Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair

Lead Research Organisation: University of Glasgow
Department Name: School of Engineering

Abstract

Cells are immersed in a dynamic environment. They actively interact with it and reorganise it. These interactions help them to form specific tissues in our body, and carry out their functions to maintain them. Artificial materials have been designed by simulating different aspects of healthy tissues, like their chemical and mechanical properties, with the aim of using them to support cells in the repair of damaged tissues. However, most of the materials developed up to now for this purpose ignore the changing, viscous nature of the cells' surroundings. In this proposal, we will develop advanced artificial materials that instead take into account the dynamic aspect of cells' interactions with their environment and exploit it to stimulate cells to regenerate highly dynamic tissues, such as the cartilage present in the joints. These synthetic "microenvironments" will be inspired by how living cartilage cells reach out to their surroundings; we will use proteins that cells employ as places to anchor themselves in the tissue they are in or to other cells, and important small molecules that act as signals for the cells. Our materials will control the dynamic display of these molecules and allow us to investigate, understand and control the mechanisms of cartilage formation in a real dynamic environment. This knowledge will give us the tools to design biomaterials that will promote the repair of damaged cartilage.

Technical Summary

The tissues that cells inhabit in vivo are dynamic and dissipative environments, where rapid and adaptive processes drive the interactions between cells and extracellular matrices (ECMs). However, most synthetic material systems designed up to now to promote the healing of damaged tissues employ static environments, mechanically designed to mimic solely the elastic properties of the native tissue. The viscous behaviour of the substrate, which is an intrinsic property of physiological cell surroundings, is traditionally ignored. This proposal aims at engineering advanced microenvironments that instead exploit these dissipative interactions to promote cell differentiation and tissue repair, for application in the regeneration of tissues characterised by high viscous properties, such as cartilage. In order to dissect the contributions of the different components of the ECM to its overall viscous properties and their role in driving chondrogenic differentiation, we will engineer materials with controlled mobility and hence viscosity, functionalised with relevant ligand molecules. These material platforms will be based on supported lipid bilayers, supported polymer films and hydrogels. The ligands molecules employed for their functionalisation will include peptide ligands that regulate cell adhesion (e.g. collagen II ligands), cell-cell contacts (e.g. N-cadherin ligands) and intercellular communication through soluble signalling molecules (e.g. growth factors involved in cartilage repair). The behaviour of mesenchymal stem cells on these functional interfaces will allow a paradigm for cell response to dissipative interactions in the context of chondrogenic differentiation to be derived. This will ultimately guide the incorporation of viscosity into the design of bulk hydrogel systems with a dynamic display of ligands identified as fundamental for the promotion of cartilage repair.
 
Title Research data supporting "Functionalisation of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks" 
Description Raw research data supporting the publication Sprott et al. "Functionalisation of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks", doi: 10.1002/adhm.201801469 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact This research data led to the publication "Functionalisation of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks", doi: 10.1002/adhm.201801469 
URL https://doi.org/10.5525/gla.researchdata.715
 
Description Collaboration with Dr. Gloria Gallego Ferrer in Universitat Politècnica de València, Spain to characterise polymer systems 
Organisation Polytechnic University of Valencia
Country Spain 
Sector Academic/University 
PI Contribution MS was hosted at Dr. Gallego Ferrer's institute, taking the work developed from this grant. He performed material characterisation of the polymer system and wrote the associated paper.
Collaborator Contribution Dr. Gloria Gallego Ferrer as a member of the Centro de Biomateriales e Ingenieria Tisular (CBIT) and Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), hosted MS at her institute and guided in use of equipment and characterisation planning. GGF also aided in reviewing the paper published from this work and future paper to be published.
Impact One paper, international conference and several posters and abstracts have been published from this work; including "Functionlization of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks" (paper), "Biomimetic Functionalisation of PLLA With Acrylate Brushes" Presentation at 45th European Society for Artificial Organs, Madrid 2018 (oral presentation), Poster for Glasgow Orthopaedic Research Initiative 2018 Abstracts for ESAO 2018, GLORI 2018 and 2019.
Start Year 2017
 
Description Collaboration with prof. Tomasz J Guzik of the University of Glasgow 
Organisation University of Glasgow
Department Institute of Cardiovascular and Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have optimised a measurement technique to quantify the mechanical properties of tissue sections using atomic force microscopy. We have used this technique to measure the mechanical properties of mouse aortas provided by the collaborator, with the objective of confirming the role of MiR-214 in the regulation of vascular stiffening during perivascular fibrosis.
Collaborator Contribution Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. This study reveals that T cell MiR-214 is required for perivascular fibrosis, vascular stiffening, and endothelial dysfunction in hypertension. Hence, MiR-214 may provide a future therapeutic target in perivascular fibrosis.
Impact Nosalski R, Siedlinski M, Denby L, McGinnigle E, Nowak M, Nguyen Dinh Cat A, Medina-Ruiz L, Cantini M, Skiba D, Wilk G, Osmenda G, Rodor J, Salmeron-Sanchez M, Graham G, Maffia P, Graham D, Baker AH, Guzik TJ. T Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension. Circ Res. 2020 Feb 17. doi: 10.1161/CIRCRESAHA.119.315428. [Epub ahead of print] PubMed PMID: 32065054. The collaboration is multidisciplinary: engineering, biology, cardiovascular and medical sciences
Start Year 2018
 
Description Biomedical Engineering Away Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Organisation and participation to an Away Day for people working in the Biomedical Engineering Research Division of the University of Glasgow, with the objective of showcasing the broad range of activities that are carried out across the Division, networking and finding new collaborations.
Year(s) Of Engagement Activity 2020
 
Description Biomedical Engineering Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Organisation and participation to lab tours and poster presentations for undergraduate and postgraduate recruitment events.
Year(s) Of Engagement Activity 2019,2020