Quantifying Cell-Derived Changes in Collagen Synthesis, Alignment, and Mechanics in a 3D Connective Tissue Model

Quantifying Cell-Derived Changes in Collagen Synthesis, Alignment, and Mechanics in a 3D Connective Tissue Model

Overview

The extracellular matrix (ECM) of the body is the network of proteins and other molecules that surrounds cells and tissues. The ECM is directly involved in a variety of essential cellular processes including structural support, cellular communication, growth, tissue organization and environmental signaling. The importance of ECM in tissue homeostasis and regulation is becoming increasingly recognized, as the hallmark of several diseases such as fibrosis and cancer is the dysregulation in ECM synthesis, organization and/or mechanics. In this way, there is a significant need for the development of engineered tissue models that can recapitulate native ECM architecture and function to better understand disease pathophysiology and inform the development of therapeutics. The disclosed technology utilizes primary human fibroblasts seeded into custom fabricated 3D non-adhesive agarose molds to generate 3D tissue constructs with properties that recapitulate key features of the ECM.

Market Opportunity

The ECM plays a key role in several diseases, including cancer where ECM remodeling impacts tumor malignancy and metastasis; fibrotic disease such as pulmonary fibrosis and cardiovascular disease; skin diseases in which there is a disruption in ECM homeostasis; and aging which leads to changes in ECM composition, structure, mechanics and subsequently function. Of particular relevance is connective tissues, such as ligaments and tendons, where fibroblasts and collagen-1 are the predominant component. In these tissues, the ECM consists of highly aligned, hierarchical fibrils that enable the tissues to resist high tensile loads which corresponds in maintaining joint stability during skeletal motion. Yet breakdown of the ECM, which is predominant in connective tissue disorders, impede the ability of the tissue to function properly. The disclosed technology utilizes a bottom-up, cell-based approach as opposed to other models which rely on scaffolds or externally applied forces to direct cell alignment. In this way, the present model has the capability to study a diverse set of diseases and has increased relevance because the direct impact of conditions and therapeutics on ECM maintenance and cellular function can be evaluated.

Innovation and Meaningful Advantages

Monodisperse cell culture and most in vitro tissue models fail to recapitulate the 3D multi-scale hierarchical architecture of collagen-rich tissues and therefore are unable to accurately model the behavior of healthy and diseased tissue. The disclosed technology utilizes a cell-based tissue engineering approach with sophisticated, yet easy-to-adapt techniques to generate 3D tissue models. Due to the absence of an exogenously added scaffolding material, this model can directly quantify cell-derived changes in 3D matrix synthesis, alignment, and mechanics in response to the addition or removal of relevant biomolecular perturbations. Further, pathogenic gene variants for connective tissue disorders such as Marfan Syndrome, Ehlers-Danlos syndrome and Osteogenesis Imperfecta can be accommodated, overcoming the considerable challenge of recapitulating these genetic changes in animal models.

Collaboration Opportunity

We are interested in exploring research collaborations and licensing opportunities 

References

• US18/175,417
• Wilks, B.T., Evans, E.B., Howes, A., Hopkins, C.M., Nakhla, M.N., Williams, G. and Morgan, J.R., 2022. Quantifying Cell‐Derived Changes in Collagen Synthesis, Alignment, and Mechanics in a 3D Connective Tissue Model. Advanced Science, 9(10), p.2103939. https://doi.org/10.1002/advs.202103939