The METIS project is dedicated to the study of the biomechanics of connective tissues. Soft connective tissues such as skin, tendon or cornea are made of more than 90% of extracellular matrix proteins, fibrillar collagens being by far the predominant component. These structural proteins show a remarkable diversity in molecular and supramolecular organization, tissue distribution and function. They play a unique role in providing supportive scaffolding to which cells attach and in maintaining the structural integrity of most tissues. Decreased collagen synthesis or synthesis of aberrant collagen molecules generally leads to impairment of tissue mechanical properties and/or delayed wound healing. For instance, dysregulation of collagen fibrillogenesis is a hallmark of several subtypes of Ehlers-Danlos syndrome (EDS). The classic form of EDS is a connective tissue heritable disorder caused by mutations in collagen V genes that is characterized by loose joints and hyperextensibility of the skin and poor wound healing with atrophic scarring.
The rationale of this project is to understand the link between the microstructure of connective tissues and their macroscopic mechanical properties. Such studies have been impeded up to now by two major difficulties. First, direct observation of the collagen microstructure during a mechanical assay was not possible, except in some very specific cases, or through “post-mortem” analysis. Second, a full investigation of the microstructure role requires a model tissue with adjustable microstructure. Our consortium brings together physicists, biologists and mechanics to overcome these difficulties by use of a completely novel approach.
Visualization of skin microstructure will be performed continuously during mechanical assay by mean of multiphoton microscopy. This 3D imaging technique offers deep penetration within tissues and enables multimodal imaging of unstained tissues by use of complementary endogenous modes of contrast. In particular, Second Harmonic Generation (SHG) signals reveal fibrillar collagens with unequalled contrast and specificity. We have recently developed a new experimental device validated on tendons that combined SHG imaging to uniaxial mechanical testing modality.
As a model system, we will study a series of different mice models of the classic EDS. Several mouse lines have been established to model EDS and/or to understand the role of collagen V in skin. We will have access this way to four different collagen structural organizations in mouse skin, which will be fully characterized biologically during the course of our project.
To evaluate changes in the biomechanical properties of skin in disease, wound healing and ageing, in situ mechanical assays will be performed on skin biopsies using uniaxial loading. An extension to biaxial loadings will be an interesting plus-value as skins are naturally submitted by biaxial loadings. Extension of these results is a collection of different microstructures, associated with their mechanical properties. These data will be compiled into a mechanical model, which should predict correctly the link between the collagen organization at the micrometer scale and the properties at the millimeter scale.
The outputs of the project are new data on the physiopathology of EDS disease, including careful mechanical analysis and collagen organization, which will help the very fundamental understanding of this disease. More generally, our project will provide a unique tool to study the biomechanics of collagen-rich tissues. This tool should be easily generalized to study other collagen-related diseases and/or tissues, or to guide engineering of tissue substitutes with appropriate biomechanical responses.
This is an improved version of a project ranked in the complementary list last year. It addresses the critics that focused on the quality of the characterization of the skin mechanical properties and on the project costs.
Monsieur Jean-Marc ALLAIN (Laboratoire de Mécanique des Solides)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CNRS DR ILE DE FRANCE SUD
IGFL Institut de Génomique Fonctionnelle
LMS Délégation régionale IDF SUD
LMS Laboratoire de Mécanique des Solides
LOB Laboratoire d'Optique et Biosciences
Help of the ANR 530,957 euros
Beginning and duration of the scientific project: March 2014 - 36 Months