The Critical Role of Primary Cell Tissue Chips in Drug Research
Safety, efficacy, and translatability are the major concerns at the preclinical stage of pharmaceutical research. Immortalized cell lines and animal models have long been used to predict the success of new drugs; however, the limitations of these methods are becoming more apparent as new modality therapeutics emerge. Gene therapies require models that have species specificity and tissue level complexity to validate efficacy and distribution. Primary cell derived tissue chips are the solution.
Here, we will discuss the different cellular and animal models used in preclinical research to emphasize the benefits of tissue chip technology. Javelin harnesses the potential of primary cells in their pharma-focused tissue chip, designed for effortless workflow integration for drug safety and efficacy studies.
Animal Models: Tradeoffs to translatability
Animal models are the gold standard in preclinical drug discovery research. They have the benefit of showing systemic effects of a drug to judge off target effects as well as pharmacodynamic and -kinetics. But animal models, usually mouse or rat, are obviously not human. As a result, animal models have genomic, physiological and anatomical differences that alter their immune responses and drug metabolism compared to the patients these drugs are designed to treat. A relatable example of this discrepancy is aspirin, in animal models aspirin was deemed toxic and yet it is in medicine cabinets everywhere safe for human use. For new modality drugs, like antibody and gene therapies that are targeting human disease, these drugs require human specificity. Differences found in genes or proteins can make the human targeting drugs ineffective in animal models. As a result, surrogate drugs or humanized animal models are developed to prove safety and efficacy. These are expensive and time-consuming experiments that do not accurately predict drug success. The trend is so evident that the US Food and Drug Administration (FDA) announced a plan to phase out animal testing requirements and encouraging organoid and organ chip models in April 2025.
Tissue Chips: Helpfully humanized
Tissue chips go by a few different names— microphysiological systems, organ chips, microfluidic cultures— there is discussion over the most descriptive and accurate term. The phrase organ chip is most often used conversationally, but tissue chip is more exact and will be used throughout this discussion. Tissue chips incorporate 3D microenvironments, multiple cell types, fluidic shear force, and/or additional mechanical stimuli to engineer a physiologically relevant, human model. Tissue chips balance the complexity of a tissue with the control and accessibility of cell culture. Cells can be observed in real time to detect the first hints of toxicity, earlier than in an organism level experiment. Samples can be collected from the media for quick midpoint readouts matching clinically relevant biomarkers like ALT for liver damage or inflammatory readouts indicating Cytokine Release Syndrome. And, at the endpoint, cells can be extracted to measure protein or gene expression to measure transfection efficiency or pharmacodynamics of a new drug. There are a few options for cells to implement in tissue chips: cell lines, stem cells, and primary cells.
Cell Lines: Convenience comes at a cost
Cell lines are a simple and accessible first step in research as they proliferate and are sturdy. But the attributes that make cell lines simple to use contribute to their downfall. Cell lines are often from a cancer source or genetically modified to proliferate in a dish, both are mutations of the healthy cells we wish to study. In studies of metabolism, differentiation, and drug response, cell line behavior diverges from normal due to these genetic differences. Additionally, cell lines do not typically model a disease phenotype to test the efficacy of a new drug. (Unless the disease of interest is cancer).
Stem Cell-Derived: Maturity matters
Stem cells, either from an embryo or isolated and induced to a pluripotent state, are another proliferative source of human cells used for research. In culture, stem cells require precise protocols and expensive reagents to differentiate the cells to the tissue of interest. These methods are time intensive and require skilled labor to ensure sterility as antibiotics are often omitted due to their impact on proliferation and differentiation. Even when the stem cells are differentiated to their target cell type they lack the maturity of the cell found in the adult human body. Their immaturity can limit their utility in predicting drug responses and modeling disease.
Primary Cells: Form and Function
Primary cells, harvested from human tissues, maintain the physiological characteristics of their desired tissue providing a reliable model of healthy (or diseased) biology. These unedited human cells better match the tissue of interest than cell lines or stem cells, relaying results that translate to the clinic. When cells sourced from a diseased individual, primary cells maintain the disease state in vitro creating an ideal model to validate drug efficacy. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a disorder where lipids accumulate in the liver of patients, increasing their risk for liver cancer, cirrhosis, and cardiovascular disease. There are at least 5 genes that make a person more likely to develop MASLD, the disorder is considered 25-50% heritable. To design early drug interventions and gene therapies for MASLD prone patients, the exact mutations, gene expression and phenotypic outcomes are found in primary sourced cells. A primary cell model enables the best understanding of pathology and drug efficacy considering the different combination of gene mutations present in a MASLD patient. Incorporating primary cells into a tissue chip is even more relevant providing mechanical cues, like fluid flow and/or a 3D extracellular matrix, to match the in vivo niche and predict drug candidate success. As researchers push the boundaries of medicine from small molecules to gene therapies, tissue chips utilizing primary cell sources are essential for efficient and successful drug programs.
Javelin’s Primary Cell Platform
At Javelin, we have engineered a Liver Tissue Chip (LTC) of primary cells to take advantage of the previously described benefits for drug discovery research. Primary cells, particularly of the liver, have short lived culture functionality. Hepatocytes in 2D culture dedifferentiate and die over 5-10 days, but on Javelin’s LTC hepatocytes survive 15+ days and maintain albumin and urea production as well as drug metabolism. Our LTC combines up to four primary cells—hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells—in a 3D microenvironment with physiological flow to create a complex biomimetic model. And our LTC+ device enables culture with additional tissues like kidney or gut, expanding disease targets and safety parameters that can be screened in our platform. Our in house and customer results have validated the ability of Javelin’s LTC to read out relevant biomarkers of health and disease including but not limited to inflammation, fat accumulation, and fibrosis. Improve your drug discovery pipeline, from small molecules to gene therapies, by incorporating Javelin’s primary cell tissue chip into your workflow.
