Zhangli Peng

Premature clearance and limited organ targeting remain major barriers for nanoparticle (NP) drug delivery. Hitchhiking NPs on red blood cells (RBCs) can enhance circulation and organ‐selective accumulation, but most approaches require ex vivo RBC extraction and reinfusion, limiting clinical translation. Here, we report an in situ RBC‐hitchhiking strategy, named i‐Bind, which employs polyphenol surface functionalization to enable spontaneous NP attachment to RBCs directly in the bloodstream. Driven by strong interactions of phenolic motifs with RBC membranes, i‐Bind NPs exhibited markedly enhanced and more stable hitchhiking onto RBCs under flowing whole blood conditions. In both healthy and diseased mice, i‐Bind NPs preferentially target the lungs, resulting in an over 20‐fold increase in lung‐to‐liver deposition ratio compared to unmodified NPs. Additionally, i‐Bind NPs show preferential targeting to distinct lung immune cell subsets in a pathology‐dependent manner, including cDC2s in healthy lungs, neutrophils in acute lung injury, and cDC1s in lung metastases. In a melanoma lung metastasis model, delivery of the STING agonist diABZI via i‐Bind NPs significantly inhibited lung metastasis progression by reprogramming the lung immune microenvironment. Collectively, i‐Bind provides a simple and versatile platform for organ‐targeted drug delivery and immune reprogramming.

Numerical modeling has played a pivotal role in advancing inertial microfluidics, tracing its development from inception and offering deeper insights into the microscale phenomena governing inertial focusing. These computational approaches have simultaneously supported the proliferation of on-chip technologies. Initially adopted across diverse industries for passive and high-throughput operations such as trapping, separation, and sorting of particles, the greatest potential of inertial microfluidics lies in biomedical applications, where it serves as a cornerstone for processing cells in clinical and research settings. As the range of applications continues to expand, microfluidic devices are evolving into increasingly complex systems capable of handling diverse cell types and particles within miniature chip architectures. This growing complexity necessitates the enhancement of conventional numerical techniques and the integration of innovative computational approaches to address these emerging challenges. This review aims to provide an overview of the available numerical techniques, highlighting their advantages and limitations. We explore recent strides in computational inertial microfluidics, emphasizing advancements within the last four years and the emergence of innovative methodologies such as smoothed particle hydrodynamics. Furthermore, we describe the nascent role of machine learning in inertial microfluidics, noting its limited adoption compared to conventional microfluidics and highlighting the potential to transform the field, as well as challenges that need to be overcome.

Inertial focusing has been utilized to advance assisted reproductive technologies (ART) for animal breeding and in vitro fertilization (IVF) by separating sperm cells from biofluids with complex cell backgrounds. While existing studies have aimed to design and optimize sperm separation devices, the fundamental mechanism behind the unique focusing behavior of sperm in spiral channels remains largely unknown: sperm cells focus near the outer wall, whereas most other cells focus near the inner wall. This is primarily due to the lack of a direct modelling scheme for capturing the detailed inertial migration of sperm cells in the spiral channels. In this work, we developed a 3D DNS-PT modeling approach that can predict the inertial focusing of sperm cells with long tails. Unlike previous studies that considered rotating spheres, the novelty of our approach is in extracting the inertial lift force for a triaxial ellipsoid (which represents the asymmetric oval-shaped sperm head) and accounting for the tail effect through appropriate boundary conditions, thus capturing their cumulative impact on sperm focusing behavior. Furthermore, we conducted inertial microfluidics experiments with fluorescent images of spermatozoa to validate the modelling results. We discovered that the effect of the tail, rather than the sperm head shape or orientation, is the primary determinant of the unique inertial focusing position of sperm cells in microchannels. The modelling results provided significant insights into the evolution of particle distribution in the channel cross-section along the flow direction, which was previously unknown due to the limitations of imaging techniques. The predicted particle trajectories enabled detailed analysis and explanation of the distinct migration paths of sperm cells and spherical particles. This work bridges the gap in our understanding of the inertial migration of sperm and other flagellated cells, facilitating the better design and optimization of sorting and separation devices.

A primary cilium, made of nine microtubule doublets enclosed in a cilium membrane, is a mechanosensing organelle that bends under an external mechanical load and sends an intracellular signal through transmembrane proteins activated by cilium bending. The nine microtubule doublets are the main load‐bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing component. No distinction was made between these two components in all existing models, where the stress calculated from the structural component (nine microtubule doublets) was used to explain the sensing location, which may be totally misleading. For the first time, we developed a microstructure‐based primary cilium model by considering these two components separately. First, we refined the analytical solution of bending an orthotropic cylindrical shell for individual microtubule, and obtained excellent agreement between finite element simulations and the theoretical predictions of a microtubule bending as a validation of the structural component in the model. Second, by integrating the cilium membrane with nine microtubule doublets and simulating the tip‐anchored optical tweezer experiment on our computational model, we found that the microtubule doublets may twist significantly as the whole cilium bends. Third, besides being cilium‐length‐dependent, we found the mechanical properties of the cilium are also highly deformation‐dependent. More important, we found that the cilium membrane near the base is not under pure in‐plane tension or compression as previously thought, but has significant local bending stress. This challenges the traditional model of cilium mechanosensing, indicating that transmembrane proteins may be activated more by membrane curvature than membrane stretching. Finally, we incorporated imaging data of primary cilia into our microstructure‐based cilium model, and found that comparing to the ideal model with uniform microtubule length, the imaging‐informed model shows the nine microtubule doublets interact more evenly with the cilium membrane, and their contact locations can cause even higher bending curvature in the cilium membrane than near the base.

We conducted a systematic numerical investigation of spherical, prolate and oblate particles in an inertial shear flow between two parallel walls, using smoothed particle hydrodynamics (SPH). It was previously shown that above a critical Reynolds number, spherical particles experience a supercritical pitchfork bifurcation of the equilibrium position in shear flow between two parallel walls, namely that the central equilibrium position becomes unstable, leading to the emergence of two new off-centre stable positions (Fox et al., J. Fluid Mech., vol. 915, 2021). This phenomenon was unexpected given the symmetry of the system. In addition to confirming this finding, we found, surprisingly, that ellipsoidal particles can also return to the centre position from the off-centre positions when the particle Reynolds number is further increased, while spherical particles become unstable under this increased Reynolds number. By utilizing both SPH and the finite element method for flow visualization, we explained the underlining mechanism of this reverse of bifurcation by altered streamwise vorticity and symmetry breaking of pressure. Furthermore, we expanded our investigation to include asymmetric particles, a novel aspect that had not been previously modelled, and we observed similar trends in particle dynamics for both symmetric and asymmetric ellipsoidal particles. While further validation through laboratory experiments is necessary, our research paves the road for development of new focusing and separation methods for shaped particles.

The nuclear lamina is widely recognized as the most crucial component in providing mechanical stability to the nucleus. However, it is still a significant challenge to model the mechanics of this multilayered protein network. We developed a constitutive model of the nuclear lamina network based on its microstructure, which accounts for the deformation phases at the dimer level, as well as the orientational arrangement and density of lamin filaments. Instead of relying on homology modeling in the previous studies, we conducted molecular simulations to predict the force-extension response of a highly accurate lamin dimer structure obtained through X-ray diffraction crystallography experimentation. Furthermore, we devised a semiflexible worm-like chain extension-force model of lamin dimer as a substitute, incorporating phases of initial stretching, uncoiling of the dimer coiled-coil, and transition of secondary structures. Subsequently, we developed a 2D network continuum model for the nuclear lamina by using our extension-force lamin dimer model and derived stress resultants. By comparing with experimentally measured lamina modulus, we found that the lamina network has sharp initial strain-hardening behavior. This also enabled us to carry out finite element simulations of the entire nucleus with an accurate microstructure-based nuclear lamina model. Finally, we conducted simulations of transendothelial transmigration of a nucleus and investigated the impact of varying network density and uncoiling constants on the critical force required for successful transmigration. The model allows us to incorporate the microstructure characteristics of the nuclear lamina into the nucleus model, thereby gaining insights into how laminopathies and mutations affect nuclear mechanics.

Soft objects squeezing through small apertures are crucial for many in vivo and in vitro processes. Red blood cell transit time through splenic inter-endothelial slits (IESs) plays a crucial role in blood filtration and disease progression, while droplet velocity through constrictions in microfluidic devices is important for effective manipulation and separation processes. As these transit phenomena are not well understood, we sought to establish analytical and numerical solutions of viscous droplet transit through a rectangular slit. This study extends from our former theory of a circular pore because a rectangular slit is more realistic in many physiological and engineering applications. Here, we derived the ordinary differential equations (ODEs) of a droplet passing through a slit by combining planar Poiseuille flow, the Young–Laplace equations, and modifying them to consider the lubrication layer between the droplet and the slit wall. Compared to the pore case, we used the Roscoe solution instead of the Sampson one to account for the flow entering and exiting a rectangular slit. When the surface tension and lubrication layer were negligible, we derived the closed-form solutions of transit time. When the surface tension and lubrication layer were finite, the ODEs were solved numerically to study the impact of various parameters on the transit time. With our solutions, we identified the impact of prescribed pressure drop, slit dimensions, and droplet parameters such as surface tension, viscosity, and volume on transit time. In addition, we also considered the effect of pressure drop and surface tension near critical values. For this study, critical surface tension for a given pressure drop describes the threshold droplet surface tension that prevents transit, and critical pressure for a given surface tension describes the threshold pressure drop that prevents transit. Our solutions demonstrate that there is a linear relationship between pressure and the reciprocal of the transit time (referred to as inverse transit time), as well as a linear relationship between viscosity and transit time. Additionally, when the droplet size increases with respect to the slit dimensions, there is a corresponding increase in transit time. Most notably, we emphasize the initial antagonistic effect of surface tension which resists droplet passage but at the same time decreases the lubrication layer, thus facilitating passage. Our results provide quantitative calculations for understanding cells passing through slit-like constrictions and designing droplet microfluidic experiments.

The splenic interendothelial slits fulfill the essential function of continuously filtering red blood cells (RBCs) from the bloodstream to eliminate abnormal and aged cells. To date, the process by which 8 μ m RBCs pass through 0.3 μ m-wide slits remains enigmatic. Does the slit caliber increase during RBC passage as sometimes suggested? Here, we elucidated the mechanisms that govern the RBC retention or passage dynamics in slits by combining multiscale modeling, live imaging, and microfluidic experiments on an original device with submicron-wide physiologically calibrated slits. We observed that healthy RBCs pass through 0.28 μ m-wide rigid slits at 37 °C. To achieve this feat, they must meet two requirements. Geometrically, their surface area-to-volume ratio must be compatible with a shape in two tether-connected equal spheres. Mechanically, the cells with a low surface area-to-volume ratio (28% of RBCs in a 0.4 μ m-wide slit) must locally unfold their spectrin cytoskeleton inside the slit. In contrast, activation of the mechanosensitive PIEZO1 channel is not required. The RBC transit time through the slits follows a − 1 and − 3 power law with in-slit pressure drop and slip width, respectively. This law is similar to that of a Newtonian fluid in a two-dimensional Poiseuille flow, showing that the dynamics of RBCs is controlled by their cytoplasmic viscosity. Altogether, our results show that filtration through submicron-wide slits is possible without further slit opening. Furthermore, our approach addresses the critical need for in vitro evaluation of splenic clearance of diseased or engineered RBCs for transfusion and drug delivery.