Javelin Platform for High-Fidelity Modeling of Chronic and Progressive Liver Diseases

Developing effective therapies for chronic and progressive metabolic diseases, such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH), remains a major challenge due to the lack of predictive, human-relevant preclinical models. Although widely used, conventional systems ranging from in vitro cultures to animal models often fail to replicate the cellular complexity, human-specific pathophysiology of chronic metabolic diseases, and the prolonged disease dynamics observed in patients. These limitations contribute to poor translation of efficacy and safety findings, resulting in high clinical attrition rates and delayed therapeutic development.

Addressing this gap requires advanced in vitro platforms capable of faithfully simulating disease biology and capturing key human disease hallmarks and mechanisms over extended durations. The Javelin Liver Tissue Chip (LTC) was designed to meet this need by enabling controlled, long-term studies of metabolic liver disease in a biologically relevant context. By supporting the investigation of disease progression and therapeutic response in a human-based system, Javelin LTC represents a critical step forward in improving the translational value of preclinical research.

1.         Modeling Progressive Liver Disease Through Long-Term Culture

Studying the progression and resolution of chronic liver disease requires systems that allow continuous monitoring of biological processes over extended timeframes. Many in vitro models lack the longevity needed to observe the cellular and molecular changes associated with disease progression and recovery. The LTC enables extended culture of human liver tissue by supporting the viability and function of hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells for several weeks. This makes it possible to track the development of disease features including steatosis, inflammatory cytokine production, fibrosis, and the effects of therapeutic compounds. Because the system uses recirculating flow without routine medium replacement, signaling molecules accumulate over time and contribute to disease progression. For example, cytokines produced by immune cells can drive fibrosis without the need for external stimulation. This supports a more physiological mode of disease induction that better reflects in vivo conditions. By closely replicating the timing and sequence of events seen in human disease, Javelin LTC helps improve the relevance of preclinical findings and supports the development of therapies that are more likely to succeed in clinical trials.

2.         Complex Microarchitecture and Multi-Organ Interaction

Javelin LTC is a biomimetic liver microarchitecture that incorporates four human liver cell types: hepatocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These cells are organized to reflect the functional microvascular structure of the human liver, with LSECs exposed to physiological shear stress through controlled, recirculating flow conditions that maintain consistent nutrient and waste exchange, while allowing the gradual accumulation of lipotoxic species and cytokines that contribute to chronic liver injury. This organization recreates the layered spatial arrangement of liver tissue, as visualized in Figure 1, where distinct layers of parenchymal and non-parenchymal cells extend across the tissue depth. The spatial separation of cell types enables defined, physiologically relevant interactions and supports cell-specific analysis during disease progression. This architecture also facilitates targeted evaluation of gene therapy modalities, including AAV and LNP delivery systems, by enabling resolution of both direct and off-target effects across liver cell types.

In addition to its vascular and immune competent structure, Javelin LTC also supports inter-organ integration, which is essential for modeling the systemic nature of metabolic diseases. Crosstalk between the liver, adipose tissue, pancreas, and gut plays a central role in disease progression and therapeutic response. To enable these interactions in a controlled and modular format, the platform includes an optional add-on chamber that can be attached or removed depending on the experimental objective. This secondary chamber allows researchers to introduce a second tissue, such as adipose, at a defined timepoint, offering flexibility for sequential seeding, precise timing of inter-organ interaction, and simplified experimental setup. This design supports investigation of organ-organ communication under physiologically relevant conditions.

While many microphysiological systems have addressed individual aspects of long-term culture, cellular complexity, or modularity, Javelin LTC brings these features together in a single, integrated platform. By combining sustained tissue function, spatial organization, multi-tissue capability, and analytical flexibility, it offers a comprehensive solution for modeling chronic human disease in a format that is both experimentally tractable and biologically relevant.

Figure 1: Cross sectional view of liver MPS in Javelin LTC.

3.         Clinically Relevant Drug Testing and Biomarker Analysis
Preclinical systems intended to model human disease must support clinically relevant testing strategies, including flexible dosing regimens, combination therapies, longitudinal sampling, and biomarker analysis. Javelin LTC enables precise therapeutic delivery, accommodating chronic, pulsed, and metronomic dosing schedules. Researchers can adjust dosing timelines and disease stimulus to simulate distinct pathophysiological stages, including steatosis, inflammation, and fibrosis. The platform supports longitudinal studies of disease biology, treatment response, and biomarker dynamics through repeated sampling. With a working volume of over 2 mL per chip, Javelin LTC supports high-content assays and multiplexed analysis of cytokines, metabolites, and other biomarkers from the same system. This enhances data richness, reduces variability, and allows tracking of transient, stage-specific biomarker shifts. Live imaging can be used alongside biochemical assays to monitor disease features, such as lipid droplet accumulation, without disrupting tissue integrity. The platform accommodates a wide range of therapeutic modalities, including small molecules, biologics, and gene therapies delivered via AAV, LNPs, or other emerging vectors. This enables evaluation of delivery efficiency, target specificity, functional outcomes across liver cell types, and associated toxicity responses.

Javelin LTC integrates human-relevant biology, multicellular complexity, assay flexibility, and multi-organ connectivity in a single platform, setting a new benchmark for chronic liver disease modeling. Its ability to support flexible dosing, combination treatments, repeated sampling, and multiparametric readouts enables detailed pharmacokinetic and pharmacodynamic (PK/PD) analysis across diverse therapeutic modalities. The platform’s alignment with clinically relevant biomarkers and evolving disease features makes it a valuable tool for advancing precision medicine, allowing researchers to model patient variability, predict differential responses, and support biomarker-driven patient stratification. As regulatory frameworks increasingly prioritize mechanism-informed, human-based data, Javelin LTC offers a scalable and translationally relevant solution for improving decision-making in metabolic disease research and beyond.