There is a need for tissue-based tools to drive drug development in both pre-clinical and clinical phases to improve the success rate of drug development. Drug development is a long, complex and expensive process. On average, it takes about 10 years to go from an idea to an approved drug. It also costs billions of dollars to develop a drug, including developing drugs that do not get approved.

Therefore, it is important to increase the likelihood of success so that innovation is not weakened. Accordingly, the FDA and EMA have expressed the view that biomarker-based drug development strategies, in combination with translational research, may offer a biology-focused approach that reduces time and cost and increases the overall likelihood of success.


The need to translate results from basic to clinical research arises from the nature of initial in vitro experiments, which are simplified models of the more complex clinical setting. For example, primary chondrocytes cultured in single-cell layers with serum have different conditions and are less clinically relevant than chondrocytes scattered in a dense ECM in the articular cartilage of a human joint. Ex vivo cultures have slightly greater clinical relevance than in vitro experiments due to their more natural ECM environment, but are also more complex and can be more difficult to manipulate experimentally. Nordic's models aim to approximate the high throughput of intro studies and the superior translation of in-models by characterizing cellular function in a more transferable 3D environment. Of course, ex vivo models are still grown under artificial conditions in the laboratory and should be supported by in vivo and clinical research.

Current models and the translational gap

A wide range of in vitro models are commonly used to test the effects of targets and the stability of profiles, and to test cellular modulation. What many of these models have in common is that they lack the necessary complexity and profiling of downstream effects on tissue, making them less suitable for translational application further down the drug development chain.

From arthritic diseases to various forms of fibrosis and cancer, the need for translational models that can accurately profile the extracellular matrix and support decision-making in clinical development is becoming increasingly important.

Nordic Bioscience's translational models use ex vivo, fibroblast, or primary cell cultures cultured in or on appropriate matrices, allowing active profiling of tissue turnover using protein fingerprint biomarkers. For example, an in vitro NAFLD model won't provide the same depth of information as an ex vivo model would:

  • Quantitative and dynamic measurement of tissue turnover
  • In vivo replication where cells are maintained in a near-native matrix.
  • Translational from in vitro to the clinic, allowing the same biomarker to be used at different stages of development.

The tissue-derived Protein Fingerprint biomarkers can be measured in supernatants from cell or ex vivo culture systems to accurately quantify tissue-specific changes arising from cellular activity in the individual tissues. An example of the application of biomarkers to describe tissue-specific turnover is shown in the figure below.


The cartilage explant model allows us to study cellular function and structural changes in a native-like 3D environment of bovine or human knee cartilage. and evaluate anti-catabolic or anabolic treatment efficacy.

The model can be used to evaluate the efficacy of novel treatments on chondrocyte function and cartilage ECM turnover and interrogate compound mode of action by measuring protein fingerprint markers in the culture supernatant.

Cartilagedegradationquantified by aggrecanasedegradedaggrecan (AGNx1) cartilage formation quantified by release of the type II collage pro-peptide PRO-C2 in bovinecartilageexplantstreated with either pro-inflammatorycytokines or growh factors.

Reference: Thudium et. al., JoVE (2020)

Mechanical compression is essential for cartilage maintenance and homeostasis. Cartilage can be loaded in a multi-well setup to mimic physiological or pathological loading in vitro or to investigate the efficacy of novel treatments under physiological-like conditions. Protein Fingerprint biomarkers are measured in the culture supernatants to characterize tissue turnover.


Time-dependent levels of the biomarkers C3M and acMMP3 in supernatants of human osteoarthritic synovial explant cultures after treatment with cytokines.

The synovial membrane explant model allows us to study the cellular function and structural changes in a native-like 3D environment of a human knee synovium and evaluate the effect of cytokines, growth factors, or novel treatments. Protein Fingerprint biomarkers are measured directly in the supernatant and allow dynamic profiling of tissue turnover.


Time-dependent levels of the biomarkers C3M and acMMP3 in supernatants of human osteoarthritic synovial explant cultures after treatment with cytokines.

Reference: Kjelgaard-Petersen C. et. al., Biomarkers (2015)

The Fibroblast like synoviocyte (FLS) model is a well-established model to characterize the function of synovial cells in rheumatology. The cells can be isolated directly from human synovium and by stimulating primary synoviocytes with inflammatory or pro-fibrogenic cytokines and stimuli we can model the inflammatory environment of the synovium in vitro and evaluate direct anti-inflammatory or anti-fibrotic treatment efficacy. Nordic Bioscience biomarkers are measured in the supernatants to determine tissue turnover and efficacy.

Culture of primary human osteoclasts is a well-established method to investigate osteoclastogenesis and bone resorption. This model allows the study of osteoclast function in response to cytokines and evaluates anti-resorptive or osteoclastogenic treatment efficacy. Biomarkers are measured in the supernatants to determine efficacy.


Reference: Sørensen MG et al, Journal of Bone and Mineral Metabolism (2007)

Precision-cut Lung Slices (PCLS) of human fibrotic tissue is an established ex vivo model of pulmonary fibrosis. This model allows us to study the three-dimensional lung tissue from a patient and evaluate anti-fibrotic treatment efficacy. Nordic Bioscience biomarkers are measured in the supernatants to determine efficacy.


Reference: Leeming DJ and Sand JMB et al, presented at ERS 2018

The prolonged Scar-in-a-Jar is a novel model that employs macro-molecular crowding to promote the formation, maturation, and deposition of extracellular matrix in vitro. Stimulating primary fibroblasts with pro-fibrogenic cytokines and stimuli we can model fibrosis in vitro and evaluate direct anti-fibrotic treatment efficacy. Nordic Bioscience biomarkers are measured in the supernatants to determine efficacy.

Types of fibroblasts:
     - Pulmonary fibroblasts
     - Dermal fibroblasts
     - Cardiac fibroblasts
     - Hepatic stellate cells
     - Cancer associated fibroblasts
     - Fibroblast-like synoviocytes (FLS)

The Scar-in-a-Jar model for the above-mentioned different cell types is described respectively below.


Stimulating primary pulmonary fibroblasts with pro-fibrogenic cytokines and stimuli we can model lung fibrosis in vitro and evaluate direct anti-fibrotic treatment efficacy. Nordic Bioscience biomarkers are measured in the supernatants to determine efficacy.


Reference: Rønnow SR et al. 2020 Respir Res.

Cancer-associated fibroblasts (CAFs) are key players in orchestrating a pro-tumorigenic microenvironment amongst others by altering the ECM deposition and remodeling (desmoplasia) affecting cancer cells and immune cells. Therefore, CAFs are a potential target for optimizing therapeutic strategies against cancer, and attempts to modulate CAFs for therapeutic benefit are ongoing. Nonetheless, limitations in our current understanding of CAFs challenge this strategy. The SiaJ model offers a simple in vitro tool to address CAF biology and the direct impact of therapeutic intervention, in particular related to ECM remodeling.


Stimulating primary hepatic stellate cells with pro-fibrogenic cytokines and stimuli we can model liver fibrosis in vitro and evaluate direct anti-fibrotic treatment efficacy. Nordic Bioscience biomarkers are measured in the supernatants to determine efficacy. Unpublished data

Protein Fingerprint biomarkers allow for testing of anti-fibrotic effects of novel treatments by measuring protein formation fragments in the Scar-In-a-Jar model. Dermal fibroblasts are driven into a fibrotic state by growth factors. This fibrotic stimulation may be inhibited by anti-fibrotic drugs, here exemplified by Nintedanib.


Accumulation of extracellular matrix (ECM) proteins is the hallmark of fibrosis, which can lead to altered tissue homeostasis, organ failure, and ultimately death. Many different cell types and growth factors are involved in this process, but fibroblasts are the main source of ECM proteins. By modeling fibrogenesis using the in vitro Scar-in-a-Jar (SiaJ) system, we can provide insight in potential pro-fibrotic signaling mediated by different molecules, such as TGF-β.

The SiaJ model uses fibroblasts in a crowded environment in order to study fibrogenesis. This process is quantified by measuring the formation of ECM proteins using Nordic Bioscience biomarkers.


The SiaJ model goes 3D with the new 3DPROFIB in partnership with Ectica Technologies. This new platform offers the possibility to analyze Nordic Bioscience ECM formation biomarkers from the supernatant of fibroblasts growing in a 3D synthetic and animal-free hydrogel matrix, increasing the translational character of our model and supplementing the biomarker readout with imaging-based readouts.

This platform:

  • can be used to study the effect of anti-fibrotic compounds on production of extracellular matrix by fibroblasts in an environment that maintains their in vivo-like phenotype (as compared to cells cultured on plastic);
  • allows for phenotypical observations with imaging techniques;
  • is available with cardiac, pulmonary, dermal fibroblasts, bone marrow mesenchymal stromal cells and hepatic stellate cells;
  • allows for co-culture with inflammatory cells, endothelial cells and epithelial cells.

Don't hesitate to reach out to us if you wish to learn more about 3DPROFIB.

The 3D network of primary fibroblasts responds to pro-fibrotic cytokine stimulation (ions of PDGF-BB and TGF-β).

Please don't hesitate to contact us if you have any questions or other inquiries.

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