Pluripotent stem cell derived 3D cartilage constructs in bioprinted novel hydrogels for joint repair
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
This project aims at developing in vivo articular cartilage repair through the integration of bioactivated hydrogels using an advanced bioprinting platform and pluripotent stem cell-chodrocytes capable of 1) generating cartilage tissue emulating the biomechanical function of the natural tissue; 2) regulating temporal-spatial chondrocyte activity and deposition of neo ECM with adequate physicochemical properties.
Osteochondral (OC) defects are one of the major causes of immobility and poor quality of life for millions of individuals world wide.In the UK >8.75 million over 45s have sought treatment for Osteoarthritis (OA) and are responsible for over 30 million working days lost each year (Arthritis Research UK). Care for these conditions accounts for the third largest area of NHS spend at £4.7 billion. Because current medical treatments have proven to be insufficient for the long-term regeneration of OC defects, tissue Engineering (TE) strategies based on the combination of scaffolds or hydrogels, cells and bioactive molecules, have come to the fore. Scaffolds or hydrogels must be able to mimic the multi-functional and multi-compositional organization of the native tissue in order to support and promote chondrogenic cell adhesion, proliferation and differentiation. However many such systems have given disappointing results as the combination of cells with scaffold have not appropriately activated or maintained chondrocyte function. Support scaffolds or hydrogels need to mimic the native extracellular matrix (ECM) microenvironment with appropriate biophysical and chemical properties responsible for coordinating intracellular signalling and triggering downstream biological responses which regulate cell function. In this project we will use an established and refined protocol for the generation of chondrogenic cells from human pluripotent stem cells (hPSCs) in combination with new methods of cell selection and novel promising printable hydrogels. We will use stem cells which are suitable for use in patients, once differentiated, because they were derived at Good Manufacturing Practice (GMP) standard. Our previous work identified a hydrogel which pilot data shows supports maintenance of hPSC-derived chondrocytes in vitro in a way far superior to other support materials tested. Recent literature has highlighted new cell surface antigens expressed by embryonic chondrocytes which will be used to select chondrocyte-committed hPSC derived cells.
In this project we therefore propose a combinatorial approach that brings together 3 key elements for the design of OC implants: 1) accurate cell-selection 2) iPSC chondrogenesis via a GMP compatible protocol, and 3) a novel hydrogel-based material as suitable bioink for 3D printing. The ultimate test of such a combined strategy will be that the construct is able to repair a cartilage defect. In this project we will use an established rat model to test the ability of the cell construct to generate cartilage in the knee joint. The combination of supervisors: an orthopaedic clinician, a stem cell scientist and an expert in hydrogels and bioprinting methods will generate an ideal bench to bedside environment for the successful translation of this work into the clinic.
Osteochondral (OC) defects are one of the major causes of immobility and poor quality of life for millions of individuals world wide.In the UK >8.75 million over 45s have sought treatment for Osteoarthritis (OA) and are responsible for over 30 million working days lost each year (Arthritis Research UK). Care for these conditions accounts for the third largest area of NHS spend at £4.7 billion. Because current medical treatments have proven to be insufficient for the long-term regeneration of OC defects, tissue Engineering (TE) strategies based on the combination of scaffolds or hydrogels, cells and bioactive molecules, have come to the fore. Scaffolds or hydrogels must be able to mimic the multi-functional and multi-compositional organization of the native tissue in order to support and promote chondrogenic cell adhesion, proliferation and differentiation. However many such systems have given disappointing results as the combination of cells with scaffold have not appropriately activated or maintained chondrocyte function. Support scaffolds or hydrogels need to mimic the native extracellular matrix (ECM) microenvironment with appropriate biophysical and chemical properties responsible for coordinating intracellular signalling and triggering downstream biological responses which regulate cell function. In this project we will use an established and refined protocol for the generation of chondrogenic cells from human pluripotent stem cells (hPSCs) in combination with new methods of cell selection and novel promising printable hydrogels. We will use stem cells which are suitable for use in patients, once differentiated, because they were derived at Good Manufacturing Practice (GMP) standard. Our previous work identified a hydrogel which pilot data shows supports maintenance of hPSC-derived chondrocytes in vitro in a way far superior to other support materials tested. Recent literature has highlighted new cell surface antigens expressed by embryonic chondrocytes which will be used to select chondrocyte-committed hPSC derived cells.
In this project we therefore propose a combinatorial approach that brings together 3 key elements for the design of OC implants: 1) accurate cell-selection 2) iPSC chondrogenesis via a GMP compatible protocol, and 3) a novel hydrogel-based material as suitable bioink for 3D printing. The ultimate test of such a combined strategy will be that the construct is able to repair a cartilage defect. In this project we will use an established rat model to test the ability of the cell construct to generate cartilage in the knee joint. The combination of supervisors: an orthopaedic clinician, a stem cell scientist and an expert in hydrogels and bioprinting methods will generate an ideal bench to bedside environment for the successful translation of this work into the clinic.
Planned Impact
Regenerative medicine aims to develop biomaterial and cell-based therapies that restore function to damaged tissues and organs. It is a priority of the University and the nation, and a central focus of the EPSRC challenge theme "Healthcare Technologies". It is also an MRC strategic priority, "Repair and replacement: to translate burgeoning knowledge in regenerative medicine into new treatment strategies". It is in recognition of the challenges associated with clinical translation of regenerative medicine that EPSRC, MRC, BBSRC and TSB jointly funded the £25m UK Regenerative Medicine Platform - UoM is a partner on all three funded national hubs: 'Engineering and exploiting the stem cell niche', 'Acellular technologies, 'Safety and efficacy'. Our Centre for Doctoral Training in Regenerative Medicine, and hub partnerships, will have major impact by delivering a cohort of highly training scientists and clinicians who can take regenerative medicine to the next level of therapeutic efficacy, and engage with these national hubs. This capability will enable the UK to retain its position as a world-leader in regenerative medicine.
Specific impacts include:
(i) Biomedical scientists, the UK regenerative medicine community and international colleagues
Major impact will be achieved by training our students in the scientific methods required to: understand how the microenvironment (niche) directs cells to remodel tissues; design (nano)materials that interact at a mechanical and biochemical level with cells and orient their behaviour; understand how inflammatory processes affect regeneration; translate this knowledge to patients.
Our students will have the outstanding opportunity of benefiting directly from, and contributing directly to all the national UK Regenerative Medicine Platform hubs.
Added value will be achieved through research collaborations and data/reagent sharing across the University of Manchester and the Manchester Academic Health Science Centre, nationally through the hubs, and internationally through our six world-leading doctoral centre partners.
The Centre's strong links with MIMIT (Manchester: Integrating Medicine and Innovative Technology; linked to CIMIT, Boston USA), which develops clinical solutions for tissue repair and related unmet clinical needs, and with the Manchester Collaborative Centre for inflammation Research, enable our students to develop new regenerative strategies that encompass inflammatory control.
(ii) Biopharma
The ability to direct the effective repair or regeneration of tissues is highly sought after by cell therapy/regenerative medicine/tissue engineering companies wishing to translate these discoveries to new therapeutic products, and to Biopharma to inform the design and delivery of niche-based biologics and MSC-based anti-inflammatory therapies. We have more than 30 industrial partners, attesting to the strength of our Centre plan.
Our students will be advised by the University of Manchester Intellectual Property (UMIP) in all aspects of commercialisation, e.g. selling/licensing of reagents, provision of research expertise, in-house assays/techniques, co-development of technologies or licensing of IP.
(iii) General Public
The Centre will be a powerful platform for the Centre students to inform the public about our regenerative medicine activities and therapeutic advances.
The students will write review articles for popular press and student science magazines; develop skills in communications and public engagement; participate in Manchester Science Week and internet fora; develop outreach materials to inform local, national and international audiences, and meet patient groups.
Specific impacts include:
(i) Biomedical scientists, the UK regenerative medicine community and international colleagues
Major impact will be achieved by training our students in the scientific methods required to: understand how the microenvironment (niche) directs cells to remodel tissues; design (nano)materials that interact at a mechanical and biochemical level with cells and orient their behaviour; understand how inflammatory processes affect regeneration; translate this knowledge to patients.
Our students will have the outstanding opportunity of benefiting directly from, and contributing directly to all the national UK Regenerative Medicine Platform hubs.
Added value will be achieved through research collaborations and data/reagent sharing across the University of Manchester and the Manchester Academic Health Science Centre, nationally through the hubs, and internationally through our six world-leading doctoral centre partners.
The Centre's strong links with MIMIT (Manchester: Integrating Medicine and Innovative Technology; linked to CIMIT, Boston USA), which develops clinical solutions for tissue repair and related unmet clinical needs, and with the Manchester Collaborative Centre for inflammation Research, enable our students to develop new regenerative strategies that encompass inflammatory control.
(ii) Biopharma
The ability to direct the effective repair or regeneration of tissues is highly sought after by cell therapy/regenerative medicine/tissue engineering companies wishing to translate these discoveries to new therapeutic products, and to Biopharma to inform the design and delivery of niche-based biologics and MSC-based anti-inflammatory therapies. We have more than 30 industrial partners, attesting to the strength of our Centre plan.
Our students will be advised by the University of Manchester Intellectual Property (UMIP) in all aspects of commercialisation, e.g. selling/licensing of reagents, provision of research expertise, in-house assays/techniques, co-development of technologies or licensing of IP.
(iii) General Public
The Centre will be a powerful platform for the Centre students to inform the public about our regenerative medicine activities and therapeutic advances.
The students will write review articles for popular press and student science magazines; develop skills in communications and public engagement; participate in Manchester Science Week and internet fora; develop outreach materials to inform local, national and international audiences, and meet patient groups.
Organisations
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| Leela Biant (Primary Supervisor) |