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In cancer cells, septins assemble into enigmatic higher-order structures of 300-700 nanometers, including long needle-like filaments, thick perinuclear rings, and cytoplasmic bundles or aggregates. The absence of genetic or pharmacological tools to recapitulate these architectures in-vitro has impeded mechanistic studies of their formation, function, and therapeutic targeting. Here, first, determining the overexpression of septin-2 in epithelial ovarian cancer (EOC) and its association with increased mortalities and dependencies, we select SKOV-3 ovarian cancer cells as a tractable model in which septin supramolecular assemblies can be recreated in-vitro and interrogated. This system shows that the forchlorfenuron (FCF) analog UR214-9 remodels septin architecture, converting co-expressed human septin octamers (SEPT2-SEPT6-SEPT7-SEPT9-SEPT9-SEPT7-SEPT6-SEPT2) into large cytoplasmic aggregates. In parallel, transiently expressed SEPT2 is reorganized into septin-rich noodle-like filaments, perinuclear rings, and web-like networks encircling the nucleus upon UR214-9 treatment. Mechanistically, UR214-9 disrupts the incorporation of SEPT2, SEPT7, and SEPT9 into canonical septin hetero-octamers, resulting in assembly-defective or imperfect oligomers that preferentially reorganize into these aberrant higher-order structures. This aggregation likely prevents septin-2 migration during interphase-to-cleavage furrow transition in NRK-49F-SEPT2-EGFP homozygous cells and impacts SKOV-3 cytokinesis, cell proliferation, adhesion and invasion and migration while sparing ceramide transport to the Golgi, preserving ER and cis-Golgi structure. These effects manifested in reduced growth of ovarian, endometrial and breast cancer xenografts without attracting significant off-target engagements per the global transcriptomic analysis of JIMT1 breast cancer and PANC-1 pancreatic cells. UR214-9 treated animals showed observable safety in animals. Thus, a tool to recreate aberrant septin structures and identification of septins as a druggable cytoskeletal target for ovarian, endometrial, breast and pancreatic cancer by perturbing their hetero-octamerization assembly is presented. We provide a method to reconstruct the higher-order septin architecture observed in cancer cells, to study their assembly and functions. Intriguingly, cancer cells tolerate hetero-oligomeric septins lacking specific subunits, suggesting that compositionally deficient oligomers are not efficiently targeted for degradation, unlike unincorporated septin monomers in normal cells. This tolerance may enable accumulation of structurally aberrant septin complexes acquiring long-needles, rings or thick-aggregates in disease cells. We further show that septin oligomerization can be pharmacologically perturbed. By integrating structural, cellular, and energetic readouts using in-silico techniques, we establish a quantitative framework for septin-targeted modulation, generating UR214-9 as a new chemotype that disrupts septin oligomeric assembly via preventing incorporation of SEPT2/7/9, into canonical hetero-octamers, causes defects in cytokinesis, altered cell migration, viability, and remodels septin-actin architectures, ultimately impairing tumor cell growth. Thus, pharmacological targeting of septin assembly represents a tractable strategy to perturb septin-dependent cellular processes in cancer and neurodegenerative diseases with reported septin dysregulation.
Almost every cell in vivo is surrounded by the extracellular matrix (ECM), which contributes to cell and tissue fate. Biomaterials, especially engineered hydrogels, have emerged as platforms to recreate the biochemical and mechanical properties of ECM. Yet most approaches still assume that cells directly respond to the engineered hydrogel, although there is increasing evidence that numerous cell types rapidly deposit newly synthesized (nascent) ECM (nECM). Studies have now shown that this nECM accumulates at the cell-hydrogel interface, where it also contributes to a cell's fate. In this perspective, we first highlight key studies describing the nECM as a regulator of cell fate. Next, we provide guidelines based on physicochemical principles for studying nECM through spatiotemporal mapping, mechanical/structural measurements, biochemical characterization, and functional assays. Finally, building upon existing hydrogel engineering tools, we propose chemical- and protein-engineering approaches to specifically engineer the nECM to more precisely control cell-matrix interactions.
Meiosis is a key stage in the sexual reproduction of eukaryotes. It ensures the continuity of genetic information from generation to generation, while also generating the necessary genetic diversity for the survival and evolution of species. Meiotic progression is often compromised in hybrids between related subspecies, resulting in hybrid sterility and irreversible reproductive isolation. However, most genetic studies to date have not focused on the meiotic phenotypes of hybrid sterility and their molecular mechanisms. This review examines the genetic architecture, as well as the meiotic and molecular phenotypes, of hybrid sterility in the house mouse (Mus musculus) and other mammals. House mice subspecies provide the most widely understood mammalian model of hybrid sterility because of their recent evolutionary divergence, powerful genetic tools and comprehensive cytology of individual meiotic stages. We emphasize the potential impact of meiotic surveillance mechanisms, checkpoint pathways, particularly those leading to the meiotic sex chromosome inactivation and we draw parallels between intraspecific genic and chromosomal sterility and intersubspecific hybrid sterility. Finally, we review the Prdm9-Mir465 incompatibility system, the only vertebrate hybrid sterility model for which the three major genetic components necessary and sufficient to recreate the hybrid sterility genome have been identified. This three-part genetic architecture links Prdm9-dependent meiotic recombination hotspot activation, heterosubspecific homolog pairing, and microRNA-mediated meiotic checkpoint regulation to spermatogenic arrest and male sterility. MiR-465 is apparently the first microRNA which functions as a guardian of the pachytene checkpoint.
Autism Spectrum Disorder (ASD) has been linked to disturbance of the coordinated transcriptional mechanisms that govern neurogenesis, neuronal differentiation, and synaptic maturation in human cortical development. Nevertheless, the regulatory networks and cellular heterogeneity that underlie these processes are still poorly understood. Using an in vitro human cortical development dataset (GSE210960), single-cell RNA sequencing (scRNA-seq) and systems biology techniques were used to examine neurodevelopmental pathways associated with ASD. Different cellular populations representing neural progenitors and differentiated neuronal states were resolved by Seurat-based preprocessing and clustering, and developmental progressions from progenitor cells towards adult neuronal lineages were recreated using trajectory inference. Key biological processes linked to RNA splicing, energy consumption, and the formation of neural projections were found by differential expression and gene set enrichment analysis. Highly connected hub genes, such as RACK1 and NRXN1, which are essential for synaptic signalling and neuronal development and have been linked to an increased risk of ASD, were given priority in protein-protein interaction network analysis. Stable binding of tretinoin (all-trans-retinoic acid) to RACK1 was discovered by virtual drug screening, molecular docking, and molecular dynamics simulations. This was corroborated by favourable docking scores and persistent conformational stability across a 100 ns simulation. All things considered, these results offer a systems-level single-cell transcriptomic framework for locating potential molecular targets and neurodevelopmental pathways related to ASD.
The extracellular matrix (ECM) provides a dynamic microenvironment that regulates cell proliferation, migration, and tissue remodeling during wound healing. However, replicating the structural and functional complexity and ECM heterogeneity of native skin ECM remains challenging with conventional single-material hydrogels. Recent advances in multimaterial 3D bioprinting have enabled the spatial integration of diverse biomaterials within a single construct. Lignocellulose has attracted increasing attention as a promising biomaterial for recreating key structural features of the native ECM because of its fibrous architecture, mechanical strength, and biocompatibility. This review offers a comprehensive and integrated perspective on the use of lignocellulose-based multimaterial printing to recreate ECM-mimicking architectures, an underexplored area at the intersection of biomaterials and biofabrication. The roles of cellulose, hemicellulose, and lignin in printability, scaffold stability, porosity, bioactivity, and wound-healing performance are discussed. Representative studies have demonstrated that lignocellulose-based multimaterial bioinks provide porous architectures that support cell adhesion, proliferation, and tissue regeneration. These benefits are accompanied by improved mechanical performance, as cellulose nanofibers exhibit elastic moduli exceeding 100 GPa, and lignin-containing hydrogels have achieved compressive moduli of up to 135 kPa. Such mechanical advantages make lignocellulosic materials particularly attractive for fabricating ECM-mimicking scaffolds that require long-term structural integrity. Finally, key design considerations and current limitations associated with lignocellulose-based multimaterial bioprinting are critically discussed. A framework for the rational design of lignocellulose-based multimaterial bioinks is presented, together with future directions toward gradient and adaptive scaffolds, smart wound dressings, and advanced wound-healing applications.
Higher-order interactions (HOIs) are widely predicted to promote coexistence, yet the underlying ecological mechanisms behind this effect remain largely unexplored in natural communities. Here, we integrate natural history and theory to show how HOIs can restructure competitive networks and influence coexistence. With over 2 years of data on a tropical ant community, we estimate pairwise competitive interactions and demonstrate that, in isolation, they fail to recreate observed community dynamics. We find that inclusion of an HOI, imposed by a parasitoid of the dominant species, can theoretically reorganize competitive networks to mirror the dynamics of the empirical system. We demonstrate how temporal variation in HOIs forces the community between dominance regimes and that the interregnum between regimes is riddled with competitive intransitivities that promote coexistence. This work provides an empirical example of the ecological mechanisms behind the coexistence-promoting effects of HOIs and suggests that HOIs and intransitivity, which are typically treated separately, can be mechanistically linked through the rewiring of species interactions.
Extensive upper-limb soft-tissue defects may exceed the surface area achievable with conventional free flaps, making reconstruction challenging when durable coverage and functional preservation are required. We describe a novel reconstructive strategy to extend soft-tissue coverage based on secondary flap-to-flap neovascularization in which a pedicled flap achieves secondary vascular independence through neovascularization from the free flap skin paddle via the subdermal vascular plexus, thereby enabling delayed division without additional microsurgical anastomoses. A 64-year-old man developed necrotizing fasciitis of the right upper limb following an insect bite. After repeated surgical debridements, a massive circumferential forearm defect extending to the elbow was associated with extensive tissue loss of the dorsal hand, first web space, and palm. A 45 × 11 cm chimeric anterolateral thigh-tensor fascia latae (ALT-TFL) free flap was harvested and anastomosed to the radial vessels, providing stable coverage of exposed extensor tendons and neurovascular structures. An ipsilateral pedicled 20 × 15 cm groin flap was inset onto the ALT skin paddle and subsequently divided, defatted, and wrapped around the thumb to recreate the first web space and resurface the palm. At 18-month follow-up, soft-tissue coverage remained stable, with complete flap survival, no recurrence of infection, and good functional recovery. Unlike sequential or conventional free-flap reconstruction, this approach does not require additional arterial inflow or flow-through anastomoses, relying instead on secondary flap-to-flap neovascularization. It may therefore represent a relevant strategy to extend reconstructive coverage beyond conventional flap dimensions in extensive upper-limb defects.
Enterovirus D68 (EV-D68) is a non-polio enterovirus that can cause a polio-like paralysis condition, acute flaccid myelitis (AFM). EV-D68-associated AFM cases waned in the US after 2018, and the reasons for this are unknown. It has recently been demonstrated that EV-D68 containing point mutations in viral structural proteins VP1 and VP3 resulted in decreased paralysis in different neonatal mouse models. However, phenotypes of these mutations in a human multicellular central nervous system (CNS) model are unknown. We hypothesize that mutations in VP1 and VP3 will similarly direct neurotropism in human spinal cord organoids (hSCOs). To investigate this, we recreated viruses with mutations in VP3 (I88V) or VP1 (L1I/N2D/T98A/E283K or L1P/V148A/K282R) and infected hSCOs. We found that VP3 I88V and VP1 L1I/N2D/T98A/E283K resulted in decreased titer and viral protein staining, consistent with attenuated neurovirulence in previously published murine models. We also found through immunofluorescence that VP1 L1P/V148/K282R mutations altered cellular tropism, primarily infecting glial cells rather than neuronal cells. When these mutations were combined, their effects on neurotropism were not additive. Sequence analysis of recently circulating EV-D68 strains reveals that VP3 I88 and VP1 E283 have remained the dominant amino acid residues since 2014, whereas VP1 sites 1, 2, and 98 have higher population diversity, indicating that these residues may be contributing to newly reduced neurovirulence after 2018.
B-cell acute lymphoblastic leukemia (B-ALL) disrupts the architecture and function of the bone marrow niche. However, current in vitro and in vivo models fail to fully capture the spatial, biochemical, and mechanical complexity of the native microenvironment. Here, we present a biomimetic bone marrow on-a-chip that integrates organ-on-a-chip technology, 3D hydrogel culture, and computational modeling to recreate the perivascular, central, and endosteal niches of human bone marrow. The Computational Fluid Dynamics (CFD) was used to guide the design and operation of the microdevice by predicting physiological interstitial flow within the culture system, enabling consistent mechanical stimuli as in vivo under conditions compatible with bone marrow physiology. The microdevice was fabricated using high-resolution 3D printing and soft lithography, and incorporates phaseguide structures for hydrogel confinement, the establishment of three distinct niches and continuous perfusion. Co-cultures of endothelial, stromal, osteoblast, and leukemic cells were maintained in a type I collagen matrix under dynamic conditions. The platform supported high cell viability and enabled compartmentalized spatial organization of multicellular co-cultures. The presence of leukemic cells was associated with changes in soluble signaling molecules within the microenvironment, including increased levels of cytokines, chemokines, and growth factors such as IL-10, IL-13, TNF-α, CCL2, CCL3, CCL5, FGF, G-CSF, and GM-CSF. These patterns are consistent with signaling processes linked to immunoregulation, leukemic supportive signaling, and therapeutic resistance in B-ALL. Together, these findings indicate that the bone-marrow-on-a-chip captures relevant aspects of niche-associated signaling and provides a versatile platform for investigating leukemia microenvironment interactions, with potential in drug screening and preclinical model development.
The evolutionary origins of asexuality remain poorly understood, despite extensive research on its ecological and evolutionary consequences. Asexuality often arises through hybridization between species with intermediate genomic divergence, implying that hybrid-induced asexuality may be partly repeatable. The Amazon molly (Poecilia formosa), the first asexual vertebrate known to science, challenges this view: repeated experimental crosses between its extant parental species have failed to recreate a stable Amazon molly-like lineage. This apparent paradox gave rise to the Rare Formation Hypothesis, which proposes that stable asexuality requires an exceptionally specific genomic combination. Here, we combine experimental crosses, molecular cytogenetics, and population genomics to test whether ancestral introgression before the hybrid speciation event set the stage for the singular origin of the Amazon molly. We show that most experimental hybrids are viable but sexual, but that a subset of F1 hybrids produce unreduced eggs through a mechanism distinct from that of the Amazon molly. Population genomic analyses reveal that introgression between parental species likely predated the formation of the Amazon molly, and shared homozygous tracts across Amazon molly genomes support inheritance from admixed progenitors. Together, our findings reconcile the repeatable and contingent views of the origin of asexuality, suggesting that ancestral introgression may be the missing mechanism assembling the rare genomic combinations required for seemingly unrepeatable evolutionary innovations, including the emergence of asexual species.
The peritoneum, the body's largest serous membrane, plays critical roles in abdominal homeostasis and immune defense. When disrupted by surgery or disease, it can lead to devastating complications including peritoneal adhesions-affecting up to 93% of surgical patients-peritonitis, and metastatic spread. Current research models fail to capture the complexity of human peritoneal biology, relying on inadequate animal models or oversimplified 2D cultures. Here, we introduce a PDMS-free microfluidic platform that recreates the structural and functional architecture of human peritoneum. Our system combines immortalized mesothelial cells (MeT5A) with patient-derived peritoneal fibroblasts in a physiologically relevant 3D environment, enabling real-time analysis of peritoneal function and dysfunction. Through systematic evaluation of stromal matrices, we identified fibrin gel as optimal for supporting healthy mesothelial monolayer formation while maintaining excellent cell viability over 14 days. Importantly, we demonstrate the platform's translational potential by successfully modeling peritoneal adhesion formation. This innovative tool may improve the understanding of peritoneal biology, accelerating drug discovery and developing personalized treatment strategies for peritoneal diseases.
Understanding complex relations between neuronal activity and animal behavior is central question in neuroscience. Rapid advancements in Artificial Intelligence (AI) methods offer powerful tools to investigate highly non-linear mapping between motor cortex activity and body movements. Here, we developed a Generative Adversarial Network (GAN) that showed that detailed videos of behaving rats can be recreated from activity of just few selected neurons. This analysis also revealed that the predictability of behavior from neuronal activity (and vice versa) initially increases as a rat learns a new task. However, after the animal performance on the motor task achieves the required accuracy, then coupling between neuronal activity and behavior decreases, without degrading task performance. A plausible interpretation is that, as training progresses from Early to Mid training days, more neurons become engaged, forming a denser, broadly distributed representation, which then in the Late training days evolves into a sparse and more energy-efficient representation, with only a small subset of tuned neurons. Neuronal network simulations showed that such changes in coding strategy may be explained by neurons minimizing their energy use. Thus, our approach reveals a non-linear relationship between learning stages and neural-behavioral coupling, which is likely driven by energy efficiency.
Neural mass models (NMMs) are often used to help understand the circuitry that underpins observed brain dynamics in basic and clinical research. A key step is to fuse models with data so that model parameter values can be inferred for a given data set-a process called model fitting or model calibration. This can shed light on putative physiological mechanisms underlying the observed signals. Calibration is notoriously challenging in biology since models are often non-identifiable, high-dimensional, and nonlinear. Established methods such as dynamic causal modelling (DCM) circumvent some of these issues, for example, by incorporating prior information and employing fast local search methods in the space of feasible parameter values ("parameter space"). However, it is pertinent to better understand the potential limitations of these methods so that we can increase our confidence in the use of models to interpret brain activity, and to develop new approaches as required. Here, we use tools from dynamical systems theory to illustrate some of the complexities of model calibration in an archetypal NMM. We use this information to motivate the use of calibration methods that work across large regions of parameter space, rather than focusing on informative priors or localised search methods. We subsequently evaluate the performance of approximate Bayesian computation (ABC) and evolutionary search metaheuristics (ESMs) for mapping feasible sets of parameters for which an NMM can recreate electroencephalographic recordings during an eyes-closed resting state. Our results demonstrate the superiority of ESMs in terms of computational efficiency and accuracy. Furthermore, we elucidate potential reasons why ESMs are able to perform better than ABC, that is, that they are less susceptible to biases induced by the complexity of underlying cost landscapes. These results highlight the importance of incorporating ESMs in future efforts to model brain dynamics.
Social determinants of health (SDH), non-medical factors that shape health and care access, play a critical role in perioperative safety and surgical outcomes. However, anaesthesiology residency programmes often lack structured training on communicating about and addressing SDH during routine clinical encounters. We developed a simulation-based curriculum to enhance anaesthesiology trainees' preparedness in recognising and responding to SDH-related challenges in perioperative care. An educational intervention consisting of three simulated perioperative case scenarios was integrated into an existing residency training course. Standardised patients were used to recreate realistic social and clinical challenges encountered in preoperative clinic, obstetric and paediatric settings. Sessions were followed by facilitated debriefings including the acting resident, observing peers, and a simulation faculty member to reflect on performance and key learning points. Post-simulation surveys assessed residents' perceived confidence, communication skills and awareness of institutional support resources related to SDH. Quantitative responses were summarised using descriptive statistics, and open-ended items elicited qualitative feedback. 42 anaesthesiology residents participated in this pilot. Following the intervention, residents reported increased confidence engaging patients and caregivers in discussions about social needs, improved familiarity with resource pathways such as social work and care coordination, and improved preparedness for sensitive conversations. Participants described the scenarios as authentic, relevant to clinical practice and valuable for observing peer communication approaches. This pilot project suggests that simulation may be a feasible and acceptable approach for introducing SDH-focused communication training in anaesthesiology education. Integrating realistic scenarios into perioperative curricula may help residents develop skills needed to identify social barriers and collaborate with interdisciplinary partners to promote equitable care.
The anatomical complexity and distinctive tissue environment of the human oral cavity pose major challenges to modeling oral infection and host-microbe interactions in preclinical laboratory settings. Here we present a bioengineered oral microphysiological system comprising vascularized human gingival tissue integrated with tooth analogs that together recreate a functional unit of the human oral cavity. We incorporated Streptococcus mutans and Candida albicans into this system to model cross-kingdom biofilm formation, microbial dissemination, and host-microbial interactions at the gingival-tooth interface. Single-cell RNA sequencing and global metabolomics analysis revealed that fungal colonization induces epithelial-to-mesenchymal transition associated with distinct transcriptional and metabolic signatures. Our platform also allowed us to simulate SARS-CoV-2 infection and examine gingival responses to live-virus challenge. Finally, we integrated the engineered gingival tissue with controlled human saliva flow to show that hyposalivation potentiates the pathogenic capacity of fungal infection. This work demonstrates the potential of oral microphysiological systems as an experimental platform for in vitro modeling and mechanistic investigation of host-microbe interactions under controlled, human-relevant conditions.
The Low Vision Assessment in Virtual Reality project aims to create performance assessments of activities of daily living for a broad low vision population in virtual reality. In this study, our goal is to validate representative virtual reality activities against matching real-world activities to create standardized activities of daily living in virtual reality. Experiments were conducted in a rehabilitation space with a kitchen and living room, which was recreated in virtual reality with photorealistic rendering. We created 25 activities in Unity based on our previously developed visual functioning questionnaire and performed a validation study.
Disease models are used to evaluate drug candidates, and compounds that are highly effective in vivo models have traditionally been prioritized for development. While conventional 'gold standard' animal models have been central to autoimmune drug discovery, there is increasing recognition that addressing unmet medical needs requires models capable of capturing patient pathophysiology beyond the scope of these classical systems. Accordingly, models that reflect human disease mechanisms not reproducible in conventional animals are becoming increasingly important. Humanized mice are immunodeficient mice transplanted with human immune cells, hepatocytes, thymic tissue, and other components to create a human-like biological environment that cannot be replicated in wild-type mice. Research on humanized mice has advanced through efforts to reconstitute a diverse human immune system in mice, together with accumulating knowledge of patient-specific factors such as autoantibodies and autoreactive T cells. Additionally, single-cell analyses and human tissue studies are underway to recreate the human-specific disease phenomena in humanized mice. In this review, immune-system-humanized mice are used to provide a comprehensive overview of recent advances in immune-system-humanized mouse technologies, their applications to immune-related disease models, and their current utilization in drug discovery research.
This paper attempts to recreate and reconstruct the process of 'translation-transformation-application' of arsenical knowledge in the late Qing Dynasty by examining the four representative medical translations: An Outline of Western Medicine (Xi Yi Lue Lun), Explanations of Western Medicine (Xi Yi Lue Shi), Universal Prescriptions (Wan Guo Yao Fang), and A Compendium of Western Drugs (Xi Yao Da Cheng). It was found that in terms of nomenclature, the early coexistence of heterogeneous vernacular names such as Xin () and Xin Shi () underwent evolution and adjustment within medical texts, eventually coexisting with chemical nomenclature such as Shen (、). This resulted in a hybrid terminology system that integrated traditional experiences with modern chemical elements. In terms of dosage forms and quantity, arsenicals expanded from a single medicinal liquor into five major categories - solution, ointments, solids, pastes, and pills. This evolution presented a trajectory from an early phase of 'extensive collection' to a later phase of 'simplified consolidation' based on chemical classification. In terms of chemistry and toxicology, the translated works helped to establish a quantifiable and verifiable framework of modern pharmacology for substances long regarded as 'poisons' initially by successively introduced experimental detection techniques (such as the Marsh test), valence-based classifications, and semi-sinicized chemical formulas. In terms of authoritative citation, translators attempted to establish a chemical basis for arsenicals, facilitating their transformation from empirical poisons into 'scientific drugs' by drawing extensively on experimental data from European and American chemists and physicians. This study argues that the transfer of Western arsenical knowledge in the late Qing Dynasty was a process of continuous communication between translators and the medical community by introducing the knowledge and local practice rather than a simple linear process of scientization. 本文以《西医略论》《西医略释》《万国药方》《西药大成》4种代表性医学译著为核心史料，重构晚清砷剂知识的“译—化—用”全过程。研究发现：命名上，由早期俗名杂陈“信”“信石”，经医学文本的沿革与调整，最终与化学命名“鉮”“信金”并置，形成兼容传统经验与现代化学元素的复合术语体系；剂型与数量上，从单一药酒扩展至药水、油膏、固体、糊剂、丸剂5大类，呈现出从早期广搜博采，向后期基于化学分类的精简归并转变；化学与毒理上，译本先后引入实验检测技术（如马尔施试验）、化合价分类与类汉字化学式，首次将“毒药”确立了可量化、可验证的近代药物学框架；权威引证上，译者通过大量援引欧美化学家、医师的实验数据，为砷剂确立起化学依据，促成其由经验毒药向“科学药物”转型。本研究以期证明，晚清西药砷剂的知识迁移并非线性科学化，而是翻译者与医学界在知识引进与本土实践中不断磨合的过程。.
Effective mitral valve repair remains significantly operator-dependent partially due to the lack of standardized training substrates. We aimed to develop a simplified, parametric mathematical model of the mitral valve apparatus and physically validate its ability to accurately recreate the geometry and hemodynamic function of both a healthy valve and specified pathological valves when tested in a dynamic pulse duplicator system. A parametric mathematical framework was employed to define the 3-dimensional saddle-shaped annulus and its leaflet architecture using core, clinically measurable geometric coefficients (eg, annular diameters and segment-specific leaflet lengths). Five distinct silicone valve replicas were manufactured to match the mathematical specifications: 2 healthy baselines and 3 Carpentier Type II Prolapse valve variants (P1, P2, and P3) induced by localized leaflet length adjustments. Each physical model was tested in a dynamic pulse duplicator under physiological pressure and flow conditions. Valve function, geometry and regurgitation severity were quantified using cardiac ultrasound. Derived measurements from the physical valve replicas accurately matched expected anatomical ranges from patient cohorts. The healthy baseline models consistently demonstrated competent function with no regurgitation. Pathological models, generated solely by manipulating the core geometric coefficients (lengthened P-segment, increased annular diameter), consistently exhibited characteristic segmental prolapse and moderate to severe mitral regurgitation. The resulting functional metrics, including regurgitant jet severity, confirmed the predictable functional outcome driven by the specified geometric inputs. We present a physically validated, anatomically configurable mathematical model that demonstrates a direct and predictable link between core geometric parameters and mitral valve functional behavior. Unlike existing physical simulation platforms that rely on biological tissue, this approach provides a standardized, reproducible, and customizable platform for surgical training and in vitro testing of novel repair techniques for segmental mitral valve disease.
Tumor heterogeneity and drug resistance limit the efficacy of cancer therapies and highlight the need for patient-specific preclinical models. Here, we develop a microfluidic tumor-on-chip (TOC) platform that integrates patient-derived organoids with a functional endothelial barrier and utilizes liquid flow to recreate drug delivery from the vasculature into tumor tissue. This system enables evaluation of therapeutic efficacy and toxicity under physiologically relevant conditions. Additionally, the platform is utilized to assess immune cell migration induced by tumor-derived factors in the absence of an endothelial barrier. In pancreatic cancer, the TOC model captures cellular features associated with treatment resistance and pathway rewiring at single-cell resolution, with drug response patterns showing a trend toward alignment with patient clinical outcomes in a limited, retrospective, exploratory setting. By simulating vascular drug transport, the platform provides a scalable and clinically relevant tool for studying treatment response mechanisms and evaluating drug responses under physiologically constrained delivery conditions.