Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) remain major global health concerns, yet preclinical models continue to rely heavily on rodent adipose tissue, despite well-documented interspecies differences in depot structure, immune composition, and adrenergic responsiveness. While three-dimensional adipose tissue organoids have improved physiological relevance compared to two-dimensional cultures, their static nature imposes limitations in oxygen and nutrient diffusion, mechanical stimulation, and real-time metabolic monitoring. In recent years, adipose tissue on chip platforms have emerged as a promising microphysiological alternative, offering a dynamic environment in which human adipocytes can be studied under controlled perfusion and physiological flow.
These systems integrate mature or stem cell-derived adipocytes within microfluidic devices that support co-culture with endothelial and immune cells, enabling real-time analysis of endocrine signaling, lipid metabolism, and inflammatory responses. Various approaches have demonstrated the ability to recapitulate insulin resistance, lipotoxicity, cytokine release, and cross-tissue metabolic interactions, including adipose–liver crosstalk in NAFLD models. As shown in recent studies, the incorporation of vascular compartments, extracellular matrix tuning, and immunocompetent niches further improves the functional maturity and disease relevance of adipose tissue chips.
Positioned within the growing category of NAMs and supported by regulatory guidance from the U.S. FDA and OECD, adipose tissue-on-chip systems are gaining traction as predictive, human-relevant models for therapeutic screening and mechanistic discovery. This article reviews the development and application of adipose-on-chip technologies, focusing on design strategies, physiological modeling, disease-specific adaptations, and integration within multi-organ platforms.
1 │ From Static Spheroids to Dynamic Adipose Tissue on Chip Platforms
Three-dimensional adipose organoids marked a decisive step beyond monolayer culture, yet their static configuration still confronts two fundamental constraints. First, diffusion limits: in scaffold-free or hydrogel spheroids O₂ and nutrient gradients develop rapidly, producing lipid-poor multilocular adipocytes and compromising long-term endocrine read-outs. Reviews of dysfunctional-fat models identify this gradient as a primary reason unilocular white-fat morphology and stable adiponectin secretion are rarely maintained beyond 2–3 weeks(1). Second, the absence of mechanical and fluid cues: without interstitial flow, adipocytes never experience the shear, convective transport or continual endocrine clearance that define in-vivo depots.
Microfluidic fat-on-chip systems tackle both shortcomings by housing adipocytes in perfused chambers that are hydraulically isolated from damaging shear yet continuously supplied with medium. Liu and co-workers demonstrated that a laminar flow of 8 nL s⁻¹ across a three-compartment device supported weeks-long culture of differentiating human pre-adipocytes, with lipid droplets expanding under constant nutrient exchange and waste removal(2). Rogal’s “WAT-on-a-chip” extended the concept to mature primary adipocytes, integrating shielding side channels so buoyant cells remain viable while a vascular-like conduit enables online monitoring of fatty-acid uptake and isoproterenol-induced lipolysis(3).
Dynamic perfusion further unlocks immunometabolic investigation. In Kongsuphol’s inflamed-adipose model, co-culturing peripheral-blood mononuclear cells with on-chip adipocytes produced time-resolved cytokine waves (IL-6, TNF-α) and a concomitant drop in insulin-stimulated glucose uptake; features difficult to capture in static transwells(4). Huff et al. refined vascular integration, embedding endothelial cells across a 3 µm porous membrane; the resulting endothelial barrier controlled molecular diffusion and preserved >90 % cell viability under dual-flow conditions while allowing non-invasive sampling of triglycerides and resazurin metabolism(5).
Beyond single-tissue fidelity, perfused adipose chips are readily networked with additional organs. Slaughter’s adipose–liver circuit showed that free-fatty-acid–rich effluent from hypertrophic fat exacerbates hepatocyte steatosis and alters CYP3A4 activity, inter-organ effects unobservable in isolated cultures(6). Such studies position the adipose chip squarely within the expanding repertoire of MPS recognized by regulators as NAMs for metabolic disease research.
Collectively, evidence from first-generation platforms indicates that transitioning from static organoids to perfused adipose tissue on chip devices yields more mature lipid architecture, real-time endocrine profiling and mechanistic access to immune and multi-organ crosstalk, capabilities essential for predictive drug discovery in obesity, diabetes and NAFLD pipelines.
2 │ Cells, Channels & Matrices: Core Design Principles of the Adipose Tissue on Chip
Successful microphysiological modelling of human adipose tissue begins with the cellular constituency. Early devices relied on pre-adipocyte lines differentiated on-chip, yet lipid accumulation and endocrine output remained modest. Subsequent studies turned to patient-derived stromal-vascular fractions (SVF) or purified mature adipocytes. Rogal et al. showed that buoyant primary adipocytes can be stabilized inside shallow micro-cavities, preserving unilocular morphology and leptin secretion for three weeks under flow(3). Huff et al. achieved comparable stability with SVF-derived adipocytes differentiated within hyaluronic-acid hydrogels, reporting >90 % viability and robust triglyceride turnover after 28 days(5). For brown-fat applications, ADSC or hiPSC progenitors seeded on-chip can be thermogenically driven to produce UCP1‐positive constructs that oxidize fatty acids at rates unattainable in static cultures.
Vascular architecture is the second pillar. Two strategies dominate. The parallel-channel design places an endothelialized micro-channel beside the adipose chamber; nutrients and cytokines diffuse across a porous membrane while adipocytes remain shielded from damaging shear (<0.05 dyn cm⁻²). The self-assembled niche embeds endothelial cells directly within the matrix; spontaneous sprouting yields capillary-like meshes that infiltrate spheroids, supporting hypertrophy and improving insulin responsiveness, as demonstrated by Baganha et al.(7). Both geometries permit continuous sampling of effluent for adipokines, glycerol and non-esterified fatty acids.
Matrix selection modulates depot identity. Soft (≈2 kPa) collagen- or HA-based hydrogels encourage formation of large unilocular droplets characteristic of white adipose tissue, whereas stiffer GelMA or PEG-RGD formulations bias differentiation toward beige/brown phenotypes via YAP-mediated mechanosignalling(1). Decellularized adipose ECM offers compositional fidelity but introduces donor variability; photo-tunable synthetic matrices now allow stiffness ramps during culture to mimic progressive fibrosis.
Integrated sensing closes the loop between structure and function. Huff’s platform incorporates oxygen and pH micro-electrodes in flow channels, correlating hypoxic shifts with bursts of IL-6 during lipotoxic challenges(5). Rogal couples resazurin reduction, glucose amperometry and automated microscopy, enabling real-time calculation of lipolytic rate constants during β-adrenergic stimulation(3).
Inflammation is a principal driver of metabolic dysfunction, and recent designs therefore add an immune compartment. Kongsuphol et al. perfused peripheral-blood mononuclear cells through an adipose chamber; migrating macrophages elicited TNF-α and IL-6 surges and reduced insulin-stimulated glucose uptake, reproducing early events of obesity-linked insulin resistance(4). Similar approaches seed resident SVF macrophages or mast cells directly into the matrix, preserving an M2-skewed phenotype under homeostatic flow and enabling controlled polarization to M1 for chronic-inflammation studies.
Finally, modularity facilitates cross-tissue interrogation. Adipose chambers have been perfused in series with liver spheroids to model NAFLD, with hepatocyte steatosis scaling to free-fatty-acid flux from upstream fat tissue(6). Coupling to tumor models tracks lipid transfer that fuels invasion, while pancreas-on-chip integration aims to capture adipose-driven β-cell stress. With tunable cell sources, engineered vasculature, mechano-responsive matrices and immune inclusivity, the adipose tissue on chip provides a versatile foundation for predictive studies of metabolic disease and therapeutic screening.
3 │ Disease Modelling and Drug Discovery with Perfused Adipose Tissue on Chip
Microfluidic adipose platforms increasingly serve as experimental “disease depots,” allowing pathologies to be induced and monitored under precisely controlled biochemical and mechanical conditions. Inflammatory insulin resistance is a primary use-case. In the inflamed-adipose model of Kongsuphol et al., peripheral-blood mononuclear cells perfused through SVF-derived adipocytes triggered ten-fold surges in TNF-α and IL-6 and reduced insulin-stimulated glucose uptake by 60 %, faithfully mirroring early obesity-linked dysfunction(4). Liu et al. layered cyclic high-glucose pulses onto a similar chip; the combination of immune flow and glucotoxic stress produced sustained serine phosphorylation of IRS-1, an effect absent in static spheroids(2).
Hypertrophic growth, another hallmark of visceral obesity, has been reproduced through matrix engineering and long-term perfusion. Huff et al. tuned hyaluronic-acid stiffness to 2 kPa and applied low-shear flow for 28 days; adipocytes expanded to a mean diameter of 110 µm, secreted leptin at > 30 ng mL-¹ day-¹ and displayed elevated basal lipolysis, closely matching clinical observations(5). Leung et al. achieved comparable hypertrophy without exogenous cytokines by perfusing palmitate/oleate through an HA scaffold; IL-6 rose four-fold and lipid-droplet area doubled, providing a physiologically driven obesity model suited to downstream muscle or liver coupling(8). Rogal’s WAT-on-a-chip, using primary mature adipocytes, coupled real-time resazurin reduction and glycerol amperometry to quantify metabolic-rate shifts during hypertrophy(3).
Perfused adipose modules also enable inter-organ crosstalk studies. In a two-tissue circuit, Slaughter et al. placed a hypertrophic adipose tissue on chip upstream of primary human hepatocytes; free-fatty-acid and cytokine flux from the fat module increased hepatocyte triglyceride accumulation by 45 % and suppressed CYP3A4 activity, modelling the transition from simple steatosis to inflammatory NAFLD(6). Similar topologies couple vascularized adipose tissue to ovarian-cancer chips; sustained lipid delivery fuels tumor invasion and chemoresistance, underscoring the systemic reach of dysfunctional fat.
Drug-screening applications illustrate the translational value of these disease analogues. On Kongsuphol’s inflamed chip, the dual PPARα/δ agonist elafibranor normalised IL-6 secretion and restored > 80 % of insulin sensitivity at 10 µM, whereas identical dosing in static transwells showed only marginal benefit(4). Huff’s platform enabled non-invasive mitochondrial stress testing; rosiglitazone reversed palmitate-induced reductions in spare-respiratory capacity within 48 h, an effect captured via on-chip oxygen electrodes(5). Rogal demonstrated that isoproterenol-stimulated lipolysis curves shift rightward after chronic dexamethasone exposure and normalize with metformin, providing quantitative EC₅₀ values in real time(3).
High-throughput formats are now feasible. Compera et al. integrated large-scale pneumatic valves to create a 96-unit micro-adipose array; alternating high/low glucose pulses every six hours generated time-resolved proteomic maps (> 1 800 proteins) without compromising viability, indicating that multi-parameter omics screens can be run at scale on adipose tissue on chip technology(9). Because microfluidic perfusion permits repeated sampling without disturbing tissue architecture, longitudinal dose–response profiles and wash-out kinetics can be obtained from a single donor construct, aligning with 3Rs principles and reducing variability.
Collectively, the evidence shows that perfused adipose tissue on chip platforms faithfully replicate chronic inflammation, hypertrophy, inter-organ lipid flux and pharmacological responses, offering human-relevant read-outs that outperform static 3D cultures and traditional animal models in predictive fidelity.
Outlook: Towards Multi-Organ, Patient-Specific Metabolic MPS
Adipose tissue-on-chip systems have advanced significantly as human-relevant models for studying metabolic disease. However, several critical challenges remain that continue to shape the direction of future research.
One priority is the integration of adipose tissue within multi-organ circuits. Metabolic diseases such as obesity and NAFLD involve dynamic crosstalk between adipose tissue, liver, muscle, and endocrine organs. Adipose modules connected to hepatic or cancer chips have already revealed inter-tissue effects that static cultures cannot replicate. Fluidic coupling with controlled directionality will be essential for capturing systemic feedback loops and evaluating therapeutic interventions in a physiologically relevant context.
A second focus is the refinement of materials and sensing strategies. Transitioning from animal-derived matrices to defined, tunable hydrogels is key to improving reproducibility and regulatory compliance. Embedding oxygen, pH, and metabolite sensors into microfluidic chips allows continuous, non-invasive monitoring of metabolic function. These technologies provide real-time insights into adipocyte viability, lipolytic activity, and inflammatory shifts, parameters that are otherwise difficult to measure in vitro.
Lastly, efforts are moving toward scalable, genotype-specific platforms for personalized drug discovery. Microfluidic arrays seeded with hiPSC-derived adipocytes enable comparative studies across patient backgrounds, supporting precision applications in metabolic screening. High-content omics, longitudinal readouts, and minimal cell requirements position these systems as ideal tools for high-throughput therapeutic evaluation.
Together, these developments signal a transition from isolated adipose constructs to modular, multi-organ MPS designed for predictive, human-based modeling. As standardization improves and integration advances, adipose-on-chip platforms are poised to play a central role in the future of NAMs.
Resources
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