搜索结果：APL bioengineering

[This corrects the article DOI: 10.1063/5.0280958.].

Acute promyelocytic leukemia (APL) is characterized by immature myeloid cells with unlimited proliferative capacity. All-trans retinoic acid (ATRA) can induce these cells to differentiate, but patients may develop differentiation syndrome (DS), a life-threatening complication linked to abnormal leukocyte recruitment. The mechanisms of DS remain poorly understood, despite insights gained from studies on APL cell lines. In this study, ATRA-differentiated HL-60 cells were perfused into a flow chamber simulating the physiological environment and functionalized with P-selectin to mimic the initial step of leukocyte recruitment. We quantified the adhesive behavior of these cells by measuring the PSGL-1-P-selectin bond lifetime and adhesion rate with and without ATRA treatment. Both parameters increased following ATRA treatment. Flow cytometry revealed that the difference in PSGL-1 expression was minimal. To explore the impact of cell stiffness on adhesion, we fixed cells and performed additional flow chamber experiments. The bond lifetime and adhesion rate of differentiated cells decreased after fixation, suggesting that the altered adhesion behavior was mainly due to changes in cell deformability, with a minimal role played by PSGL-1 expression. These findings highlight the potential role of cell deformability in the enhanced adhesion of ATRA-differentiated cells, offering new insights into the mechanisms of DS and paving the way for improved prevention and treatment strategies for DS in APL patients.

Visualization of colorectal cancer (CRC) lesions is complicated by their location in the colon and tumor morphology. Reliance on a single surface biomarker for direct identification risks false negatives due to temporal changes and/or tumor heterogeneity. We developed a multiplexed system of complementary biomarker targets in an effort to capture a broader range of lesions with diverse temporal and/or phenotypic expression. We identified Mucin-1 (MUC1) and epithelial cell adhesion molecule (EPCAM) as useful targeting pairs by examining multiple colon tumor subtypes in a standard tissue array, and by surveying multiple CRC cell lines, both as 2D cultures and as 3D tumoroids, for the presence of the CRC surface biomarkers. We demonstrated the utility of a "universal" surface functionalization approach using Antibody-Protein L functionalized microparticles (APL-MPs) that enabled the simultaneous incorporation of antibodies recognizing MUC1 and EPCAM. Using CRC cell heterogeneous tumoroids expressing both MUC1 and EPCAM (HET-tumoroids) and orthotopic animal cancer models designed to express both surface antigens, we demonstrated that: 1) APL-MPs identified MUC1- and EPCAM-positive tumoroids in proportion to antigen expression; 2) APL-MPs detected CRC surface antigens on the luminal colon surface in vivo, and 3) concurrent targeting of multiple surface antigens enhanced the sensitivity of detection of heterogeneous CRC lesions. This approach opens the door for the use of antibody-protein L dual-targeting MPs in a variety of applications to detect heterogeneous cancer lesions.

Morphological changes in spheroids and organoids are widely used as in vitro indicators of healthy and diseased tissue function, but selecting appropriate methods to quantify these changes remains challenging. Shape factors (or shape descriptors) are dimensionless metrics often computed using ImageJ/FIJI; however, their ability to classify specific morphological features can vary. To address this challenge, we developed a clinically inspired, custom MATLAB algorithm to quantify the variance in radial lengths of invasive protrusions in spheroids and organoids. We then compared the advantages and limitations of this approach with conventional ImageJ/FIJI shape descriptors to guide users in selecting the most appropriate method for classifying spheroid and organoid morphology in their specific settings. To this end, we first analyzed digital phantoms and then performed the same comparisons using images from experimental spheroid and organoid datasets. By enabling numerical morphological readouts, shape factor analysis can enhance phenotypic profiling of spheroids and organoids and provide valuable metrics for in vitro studies, including high-throughput and drug screening workflows.

Implanted vagus nerve stimulation is FDA-approved to treat epilepsy, depression, and stroke sequelae and is under development for other disorders such as heart failure and rheumatoid arthritis. Anatomically realistic computational models enable the design of electrodes and stimulation parameters that activate nerve fibers that mediate therapeutic responses, and avoid activating fibers that cause side effects. Conventional modeling techniques assume constant longitudinal morphology, extruding a single cross section to define the three-dimensional nerve geometry. However, recent imaging data showed that human vagus nerves have extensive fascicle splitting and merging along their length. Therefore, we developed a pipeline to simulate true three-dimensional (true-3D) models of peripheral nerve stimulation from segmentations of micro-computed tomography imaging. We implemented models of n = 4 human vagus nerves and systematically evaluated extrusion vs true-3D model responses to electrical stimulation across population dose-response relationships, fiber-specific thresholds, recruitment order, and spatial selectivity. Despite the complex morphology of the human vagus nerve, extrusion models replicated the true-3D neural responses if: (1) the nerve morphology was deformed to a circular cross section, as occurs with chronic cuff implants, and (2) the extruded cross section was centered under the depolarizing electrode contact. Our pipeline provides a foundation for advanced modeling of peripheral nerve stimulation and the design of more selective stimulation therapies.

As a primary method for tissue repair and functional reconstruction, flap transplantation has achieved a clinical success rate of over 90%. However, the postoperative incidence of vascular crisis remains as high as 10%-30%, making it a leading cause of reoperation and disability. Flap temperature is a key indicator closely correlated with microcirculatory status, making its monitoring essential for the early detection of complications. This paper provides a systematic review of the physiological mechanisms underlying postoperative flap temperature, the characteristic temperature changes associated with venous and arterial crises, and the latest advancements in monitoring technologies. It comprehensively analyzes the principles, advantages, and limitations of various methods, including manual palpation, contact thermometry, infrared thermography, fiber optic sensing, and microwave thermometry. Furthermore, the review explores the application of intelligent technologies such as wearable sensors, artificial intelligence-driven predictive systems, implantable flexible devices, and multimodal fusion monitoring. Current challenges, including poor real-time performance, low precision, and a lack of standardization, are highlighted. Future development is directed toward precision, intelligence, and integration, with an emphasis on multidisciplinary collaboration to create more accurate, convenient, and intelligent monitoring systems. These advancements aim to achieve precise early warning and timely intervention, ultimately improving flap survival rates and patient outcomes.

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. In vivo, ApoE-/- mice fed a high-fat/high-cholesterol diet and adeno-associated virus-mediated CYBA knockdown attenuated atherosclerotic plaque formation and lipid deposition and rescued mitochondrial damage. In vitro, CYBA silencing attenuated ox-LDL-induced mitochondrial dysfunction and oxidative stress, concurrently inhibiting pro-inflammatory polarization and ferroptosis. Mechanistically, CYBA deficiency facilitated Nrf2 nuclear translocation and downstream activation of heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1, whereas pharmacological Nrf2 inhibition reversed these protective effects. Our findings unveil CYBA as a mitochondrial checkpoint that constrains Nrf2-mediated antioxidant responses, thereby promoting inflammatory polarization and ferroptosis in macrophages during AS. Targeting the CYBA offers a promising therapeutic strategy to attenuate plaque progression.

Atherosclerosis and its complications are highly prevalent worldwide, and managing oxidative stress in endothelial cells to alleviate abnormal inflammatory damage is a critical therapeutic approach. Nanomedicine delivery systems offer promising solutions by overcoming the limitations of surgical interventions and the off-target effects of oral drugs. In this study, we developed a modified mesenchymal stem cell membrane (MSCM)-encapsulated nanoparticle drug delivery system that effectively delivers kaempferol to atherosclerotic sites. These biomimetic nanoparticles were able to specifically target endothelial cells in an inflammatory environment while evading macrophage-mediated endocytosis. Moreover, the modified MSCM-encapsulated kaempferol nanoparticles (KPM) had a protective effect on oxidatively damaged endothelial cells. In vivo, the modified nanoparticles successfully migrated toward atherosclerotic lesions, as demonstrated in a mouse model of susceptible atherosclerotic plaques. Intravenous injection of KPM significantly reduced the lipid plaque load and improved plaque structure. Furthermore, the biosafety of KPM was comprehensively assessed both in vitro and in vivo, with no significant effects on blood count, lipid balance, cellular activity, body weight, or liver or kidney function. This is the first report of the use of MSCM to encapsulate kaempferol nanodrugs to treat atherosclerosis. This strategy presents a novel and effective therapeutic system for targeted delivery of antioxidant therapy to atherosclerotic sites, offering potential for the treatment of atherosclerosis in cardio-cerebrovascular diseases.

Therapeutic ultrasound (US) and photobiomodulation (PBM) are promising treatment modalities for restoring articular cartilage. Owing to their different mechanisms of action, individual or combined stimulation may elicit different bioeffects on chondrocytes. This study aimed to evaluate the potential of US and PBM, applied alone or combined, in augmenting chondrocytes' responses toward cartilage matrix synthesis and reverting their catabolic activities, with or without interleukin-1β (IL-1β) incubation. Human chondrocytes were cultured under basal or proinflammatory conditions (1 ng/ml IL-1β) and stimulated daily for 6 days with US, PBM, US followed by PBM, and PBM followed by US. Chondrocyte activity, along with protein and mRNA expression of cartilage synthesis- and degradation-related markers, was analyzed. IL-1β incubation did not significantly affect chondrocytes' metabolic activity or sulfated glycosaminoglycans (GAGs) production. Both US and PBM, alone or combined, increased the protein and mRNA of collagen type II (COL II) and aggrecan (ACAN) under basal and proinflammatory conditions. PBM had a stimulatory effect on GAG synthesis. While PBM did not influence the expression of cartilage destruction markers, US potentiated the chondrocytes' response to inflammation by increasing metalloproteinases and IL-1β mRNA levels. The sequential combination of US and PBM induced distinct bioeffects depending on the application order, but these were not superior to the effects of individual treatments. As this study used chondrocytes from a single donor, generalizability may be limited. While both US and PBM stimulated matrix synthesis, PBM showed a comparatively greater ability to mitigate chondrocyte degradation and may be of interest for cartilage repair strategies.

Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression of MMP1, consistent with cavitation via cell invasion. Mimicking the interstitial flow of nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype.

Closed-loop bioelectronic devices offer a promising platform for responsive treatment to heterogeneous disease states. Glioblastoma, an aggressive form of brain cancer, has recently emerged as a focus of bioelectronic medicine through delivery of electrotherapies. This perspective article posits that true progress in the management of this extremely heterogeneous disease requires the integration of continuous monitoring from the tumor microenvironment as well as on-device analytics to enact closed-loop control. Four promising candidate biological changes present in the glioblastoma microenvironment are highlighted (local field potentials, bioimpedance, local pH, biomarkers) alongside the bioelectronic sensors that can enable the development of multifunctional bioelectronic devices to monitor the changes. Finally, three key principles (patient involvement, data analytics, and device fabrication) governing the successful implementation of closed-loop sensors are proposed to create a roadmap for academics and industry partners to successfully develop multimodal devices for the treatment of glioblastoma.

Quantitative cell biology often examines migration and cell-cycle (CC) progression separately, limiting insights into their interplay under spatial constraints. Here, we present a vertically integrated platform combining multiplexed fluorescent reporters for CC phases, actin, and tubulin with photopatterned extracellular matrix islands of defined sizes, alongside an automated imaging pipeline (Fab2Mic) for high-throughput, live-cell tracking of migration and CC dynamics under planar confinement. Using HT1080 fibrosarcoma cells, we observed that planar confinement progressively reduced cell area and cytoskeletal spread, altered CC phase distributions, and increased abnormal CC events, including prolonged G1 and mitotic slippage, which is unique to confined conditions. Dynamic imaging revealed CC-dependent motility variations, with faster migration in G1. This system enables systematic, CC-aware mechanobiology studies under controlled confinement, providing access to dynamic phenotypes inaccessible to static assays and offering a scalable approach for mechanistic investigations and screening applications.

Chirality is an intrinsic characteristic of living systems, manifesting as a pervasive asymmetry from the molecular to the cellular level. This asymmetry regulates normal life activities through precise stereospecific recognition between molecules and between molecules and cells. Under physiological conditions, L-amino acids constitute proteins that support metabolic functions, right-handed helical deoxyribonucleic acid (DNA) stores genetic information, and right-handed sugars provide energy. At the cellular level, the non-centrosymmetric arrangement of the cytoskeleton guides the left-right axial positioning during embryonic development and organ formation. A certain degree of chiral inversion occurs under normal physiological conditions-for instance, trace amounts of D-amino acids modulate neurotransmitter release, and low level of left-handed DNA promotes double-strand unwinding, facilitating transcription. However, excessive accumulation of D-amino acids is closely associated with Alzheimer's disease, chronic kidney di'ease, diabetes, and aging. Similarly, the presence of substantial left-handed DNA fragments can lead to genomic instability, "increasin" sus'eptibility to tumorigenesis. Moreover, abnormalities in cellular chirality may contribute to vascular endothelial barrier disruption and improper left-right organ positioning. Therefore, monitoring aberrant chiral molecules and cells that deviate from the normal range holds promise for the early diagnosis of diseases such as nephropathy, Alzheimer's disease, diabetes, and cancer. This article primarily reviews the dynamic chiral balance under physiological and pathological conditions, providing a reference for the application of chirally inverted molecules and cells Is potential novel biomarkers for the early diagnosis of diseases.

Human induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) hold great potential to resolve cardiovascular disease but are stymied by their functional immaturity. The complex electric potentials measured during cardiogenesis point to the potential of exogenous electrical stimulation in improving cardiac differentiation and functionality. Herein, we create, validate, and implement a low-cost electrical stimulation device to stimulate human induced pluripotent stem cells during cardiac differentiation. Notably, our open-source device enables the generation of dynamic electrical stimulation regimens that may vary in frequency and pulse duration over time. Our results show that cardiac differentiation under dynamic electrical stimulation improves cardiac differentiation efficiency, beating synchronicity, and intracellular calcium handling and flow but impedes contraction compared to static electrical stimulation and no stimulation controls. We also show that pulse duration is an important stimulation parameter to optimize for hiPSC-CM differentiation and functionality. Across nearly all measured metrics, hiPSC-CMs subjected to dynamic pulse duration stimulation during differentiation outperformed those generated under dynamic frequency stimulation. We anticipate that more complex dynamic electrical stimulation regimens may be generated to further optimize hiPSC-CM functionality and maturity.

Bone defect repair remains a significant clinical challenge, necessitating scaffold materials that combine excellent mechanical properties, bioactivity, and anti-infective capabilities, which are central to bone tissue engineering. Triply periodic minimal surface (TPMS) structures have garnered considerable attention due to their superior mechanical and biological characteristics, demonstrating great potential in the design of bone repair scaffolds. This review summarizes the latest advances in three-dimensional printed anti-infective tissue engineering scaffolds based on TPMS structures within the field of bone regeneration. It highlights the design advantages of TPMS architectures, the performance of composite materials such as polylactic acid/magnesium titanate, and the antimicrobial mechanisms of these scaffolds. Furthermore, the synergistic effects of promoting osteogenesis and combating infection are analyzed. By systematically collating current research findings, this article aims to provide a theoretical foundation and guidance for the development of next-generation multifunctional bone repair materials.

Evidence has shown that high-intensity laser therapy (HILT) may be beneficial for recovery after peripheral nerve injury (PNI). However, the optimized doses and effective mechanisms remain unclear. The present study sought to explore the effects of various doses of HILT on the recovery of nerve function in sciatic nerve injury (SNI) rats. The potential mechanism of action of HILT alleviating PNI was also assessed. Behavioral testing, polymerase chain reaction, immunoblotting, and immunofluorescence analyses were applied to explore whether HILT promotes the repair of injured nerves and its underlying mechanisms. SNI induces mechanical nociceptive hypersensitivity, disrupts sciatic nerve structure and function, causes gastrocnemius muscle atrophy, and increases oxidative stress and expression levels of inflammatory factors. HILT effectively ameliorated these SNI-induced alterations. Notably, the Bone Morphogenetic Protein 4 (BMP4)-SMAD Family Member 9 (Smad9) pathway mediates the therapeutic effects of HILT on SNI repair. These findings show for the first time that HILT stimulates the BMP4-Smad9 signaling pathway by increasing Smad9 expression to regulate inflammation and oxidative stress, which ultimately ameliorates SNI.

Magnetic resonance imaging (MRI) offers potential advantages for endovascular intervention, including excellent soft-tissue contrast, multi-planar visualization, and the possibility of radiation-free guidance. Emerging robotic platforms, MRI-compatible catheter systems, and MRI-native navigation frameworks indicate that MRI-guided endovascular robotics is moving beyond isolated feasibility concepts. Yet routine MRI-guided robotic endovascular procedures remain rare. This gap is not explained by the absence of a single enabling technology, but by the interaction of tightly coupled constraints spanning instruments, imaging and feedback, navigation, and system integration. In endovascular settings, these constraints are amplified by the need for miniaturized, flexible, and steerable tools operating under limited and phase-dependent feedback. This perspective argues that progress in MRI-guided endovascular robotics requires moving beyond compatibility-driven adaptation toward MRI-robot co-design. First, the emerging landscape of representative robotic platforms, MRI-compatible and MRI-actuated catheter systems, and MRI-navigation-enabling technologies is outlined. The coupled constraints that continue to limit translation are then analyzed, showing why component-level solutions often remain fragile when integrated into full procedural workflows. Building on this framework, four research axes toward MRI-native endovascular robotic systems are proposed: MRI-native instruments, MRI-native feedback, navigation under bandwidth-limited imaging, and integrated systems built through workflow-aware validation and benchmarking. Across these axes, the discussion emphasizes the importance of miniaturized actuation, robot-aware MRI pipelines, feedback-efficient shared control, realistic simulation, benchmarking, and workflow-aware validation. MRI-guided endovascular robotics should therefore be understood as a systems integration challenge rather than a single-device problem. MRI-native robotic systems offer a concrete pathway toward safer, more precise, and radiation-free endovascular intervention.

Mechanical cues control key aspects of cardiac structure formation and function from heart development through adult life. Because the heart is a pump, forces from muscle contraction and blood flow generate normal and shear stresses that, together with matrix stiffness, regulate cell fate, growth, and homeostasis through mechanotransduction. This review describes how mechanosensors in cardiomyocytes, endothelial cells, and fibroblasts, including integrins and stretch-activated ion channels, couple mechanical stimuli to their cellular responses. We outline pathways that translate force into key phenotypes relevant to morphogenesis, homeostasis, and disease progression, with emphasis on RhoA/ROCK, calcium, and Yes-associated protein (YAP) signaling. We also explain how elevated mechanical load driven by hypertension activates hypertrophic and fibrotic remodeling of cardiac chambers, particularly through transforming growth factor-β, integrins, YAP, and calcineurin signaling. Finally, we highlight emerging roles for mechanosensitive microRNAs in coordinating proliferation, metabolism, electrophysiology, and extracellular matrix dynamics in the heart. Since most, if not all, of these pathways are interconnected, a comprehensive understanding will require high-resolution maps of cardiac mechanical environments and clear links between defined stimuli and cell-type-specific responses. These insights will advance fundamental understanding and guide the development of more effective therapeutic strategies.

Resident cardiac macrophages, derived from primitive yolk sac precursors during embryogenesis, have increasingly been recognized for their distinct phenotype and functions in regulating homeostasis of the human heart. However, the profile of their extracellular vesicles (EVs) in cardiac signaling and regulation remains uncharted. Here, we employ differentiation of human pluripotent stem cell-derived primitive macrophages (Mac), harvesting their secreted EVs and performing in-depth characterization of associated microRNAs (miRNAs). Primitive macrophages secreted nanoscale EVs that expressed canonical EV markers, and miRNA sequencing highlighted a diverse and unique profile of miRNAs when compared to EVs sourced from other principal cardiac cell lineages and published data from monocyte-derived cells. In particular, we noted the abundance and enrichment of vascular-modulatory let-7 miRNAs and miR-126-3p. Functional screening of Mac-EVs in a 3D model of in vitro cardiac vasculogenesis confirmed enhanced early endothelial cell organization and branching. Establishing a reference for the human Mac-EV miRNome enables further hypothesis-driven mechanistic tests of Mac-EV miRNAs in mediating cardiac physiology and disease, opening the door to identification of therapeutic targets and modalities for cardiac repair.