Dynamic Regulation of Cell Mechanotransduction through Sequentially Controlled Mobile Surfaces.

The physical properties of nanoscale cell-extracellular matrix (ECM) ligands profoundly impact biological processes, such as adhesion, motility, and differentiation. While the mechanoresponse of cells to static ligands is well-studied, the effect of dynamic ligand presentation with "adaptive" properties on cell mechanotransduction remains less understood. Utilizing a controllable diffusible ligand interface, we demonstrated that cells on surfaces with rapid ligand mobility could recruit ligands through activating integrin α5ß1, leading to faster focal adhesion growth and spreading at the early adhesion stage. By leveraging UV-light-sensitive anchor molecules to trigger a "dynamic to static" transformation of ligands, we sequentially activated α5ß1 and αvß3 integrins, significantly promoting osteogenic differentiation of mesenchymal stem cells. This study illustrates how manipulating molecular dynamics can directly influence stem cell fate, suggesting the potential of "sequentially" controlled mobile surfaces as adaptable platforms for engineering smart biomaterial coatings.

Size-dependent response of cells in epithelial tissue modulated by contractile stress fibers.

Although cells with distinct apical areas have been widely observed in epithelial tissues, how the size of cells affects their behavior during tissue deformation and morphogenesis as well as key physical factors modulating such influence remains elusive. Here, we showed that the elongation of cells within the monolayer under anisotropic biaxial stretching increases with their size because the strain released by local cell rearrangement (i.e., T1 transition) is more significant for small cells that possess higher contractility. On the other hand, by incorporating the nucleation, peeling, merging, and breakage dynamics of subcellular stress fibers into classical vertex formulation, we found that stress fibers with orientations predominantly aligned with the main stretching direction will be formed at tricellular junctions, in good agreement with recent experiments. The contractile forces generated by stress fibers help cells to resist imposed stretching, reduce the occurrence of T1 transitions, and, consequently, modulate their size-dependent elongation. Our findings demonstrate that epithelial cells could utilize their size and internal structure to regulate their physical and related biological behaviors. The theoretical framework proposed here can also be extended to investigate the roles of cell geometry and intracellular contraction in processes such as collective cell migration and embryo development.

All-Optical Modulation of Single Defects in Nanodiamonds: Revealing Rotational and Translational Motions in Cell Traction Force Fields.

Measuring the mechanical interplay between cells and their surrounding microenvironment is vital in cell biology and disease diagnosis. Most current methods can only capture the translational motion of fiduciary markers in the deformed matrix, but their rotational motions are normally ignored. Here, by utilizing single nitrogen-vacancy (NV) centers in nanodiamonds (NDs) as fluorescent markers, we propose a linear polarization modulation (LPM) method to monitor in-plane rotational and translational motions of the substrate caused by cell traction forces. Specifically, precise orientation measurement and localization with background suppression were achieved via optical polarization selective excitation of single NV centers with precisions of ∼0.5°/7.5 s and 2 nm/min, respectively. Additionally, we successfully applied this method to monitor the multidimensional movements of NDs attached to the vicinity of cell focal adhesions. The experimental results agreed well with our theoretical calculations, demonstrating the practicability of the NV-based LPM method in studying mechanobiology and cell-material interactions.

Compact GaN-based optical inclinometer.

In this Letter, a compact optical inclinometer in sub-centimeter size is proposed and demonstrated. A 1×1 mm2 GaN-on-sapphire chip composed of a light-emitting diode and photodetector is fabricated through wafer-scale processes and integrated with a spherical glass cavity with a diameter of 5 mm, which contains ethanol as a liquid pendulum. When applying inclinations relative to the horizon, the extent to which the chip is immersed in ethanol changes, thereby altering the amount of light received by the on-chip detector. The underlying mechanisms of angle-dependent reflectance characteristics at the sapphire boundary are identified, and the measured photocurrent signal can be used as quantitative readouts for determining the angle of inclination from -60 to +60°. A linear response with a sensitivity of 19.4 nA/° and an estimated resolution of 0.003° is obtained over a wide linear range from -40 to +40°. Verified by a series of dynamic experiments, the developed inclinometer exhibits a high degree of repeatability and stability, which paves the way for its widespread usage and applications.

A Metal-Ion-Incorporated Mussel-Inspired Poly(Vinyl Alcohol)-Based Polymer Coating Offers Improved Antibacterial Activity and Cellular Mechanoresponse Manipulation.

Cobalt (CoII ) ions have been an attractive candidate for the biomedical modification of orthopedic implants for decades. However, limited research has been performed into how immobilized CoII ions affect the physical properties of implant devices and how these changes regulate cellular behavior. In this study we modified biocompatible poly(vinyl alcohol) with terpyridine and catechol groups (PVA-TP-CA) to create a stable surface coating in which bioactive metal ions could be anchored, endowing the coating with improved broad-spectrum antibacterial activity against Escherichia coli and Staphylococcus aureus, as well as enhanced surface stiffness and cellular mechanoresponse manipulation. Strengthened by the addition of these metal ions, the coating elicited enhanced mechanosensing from adjacent cells, facilitating cell adhesion, spreading, proliferation, and osteogenic differentiation on the surface coating. This dual-functional PVA-TP-CA/Co surface coating offers a promising approach for improving clinical implantation outcomes.

Surface Roughness and Substrate Stiffness Synergize To Drive Cellular Mechanoresponse.

Material surface topographic features have been shown to be crucial for tissue regeneration and surface treatment of implanted devices. Many biomaterials were investigated with respect to the response of cells on surface roughness. However, some conclusions even conflicted with each other due to the unclear interplay of surface topographic features and substrate elastic features as well as the lack of mechanistic studies. Herein, wide-scale surface roughness gradient hydrogels, integrating the surface roughness from nanoscale to microscale with controllable stiffness, were developed via soft lithography with precise surface morphology. Based on this promising platform, we systematically studied the mechanosensitive response of human mesenchymal stem cells (MSCs) to a broad range of roughnesses (200 nm to 1.2 µm for Rq) and different substrate stiffnesses. We observed that MSCs responded to surface roughness in a stiffness-dependent manner by reorganizing the surface hierarchical structure. Surprisingly, the cellular mechanoresponse and osteogenesis were obviously enhanced on very soft hydrogels (3.8 kPa) with high surface roughness, which was comparable to or even better than that on smooth stiff substrates. These findings extend our understanding of the interactions between cells and biomaterials, highlighting an effective noninvasive approach to regulate stem cell fate via synergetic physical cues.

Margin-Maximized Norm-Mixed Representation Learning for Autism Spectrum Disorder Diagnosis With Multi-Level Flux Features.

Early diagnosis and timely intervention are significantly beneficial to patients with autism spectrum disorder (ASD). Although structural magnetic resonance imaging (sMRI) has become an essential tool to facilitate the diagnosis of ASD, these sMRI-based approaches still have the following issues. The heterogeneity and subtle anatomical changes place higher demands for effective feature descriptors. Additionally, the original features are usually high-dimensional, while most existing methods prefer to select feature subsets in the original space, in which noises and outliers may hinder the discriminative ability of selected features. In this article, we propose a margin-maximized norm-mixed representation learning framework for ASD diagnosis with multi-level flux features extracted from sMRI. Specifically, a flux feature descriptor is devised to quantify comprehensive gradient information of brain structures on both local and global levels. For the multi-level flux features, we learn latent representations in an assumed low-dimensional space, in which a self-representation term is incorporated to characterize the relationships among features. We also introduce mixed norms to finely select original flux features for the construction of latent representations while preserving the low-rankness of latent representations. Furthermore, a margin maximization strategy is applied to enlarge the inter-class distance of samples, thereby increasing the discriminative ability of latent representations. The extensive experiments on several datasets show that our proposed method can achieve promising classification performance (the average area under curve, accuracy, specificity, and sensitivity on the studied ASD datasets are 0.907, 0.896, 0.892, and 0.908, respectively) and also find potential biomarkers for ASD diagnosis.

Widefield Diamond Quantum Sensing with Neuromorphic Vision Sensors.

Despite increasing interest in developing ultrasensitive widefield diamond magnetometry for various applications, achieving high temporal resolution and sensitivity simultaneously remains a key challenge. This is largely due to the transfer and processing of massive amounts of data from the frame-based sensor to capture the widefield fluorescence intensity of spin defects in diamonds. In this study, a neuromorphic vision sensor to encode the changes of fluorescence intensity into spikes in the optically detected magnetic resonance (ODMR) measurements is adopted, closely resembling the operation of the human vision system, which leads to highly compressed data volume and reduced latency. It also results in a vast dynamic range, high temporal resolution, and exceptional signal-to-background ratio. After a thorough theoretical evaluation, the experiment with an off-the-shelf event camera demonstrated a 13× improvement in temporal resolution with comparable precision of detecting ODMR resonance frequencies compared with the state-of-the-art highly specialized frame-based approach. It is successfully deploy this technology in monitoring dynamically modulated laser heating of gold nanoparticles coated on a diamond surface, a recognizably difficult task using existing approaches. The current development provides new insights for high-precision and low-latency widefield quantum sensing, with possibilities for integration with emerging memory devices to realize more intelligent quantum sensors.

Quantum-enhanced diamond molecular tension microscopy for quantifying cellular forces.

The constant interplay and information exchange between cells and the microenvironment are essential to their survival and ability to execute biological functions. To date, a few leading technologies such as traction force microscopy, optical/magnetic tweezers, and molecular tension-based fluorescence microscopy are broadly used in measuring cellular forces. However, the considerable limitations, regarding the sensitivity and ambiguities in data interpretation, are hindering our thorough understanding of mechanobiology. Here, we propose an innovative approach, namely, quantum-enhanced diamond molecular tension microscopy (QDMTM), to precisely quantify the integrin-based cell adhesive forces. Specifically, we construct a force-sensing platform by conjugating the magnetic nanotags labeled, force-responsive polymer to the surface of a diamond membrane containing nitrogen-vacancy centers. Notably, the cellular forces will be converted into detectable magnetic variations in QDMTM. After careful validation, we achieved the quantitative cellular force mapping by correlating measurement with the established theoretical model. We anticipate our method can be routinely used in studies like cell-cell or cell-material interactions and mechanotransduction.

Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Controllable drug release and simultaneously carrier decomposition of SiO2-drug composite nanoparticles.

Drug release simultaneously with carrier decomposition has been demonstrated in SiO2-drug composite nanoparticles. By creating a radial drug concentration gradient in the nanoparticle, controllable release of the drug is primarily driven by diffusion. Escape of the drug molecules then triggers the SiO2 carrier decomposition, which starts from the center of the nanoparticle and eventually leads to its complete fragmentation. The small size of the final carrier fragments enables their easy excretion via renal systems. Together with the known biocompatibility of SiO2, the feature of controllable drug release and simultaneous carrier decomposition achieved in the SiO2-drug nanoparticles make it ideal for a wide range of diagnostic and therapeutic applications with great promise for potential clinical translation.

Reversible conversion between skyrmions and skyrmioniums.

Skyrmions and skyrmioniums are topologically non-trivial spin textures found in chiral magnetic systems. Understanding the dynamics of these particle-like excitations is crucial for leveraging their diverse functionalities in spintronic devices. This study investigates the dynamics and evolution of chiral spin textures in [Pt/Co]3/Ru/[Co/Pt]3 multilayers with ferromagnetic interlayer exchange coupling. By precisely controlling the excitation and relaxation processes through combined magnetic field and electric current manipulation, reversible conversion between skyrmions and skyrmioniums is achieved. Additionally, we observe the topological conversion from a skyrmionium to a skyrmion, characterized by the sudden emergence of the skyrmion Hall effect. The experimental realization of reversible conversion between distinct magnetic topological spin textures represents a significant development that promises to expedite the advancement of the next generation of spintronic devices.

Static and Dynamic: Evolving Biomaterial Mechanical Properties to Control Cellular Mechanotransduction.

The extracellular matrix (ECM) is a highly dynamic system that constantly offers physical, biological, and chemical signals to embraced cells. Increasing evidence suggests that mechanical signals derived from the dynamic cellular microenvironment are essential controllers of cell behaviors. Conventional cell culture biomaterials, with static mechanical properties such as chemistry, topography, and stiffness, have offered a fundamental understanding of various vital biochemical and biophysical processes, such as cell adhesion, spreading, migration, growth, and differentiation. At present, novel biomaterials that can spatiotemporally impart biophysical cues to manipulate cell fate are emerging. The dynamic properties and adaptive traits of new materials endow them with the ability to adapt to cell requirements and enhance cell functions. In this review, an introductory overview of the key players essential to mechanobiology is provided. A biophysical perspective on the state-of-the-art manipulation techniques and novel materials in designing static and dynamic ECM-mimicking biomaterials is taken. In particular, different static and dynamic mechanical cues in regulating cellular mechanosensing and functions are compared. This review to benefit the development of engineering biomechanical systems regulating cell functions is expected.

Super-resolution multicolor fluorescence microscopy enabled by an apochromatic super-oscillatory lens with extended depth-of-focus.

Planar super-oscillatory lens (SOL), a far-field subwavelength-focusing diffractive device, holds great potential for achieving sub-diffraction-limit imaging at multiple wavelengths. However, conventional SOL devices suffer from a numerical-aperture-related intrinsic tradeoff among the depth of focus (DoF), chromatic dispersion and focusing spot size. Here, we apply a multi-objective genetic algorithm (GA) optimization approach to design an apochromatic binary-phase SOL having a prolonged DoF, customized working distance (WD), minimized main-lobe size, and suppressed side-lobe intensity. Experimental implementation demonstrates simultaneous focusing of blue, green and red light beams into an optical needle of ~0.5λ in diameter and DOF > 10λ at WD = 428 µm. By integrating this SOL device with a commercial fluorescence microscope, we perform, for the first time, three-dimensional super-resolution multicolor fluorescence imaging of the "unseen" fine structures of neurons. The present study provides not only a practical route to far-field multicolor super-resolution imaging but also a viable approach for constructing imaging systems avoiding complex sample positioning and unfavorable photobleaching.

Multimodal dynamic and unclonable anti-counterfeiting using robust diamond microparticles on heterogeneous substrate.

The growing prevalence of counterfeit products worldwide poses serious threats to economic security and human health. Developing advanced anti-counterfeiting materials with physical unclonable functions offers an attractive defense strategy. Here, we report multimodal, dynamic and unclonable anti-counterfeiting labels based on diamond microparticles containing silicon-vacancy centers. These chaotic microparticles are heterogeneously grown on silicon substrate by chemical vapor deposition, facilitating low-cost scalable fabrication. The intrinsically unclonable functions are introduced by the randomized features of each particle. The highly stable signals of photoluminescence from silicon-vacancy centers and light scattering from diamond microparticles can enable high-capacity optical encoding. Moreover, time-dependent encoding is achieved by modulating photoluminescence signals of silicon-vacancy centers via air oxidation. Exploiting the robustness of diamond, the developed labels exhibit ultrahigh stability in extreme application scenarios, including harsh chemical environments, high temperature, mechanical abrasion, and ultraviolet irradiation. Hence, our proposed system can be practically applied immediately as anti-counterfeiting labels in diverse fields.

Soft overcomes the hard: Flexible materials adapt to cell adhesion to promote cell mechanotransduction.

Cell behaviors and functions show distinct contrast in different mechanical microenvironment. Numerous materials with varied rigidity have been developed to mimic the interactions between cells and their surroundings. However, the conventional static materials cannot fully capture the dynamic alterations at the bio-interface, especially for the molecular motion and the local mechanical changes in nanoscale. As an alternative, flexible materials have great potential to sense and adapt to mechanical changes in such complex microenvironment. The flexible materials could promote the cellular mechanosensing by dynamically adjusting their local mechanics, topography and ligand presentation to adapt to intracellular force generation. This process enables the cells to exhibit comparable or even higher level of mechanotransduction and the downstream 'hard' phenotypes compared to the conventional stiff or rigid ones. Here, we highlight the relevant studies regarding the development of such adaptive materials to mediate cell behaviors across the rigidity limitation on soft substrates. The concept of 'soft overcomes the hard' will guide the future development and application of biological materials.

Emerging Diamond Quantum Sensing in Bio-Membranes.

Bio-membranes exhibit complex but unique mechanical properties as communicative regulators in various physiological and pathological processes. Exposed to a dynamic micro-environment, bio-membranes can be seen as an intricate and delicate system. The systematical modeling and detection of their local physical properties are often difficult to achieve, both quantitatively and precisely. The recent emerging diamonds hosting quantum defects (i.e., nitrogen-vacancy (NV) center) demonstrate intriguing optical and spin properties, together with their outstanding photostability and biocompatibility, rendering them ideal candidates for biological applications. Notably, the extraordinary spin-based sensing enable the measurements of localized nanoscale physical quantities such as magnetic fields, electrical fields, temperature, and strain. These nanoscale signals can be optically read out precisely by simple optical microscopy systems. Given these exclusive properties, NV-center-based quantum sensors can be widely applied in exploring bio-membrane-related features and the communicative chemical reaction processes. This review mainly focuses on NV-based quantum sensing in bio-membrane fields. The attempts of applying NV-based quantum sensors in bio-membranes to investigate diverse physical and chemical events such as membrane elasticity, phase change, nanoscale bio-physical signals, and free radical formation are fully overviewed. We also discuss the challenges and future directions of this novel technology to be utilized in bio-membranes.

Ligand Mobility-Mediated Cell Adhesion and Spreading.

Cells live in a highly dynamic environment where their physical connection and communication with the outside are achieved through receptor-ligands binding. Therefore, a precise knowledge of the interaction between receptors and ligands is critical for our understanding of how cells execute different biological duties. Interestingly, recent evidence has shown that the mobility of ligands at the cell-extracellular matrix (ECM) interface significantly affects the adhesion and spreading of cells, while the underlying mechanism remains unclear. Here, we present a modeling investigation to address this critical issue. Specifically, by adopting the Langevin dynamics, the random movement of ligands was captured by assigning a stochastic force along with a viscous drag on them. After that, the evolution of adhesion and subsequent spreading of cells were analyzed by considering the force-regulated binding/breakage of individual molecular bonds connecting polymerizing actin bundles inside the cell to the ECM. Interestingly, a biphasic relationship between adhesion and ligand diffusivity was predicted, resulting in maximized cell spreading at intermediate mobility of ligand molecules. In addition, this peak position was found to be dictated by the aggregation of ligands, effectively reducing their diffusivity, and how fast bond association/dissociation can occur. These predictions are in excellent agreement with our experimental observations where distinct ligand mobility was introduced by tuning the interactions between the self-assembly polymer coating and the surface.

A Versatile, Incubator-Compatible, Monolithic GaN Photonic Chipscope for Label-Free Monitoring of Live Cell Activities.

The ability to quantitatively monitor various cellular activities is critical for understanding their biological functions and the therapeutic response of cells to drugs. Unfortunately, existing approaches such as fluorescent staining and impedance-based methods are often hindered by their multiple time-consuming preparation steps, sophisticated labeling procedures, and complicated apparatus. The cost-effective, monolithic gallium nitride (GaN) photonic chip has been demonstrated as an ultrasensitive and ultracompact optical refractometer in a previous work, but it has never been applied to cell studies. Here, for the first time, the so-called GaN chipscope is proposed to quantitatively monitor the progression of different intracellular processes in a label-free manner. Specifically, the GaN-based monolithic chip enables not only a photoelectric readout of cellular/subcellular refractive index changes but also the direct imaging of cellular/subcellular ultrastructural features using a customized differential interference contrast (DIC) microscope. The miniaturized chipscope adopts an ultracompact design, which can be readily mounted with conventional cell culture dishes and placed inside standard cell incubators for real-time observation of cell activities. As a proof-of-concept demonstration, its applications are explored in 1) cell adhesion dynamics monitoring, 2) drug screening, and 3) cell differentiation studies, highlighting its potential in broad fundamental cell biology studies as well as in clinical applications.