Enzymatic Reaction Enhanced Diffusion Accelerates Cargo Transport through Micro/Nano-Channels.

Energy conversion and transfer of enzyme-catalyzed reactions at molecular level are an interesting and challenging scientific topic that helps understanding biological processes in nature. In this study, it is demonstrated that enzyme-catalyzed reactions can enhance diffusion of surrounding molecules and thus accelerate cargo transport within 1D micro/nanochannels. Specifically, urease is immobilized on the inner walls of silica micro/nano-tubes to construct bio-catalytically active micro/nanochannels. The catalytic reaction inside the channels drives a variety of cargoes, including small dye molecules, polymers, and rigid nanoparticles (e.g., quantum dots, QDs), to pass through these micro/nanochannels much faster than they will by free diffusion. The enhanced diffusion of molecular species inside the channels is validated by direct observation of the Brownian motion of tracer particles, and further confirmed by significantly enhanced Raman intensity of reporter molecules. Finite element and Brownian dynamics simulations provide a theoretical understanding of these experimental observations. Furthermore, the effect of the channels' size on the diffusion enhancement is examined. The acceleration effect of the cargo transport through these enzymatically active micro/nanochannels can be turned on or off via chemical activators or inhibitors. This study provides valuable insights on the design of biomimetic channels capable of controlled and efficient transmembrane transport.

Supramolecular Modular Assembly of Imaging-Trackable Enzymatic Nanomotors.

Self-propelled micro/nanomotors (MNMs) have shown great application potential in biomedicine, sensing, environmental remediation, etc. In the past decade, various strategies or technologies have been used to prepare and functionalize MNMs. However, the current preparation strategies of the MNMs were mainly following the pre-designed methods based on specific tasks to introduce expected functional parts on the various micro/nanocarriers, which lacks a universal platform and common features, making it difficult to apply to different application scenarios. Here, we have developed a modular assembly strategy based on host-guest chemistry, which enables the on-demand construction of imaging-trackable nanomotors mounted with suitable driving and imaging modules using a universal assembly platform, according to different application scenarios. These assembled nanomotors exhibited enhanced diffusion behavior driven by enzymatic reactions. The loaded imaging functions were used to dynamically trace the swarm motion behavior of assembled nanomotors with corresponding fuel conditions both in vitro and in vivo. The modular assembly strategy endowed with host-guest interaction provides a universal approach to producing multifunctional MNMs in a facile and controllable manner, which paves the way for the future development of MNMs systems with programmable functions.

Modularized microrobot with lock-and-detachable modules for targeted cell delivery in bile duct.

The magnetic microrobots promise benefits in minimally invasive cell-based therapy. However, they generally suffer from an inevitable compromise between their magnetic responsiveness and biomedical functions. Herein, we report a modularized microrobot consisting of magnetic actuation (MA) and cell scaffold (CS) modules. The MA module with strong magnetism and pH-responsive deformability and the CS module with cell loading-release capabilities were fabricated by three-dimensional printing technique. Subsequently, assembly of modules was performed by designing a shaft-hole structure and customizing their relative dimensions, which enabled magnetic navigation in complex environments, while not deteriorating the cellular functionalities. On-demand disassembly at targeted lesion was then realized to facilitate CS module delivery and retrieval of the MA module. Furthermore, the feasibility of proposed system was validated in an in vivo rabbit bile duct. Therefore, this work presents a modular design-based strategy that enables uncompromised fabrication of multifunctional microrobots and stimulates their development for future cell-based therapy.

Reactive wetting enabled anchoring of non-wettable iron oxide in liquid metal for miniature soft robot.

Magnetic liquid metal (LM) soft robots attract considerable attentions because of distinctive immiscibility, deformability and maneuverability. However, conventional LM composites relying on alloying between LM and metallic magnetic powders suffer from diminished magnetism over time and potential safety risk upon leakage of metallic components. Herein, we report a strategy to composite inert and biocompatible iron oxide (Fe3O4) magnetic nanoparticles into eutectic gallium indium LM via reactive wetting mechanism. To address the intrinsic interfacial non-wettability between Fe3O4 and LM, a silver intermediate layer was introduced to fuse with indium component into AgxIny intermetallic compounds, facilitating the anchoring of Fe3O4 nanoparticles inside LM with improved magnetic stability. Subsequently, a miniature soft robot was constructed to perform various controllable deformation and locomotion behaviors under actuation of external magnetic field. Finally, practical feasibility of applying LM soft robot in an ex vivo porcine stomach was validated under in-situ monitoring by endoscope and X-ray imaging.

High-fat diet promotes tumor growth in the patient-derived orthotopic xenograft (PDOX) mouse model of ER positive endometrial cancer.

Endometrial cancer, one of the common gynecological malignancies, is affected by several influencing factors. This study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model for the study of influencing factors in ER positive endometrial cancer. The aim of this study was to demonstrate that a high-fat diet can affect the growth of ER positive endometrial cancer PDOX model tumors. The tumor tissues were expanded by subcutaneous transplantation in nude mice, and then the subcutaneous tumor tissues were orthotopically implanted into the nude mouse uterus to establish the PDOX model. After modeling, they were divided into high-fat diet group and normal diet group for 8 weeks of feeding, which showed that high-fat diet significantly promoted tumor growth (P < 0.001) and increased the protein expression level of ERα in tumor tissues. This study demonstrates that PDOX models of endometrial cancer can embody the role of dietary influences on tumor growth and that this model has the potential for preclinical studies of cancer promoting factors.

A novel prognostic model based on AFP, tumor burden score and Albumin-Bilirubin grade for patients with hepatocellular carcinoma undergoing radiofrequency ablation.

PURPOSE: The aim of this study was to develop prognostic scores, including the tumor burden score (TBS) and albumin-bilirubin (ALBI) grade, for evaluating the outcomes of hepatocellular carcinoma (HCC) patients after radiofrequency ablation (RFA). MATERIALS AND METHODS: This retrospective study enrolled treatment-naïve HCC patients with BCLC 0-A who underwent RFA between January 2009 and December 2019. Regular follow-up was conducted after RFA to determine progression-free survival (PFS) and overall survival (OS). The patients were randomly allocated to the training or validation datasets in a 1:1 ratio. Preoperative prognostic scores were developed based on the results of multivariate analysis. The discriminatory ability of the scores was assessed using time-dependent AUC and compared with other models. RESULTS: Serum alpha-fetoprotein (AFP) level and TBS were identified as independent prognostic factors for PFS, while serum AFP, TBS, and ALBI were identified as independent prognostic factors for OS in HCC patients after RFA. The time-dependent AUCs of the AFP-TBS score for the 1-, 3-, and 5-year PFS were 0.651, 0.667, and 0.620, respectively, in the training set, and 0.657, 0.687, and 0.704, respectively, in the validation set. For the 1-, 3-, and 5-year OS, the time-dependent AUCs were 0.680, 0.712, and 0.666, respectively, in the training set, and 0.712, 0.706 and 0.726 in the validation set for the AFP-TBS-ALBI score (ATA). The C-indices and AIC demonstrated that the scores provided better clinical benefits compared to other models. CONCLUSION: The ATA/AT score, derived from clinical and objective laboratory variables, can assist in individually predicting the prognosis of HCC patients undergoing curative RFA.

Ultrasonic-Enabled Nondestructive and Substrate-Independent Liquid Metal Ink Sintering.

Printing or patterning particle-based liquid metal (LM) ink is a good strategy to overcome poor wettability of LM for its circuits' preparation in flexible and printed electronics. Subsequently, a crucial step is to recover conductivity of LM circuits consisting of insulating LM micro/nano-particles. However, most widely used mechanical sintering methods based on hard contact such as pressing, may not be able to contact the LM patterns' whole surface conformally, leading to insufficient sintering in some areas. Hard contact may also break delicate shapes of the printed patterns. Hereby, an ultrasonic-assisted sintering strategy that can not only preserve original morphology of the LM circuits but also sinter circuits on various substrates of complex surface topography is proposed. The influencing factors of the ultrasonic sintering are investigated empirically and interpreted with theoretical understanding by simulation. LM circuits encapsulated inside soft elastomer are successfully sintered, proving feasibility in constructing stretchable or flexible electronics. By using water as energy transmission medium, remote sintering without any direct contact with substrate is achieved, which greatly protect LM circuits from mechanical damage. In virtue of such remote and non-contact manipulation manner, the ultrasonic sintering strategy would greatly advance the fabrication and application scenarios of LM electronics.

Swarming self-adhesive microgels enabled aneurysm on-demand embolization in physiological blood flow.

The recent rise of swarming microrobotics offers great promise in the revolution of minimally invasive embolization procedure for treating aneurysm. However, targeted embolization treatment of aneurysm using microrobots has significant challenges in the delivery capability and filling controllability. Here, we develop an interventional catheterization-integrated swarming microrobotic platform for aneurysm on-demand embolization in physiological blood flow. A pH-responsive self-healing hydrogel doped with magnetic and imaging agents is developed as the embolic microgels, which enables long-term self-adhesion under biological condition in a controllable manner. The embolization strategy is initiated by catheter-assisted deployment of swarming microgels, followed by the application of external magnetic field for targeted aggregation of microrobots into aneurysm sac under the real-time guidance of ultrasound and fluoroscopy imaging. Mild acidic stimulus is applied to trigger the welding of microgels with satisfactory bio-/hemocompatibility and physical stability and realize complete embolization. Our work presents a promising connection between the design and control of microrobotic swarms toward practical applications in dynamic environments.

Active Micro/Nanoparticles in Colloidal Microswarms.

Colloidal microswarms have attracted increasing attention in the last decade due to their unique capabilities in various complex tasks. Thousands or even millions of tiny active agents are gathered with distinctive features and emerging behaviors, demonstrating fascinating equilibrium and non-equilibrium collective states. In recent studies, with the development of materials design, remote control strategies, and the understanding of pair interactions between building blocks, microswarms have shown advantages in manipulation and targeted delivery tasks with high adaptability and on-demand pattern transformation. This review focuses on the recent progress in active micro/nanoparticles (MNPs) in colloidal microswarms under the input of an external field, including the response of MNPs to external fields, MNP-MNP interactions, and MNP-environment interactions. A fundamental understanding of how building blocks behave in a collective system provides the foundation for designing microswarm systems with autonomy and intelligence, aiming for practical application in diverse environments. It is envisioned that colloidal microswarms will significantly impact active delivery and manipulation applications on small scales.

Enzyme-Powered Tubular Microrobotic Jets as Bioinspired Micropumps for Active Transmembrane Drug Transport.

In nature, there exist a variety of transport proteins on cell membranes capable of actively moving cargos across biological membranes, which plays a vital role in the living activities of cells. Emulating such biological pumps in artificial systems may bring in-depth insights on the principles and functions of cell behaviors. However, it poses great challenges due to difficulty in the sophisticated construction of active channels at the cellular scale. Here, we report the development of bionic micropumps for active transmembrane transportation of molecular cargos across living cells that is realized by enzyme-powered microrobotic jets. By immobilizing urease onto the surface of a silica-based microtube, the prepared microjet is capable of catalyzing the decomposition of urea in surrounding environments and generating microfluidic flow through the inside channel for self-propulsion, which is verified by both numerical simulation and experimental results. Therefore, once naturally endocytosed by the cell, the microjet enables the diffusion and, more importantly, active transportation of molecular substances between the extracellular and intracellular ends with the assistance of generated microflow, thus serving as an artificial biomimetic micropump. Furthermore, by constructing enzymatic micropumps on cancer cell membranes, enhanced delivery of anticancer doxorubicin into cells as well as improved killing efficacy are achieved, which demonstrates the effectiveness of the active transmembrane drug transport strategy in cancer treatment. This work not only extends the applications of micro/nanomachines in biomedical fields but also provides a promising platform for future cell biology research at cellular and subcellular scales.

Wirelessly powered deformable electronic stent for noninvasive electrical stimulation of lower esophageal sphincter.

Electrical stimulation is a promising method to modulate gastrointestinal disorders. However, conventional stimulators need invasive implantation and removal surgeries associated with risks of infection and secondary injuries. Here, we report a battery-free and deformable electronic esophageal stent for wireless stimulation of the lower esophageal sphincter in a noninvasive fashion. The stent consists of an elastic receiver antenna infilled with liquid metal (eutectic gallium-indium), a superelastic nitinol stent skeleton, and a stretchable pulse generator that jointly enables 150% axial elongation and 50% radial compression for transoral delivery through the narrow esophagus. The compliant stent adaptive to the dynamic environment of the esophagus can wirelessly harvest energy through deep tissue. Continuous electrical stimulations delivered by the stent in vivo using pig models significantly increase the pressure of the lower esophageal sphincter. The electronic stent provides a noninvasive platform for bioelectronic therapies in the gastrointestinal tract without the need for open surgery.

Matrix reconstruction with reliable neighbors for predicting potential MiRNA-disease associations.

Numerous experimental studies have indicated that alteration and dysregulation in mircroRNAs (miRNAs) are associated with serious diseases. Identifying disease-related miRNAs is therefore an essential and challenging task in bioinformatics research. Computational methods are an efficient and economical alternative to conventional biomedical studies and can reveal underlying miRNA-disease associations for subsequent experimental confirmation with reasonable confidence. Despite the success of existing computational approaches, most of them only rely on the known miRNA-disease associations to predict associations without adding other data to increase the prediction accuracy, and they are affected by issues of data sparsity. In this paper, we present MRRN, a model that combines matrix reconstruction with node reliability to predict probable miRNA-disease associations. In MRRN, the most reliable neighbors of miRNA and disease are used to update the original miRNA-disease association matrix, which significantly reduces data sparsity. Unknown miRNA-disease associations are reconstructed by aggregating the most reliable first-order neighbors to increase prediction accuracy by representing the local and global structure of the heterogeneous network. Five-fold cross-validation of MRRN produced an area under the curve (AUC) of 0.9355 and area under the precision-recall curve (AUPR) of 0.2646, values that were greater than those produced by comparable models. Two different types of case studies using three diseases were conducted to demonstrate the accuracy of MRRN, and all top 30 predicted miRNAs were verified.

Deep Reinforcement Learning Framework-Based Flow Rate Rejection Control of Soft Magnetic Miniature Robots.

Soft magnetic miniature robots (SMMRs) have potential biomedical applications due to their flexible size and mobility to access confined environments. However, navigating the robot to a goal site with precise control performance and high repeatability in unstructured environments, especially in flow rate conditions, still remains a challenge. In this study, drawing inspiration from the control requirements of drug delivery and release to the goal lesion site in the presence of dynamic biofluids, we propose a flow rate rejection control strategy based on a deep reinforcement learning (DRL) framework to actuate an SMMR to achieve goal-reaching and hovering in fluidic tubes. To this end, an SMMR is first fabricated, which can be operated by an external magnetic field to realize its desired functionalities. Subsequently, a simulator is constructed based on neural networks to map the relationship between the applied magnetic field and robot locomotion states. With minimal prior knowledge about the environment and dynamics, a gated recurrent unit (GRU)-based DRL algorithm is formulated by considering the designed history state-action and estimated flow rates. In addition, the randomization technique is applied during training to distill the general control policy for the physical SMMR. The results of numerical simulations and experiments are illustrated to demonstrate the robustness and efficacy of the presented control framework. Finally, in-depth analyses and discussions indicate the potentiality of DRL for soft magnetic robots in biomedical applications.

Dynamic morphological transformations in soft architected materials via buckling instability encoded heterogeneous magnetization.

The geometric reconfigurations in three-dimensional morphable structures have a wide range of applications in flexible electronic devices and smart systems with unusual mechanical, acoustic, and thermal properties. However, achieving the highly controllable anisotropic transformation and dynamic regulation of architected materials crossing different scales remains challenging. Herein, we develop a magnetic regulation approach that provides an enabling technology to achieve the controllable transformation of morphable structures and unveil their dynamic modulation mechanism as well as potential applications. With buckling instability encoded heterogeneous magnetization profiles inside soft architected materials, spatially and temporally programmed magnetic inputs drive the formation of a variety of anisotropic morphological transformations and dynamic geometric reconfiguration. The introduction of magnetic stimulation could help to predetermine the buckling states of soft architected materials, and enable the formation of definite and controllable buckling states without prolonged magnetic stimulation input. The dynamic modulations can be exploited to build systems with switchable fluidic properties and are demonstrated to achieve capabilities of fluidic manipulation, selective particle trapping, sensitivity-enhanced biomedical analysis, and soft robotics. The work provides new insights to harness the programmable and dynamic morphological transformation of soft architected materials and promises benefits in microfluidics, programmable metamaterials, and biomedical applications.

EphA2 Promotes the Development of Cervical Cancer through the CXCL11/PD-L1 Pathway.

Erythropoietin-producing hepatoma receptor A2 (EphA2), receptor tyrosine kinase, the most widespread member of the largest receptor tyrosine kinase family, plays a critical role in physiological and pathological conditions. In recent years, the role of EphA2 in the occurrence and development of cancer has become a research hotspot and is considered a promising potential target. Our previous studies have shown that EphA2 has an indisputable cancer-promoting role in cervical cancer, but its related mechanism requires further research. In this study, high-throughput sequencing was performed on EphA2 knockdown cervical cancer cells and the control group. An analysis of differentially expressed genes revealed that EphA2 may exert its cancer-promoting effect through C-X-C motif chemokine ligand 11 (CXCL11). In addition, we found that EphA2 could further regulate programmed cell death ligand 1 (PD-L1) through CXCL11. This has also been further demonstrated in in vivo experiments. Our study demonstrated that EphA2 plays a tumor-promoting role in cervical carcinoma through the CXCL11/PD-L1 pathway, providing new guidance for the targeted therapy and combination therapy of cervical carcinoma.

Probing Fast Transformation of Magnetic Colloidal Microswarms in Complex Fluids.

The rapidly transformed morphology of natural swarms enables fast response to environmental changes. Artificial microswarms can reconfigure their swarm patterns like natural swarms, which have drawn extensive attention due to their active adaptability in complex environments. However, as a prerequisite for biomedical applications of microswarms in confined environments, achieving on-demand control of pattern transformation rates remains a challenge. In this work, we report a strategy for optimizing pattern transformation rates of colloidal microswarms by coordinating the inner interactions. The influences of magnetic field parameters on pattern transformation rates are theoretically and experimentally studied, which elucidates the mechanism for optimal transformation rate control. The feasibility of the strategy is then validated in viscous Newtonian fluids and non-Newtonian biofluids. Moreover, the strategy is further validated in dynamic flow environments, exhibiting a promising future for practical applications in targeted delivery tasks with an optimal pattern transformation manner.

PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies.

Breast cancer and gynecological tumors seriously endanger women's physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.

Rapid and Multimaterial 4D Printing of Shape-Morphing Micromachines for Narrow Micronetworks Traversing.

Micromachines with high environmental adaptability have the potential to deliver targeted drugs in complex biological networks, such as digestive, neural, and vascular networks. However, the low processing efficiency and single processing material of current 4D printing methods often limit the development and application of shape-morphing micromachines (SMMs). Here, two 4D printing strategies are proposed to fabricate SMMs with pH-responsive hydrogels for complex micro-networks traversing. On the one hand, the 3D vortex light single exposure technique can rapidly fabricate a tubular SMM with controllable size and geometry within 0.1 s. On the other hand, the asymmetric multimaterial direct laser writing (DLW) method is used to fabricate SMMs with designable 3D structures composed of hydrogel and platinum nanoparticles (Pt NPs). Based on the presence of ferroferric oxide (Fe3 O4 ) and Pt NPs in the SMMs, efficient magnetic, bubble, and hybrid propulsion modes are achieved. Finally, it is demonstrated that the spatial shape conversion capabilities of these SMMs can be used for narrow micronetworks traversing, which will find potential applications in targeted cargo delivery in microcapillaries.

Untethered small-scale magnetic soft robot with programmable magnetization and integrated multifunctional modules.

Intelligent magnetic soft robots capable of programmable structural changes and multifunctionality modalities depend on material architectures and methods for controlling magnetization profiles. While some efforts have been made, there are still key challenges in achieving programmable magnetization profile and creating heterogeneous architectures. Here, we directly embed programmed magnetization patterns (magnetization modules) into the adhesive sticker layers to construct soft robots with programmable magnetization profiles and geometries and then integrate spatially distributed functional modules. Functional modules including temperature and ultraviolet light sensing particles, pH sensing sheets, oil sensing foams, positioning electronic component, circuit foils, and therapy patch films are integrated into soft robots. These test beds are used to explore multimodal robot locomotion and various applications related to environmental sensing and detection, circuit repairing, and gastric ulcer coating, respectively. This proposed approach to engineering modular soft material systems has the potential to expand the functionality, versatility, and adaptability of soft robots.

Decoupling and Reprogramming the Wiggling Motion of Midge Larvae Using a Soft Robotic Platform.

The efficient motility of invertebrates helps them survive under evolutionary pressures. Reconstructing the locomotion of invertebrates and decoupling the influence of individual basic motion are crucial for understanding their underlying mechanisms, which, however, generally remain a challenge due to the complexity of locomotion gaits. Herein, a magnetic soft robot to reproduce midge larva's key natural swimming gaits is developed, and the coupling effect between body curling and rotation on motility is investigated. Through the authors' systematically decoupling studies using programmed magnetic field inputs, the soft robot (named LarvaBot) experiences various coupled gaits, including biomimetic side-to-side flexures, and unveils that the optimal rotation amplitude and the synchronization of curling and rotation greatly enhance its motility. The LarvaBot achieves fast locomotion and upstream capability at the moderate Reynolds number regime. The soft robotics-based platform provides new insight to decouple complex biological locomotion, and design programmed swimming gaits for the fast locomotion of soft-bodied swimmers.