Cells-self Extracellular Matrices-based Bioinks to create accurate 3D diseased skin tissue models

Project Information

ECM_INK

Grant agreement ID: 726061

DOI

10.3030/726061

Project closed

EC signature date 24 April 2017

Start date 1 May 2017

End date 31 July 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 998 938,92

EU contribution

€ 1 998 938,92

Coordinated by

UNIVERSIDADE DO MINHO
Portugal

Periodic Reporting for period 5 - ECM_INK (Cells-self Extracellular Matrices-based Bioinks to create accurate 3D diseased skin tissue models)

Reporting period: 2022-11-01 to 2023-07-31

Summary of the context and overall objectives of the project

In recent years, 3D in vitro cell models have drawn increasing interest from the scientific community contributing to refine novel tools for disease modelling and drug discovery, minimizing the need for animal experimentation. While this has led to the surge of new human tissue bioengineering models, due to the high degree of complexity of the native tissue, those models still do not fully reflect its features and composition. Bioprinting technology has recently gained popularity since it enables for a more accurate recreation of 3D structural human tissue properties. However, more functional bioinks, a key element of bioprinting, remain necessary and much effort is still required to achieve formulations that enable engineered tissue to function as desired.
For this purpose, this project aimed to develop new bioinks based on native extracellular hypothesizing that this is mandatory to build accurate skin models fully representative of the pathophysiology of diseases such as pemphigus vulgaris, dystrophic epidermolysis bullosa and squamous cell carcinoma

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Dermis is the major compartment of skin tissue, dictating the overall functionality of the tissue in large part through its extracellular matrix. Due to the clinical dissimilarities of the studied skin diseases, we first questioned whether those were related to alterations in the extracellular matrix of the dermis. We found that each type of disease has its own fingerprint; yet, despite the highly different clinical manifestation of the varied dystrophic epidermolysis bullosa variants, common unique traits may serve as therapeutic targets. The next step towards the generation of extracellular matrix-based bioinks, led to the establishment of a new method of extraction and fractioning of extracellular matrix without losing key components. Importantly, the obtained extracts featured specific biological functions providing important cues to the different bioink formulations. Key technological tools such as a printer that allow using different inks to fabricate a single 3D structure, and a dynamic culture platform that facilitates the generation and maintenance of mature and functional complex tissues/multi-tissues, were developed concurrently.
Ultimately, fully biological dystrophic epidermolysis bullosa and squamous cell carcinoma models were fabricated demonstrating that native extracellular matrix comprises key components that must be included in the recreation of bioengineering models, particularly for disease modelling.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

ECM_INK project goes beyond the state of the art by: i) generating ground-breaking knowledge of the proteome of fibroblasts from skin diseases with very different etiologies; ii) establishing a novel method for the extraction and fractioning of the extracellular matrix components, retaining many that are significantly lost with current/standard decellularization approaches; iii) formulating extracellular-based inks comprising components with complementary functions that have application in a wide range of contexts in the field of regenerative medicine; iv) developing a versatile dynamic culture system to generate and maintain complex tissues/multi-tissues; v) developing new fully biologic dystrophic epidermolysis bullosa and squamous cell carcinoma in vitro models as in vitro study platforms.
Moreover, while directly applied to skin tissue and skin diseases, the project outputs can be further expanded in the fabrication of unprecedented human-origin 3D in vitro systems in which a wide range of mechanistic questions can be addressed. Together with the proteome findings more accurate and translatable therapeutic targets or therapy-related knowledge generated than those obtained with animal experimentation can be revealed.

Dynamic culture Platform featuring skin model