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ABM CDT Comparison of pluripotent and multipotent stem cells in articular cartilage bioprinting


   EPSRC Centre for Doctoral Training in Advanced Biomedical Materials


About the Project

Articular cartilage (AC) defects are one of the major causes of immobility and poor quality of life for millions of individuals worldwide, but current medical therapies fail to provide long-term restoration of pain-free function. As a result, tissue engineered therapies are proposed, primarily using either human pluripotent stem cells [embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)] or multipotent adult mesenchymal stem cells (MSCs). Human ESCs and MSCs have been shown to be capable of forming articular cartilage, but it lacks proper organisation and so is unlikely to function properly once implanted. 3D bioprinting opens the possibility of generating complex cartilage implants that better mimic native tissue via the precise patterning of cells and biomaterials. This project will extend on-going research in our groups to develop novel graphene oxide (GO)-functionalised bioinks for 3D bioprinting of AC implants with control over delivery of growth factors capable of guiding stem cell differentiation and ultimately cartilage formation. The student will compare the tissue formed by ESCs and MSCs to identify similarities and differences. This knowledge will enable the most accurate cartilage models to be developed both for application in drug testing and also for future clinical implantation.

Background:

Articular cartilage (AC) defects are one of the major causes of immobility and poor quality of life for millions of individuals worldwide. Current medical therapies have proven to be insufficient for the long-term regeneration of AC defects. As a result, there has been a growing interest in cell-based tissue engineering approaches involving both human pluripotent stem cells (embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs)) and multipotent adult mesenchymal stem cells (MSCs). While we (and others) have shown that human ESCs, iPSCs and MSCs are all capable of undergoing chondrogenesis and synthesising a cartilaginous extracellular matrix (ECM), there have been few studies directly comparing the resulting tissue making it difficult to determine the optimal cell source. Further complicating the development of AC regenerative therapies is the fact that tissue engineered cartilage fails to mimic the complex hierarchical organisation of the native AC ECM. However, 3D bioprinting opens the possibility of generating complex AC implants via the precise spatial deposition of multiple cells and biomaterials. This project will extend on-going efforts to develop novel graphene oxide (GO)-functionalised bioinks for 3D bioprinting of AC implants with spatial control/delivery of bioactive molecules (e.g. TGFβ and BMPs) capable of guiding stem cell differentiation towards chondrogenic lineages.

Main questions to be answered:

This project will integrate expertise in human pluripotent stem cell (Kimber) and multipotent stem cell (Richardson) chondrogenesis, with expertise in bioinks and 3D bioprinting (Domingos) to bioengineer and comprehensively characterise stem cell-based AC models. As such, the project will focus on the following primary questions:

  • How does the cell phenotype and deposited ECM compare between ESCs and MSCs when stimulated with graphene oxide-delivered chondrogenic factors (e.g. BMP/TGFβ)?
  • How do ESCs and MSCs respond to patterning within 3D bioprinted AC constructs generated using recently-developed novel bioinks?
  • Can 3D bioprinting of ESC/MSC-seeded, GO-functionalised bioinks be used to create hierarchically-ordered AC constructs that mimic native AC tissue?

References

Héctor Martínez Ávila, Silke Schwarz, Nicole Rotter, Paul Gatenholm. 3D bioprinting of human chondrocyte-laden nanocellulose hydrogels for patient-specific auricular cartilage regeneration, https://doi.org/10.1016/j.bprint.2016.08.003
Heinegaard D and Saxin T. The role of cartilage matrix in Osteoarthritis, Nat Review Rheumatol. 7, 50-56. 2011. doi: 10.1038/nrrheum.2010.198.
Cheng A, Kapacee Z, Peng J. Lucas R, Lu S, Lucas R, Hardingham TE & Kimber SJ (2014) Cartilage Repair Using Human Embryonic Stem Cell-derived Chondroprogenitors. Stem Cell Translational Medicine 3, 1287-1294

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