APL Bioengineering最新文献

Organoid culture systems have emerged as powerful platforms for studying development, disease modeling, and regenerative medicine. However, current models primarily rely on spontaneous self-organization within biomimetic matrices such as Matrigel, which lack precise control over biomechanical cues. Recent advances in mechanobiological engineering highlight the critical role of matrix-derived physical and mechanical properties-such as adhesion presentation, stiffness, viscoelasticity, and geometry-in directing organoid morphogenesis and functional maturation. This review explores how translating in vivo biomechanics into in vitro organoid culture strategies can overcome existing limitations, enhance reproducibility, and enable the development of physiologically relevant organoid systems.

Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous tumor driven by the dysregulation of multiple genes. Tubulin tyrosine ligase-like 4 (TTLL4) has been linked to tumor progression, but its specific role in HCC pathogenesis remains unclear. RNA sequencing data, somatic mutation profiles, and clinical characteristics were analyzed from TCGA, GEO, and TIMER databases. The effects of TTLL4 on cell proliferation, migration, and apoptosis were studied using functional assays and flow cytometry. In vivo, tumor growth and metastasis were evaluated through subcutaneous implantation and tail vein injection. Immunohistochemistry assessed TTLL4 and Ki-67 expression. TTLL4 was upregulated in HCC and associated with poor prognosis, linking it to cancer progression and the PI3K-AKT signaling pathway. Knockdown of TTLL4 in HCC cells reduced proliferation, migration, and colony formation while increasing apoptosis. In vivo, TTLL4 knockdown slowed tumor growth and reduced lung metastasis. It also decreased the expression of proteins in the PI3K/AKT/MDM2 pathway, while overexpression upregulated these proteins. Rescue experiments further suggest that TTLL4 may exert its regulatory effects on this pathway by modulating PI3K expression levels. TTLL4 plays a significant role in HCC progression via the PI3K/AKT/MDM2 pathway and may serve as a novel therapeutic target for HCC diagnosis and treatment.

Monocytes, key mediators of innate immunity, exhibit remarkable sensitivity to mechanical cues such as extracellular matrix (ECM) stiffness, substrate rigidity, shear stress, compression, and hydrostatic pressure, which shape their activation, differentiation, and functional polarization. Monocytes develop from the bone marrow and populate the vasculature throughout the body. During inflammation, they are recruited to injured or diseased tissues by chemokines and proinflammatory cytokines, modulating local immune responses during embryonic development and adulthood via mechanosensing and mechanotransduction pathways. This review synthesizes recent advances in monocyte mechanobiology. It highlights how the bone marrow ECM mechanics orchestrates myelopoiesis, the role of endothelium and hemodynamic forces in migration, and how tissue mechanics influences monocyte fate in chronic inflammation, fibrosis, and cancer. We discuss the mechanosensitive pathways that govern monocyte behavior in health and disease and therapeutic opportunities that emerge from targeting these mechanisms via biomaterial approaches. Additionally, future directions toward developing mechanotherapy for immune modulation are discussed. By bridging mechanobiology and immunology, this review underscores the potential of mechanical cues as therapeutic targets to reprogram monocyte behavior in disease.

Retinal diseases, such as age-related macular degeneration and diabetic macular edema, are significant contributors to vision loss. While injection of anti-vascular endothelial growth factors is the current gold standard treatment, their invasive nature reduces patient compliance and treatment outcomes and increases the risk of complications. In this review, we explore the recent advancements in drug delivery systems designed to overcome ocular barriers to effectively deliver drugs to the retina. We examine advancements in intravitreal injections, such as novel formulations, therapeutic molecules, and sustained-release implants. Moreover, we discuss innovations in noninvasive strategies, such as topical delivery systems incorporating cell-penetrating peptides, solid lipid nanoparticles, dendrimers, and nano-micelles. These technologies aim to enhance drug penetration, stability, and bioavailability. Although preclinical and clinical trials have yielded promising results, challenges remain in ensuring long-term safety and efficacy. This review highlights future research directions to optimize these approaches and develop more effective, patient-friendly therapies for retinal diseases.

Tendons are essential for musculoskeletal function, facilitating movement by transmitting forces from muscles to bones. However, aging alters the tendon microenvironment, disrupting the delicate interactions between tenocytes and the extracellular matrix (ECM), contributing to tissue degeneration. While prior studies have characterized the mechanical and structural changes in tendons during maturation, the epigenetic regulation of tenocyte function during aging remains poorly understood. Here, we investigate age-dependent mechanobiological and epigenetic changes in murine tenocytes. Our findings demonstrate that mature tenocytes generate higher traction forces and migrate faster. Furthermore, we reveal increased chromatin condensation in mature tenocytes, accompanied by elevated levels of the repressive histone mark H3K27me3 and reduced levels of the activating mark H3K4me3. Chromatin immunoprecipitation sequencing indicates that these histone modifications regulate genes associated with cellular contractility, ECM production, and mechanotransduction, highlighting the critical role of epigenetic mechanisms in governing tenocyte function. These findings suggest that age-related epigenetic changes may contribute to both the maintenance of tissue homeostasis and the suppression of degenerative diseases in tendons, providing new avenues for therapeutic strategies aimed at restoring tenocyte function and enhancing tendon regeneration.

Fibroblasts play crucial roles in wound healing, cancer, and fibrosis. Many aspects of these roles are driven by the process known as fibroblast activation. The generally accepted definition of fibroblast activation is the transition from a quiescent state to a state in which fibroblasts participate in a number of active processes, including extracellular matrix (ECM) production and remodeling, elevated contractility, and enhanced migratory capacity, although there is no universal consensus on what exactly constitutes "activation." Interestingly, the time scale of activation is not consistent across tissues and disease states; some fibroblasts quickly return to quiescence after activation (e.g., in wound healing), others undergo apoptosis, while a subset become persistently activated. This activation, both acute and persistent, is inherently a mechanical process, given the increase in ECM production and remodeling and the enhanced traction force generation. Thus, there exists a dynamic reciprocity, or cell-ECM feedback, in which activated fibroblasts produce a mechanical microenvironment that in turn supports persistent activation. This has a wide variety of implications for disease, most notably fibrosis and cancer, as the fibroblasts that become persistently activated in connection with these conditions can contribute to disease state progression. Like other mechanosensitive processes, this mechanically induced persistent fibroblast activation is driven by a number of mechanotransduction signaling pathways. Thus, an opportunity exists in which the mechanosensitive underpinning of fibroblast activation can be leveraged to improve clinical outcomes. Here, we highlight these opportunities and make a call to the field to consider the mechanosensitive pathways governing fibroblast activation as an important frontier in mechanomedicine.

The glymphatic system is a critical pathway for clearing metabolic waste from the brain by mediating cerebrospinal fluid and interstitial fluid exchange. In Alzheimer's disease (AD), tau protein accumulation is strongly associated with impaired glymphatic clearance, yet the underlying mechanism remains poorly defined. In this study, we employed a three-dimensional human glymphatics-on-chip model to investigate fluid transport and mass clearance in a brain-mimetic extracellular matrix containing engineered blood vessels (BV) surrounded by primary astrocytes. We found that phosphorylated tau (p-tau) induced morphological transformation of astrocytes into a hypertrophic, hypercontractile state, leading to astrocyte-mediated vasoconstriction and impaired glymphatic clearance. Notably, p-tau did not affect blood endothelial cells directly, implicating astrocyte-dependent mechanisms in glymphatic deregulation. Pharmacological inhibition of non-muscle myosin II with blebbistatin reversed astrocytic hypercontractility, restored BV diameters, and rescued glymphatic function. These findings elucidate a glial-specific mechanism of tau-induced glymphatic dysfunction and underscore astrocytic contractility as a promising therapeutic target in AD.

Mechanosensing and mechanotransduction enable cells to perceive and respond to mechanical forces, underpinning essential physiological processes and disease pathways. Central to these phenomena are force-transmission supramolecular linkages, which undergo structural transitions and regulate signaling proteins in response to mechanical stimuli. This review examines the mechanisms of these force-bearing linkages, focusing on force duration, dictated by the stability of protein-protein interfaces, and force-dependent mechanical structural changes of force-bearing domains in the linkage, which activates or deactivates mechanosensing domains. We discuss the emerging potential of these linkages as pharmaceutical targets, exploring drugs and peptides designed to modulate these mechanical properties. In addition, we highlight the application of artificial intelligence in protein engineering to enhance therapeutic precision by dynamically tuning these mechanosensing characteristics. Our synthesis of current findings and future perspectives aims to inform novel approaches to drug design and inspire future research in the field of mechanomedicine.

Nitric oxide (NO) is a versatile signaling molecule with significant roles in various physiological processes, including synaptic plasticity and memory formation. In the cerebellum, NO is produced by neural NO synthase and diffuses to influence synaptic changes, particularly at parallel fiber-Purkinje cell synapses. This study aims to investigate NO's role in cerebellar learning mechanisms using a biologically realistic simulation-based approach. We developed the NO Diffusion Simulator (NODS), a Python module designed to model NO production and diffusion within a cerebellar spiking neural network framework. Our simulations focus on the eye-blink classical conditioning protocol to assess the impact of NO modulation on long-term potentiation and depression at parallel fiber-Purkinje cell synapses. The results demonstrate that NO diffusion significantly affects synaptic plasticity, dynamically adjusting learning rates based on synaptic activity patterns. This metaplasticity mechanism enhances the cerebellum's capacity to prioritize relevant inputs and mitigate learning interference, selectively modulating synaptic efficacy. Our findings align with theoretical models, suggesting that NO serves as a contextual indicator, optimizing learning rates for effective motor control and adaptation to new tasks. The NODS implementation provides an efficient tool for large-scale simulations, facilitating future studies on NO dynamics in various brain regions and neurovascular coupling scenarios. By bridging the gap between molecular processes and network-level learning, this work underscores the critical role of NO in cerebellar function and offers a robust framework for exploring NO-dependent plasticity in computational neuroscience.