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.
Organisations
- University of Glasgow (Fellow, Lead Research Organisation)
- Institute for Bioengineering of Catalonia (Collaboration)
- Istituto Officina dei Materiali (Collaboration)
- Polytechnic University of Valencia (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- UNIVERSITY OF YORK (Collaboration)
- UNIVERSITY OF STRATHCLYDE (Collaboration)
- Polytechnic University of Milan (Collaboration)
Publications
Re F
(2019)
3D gelatin-chitosan hybrid hydrogels combined with human platelet lysate highly support human mesenchymal stem cell proliferation and osteogenic differentiation.
in Journal of tissue engineering
Sprott MR
(2019)
Functionalization of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks.
in Advanced healthcare materials
Nosalski R
(2020)
T-Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension
in Circulation Research
Ngandu Mpoyi E
(2020)
Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts.
in Biomaterials
Cantini M
(2020)
The Plot Thickens: The Emerging Role of Matrix Viscosity in Cell Mechanotransduction.
in Advanced healthcare materials
Papalazarou V
(2020)
The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis.
in Nature metabolism
Witte K
(2021)
Soft Matter for Biomedical Applications
Barcelona-Estaje E
(2021)
You Talking to Me? Cadherin and Integrin Crosstalk in Biomaterial Design.
in Advanced healthcare materials
McDowall D
(2021)
Controlling the formation and alignment of low molecular weight gel 'noodles'.
in Chemical communications (Cambridge, England)
Walker M
(2021)
ChondroGELesis: Hydrogels to harness the chondrogenic potential of stem cells
in Materials Science and Engineering: C
Description | College Scholarship Application - Funding to Finlay Cunniffe |
Amount | £56,000 (GBP) |
Funding ID | Internal application reference: 01085338 |
Organisation | University of Glasgow |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2022 |
End | 03/2026 |
Description | Defined dissipative properties to investigate the role of matrix viscosity on cellular response - Funding to Eonan William Pringle |
Amount | £54,460 (GBP) |
Funding ID | 2441947 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2020 |
End | 03/2024 |
Description | ECR and new academic staff in-year small investment - School of Engineering |
Amount | £10,000 (GBP) |
Organisation | University of Glasgow |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2022 |
End | 07/2022 |
Description | Nanovibrational control of chondrogenic differentiation |
Amount | £869,172 (GBP) |
Funding ID | EP/X013057/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2023 |
End | 05/2026 |
Description | Research Grants 2023 |
Amount | £70,000 (GBP) |
Funding ID | RGS/R1/231400 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2023 |
End | 06/2024 |
Description | SULSA ECR Prize - Funding to Matthew Walker |
Amount | £2,000 (GBP) |
Organisation | Scottish Universities Life Sciences Alliance |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2023 |
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 Cristina Gonzalez-Garcia |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of viscoelastic hydrogels with controlled viscous properties. |
Collaborator Contribution | Engineering and characterization of viscoelastic microgels for tissue engineering applications. |
Impact | No output yet |
Start Year | 2022 |
Description | Collaboration with Dr Monica Soncini |
Organisation | Polytechnic University of Milan |
Country | Italy |
Sector | Academic/University |
PI Contribution | Surface modification of cell culture substrates and characterization of cell response |
Collaborator Contribution | Development of bioreactor devices |
Impact | No output yet |
Start Year | 2021 |
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 Dr. Philipp Seib of the University of Strathclyde and prof Manuel Salmeron-Sanchez of the University of Glasgow |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of hydrogels and biointerfaces with controlled viscous properties. Co-authoring a book chapter. |
Collaborator Contribution | Characterisation of cell response using iPS cells. Co-authoring a book chapter. |
Impact | Witte, K., Luo, J., Walker, M. , Cantini, M. , Seib, F.P. and Salmeron-Sanchez, M. (2021) Bioinspired and bioinstructive surfaces to control mesenchymal stem cells. In: Azevedo, H. S., Mano, J. F. and Borges, J. (eds.) Soft Matter for Biomedical Applications. Series: Soft matter series (13). Royal Society of Chemistry: Cambridge, pp. 301-325. ISBN 9781788017572 (doi: 10.1039/9781839161124-00301). The collaboration is multidisciplinary: engineering, biology, material science. |
Start Year | 2020 |
Description | Collaboration with Dr. Philipp Seib of the University of Strathclyde and prof Manuel Salmeron-Sanchez of the University of Glasgow |
Organisation | University of Strathclyde |
Department | Strathclyde Institute of Pharmacy & Biomedical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of hydrogels and biointerfaces with controlled viscous properties. Co-authoring a book chapter. |
Collaborator Contribution | Characterisation of cell response using iPS cells. Co-authoring a book chapter. |
Impact | Witte, K., Luo, J., Walker, M. , Cantini, M. , Seib, F.P. and Salmeron-Sanchez, M. (2021) Bioinspired and bioinstructive surfaces to control mesenchymal stem cells. In: Azevedo, H. S., Mano, J. F. and Borges, J. (eds.) Soft Matter for Biomedical Applications. Series: Soft matter series (13). Royal Society of Chemistry: Cambridge, pp. 301-325. ISBN 9781788017572 (doi: 10.1039/9781839161124-00301). The collaboration is multidisciplinary: engineering, biology, material science. |
Start Year | 2020 |
Description | Collaboration with Dr. Silvia Caponi of the National Research Council - Italy |
Organisation | Istituto Officina dei Materiali |
Country | Italy |
Sector | Public |
PI Contribution | Development of hydrogels with controlled viscoelastic properties |
Collaborator Contribution | Expertise in material characterisation via Brillouin Spectroscopy |
Impact | Poster presentation at BioBrillouin2020, 4th BioBrillouin conference of the COST Action CA16124 "Brillouin Light Scattering Microspectroscopy for Biological and Biomedical Research and Applications": G. Capponi, M. Cantini, M. Mattarelli, M. Vassalli, M. Walker and S. Caponi, Polyacrylamide bulk hydrogel mechanical characterization in high frequencies domain by Brillouin light scattering. |
Start Year | 2019 |
Description | Collaboration with Prof. Paul Genever of The University of York |
Organisation | University of York |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The Material provided by the collaborator is used to investigate stem cells mechanosensing of viscosity. The Material is cultured on advanced interfaces with controlled mobility and hence viscosity, functionalised with relevant ligand molecules. The behaviour of the Material on these functional substrates, alongside the behaviour of primary mesenchymal stem cells, will allow to understand the mechanisms underlying stem cell mechanotransductive response to viscosity. |
Collaborator Contribution | Clonal mesenchymal stromal/stem cell line (termed Y201), generated from primary human bone marrow MSCs immortalised with the human telomerase gene ("hTERT-MSCs"). Ref: Stem Cell Reports. 2015 Jun 9;4(6):1004-15. doi: 10.1016/j.stemcr.2015.05.005 |
Impact | No output yet |
Start Year | 2019 |
Description | Collaboration with prof Delphine Gourdon |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Development of viscoelastic hydrogels with controlled viscous properties. |
Collaborator Contribution | Engineering and characterization of ECM-mimicking protein platforms with material properties covering both physiological and pathological (tumorous) tissues. |
Impact | Asadishekari, M., Mpoyi, E. N., Li, Y., Eslami, J., Walker, M. , Cantini, M. and Gourdon, D. (2022) Three-dimensional tunable fibronectin-collagen platforms for control of cell adhesion and matrix deposition. Frontiers in Physics, 10, 806554. (doi: 10.3389/fphy.2022.806554). The collaboration is multidisciplinary: engineering, biology, material science. |
Start Year | 2021 |
Description | Collaboration with prof. Dave Adams of the University of Glasgow |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We measured the mechanical properties of gels developed by the research team of the collaborator. |
Collaborator Contribution | Development of gel 'noodles' - control of their formation and alignment |
Impact | McDowall, D., Walker, M. , Vassalli, M. , Cantini, M. , Khunti, N., Edwards-Gayle, C. J. C., Cowieson, N. and Adams, D. J. (2021) Controlling the formation and alignment of low molecular weight gel 'noodles'. Chemical Communications, 57(70), pp. 8782-8785. (doi: 10.1039/D1CC03378F) (PMID:34378594) The collaboration is multidisciplinary: engineering, material science, and chemistry. |
Start Year | 2021 |
Description | Collaboration with prof. Pere Roca-Cusachs of the Institute for Bioengineering of Catalonia |
Organisation | Institute for Bioengineering of Catalonia |
Country | Spain |
Sector | Private |
PI Contribution | Development of biointerfaces with controlled surface mobiltiy or controlled viscoelasticity to study cell mechanosensing of viscosity. |
Collaborator Contribution | Expertise in actin flow measurements to characterise cell response on viscous surfaces. |
Impact | No output yet |
Start Year | 2019 |
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 |
Description | Glasgow Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Team participation to the Glasgow Science Festival, with a stand on stem cells and their uses in regenerative medicine. |
Year(s) Of Engagement Activity | 2021 |