Fibrosis is one of medicine’s most persistent and difficult biological problems: a repair response that refuses to switch off. Across the heart, lungs, kidneys, liver and synovium, prolonged injury can activate cells that deposit excessive amounts of extracellular matrix, the structural material surrounding living cells. Over time, this matrix accumulates into dense scar tissue, distorts the architecture of organs and restricts their ability to function. The consequences range from stiffened heart muscle and progressive respiratory failure to kidney dysfunction, cirrhosis and disabling joint disease. A new review in Nature Biomedical Engineering argues that better human in vitro models could provide the realistic, controllable test systems needed to understand fibrosis and develop treatments.
The study, led by M.A.J. Morsink, S. Fleischer, T.R. Nash and colleagues, presents what it describes as a practical toolbox for modelling fibrosis outside the body. Rather than treating fibrosis as a single disease, the authors examine the biological features shared across organs while recognizing that each tissue has its own cellular composition, mechanical environment and response to injury. This distinction is critical. A model that reproduces collagen accumulation in a dish may still fail to capture the electrical properties of the heart, the air–liquid interface of the lung, the filtration architecture of the kidney or the specialized immune environment of the liver. Faithful modelling therefore requires more than adding a profibrotic chemical to cultured cells.
At the centre of fibrosis is a complex interaction between injured parenchymal cells, immune cells, vascular cells and fibroblasts. Fibroblasts are connective-tissue cells that normally help maintain the extracellular matrix and support wound healing. During chronic injury, however, they can become activated into myofibroblasts, contractile cells that produce large quantities of collagen and other matrix proteins. Signalling molecules such as transforming growth factor beta are widely associated with this transition, but fibrosis is not controlled by one pathway alone. Cytokines, growth factors, oxidative stress, altered metabolism and signals from damaged cells can all contribute. The review emphasizes that in vitro systems should reproduce this multicellular communication rather than isolate a single cell type from its biological context.
The extracellular matrix itself is not simply a passive scar. Its composition, organization and physical properties can actively direct cell behaviour. As collagen and related proteins accumulate, the tissue becomes stiffer. That mechanical change can activate mechanosensitive pathways, including signalling through integrins and transcriptional regulators such as YAP and TAZ. In turn, cells may produce even more matrix, creating a self-reinforcing cycle in which biochemical and mechanical signals amplify one another. A useful fibrosis model must therefore measure not only the quantity of deposited matrix but also its organization, crosslinking, stiffness and ability to alter cellular function. Techniques such as three-dimensional biomaterials, tunable hydrogels, traction-force measurements and advanced microscopy can help investigators observe these changes in real time.
The authors identify three-dimensional human tissue models as an important bridge between conventional cell culture and animal studies. Two-dimensional cultures are relatively inexpensive and experimentally convenient, but they flatten cells onto artificial surfaces and often expose them to conditions unlike those found in living tissue. Three-dimensional systems can allow cells to adopt more realistic shapes, form tissue-like interfaces and experience gradients of oxygen, nutrients and signalling molecules. Organoids, engineered tissue constructs and organ-on-chip platforms can further introduce fluid flow, vascular-like channels or mechanical stimulation. These features may be especially valuable for modelling organs in which physical forces are central to disease, such as the breathing lung, the beating heart and the continuously perfused kidney.
Human cells are another major advantage of these systems. Primary cells obtained from patients can retain disease-associated characteristics, while induced pluripotent stem cells can be differentiated into several human cell types and combined into more complex models. Patient-derived material may reveal why some individuals develop aggressive fibrosis after injury while others recover with limited scarring. It may also expose differences in drug response that are invisible in genetically uniform laboratory animals or immortalized cell lines. Yet the review cautions that human relevance does not automatically guarantee biological accuracy. Cells can lose their identity during expansion, stem-cell-derived populations may remain immature and donor-to-donor variability can make results difficult to compare. Rigorous characterization is therefore essential.
A major design challenge is deciding which hallmarks of fibrosis a model must reproduce. The review proposes that researchers begin with the biology of the target organ and define measurable criteria before selecting a platform. These criteria may include persistent fibroblast activation, pathological extracellular matrix deposition, tissue stiffening, inflammatory signalling, altered vascular behaviour, epithelial or endothelial dysfunction and loss of organ-specific performance. In a lung model, for example, meaningful fibrosis should involve more than collagen production; it should also reflect changes in epithelial integrity, gas-exchange-related functions and the interaction between airway or alveolar cells and immune populations. In a cardiac model, contractility and electrical activity may be as important as matrix accumulation.
The practical value of a model depends equally on how its results are measured. Traditional endpoint assays can quantify collagen or profibrotic gene expression, but they may miss changes that emerge earlier or disappear by the time a sample is collected. The authors highlight the growing importance of live imaging, single-cell and spatial molecular profiling, secreted-protein analysis, mechanical testing and functional readouts. Combining these methods can reveal which cells initiate fibrosis, how signals move through a tissue and whether a treatment reverses disease-associated function rather than merely suppressing one marker. Standardized reporting of cell sources, matrix composition, culture conditions, disease induction methods and analysis pipelines will also be necessary if results from different laboratories are to be compared.
These models could reshape the search for antifibrotic therapies, a field in which promising laboratory findings have often failed to translate into durable clinical benefits. A well-designed human tissue system could be used to test candidate drugs across several stages of disease, from early inflammatory activation to established matrix remodelling. It might also help distinguish compounds that genuinely restore tissue function from those that simply reduce a biomarker. Because fibrosis frequently involves multiple cell types and feedback loops, future platforms may be particularly useful for evaluating drug combinations and identifying patients most likely to respond. The authors ultimately present in vitro fibrosis modelling not as a replacement for clinical or animal research, but as a complementary technology capable of narrowing the gap between molecular discovery and human disease.
The review’s broader message is that the next generation of fibrosis models should be designed as integrated biological systems rather than as collections of isolated measurements. Researchers will need to combine human cells, organ-specific architecture, immune interactions, extracellular-matrix biology, mechanical forces and functional outputs in a manner that remains experimentally manageable. Advances in microfluidics, biomaterials, imaging and computational analysis could make such systems increasingly precise, while shared standards may improve reproducibility and accelerate adoption beyond specialist laboratories. By defining the hallmarks that matter most and translating them into practical design choices, the authors offer a framework for building models that are not only technically sophisticated but clinically informative. For a disease responsible for progressive organ failure across the world, that shift could turn the laboratory dish into a more powerful window on how scarring begins, persists and might finally be stopped.
Subject of Research: Human in vitro models of fibrosis across multiple organs, including the heart, lung, kidney, liver and synovium.
Article Title: A practical toolbox for modelling fibrosis in vitro
Article References: Morsink, M.A.J., Fleischer, S., Nash, T.R. et al. A practical toolbox for modelling fibrosis in vitro. Nature Biomedical Engineering (2026). https://doi.org/10.1038/s41551-026-01749-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41551-026-01749-w
Keywords: Fibrosis, in vitro models, tissue engineering, extracellular matrix, organoids, organ-on-chip, mechanobiology, human disease modelling, drug discovery, regenerative medicine.
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