Cell Aggregation Research Articles

Construction and validation of a bioinformatics‑based screen for cuproptosis‑related genes and risk model for Alzheimer's disease.

The present study aimed to validate the association between core cuproptosis genes (CRGs) and Alzheimer's disease (AD) from both bioinformatics and experimental perspectives and also to develop a risk prediction model. To this end, 78 human‑derived temporal back samples were analyzed from GSE109887, and the biological functions of the resulting CRGs were explored by cluster analysis, weighted gene co‑expression network analysis and similar methods to identify the best machine model. Moreover, an external dataset GSE33000 and a nomogram were used to validate the model. The mRNA and protein expression of CRGs were validated using the SH‑SY5Y cell model and the Sprague‑Dawley rat animal model. The RT‑qPCR and western blotting results showed that the mRNA and protein expression content of dihydrolipoamide dehydrogenase, ferredoxin 1, glutaminase and pyruvate dehydrogenase E1 subunit β decreased, and the expression of dihydrolipoamide branched chain transacylase E2 increased in AD, which supported the bioinformatic analysis results. The CRG expression alterations affected the aggregation and infiltration of certain immune cells. The present study also confirmed the accuracy and validity of AD diagnostic models and nomograms, and validated the association between five CRGs and AD, indicating a significant difference between patients with AD and healthy individuals. Therefore, CRGs are expected to serve as relevant biomarkers for the diagnosis and prognostic monitoring of AD.

Label-Free Microfluidic Apheresis of Circulating Tumor Cell Clusters.

Screening liters of blood (i.e., apheresis) represents a generalized approach to promote the reliable access to circulating tumor cell clusters (CTCCs), which are known to be highly metastasis-competent, yet ultrarare. However, no existing CTCC sorting technology has demonstrated high throughput, high yield, low shear stress, and minimal blood dilution simultaneously as required in apheresis. Here, a label-free method is introduced termed Precision Apheresis for Non-invasive Debulking of cell Aggregates (PANDA) to continuously isolate CTCCs from undiluted blood to clean buffer through size sorting, processing 1.4 billion cells per second. The cell focusing is optimized within whole blood leveraging secondary transverse flow and margination. The PANDA chip recovers >90% of spiked ≈24 rare HeLa cell clusters from 100mL undiluted blood samples (equivalent to ≈500 billion blood cells) at 1 Lh-1 throughput, with ≤20s device residence time, ≤15Pa shear stress, and >99.9% return of blood components. The technology lays the groundwork for future routine isolation to increase the recovery of these ultrarare yet clinically significant tumor cell populations from large volumes of blood to advance cancer research, early detection, and treatment.

Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex.

The Candida haemulonii complex includes emerging opportunistic human fungal pathogens with documented multidrug-resistance profiles. It comprises Candida haemulonii sensu stricto, Candida haemulonii var. vulnera, Candida duobushaemulonii, Candida pseudohaemulonii, and Candida vulturna. In recent years, rates of clinical isolation of strains from this complex have increased in multiple countries, including China, Malaysia, and Brazil. Biofilm formation, hydrolytic enzymes, surface interaction properties, phenotype switching and cell aggregation abilities, extracellular vesicles production, stress response, and immune evasion help these fungi to infect the host and exert pathological effects. Multidrug resistance profiles also enhance the threat they pose; they exhibit low susceptibility to echinocandins and azoles and an intrinsic resistance to amphotericin B (AMB), the first fungal-specific antibiotic. AMB is commonly employed in antifungal treatments, and it acts via several known mechanisms. Given the propensity of clinical Candida species to initiate bloodstream infections, clarifying how C. haemulonii resists AMB is of critical clinical importance. This review outlines our present understanding of the C. haemulonii complex's virulence factors, the mechanisms of action of AMB, and the mechanisms underlying AMB resistance.

Reduced aggregation of the Leghorn Male Hepatoma (LMH) cell line in suspension by supplementing dextran sulfate in the media.

The study aimed to improve the efficiency of Leghorn Male Hepatoma (LMH) cells for animal virus vaccine production by transitioning from adherent to suspension culture and evaluating the effects of dextran sulfate (DS) on preventing cell aggregation. The goal was to enhance cell growth, viability, and glucose metabolism and to develop efficient suspension-adapted LMH cells for large-scale vaccine production. LMH cells previously cultured in an adherent state were transferred to 125 mL Erlenmeyer flasks to conduct suspension culture. Cell culture performance, including cell density, viability, and glucose metabolism, during the cultures was measured, along with an assessment of cell aggregation. Additionally, mRNA expression levels of genes associated with cell adhesion and apoptosis were monitored. DS supplementation in suspension culture enhanced cell viability and growth, with higher cell densities and viabilities compared to control media. Additionally, DS supplementation reduced glucose consumption and waste production, indicating improved metabolic efficiency. DS also delayed cell aggregation, possibly by downregulating integrin expression and promoting anti-apoptotic gene expression. However, even after 2 months, cell aggregation persisted in both control and DS-supplemented cultures, suggesting further optimization is needed for LMH cell adaptation to suspension culture. DS supplementation in LMH cell suspension cultures led to notable improvements in cell growth, viability, and glucose metabolism, while also decreasing the cell aggregation.

The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.

B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

Recent Advances in Dielectrophoretic Manipulation and Separation of Microparticles and Biological Cells.

Dielectrophoresis (DEP) is an advanced microfluidic manipulation technique that is based on the interaction of polarized particles with the spatial gradient of a non-uniform electric field to achieve non-contact and highly selective manipulation of particles. In recent years, DEP has made remarkable progress in the field of microfluidics, and it has gradually transitioned from laboratory-scale research to high-throughput manipulation in practical applications. This paper reviews the recent advances in dielectric manipulation and separation of microparticles and biological cells and discusses in detail the design of chip structures for the two main methods, direct current dielectrophoresis (DC-DEP) and alternating current dielectrophoresis (AC-DEP). The working principles, technical implementation details, and other improved designs of electrode-based and insulator-based chips are summarized. Functional customization of DEP systems with specific capabilities, including separation, capture, purification, aggregation, and assembly of particles and cells, is then performed. The aim of this paper is to provide new ideas for the design of novel DEP micro/nano platforms with the desired high throughput for further development in practical applications.

Development of a skeletal muscle sheet with direct reprogramming-induced myoblasts on a nanogel-cross-linked porous freeze-dried gel scaffold in a mouse gastroschisis model.

In this study, we attempted to create skeletal muscle sheets made of directly converted myoblasts (dMBs) with a nanogel scaffold on a biosheet using a mouse gastroschisis model. dMBs were prepared by the co-transfection of MYOD1 and MYCL into human fibroblasts. Silicon tubes were implanted under the skin of NOG/SCID mice, and biosheets were formed. The nanogel was a nanoscale hydrogel based on cholesterol-modified pullulan, and a NanoClip-FD gel was prepared by freeze-drying the nanogel. 7mm in length was created in the abdominal wall of NOG/SCID mice as a mouse gastroschisis model. Matrigel or NanoCliP-FD gel seeded with dMBs was placed on the biosheet and implanted on the model mice. Fourteen days after surgery, dMBs with Matrigel showed a small amount of coarse aggregations of muscle-like cells. In contrast, dMBs with NanoCliP-FD gel showed multinucleated muscle-like cells, which were expressed as desmin and myogenin by fluorescent immunostaining. Nanogels have a porous structure and are useful as scaffolds for tissue regeneration by supplying oxygen and nutrients supply to the cells. Combining dMBs and nanogels on the biosheets resulted in the differentiation and engraftment of skeletal muscle, suggesting the possibility of developing skeletal muscle sheets derived from autologous cells and tissues.

DGAE(297‐391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy‐Like Tau Filaments

The microtubule‐associated protein tau forms disease‐specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to control this process for drug development purposes, it is crucial to study in vitro tau aggregation methods and investigate the structures of the obtained filaments at the atomic level. Here, we used the tau fragment dGAE, which aggregates spontaneously, to seed the formation of full‐length tau filaments. The structures of dGAE and full‐length tau filaments were investigated by magic‐angle spinning (MAS) solid‐state NMR, showing that dGAE allows propagation of a chronic traumatic encephalopathy (CTE)‐like fold to the full‐length tau. The obtained filaments efficiently seeded tau aggregation in HEK293T cells. This work demonstrates that in vitro preparation of disease‐specific types of full‐length tau filaments is feasible.

Collective condensation and auto-aggregation of Escherichia coli in uniform acidic environments

Chemotaxis–the movement of cells along chemical gradients—leads to collective behaviors when cells coordinate their movements. Here, using Escherichia coli as a model, we demonstrate a distinct type of bacterial collective response in acidic environments containing organic acids. Bacterial populations immersed in such environments collectively condensed into millimeter-sized focal points. Furthermore, this bacterial condensation fostered the formation of small, tightly packed cell aggregates, resembling non-surface-attached biofilms. These cell aggregates were physically displaced by the free-swimming condensing cells, leading to the segregation of the two cell populations. Bacterial condensation relied on feedback between the tendency of these bacteria to neutralize the pH and their chemotactic repulsion from low pH. Sustained cell condensation occurred when the bacteria occupied only part of the acidic environment, either dynamically or due to physical constraints. Such condensed bacterial populations can mitigate acid stress more efficiently, a principle that may be applicable to other stress conditions.

Antifungal activity of Cinnamaldehyde derivatives against fluconazole-resistant Candida albicans

BackgroundCandida albicans is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of C. albicans strains worldwide, it is an urgently necessary to explore alternative therapeutic options. ObjectiveThis study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against C. albicans through both in vitro experiments and in vivo murine models and to evaluate their potential as new drug candidates for treating C. albicans. Methods and resultsThe minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against C. albicans were 25 μg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against C. albicans at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against C. albicans biofilm formation, especially at 8 MIC and 16 MIC concentrations. In C. albicans biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing C. albicans cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 μg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular C. albicans infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by C. albicans, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls. ConclusionThe 4-Cl CA exhibited inhibitory effects against C. albicans through both in vivo and in vitro models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.

Local and Systemic Micro-Rheological Changes during Intestinal Anastomosis Operation: A Metabolic Dependence in an Experimental Model.

Hemorheological factors may show arterio-venous differences. Alterations in acid-base and metabolic parameters may also influence these factors. However, little is known about changes in micro-rheological parameters during abdominal surgery, influencing splanchnic circulation. In anesthetized pigs, the external jugular vein, femoral artery and vein were cannulated unilaterally, and paramedian laparotomy was performed. In the anastomosis group, after resecting a bowel segment, end-to-end jejuno-jejunostomy was completed. Blood samples (from cannulas and by puncturing the portal vein) were taken before and after the intervention. Hematological, acid-base and blood gas parameters, metabolites, red blood cell (RBC) deformability and aggregation were determined. The highest hematocrit was found in portal blood, increasing further by the end of operation. A significant pH decrease was seen, and portal blood showed the highest lactate and creatinine concentration. The highest RBC aggregation values were found in arterial, the lowest in renal venous blood. The RBC aggregation increased with higher lactate concentration and lower pH. Osmotic gradient deformability declined, with the lowest values in portal and renal venous samples. In conclusion, micro-rheological parameters showed arterio-venous and porto-renal venous differences, influenced by oxygenation level, pH and lactate concentration. The intestinal anastomosis operation caused an immediate micro-rheological deterioration with portal venous dominancy in this experiment.

Regulatory roles of APS reductase in Citrobacter sp. XT1-2-2 as a response mechanism to cadmium immobilization in rice

Citrobacter sp. XT1-2-2, a functional microorganism with potential utilization, has the ability to immobilize soil cadmium. In this study, the regulatory gene cysH, as a rate-limiting enzyme in the sulfur metabolic pathway, was selected for functional analysis affecting cadmium immobilization in soil. To verify the effect of APS reductase on CdS formation, the ΔAPS and ΔAPS-com strains were constructed by conjugation transfer. Through TEM analysis, it was found that the adsorption of Cd2+ was affected by the absence of APS reductase in XT1-2-2 strain. The difference analysis of biofilm formation indicated that APS reductase was necessary for cell aggregation and biofilm formation. The p-XRD, XPS and FT-IR analysis revealed that APS reductase played an important role in the cadmium immobilization process of XT1-2-2 strain and promoting the formation of CdS. According to the pot experiments, the cadmium concentration of roots, culms, leaves and grains inoculated with ΔAPS strain was significantly higher than that of wild-type and ΔAPS-com strains, and the cadmium removal ability of ΔAPS strain was significantly lower than that of wild-type strain. The study provided insights into the exploration of new bacterial assisted technique for the remediation and safe production of rice in cadmium-contaminated paddy soils.

Nanowire Electrode Structures Enhanced Direct Extracellular Electron Transport via Cell-Surface Multi-Heme Cytochromes in Desulfovibrio ferrophilus IS5

Extracellular electron transfer (EET) by sulfate-reducing bacteria (SRB), such as Desulfovibrio ferrophilus IS5, enables bacterial interactions with minerals, which are vital for biogeochemical cycling and environmental chemistry. Here, we explore the direct EET mechanisms through outer-membrane cytochromes (OMCs) using IS5 as a model SRB. We employed nanostructured electrodes arrayed with 0, 50, 200, and 500 nm long nanowires (NWs) coated with indium–tin–doped oxide to examine the impact of electrode morphology on the direct EET efficacy. Compared to flat electrodes, NW electrodes significantly enhanced current production in IS5 with OMCs. However, this enhancement was diminished when OMC expression was reduced. Differential pulse voltammetry revealed that NW electrodes specifically augmented redox peaks associated with OMCs without affecting those related to redox mediators, suggesting that NWs foster direct EET through OMCs. Scanning electron microscopy observations following electrochemical analyses revealed a novel vertical cell attachment and aggregation on NW electrodes, contrasting with the horizontal monolayer cell attachment on flat electrodes. This study presents the first evidence of the critical role of electrode nanoscale topography in modulating SRB cell orientation and aggregation behavior. The findings underscore the significant influence of electrode morphology on the direct EET kinetics, highlighting the potential impact of mineral morphology on mineral reduction and biogeochemical processes.

Characterization of the Secretome from Spheroids of Adipose-Derived Stem Cells (SASCs) and Its Potential for Tissue Regeneration.

Spheroids are spherical aggregates of cells that mimic the three-dimensional (3D) architecture of tissues more closely than traditional two dimensional (2D) cultures. Spheroids of adipose stem cells (SASCs) show special features such as high multilineage differentiation potential and immunomodulatory activity. These properties have been attributed to their secreted factors, such as cytokines and growth factors. Moreover, a key role is played by the extracellular vesicles (EVs), which lead a heterogeneous cargo of proteins, mRNAs, and small RNAs that interfere with the pathways of the recipient cells. The aim of this work was to characterize the composition of the secretome and exosome from SASCs and evaluate their regenerative potential. SASCs were extracted from adipose samples of healthy individuals after signing informed consent. The exosomes were isolated and characterized by Dinamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Western blotting analyses. The expression of mRNAs and miRNAs were evaluated through real-time PCR. Lastly, a wound-healing assay was performed to investigate their regenerative potential on different cell cultures. The SASCs' exosomes showed an up-regulation of NANOG and SOX2 mRNAs, typical of stemness maintenance, as well as miR126 and miR146a, related to angiogenic and osteogenic processes. Moreover, the exosomes showed a regenerative effect. The SASCs' secretome carried paracrine signals involved in stemness maintenance, pro-angiogenic and pro-osteogenic differentiation, immune system regulation, and regeneration.

Adsorption and uptake of functionalized nanoplastics (NPs) by wetland plant (Sphagnum): A unique pathway for polystyrene-NPs reduction in non-vascular plants

Wetlands are sources and sinks for nanoplastics (NPs), where adsorption and uptake by plants constitute a crucial pathway for NPs accumulation. This study found that Sphagnum exhibited a high potential (~89.75 %) to intercept NPs despite the lack of root systems and stomata. Two pathways for 100nm polystyrene NPs accumulation in Sphagnum were located: (i) Spiral interception and foliar adsorption. Efficient adsorption is credited to the micro/nano-interlocked leaf structure, which is porous, hydrophilic and rough. (ii) Intracellular enrichment through pores. Fluorescence tracking indicates pseudo-leaves (lateral > cephalic branches) as primary organs for internalization. Accumulation of differently functionalized NPs was characterized: PS-Naked-NPs (PS), PS-COOH-NPs (PC) and PS-NH2-NPs (PN) were all largely retained by pathway (i), while pathway (ii) mainly uptake PN and PC. Unlike PS aggregation in transparent cells, PC enrichment in chloroplast cells and PN in intercellular spaces reduced pigment content and fluorescence intensity. Further, the effects of the accumulated NPs on the ecological functions of Sphagnum were evaluated. NPs reduce carbon flux (assimilation rate by 57.78 %, and respiration rate by 33.50%), significantly decreasing biomass (PS = 13.12 %, PC = 26.48 %, PN = 35.23 %). However, toxicity threshold was around 10 μg/mL, environmental levels (≤1 μg/mL) barely affected Sphagnum. This study advances understanding of the behavior and fate of NPs in non-vascular plants, and provides new perspectives for developing Sphagnum substrates for NPs interception.

On-demand bactericidal and self-adaptive antifouling hydrogels for self-healing and lubricant coatings of catheters

Catheter-related infections are one of the most common nosocomial infections with increasing morbidity and mortality, and robust antibacterial or antifouling catheter coatings remain great challenges for long-term implantation. Herein, multifunctional hydrogel coatings were developed to provide persistent and self-adaptive antifouling and antibacterial effects with self-healing and lubricant capabilities. Polyvinyl alcohol (PVA) with β-cyclodextrin (β-CD) grafts (PVA-Cd) and 4-arm polyethylene glycol (PEG) with adamantane and quaternary ammonium compound (QAC) terminals (QA-PEG-Ad) were crosslinked through host-guest recognitions between adamantane and β-CD moieties to acquire PVEQ coatings. In response to bacterial infections, QACs exhibit reversible transformation between zwitterions (pH 7.4) and cationic lactones (pH 5.5) to generate on-demand bactericidal effect. Highly hydrophilic PEG/PVA backbones and zwitterionic QACs build a lubricate surface and decrease the friction coefficient 10 times compared with that of bare catheters. The antifouling hydrated layer significantly inhibits blood protein adsorption and platelet activation and reveals negligible hemolysis and cytotoxicity. The dynamic host-guest crosslinking achieves full self-healing of cracks in PVEQ hydrogels, and the mechanical profiles were recovered to over 90 % after rejuvenating the broken hydrogels, exhibiting a long-term stability after mechanical stretching, twisting, knotting and compression. After subcutaneous implantation and local bacterial infection, the retrieved PVEQ-coated catheters display no tissue adhesion and 3 log folds lower bacterial number than that of bare catheters. PVEQ coatings effectively prevent the repeated bacterial infections and there are few inflammatory reactions in the surrounding tissue, while substantial lymphoid infiltration and inflammatory cell aggregation occur in muscle tissues around the bare catheter. Thus, this study demonstrates a catheter coating strategy by on-demand bactericidal, self-adaptive antifouling, self-healing and lubricant hydrogels to address medical devices-related infections. Statement of significanceIt is estimated over two billion peripheral intravenous catheters are annually used in hospitals around the world, and catheter-associated infection has become a great clinical challenge with rapidly rising morbidity and mortality. Surface coating is considered a promising approach, but substantial challenges remain in the development of coatings that simultaneously satisfy both anti-fouling and antibacterial attributes. Even more, few attempts have been made to design mechanically robust coatings and reversible antibacterial or antifouling capabilities, which are critical for long-term medical implants. To address these challenges, we propose a concise strategy to develop hydrogel coatings from commercially available poly(ethylene glycol) and polyvinyl alcohol. In addition to self-healing and lubricant capabilities, the reversible conversion between zwitterionic and cationic lactones of quaternary ammonium compounds enables on-demand bactericidal and self-adaptive antifouling effects.

All-aqueous synthesis of alginate complexed with fibrillated protein microcapsules for membrane-bounded culture of tumor spheroids

Water-in-water (W/W) emulsions provide bio-compatible all-aqueous compartments for artificial patterning and assembly of living cells. Successful entrapment of cells within a W/W emulsion via the formation of semipermeable capsules is a prerequisite for regulating on the size, shape, and architecture of cell aggregates. However, the high permeability and instability of the W/W interface, restricting the assembly of stable capsules, pose a fundamental challenge for cell entrapment. The current study addresses this problem by synthesizing multi-armed protein fibrils and controlling their assembly at the W/W interface. The multi-armed protein fibrils, also known as ‘fibril clusters’, were prepared by cross-linking lysozyme fibrils with multi-arm polyethylene glycol (PEG) via click chemistry. Compared to linear-structured fibrils, fibril clusters are strongly adsorbed at the W/W interface, forming an interconnected meshwork that better stabilizes the W/W emulsion. Moreover, when fibril clusters are complexed with alginate, the hybrid microcapsules demonstrate excellent mechanical robustness, semi-permeability, cytocompatibility and biodegradability. These advantages enable the encapsulation, entrapment and long-term culture of tumor spheroids, with great promise for applications for anti-cancer drug screening, tumor disease modeling, and tissue repair engineering.

Novel use of a - 20°C cryoprotectant yields high viability and improved aggregation of marine sponge cells.

Novel use of a - 20°C cryoprotectant yields high viability and improved aggregation of marine sponge cells.

Particle-based modeling and GPU-accelerated simulation of cellular blood flow

Computational modeling and simulation of cellular blood flow is highly desired for understanding blood microcirculation and blood-related diseases such as thrombosis and tumor, but it remains a challenging task primarily because blood in microvessels should be described as a dense suspension of different types of deformable cells. The focus of the present work is on the development of a particle-based and GPU-accelerated numerical method that is able to quickly simulate the various behaviors of deformable cells in three-dimensional arbitrarily complex geometries. We employ a two-fluid model to describe blood flow, incorporating the deformation and aggregation of cells. A smoothed dissipative particle dynamics is used to solve the two-fluid model, and a discrete microstructure model is applied for the cell deformation, as well as a Morse potential model for the cell aggregation. The heterogeneous CPU-GPU environment is established, where each GPU thread is dedicated to a particle, and the CPU is mainly responsible for loading and exporting data. Five test cases are conducted against analytical theory, experimental data, and previous numerical results, for pure fluid, cell deformation, cell aggregation, cell suspension and the cellular flow in a complex network, respectively. It is shown that the methodology can accurately predict various behaviors of cells, and the GPU is well suited for particle-based modeling. Especially for cellular blood flow, where calculating cellular forces is a compute-intensive and time-consuming task, the GPU offers exceptional parallel capabilities, significantly enhancing the simulation efficiency. The speedup is about 3.5 times faster than the CPU parallelization with 96 cores for the pure fluid, and this acceleration nearly reaches 20 times when cells are included in the simulations. Particularly, the calculations for deformation and aggregation forces demonstrate a substantial speedup, achieving the improvements of up to 120 and 640 times, respectively, compared to their serial counterparts. The present methodology can effectively integrate various behaviors of cells, and has the potential in simulating very large microvascular networks at organ levels.

High-throughput fabrication of cell spheroids with 3D acoustic assembly devices.

Acoustic cell assembly devices are applied in cell spheroid fabrication attributed to their rapid, label-free and low-cell damage production of size-uniform spheroids. However, the spheroids yield and production efficiency are still insufficient to meet the requirements of several biomedical applications, especially those that require large quantities of cell spheroids, such as high-throughput screening, macro-scale tissue fabrication, and tissue repair. Here, we developed a novel 3D acoustic cell assembly device combined with a gelatin methacrylamide (GelMA) hydrogels for the high-throughput fabrication of cell spheroids. The acoustic device employs three orthogonal piezoelectric transducers that can generate three orthogonal standing bulk acoustic waves to create a 3D dot-array (25 × 25 × 22) of levitated acoustic nodes, enabling large-scale fabrication of cell aggregates (>13,000 per operation). The GelMA hydrogel serves as a supporting scaffold to preserve the structure of cell aggregates after the withdrawal of acoustic fields. As a result, mostly cell aggregates (>90%) mature into spheroids maintaining good cell viability. We further applied these acoustically assembled spheroids to drug testing to explore their potency in drug response. In conclusion, this 3D acoustic cell assembly device may pave the way for the scale-up fabrication of cell spheroids or even organoids, to enable flexible application in various biomedical applications, such as high-throughput screening, disease modeling, tissue engineering, and regenerative medicine.