Micro- and nanomanipulation technology has found important applications in the fields of chemistry, materials, biology, and medicine. However, traditional manual techniques, constrained by the small size and fragile nature of target samples, often lack accuracy, efficiency, and throughput. Microfluidics has become a promising tool for handling micro- and nanoscale samples, addressing the above limitations. In particular, a growing number of innovations at the intersection of robotics and microfluidics have been proposed, showcasing the incredible potential in synergizing robotics and microfluidics technologies to develop fully automated and accurate systems for versatile micro- and nanomanipulation. In this Perspective, we discuss the ongoing research and development of robotics-enhanced microfluidics for micro- and nanomanipulation. We outline the key roles of major robotics technologies such as sensing, control, and artificial intelligence (AI) in microfluidic manipulation. We also propose the future directions of AI agents in microfluidic manipulation, aiming to achieve intelligent decision-making and execution across different manipulation tasks.

Hydrogels are widely used in cell cultures and microfluidic organ-on-chip devices as a mimic for an extracellular matrix. Soft and porous, they provide a gentle scaffold for the cell colonies to develop into properly structured tissues and organoids. A key factor in this process is the transmission of forces through the hydrogel, originating from the flowing perfusate and propagating toward and among the cells. Such forces serve as mechanical cues in the proliferation and differentiation of cells and in their aggregation into functional organoids. In this work, we use a poroelastic model to study the mechanical interaction among cells that is mediated by the hydrogel. The model predicts that closely spaced cells induce the formation of prominent “tension ribbons” within the hydrogel, actively pulling neighboring cells together and prompting the development of mutual protrusions. In larger cellular arrays, the deformation patterns become highly heterogeneous, strongly dependent on the relative positions of individual cells. These insights provide valuable guidance for optimizing the design and operational parameters of organ-on-chip devices.

Particle-wall interaction is important in various applications such as cell sorting, particle separation, the entire class of hydrodynamic filtration and its derivatives, etc. Yet, accurate implementation of interactions between the wall and finite-size particles is not trivial when working with the currently available particle tracking algorithms/packages as they typically work with point-wise particles. Herein, we report a particle tracking algorithm that takes into account interactions between particles of finite size and nearby solid objects. A particle is modeled as a set of circumferential points. While fluid-particle interactions are captured during the track of particle center, interactions between particles and nearby solid objects are modeled explicitly by examining circumferential points and applying a reflection scheme as needed to ensure impenetrability of solid objects. We also report a modified variant of auxiliary structured grid method to locate hosting cells, which in conjunction with a boundary condition scheme enables the capture of interactions between particles and solid objects. As a proof-of-concept, we numerically and experimentally study the particles' motion within a deterministic lateral displacement microfluidic device. The results successfully demonstrate the zigzag and bump modes observed in our experiments. We also study a microfluidic device with pinched flow numerically and validate our results against experimental data from the literature. By demonstrating an almost 8 speedup on a system with eight performance threads, our investigations suggest that the algorithm can benefit from parallel processing on multi-thread systems. We believe that the proposed framework can pave the way for designing related microfluidic chips precisely and conveniently.

Silicon-based microfluidics enable the creation of highly complex, three-dimensional fluid networks. These comprise scalable channel sizes and monolithically integrated functionalities available from complementary-metal-oxide-semiconductor technology. On this versatile, solid-state platform, advanced manufacturing techniques exist that allow the channel walls to be directly electrified with one or multiple pairs of electrodes along the fluid-carrying channel. The electrodes have ideal electrostatic geometries, yielding homogeneous electric field distributions across the entire cross section of the microfluidic channel. As these are located directly at the channel, only low supply voltages are needed to achieve suitable field strengths. Furthermore, a controlled supply of charge carriers to the microfluidic channel is feasible. These configurations may serve numerous applications, including highly efficient mechanisms to manipulate droplets, cells, and molecular compounds, perform pico-injection or poration, trigger and control chemical reactions, or realize electrochemical and capacitive sensing modalities. In this perspective, we describe the generic design and fabrication of these electrodes and discuss their miniaturization and scaling properties. Furthermore, we forecast novel use cases and discuss challenges in the context of the most interesting applications.

Monitoring platelet aggregation is crucial for predicting thrombotic diseases and identifying the risk of bleeding or resistance to antiplatelet drugs. This study developed a microfluidic device to measure platelet activation with high sensitivity. By controlling exposure time through repeated reinjections, the device enables the detection of subtle changes in platelet activity influenced by lifestyle factors, such as alcohol consumption. Using computational fluid dynamics simulations, the design was optimized to achieve moderate shear stresses and fabricated with 3D printing. Experimental results revealed that pillars biased to one side partially accelerate the flow and inhibit platelet adhesion. A distinct difference in platelet adhesion was clearly observed before and after alcohol consumption. Despite the high standard deviations in platelet adhesion area, hematocrit, and viscosity after alcohol consumption, the area covered by adhered platelets increased by 3.12 times compared to that before alcohol consumption. This microfluidic chip offers potential for personalized health monitoring by distinguishing platelet variations caused by lifestyle or dietary habits. However, challenges such as reinjection procedures and large sample volumes require further investigation.

Platelet transfusion is a lifesaving therapy intended to prevent and treat bleeding. However, in addition to platelets, a typical unit also contains a large volume of supernatant that accumulates multiple pro-inflammatory contaminants, including residual leukocytes, microaggregates, microparticles, antibodies, and cytokines. Infusion of this supernatant is responsible for virtually all adverse reactions to platelet transfusions. Conventional methods for removing residual leukocytes (leukoreduction) and reducing the volume of transfused supernatant (volume reduction) struggle to mitigate these risks holistically. Leukoreduction filters can remove leukocytes and microaggregates but fail to reduce supernatant volume, whereas centrifugation can reduce volume, but it is ineffective against larger contaminants and damages platelets. Additionally, platelet purification based on these methods is often too logistically complex, time-consuming, and labor-intensive to implement routinely. Emerging microfluidic technologies offer promising alternatives through passive separation mechanisms that enable cell separation with minimal damage and drastically reduced instrumentation size and facility requirements. This review examines recent innovations in microfluidic cell separation that can be used for leukoreduction and volume reduction of platelets. It begins by defining the performance requirements that any separation method must meet to successfully replace conventional methods currently used to perform these tasks. Standard performance metrics are described, including leukocyte depletion efficiency, degree of volume reduction, processing throughput, and platelet recovery. Finally, the review outlines the primary challenges that must be overcome to enable simple-to-use, disposable microfluidic devices capable of both reducing the platelet unit volume and removing pro-inflammatory contaminants, while preserving most functional platelets for transfusion.

In recent years, the allure of space exploration and human spaceflight has surged, yet the effects of microgravity on the human body remain a significant concern. Immune and red blood cells rely on hematic or lymphatic streams as their primary means of transportation, posing notable challenges under microgravity conditions. This study sheds light on the intricate dynamics of cell behavior when suspended in bio-fluid under varying gravitational forces. Utilizing the dissipative particle dynamics approach, blood and white blood cells were modeled, with gravity applied as an external force along the vertical axis, ranging from 0 to 2 g in parameter sweeps. The results revealed discernible alterations in the cell shape and spatial alignment in response to gravity, quantified through metrics such as elongation and deformation indices, pitch angle, and normalized center of mass. Statistical analysis using the Mann-Whitney U test underscored clear distinctions between microgravity (<1 g) and hypergravity (>1 g) samples compared to normal gravity (1 g). Furthermore, the examination of forces exerted on the solid, including drag, shear stress, and solid forces, unveiled a reduction in the magnitude as the gravitational force increased. Additional analysis through dimensionless numbers unveiled the dominance of capillary and gravitational forces, which impacted cell velocity, leading to closer proximity to the wall and heightened viscous interaction with surrounding fluid particles. These interactions prompted shape alterations and reduced white blood cell area while increasing red blood cells. This study represents an effort in comprehending the effects of gravity on blood cells, offering insights into the intricate interplay between cellular dynamics and gravitational forces.

The death of dopamine-producing neurons in the substantia nigra in the base of the brain is a defining pathological feature in the development of Parkinson's disease (PD). PD is, however, a multi-systemic disease, also affecting the peripheral nervous system and gastrointestinal tract (GIT) that interact via the gut-brain axis (GBA). Our dual-flow GIT-brain microphysiological system (MPS) was modified to investigate the gut-to-brain translocation of the neurotoxin trigger of PD, 1-methyl-4-phenylpyridinium (MPP+), and its impact on key GIT and brain cells that contribute to the GBA. The modular GIT-brain MPS in combination with quantitative and morphometric image analysis methods reproduces cell specific neurotoxin-induced dopaminergic cytotoxicity and mitochondria-toxicity with the drug having no detrimental impact on the viability or integrity of cellular membranes of GIT-derived colonic epithelial cells. Our findings demonstrate the utility and capability of the GIT-brain MPS for measuring neuronal responses and its suitability for identifying compounds or molecules produced in the GIT that can exacerbate or protect against neuronal inflammation and cell death.

Bioaerosols produced within the respiratory system play an important role in respiratory disease transmission. These include infectious diseases such as common cold, influenza, tuberculosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among several others. It is, therefore, of immense interest to understand how bioaerosols are produced within the respiratory system. This has not been extensively investigated. The present study computationally investigates how bioaerosols are produced in a model respiratory tract due to hydrodynamic interactions between breathed air and a thin mucus layer, which lines the inner surface of the tract. It is observed that Kelvin-Helmholtz instability is established in the thin mucus layer due to associated fluid dynamics. This induces interfacial surface waves which fragment forming bioaerosols under certain conditions. A regime map is created-based on pertinent dimensionless parameters-to enable identification of such conditions. Analysis indicates that bioaerosols may be produced even under normal breathing conditions, contrary to expectations, depending on mucus rheology and thickness of the mucus layer. This is possible during medical conditions as well as during some treatment protocols. However, such bioaerosols are observed to be larger ( m) and are produced in less numbers ( ), as compared to those produced under coughing conditions. Treatment protocols and therapeutic strategies may be suitably devised based on these findings.