neoplasms/therapy , Neoplasms/pathology , Microfluidics , Extracellular MatrixABSTRACT
Metastasis is a multi-step process that is critically affected by cues from the tumor micro-environment (TME), such as from the extracellular matrix (ECM). The role of the ECM in the onset of metastasis, invasion, is not yet fully understood. A further complicating factor is that the ECM in the TME is mostly heterogeneous, in particular presenting a basement membrane (BM) directly enveloping the tumor, which acts as a barrier to invasion into the surrounding stromal ECM. To systematically investigate the role of ECM in invasion, appropriate in vitro models with control over such ECM heterogeneity are essential. We present a novel high-throughput microfluidic approach to build such a model, which enables to capture the invasion of cancer cells from the tumor, through the BM and into the stromal tissue. We used a droplet-maker device to encapsulate cells in beads of a primary hydrogel mimicking BM, Matrigel, which were then embedded in a secondary hydrogel mimicking stromal ECM, collagen I. Our technology ultimately provides control over parameters such as tissue size, cell count and type, and ECM composition and stiffness. As a proof-of-principle, we carried out a comparative study with two breast cancer cell types, and we observed typical behavior consistent with previous studies. Highly invasive MDA-MB-231 cells showed single cell invasion behavior, whereas poorly invasive MCF-7 cells physically penetrated the surrounding matrix collectively. A comparative analysis conducted between our heterogeneous model and previous models employing a single type of hydrogel, either collagen I or Matrigel, has unveiled a substantial difference in terms of cancer cell invasion distance. Our in vitro model resembles an in vivo heterogeneous cancer microenvironment and can potentially be used for high throughput studies of cancer invasion.
ABSTRACT
Biological cilia, hairlike organelles on cell surfaces, often exhibit collective wavelike motion known as metachrony, which helps generating fluid flow. Inspired by nature, researchers have developed artificial cilia as microfluidic actuators, exploring several methods to mimic the metachrony. However, reported methods are difficult to miniaturize because they require either control of individual cilia properties or the generation of a complex external magnetic field. We introduce a concept that generates metachronal motion of magnetic artificial cilia (MAC), even though the MAC are all identical, and the applied external magnetic field is uniform. This is achieved by integrating a paramagnetic substructure in the substrate underneath the MAC. Uniquely, we can create both symplectic and antiplectic metachrony by changing the relative positions of MAC and substructure. We demonstrate the flow generation of the two metachronal motions in both high and low Reynolds number conditions. Our research marks a significant milestone by breaking the size limitation barrier in metachronal artificial cilia. This achievement not only showcases the potential of nature-inspired engineering but also opens up a host of exciting opportunities for designing and optimizing microsystems with enhanced fluid manipulation capabilities.
Subject(s)
Cilia , Magnetic Fields , Physical Phenomena , Motion , Cell MembraneABSTRACT
Evolution has produced natural systems that generate motion and sense external stimuli at the micro- and nanoscales. At extremely small scales, the intricate motions and large deformations shown by these biosystems are due to a tipping balance between their structural compliance and the actuating force generated in them. Artificially mimicking such ingenious systems for scientific and engineering applications has been approached through the development and use of different smart materials mostly limited to microscale dimensions. To push the application range down to the nanoscale, we developed a material preparation process that yields a library of nanomagnetic elastomers with high magnetic particle concentrations. Through this process, we have realized a material with the highest magnetic-to-elastic force ratio, as is shown by an extensive mechanical and magnetic characterization of the materials. Furthermore, we have fabricated and actuated micro- and nanostructures mimicking cilia, demonstrating the extreme compliance and responsiveness of the developed materials.
ABSTRACT
The key risk factor for glaucoma is increased intraocular pressure (IOP). Glaucoma drainage devices implanted in the eye can reduce IOP and thus stop disease progression. However, most devices currently used in clinical practice are passive and do not allow for postsurgical IOP control, which may result in serious complications such as hypotony (i.e., excessively low IOP). To enable noninvasive IOP control, we demonstrate a novel, miniature glaucoma implant that will enable the repeated adjustment of the hydrodynamic resistance after implantation. This is achieved by integrating a magnetic microvalve containing a micropencil-shaped plug that is moved using an external magnet, thereby opening or closing fluidic channels. The microplug is made from biocompatible poly(styrene-block-isobutylene-block-styrene) (SIBS) containing iron microparticles. The complete implant consists of an SIBS drainage tube and a housing element containing the microvalve and fabricated with hot embossing using femtosecond laser-machined glass molds. Using in vitro and ex vivo microfluidic experiments, we demonstrate that when the microvalve is closed, it can provide sufficient hydrodynamic resistance to overcome hypotony. Valve function is repeatable and stable over time. Due to its small size, our implant is a promising, safe, easy-to-implant, minimally invasive glaucoma surgery device.
ABSTRACT
In cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in this process have been extensively studied, but the influence of cyclic deformation on the fibrogenic behavior of cardiac fibroblasts in the ever-beating heart is not fully understood. In fact, most investigated mechanotransduction pathways in cardiac fibroblasts seem to ultimately have profibrotic effects, which leaves an important question in cardiac fibrosis research unanswered: how do cardiac fibroblasts stay quiescent in the ever-beating human heart? In this study, we developed a human cardiac fibrosis-on-a-chip platform and utilized it to investigate if and how cyclic strain affects fibrogenic signaling. The pneumatically actuated platform can expose engineered tissues to controlled strain magnitudes of 0-25% - which covers the entire physiological and pathological strain range in the human heart - and to biochemical stimuli and enables high-throughput screening of multiple samples. Microtissues of human fetal cardiac fibroblasts (hfCF) embedded in gelatin methacryloyl (GelMA) were 3D-cultured on this platform and exposed to strain conditions which mimic the healthy human heart. The results provide evidence of an antifibrotic effect of the applied strain conditions on cardiac fibroblast behavior, emphasizing the influence of biomechanical stimuli on the fibrogenic process and giving a detailed overview of the mechanosensitive pathways and genes involved, which can be used in the development of novel therapies against cardiac fibrosis.
Subject(s)
Myocardium , Transcriptome , Humans , Myocardium/pathology , Mechanotransduction, Cellular , Fibroblasts , Fibrosis , Lab-On-A-Chip DevicesABSTRACT
Immunoassays show great potential for the detection of low levels of cytokines, due to their high sensitivity and excellent specificity. There is a particular demand for biosensors that enable both high-throughput screening and continuous monitoring of clinically relevant cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα). To this end, we here introduce a novel bioluminescent immunoassay based on the ratiometric plug-and-play immunodiagnostics (RAPPID) platform, with an improved intrinsic signal-to-background and an >80-fold increase in the luminescent signal. The new dRAPPID assay, comprising a dimeric protein G adapter connected via a semiflexible linker, was applied to detect the secretion of IL-6 by breast carcinoma cells upon TNFα stimulation and the production of low concentrations of IL-6 (â¼18 pM) in an endotoxin-stimulated human 3D muscle tissue model. Moreover, we integrated the dRAPPID assay in a newly developed microfluidic device for the simultaneous and continuous monitoring of changes in IL-6 and TNFα in the low-nanomolar range. The luminescence-based read-out and the homogeneous nature of the dRAPPID platform allowed for detection with a simple measurement setup, consisting of a digital camera and a light-sealed box. This permits the usage of the continuous dRAPPID monitoring chip at the point of need, without the requirement for complex or expensive detection techniques.
Subject(s)
Cytokines , Tumor Necrosis Factor-alpha , Humans , Interleukin-6 , Immunoassay/methods , Immunologic TestsABSTRACT
Research targeting the development of on-body sensors has been significantly growing in recent years - an example is on-skin sweat sensing. However, the wide inter and intra person variability of skin characteristics make in vivo testing of these sensors and included materials such as skin adhesives difficult, which hampers especially the initial development phase of such wearables. Besides the development of wearable sweat sensors, companies developing deodorants, cosmetics, medical adhesives and wearable textiles now need to perform expensive human subjects testing with little control over the exact sweat mechanisms. Hence, there is a need for a realistic, adaptable and stable test platform, or artificial skin. We present a versatile artificial skin platform that faithfully recapitulates skin topography, active sweat pores, skin wetting behaviour and sweat rate, and that can be tuned to mimic the specifications of the targeted body location and sweating characteristics. The developed artificial skin is capable of generating sweat rates as low as 0.1 nL min-1 pore-1 and as high as 100 nL min-1 pore-1, spanning the whole range of physiological sweat rates. Specifically, the platform can be used for the development of sweat sensors for sedentary persons whose sweat rates are commonly lower than currently delivered by any other artificial skin platform.
Subject(s)
Biosensing Techniques , Skin, Artificial , Humans , Sweating , Sweat , SkinABSTRACT
Hydrogels can exhibit a remarkably complex response to external stimuli and show rich mechanical behavior. Previous studies of the mechanics of hydrogel particles have generally focused on their static, rather than dynamic, response, as traditional methods for measuring single particle response at the microscopic scale cannot readily measure time-dependent mechanics. Here, we study both the static and the time-dependent response of a single batch of polyacrylamide (PAAm) particles by combining direct contact forces, applied by using Capillary Micromechanics, a method where particles are deformed in a tapered capillary, and osmotic forces are applied by a high molecular weight dextran solution. We found higher values of the static compressive and shear elastic moduli for particles exposed to dextran, as compared to water (KDex≈63 kPa vs. Kwater≈36 kPa, and GDex≈16 kPa vs. Gwater≈7 kPa), which we accounted for, theoretically, as being the result of the increased internal polymer concentration. For the dynamic response, we observed surprising behavior, not readily explained by poroelastic theories. The particles exposed to dextran solutions deformed more slowly under applied external forces than did those suspended in water (τDex≈90 s vs. τwater≈15 s). The theoretical expectation was the opposite. However, we could account for this behaviour by considering the diffusion of dextran molecules in the surrounding solution, which we found to dominate the compression dynamics of our hydrogel particles suspended in dextran solutions.
ABSTRACT
INTRODUCTION: The information derived from the number and characteristics of circulating tumor cells (CTCs), is crucial to ensure appropriate cancer treatment monitoring. Currently, diverse microfluidic platforms have been developed for isolating CTCs from blood, but it remains a challenge to develop a low-cost, practical, and efficient strategy. OBJECTIVES: This study aimed to isolate CTCs from the blood of cancer patients via introducing a new and efficient micropillar array-based microfluidic chip (MPA-Chip), as well as providing prognostic information and monitoring the treatment efficacy in cancer patients. METHODS: We fabricated a microfluidic chip (MPA-Chip) containing arrays of micropillars with different geometries (lozenge, rectangle, circle, and triangle). We conducted numerical simulations to compare velocity and pressure profiles inside the micropillar arrays. Also, we experimentally evaluated the capture efficiency and purity of the geometries using breast and prostate cancer cell lines as well as a blood sample. Moreover, the device's performance was validated on 12 patients with breast cancer (BC) in different states. RESULTS: The lozenge geometry was selected as the most effective and optimized micropillar design for CTCs isolation, providing high capture efficiency (>85 %), purity (>90 %), and viability (97 %). Furthermore, the lozenge MPA-chip was successfully validated by the detection of CTCs from 12 breast cancer (BC) patients, with non-metastatic (median number of 6 CTCs) and metastatic (median number of 25 CTCs) diseases, showing different prognoses. Also, increasing the chemotherapy period resulted in a decrease in the number of captured CTCs from 23 to 7 for the metastatic patient. The MPA-Chip size was only 0.25 cm2 and the throughput of a single chip was 0.5 ml/h, which can be increased by multiple MPA-Chips in parallel. CONCLUSION: The lozenge MPA-Chip presented a novel micropillar geometry for on-chip CTC isolation, detection, and staining, and in the future, the possibilities can be extended to the culture of the CTCs.
Subject(s)
Breast Neoplasms , Neoplastic Cells, Circulating , Male , Humans , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathology , Microfluidics/methods , Cell Separation/methods , Cell Line, TumorABSTRACT
Optical transparency is highly desirable in bioelectronic sensors because it enables multimodal optical assessment during electronic sensing. Ultrathin (<5 µm) organic electrochemical transistors (OECTs) can be potentially used as a highly efficient bioelectronic transducer because they demonstrate high transconductance during low-voltage operation and close conformability to biological tissues. However, the fabrication of fully transparent ultrathin OECTs remains a challenge owing to the harsh etching processes of nanomaterials. In this study, fully transparent, ultrathin, and flexible OECTs are developed using additive integration processes of selective-wetting deposition and thermally bonded lamination. These processes are compatible with Ag nanowire electrodes and conducting polymer channels and realize unprecedented flexible OECTs with high visible transmittance (>90%) and high transconductance (≈1 mS) in low-voltage operations (<0.6 V). Further, electroencephalogram acquisition and nitrate ion sensing are demonstrated in addition to the compatibility of simultaneous assessments of optical blood flowmetry when the transparent OECTs are worn, owing to the transparency. These feasibility demonstrations show promise in contributing to human stress monitoring in bioelectronics.
Subject(s)
Biosensing Techniques , Nanostructures , Humans , Polymers , ElectrodesABSTRACT
Glaucoma is a group of eye conditions that damage the optic nerve, the health of which is vital for vision. The key risk factor for the development and progression of this disease is increased intraocular pressure (IOP). Implantable glaucoma drainage devices have been developed to divert aqueous humor from the glaucomatous eye as a means of reducing IOP. The artificial drainage pathway created by these devices drives the fluid into a filtering bleb. The long-term success of filtration surgery is dictated by the proper functioning of the bleb and overlying Tenon's and conjunctival tissue. To better understand the influence of the health condition of these tissues on IOP, we have developed a mathematical model of fluid production in the eye, its removal from the anterior chamber by a particular glaucoma implant-the PRESERFLO® MicroShunt-, drainage into the bleb and absorption by the subconjunctival vasculature. The mathematical model was numerically solved by commercial FEM package COMSOL. Our numerical results of IOP for different postoperative conditions are consistent with the available evidence on IOP outcomes after the implantation of this device. To obtain insight into the adjustments in the implant's hydrodynamic resistance that are required for IOP control when hypotony or bleb scarring due to tissue fibrosis take place, we have simulated the flow through a microshunt with an adjustable lumen diameter. Our findings show that increasing the hydrodynamic resistance of the microshunt by reducing the lumen diameter, can effectively help to prevent hypotony. However, decreasing the hydrodynamic resistance of the implant will not sufficiently decrease the IOP to acceptable levels when the bleb is encapsulated due to tissue fibrosis. Therefore, to effectively reduce IOP, the adjustable glaucoma implant should be combined with a means of reducing fibrosis. The results reported herein may provide guidelines to support the design of future glaucoma implants with adjustable hydrodynamic resistances.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Humans , Fibrosis , Glaucoma/surgery , Intraocular PressureABSTRACT
Chemical monitoring communicates diverse environmental information from industrial and biological processes. However, promising and sustainable systems and associated inspection devices that dynamically enable on-site quality monitoring of target chemicals confined inside transformable and opaque channels are yet to be investigated. This paper designs stretchable photo-sensor patch sheets for nonsampling, source-free, and label-free on-site dynamic chemical monitoring of liquids flowing inside soft tubes via simple deformable surface wrapping. The device integrates carbon nanotube-based broadband photo-absorbent thin films with multilayer-laminated stretchable electrodes and substrates. The patterned rigid-soft structure of the proposed device provides durability and optical stability against mechanical deformations with a stretchability range of 70 to 280%, enabling shape-conformable attachments to transformable objects. The effective use of omnidirectional and transparent blackbody radiation from free-form targets themselves allows compact measurement configuration and enhances the functionality and simplicity of this scheme, while the presenting technology monitors concentrations of arbitrary water-soluble chemicals.