Osteochondral tissue engineering using novel 3D printed scaffolds and multi-layered cell sheet technology
Lead Research Organisation:
University of Leeds
Department Name: Mechanical Engineering
Abstract
Osteochondral tissue damage or loss is one of the most common diseases due to traumatic injuries, natural degradation of cartilaginous tissue with aging, arthritis or surgery. These clinical situations encompass serious damage to not only articular cartilage but also the underlying calcified subchondral bone. The conventional therapeutic approaches include autografts, allografts, stimulation of bone marrow and debridement. Autografts have limited stock and allografts are associated with the risk of immune rejection or disease transmission, while bone marrow stimulation treatments are only palliative and not completely curative. Therefore, the ability to treat osteochondral defects is a major clinical need.
Over the last decades, tissue engineering approaches have been utilised for regenerating articular cartilage. However the output of these is still not satisfactory. Part of the reason may be due to the unique and complex structure of articular cartilage (e.g. it does not have blood vessels, lymphatics and nerves, but it is under a biomechanical environment). Over the last a few years, researchers have suggested that a healthy subchondral bed plays a key role for the success of cartilage tissue regeneration.
In this project, a multidisciplinary approach will be utilised to combine material science, mechanical engineering (Dr Xiaodong Jia) with stem cell biology (Dr Jiang) for osteochondral tissue engineering (Dr Yang).
The multi-layered cell sheet (MLCS) technology, in close collaboration with Tokyo Women's Medical University under a formal collaborative agreement, allows us to harvest intact cell sheet with minimum damage to the cells and maximum retention of cell-cell junctions, extracellular matrix and growth factors embedded in the matrix. This technology could be useful for stem cell handling and the development of novel collagen scaffolds to mimic natural structure of articular cartilage.
Previously we have showed the potential of using epigenetic approaches to control stem cell function without change the genome. A novel histone deacetylase inhibitors (HDACi), MI192 will be used for the pre-treatment of human MSCs to enhance their osteogenic differentiation potential for new bone formation.
The combination of the bone phase and cartilage phase will provide a novel solution for repair/restoration of osteochondral defect in clinical relevant animal models.
The aim of this project is to develop a novel natural collagen scaffold and combine these scaffolds with 3D printed scaffolds, epigenetic modified stem cells as well as multi-layered cell sheet technology for osteochondral tissue engineering in vitro and in vivo.
The project fits very well within EPSRC's Healthcare and Technologies Theme - Developing Future Therapies. The objectives include:
A) Development of novel collagen scaffolds using MLCS technology.
B) Fabricate cartilage phase in vitro using epigenetic modified stem cell, MLCS technology, novel collagen scaffolds.
C) Fabricate bone phase in vitro using epigenetic modified stem cell, MLCS technology and PepGEN P-15 enhanced 3D printed porous polymer scaffold (in collaboration Otago University, UCL and University of Manchester).
D) Osteochondral tissue engineering in vivo using the bone and cartilage constructs formed above.
MLCS technology is a novel engineering method.
A novel natural collagen scaffolds will be developed with unique architecture similar to natural articular cartilage, which could be patentable.
A combination of MLCS technology, novel collagen scaffolds and 3D printed polymer scaffolds will provide a novel approach for complex tissue engineering.
Over the last decades, tissue engineering approaches have been utilised for regenerating articular cartilage. However the output of these is still not satisfactory. Part of the reason may be due to the unique and complex structure of articular cartilage (e.g. it does not have blood vessels, lymphatics and nerves, but it is under a biomechanical environment). Over the last a few years, researchers have suggested that a healthy subchondral bed plays a key role for the success of cartilage tissue regeneration.
In this project, a multidisciplinary approach will be utilised to combine material science, mechanical engineering (Dr Xiaodong Jia) with stem cell biology (Dr Jiang) for osteochondral tissue engineering (Dr Yang).
The multi-layered cell sheet (MLCS) technology, in close collaboration with Tokyo Women's Medical University under a formal collaborative agreement, allows us to harvest intact cell sheet with minimum damage to the cells and maximum retention of cell-cell junctions, extracellular matrix and growth factors embedded in the matrix. This technology could be useful for stem cell handling and the development of novel collagen scaffolds to mimic natural structure of articular cartilage.
Previously we have showed the potential of using epigenetic approaches to control stem cell function without change the genome. A novel histone deacetylase inhibitors (HDACi), MI192 will be used for the pre-treatment of human MSCs to enhance their osteogenic differentiation potential for new bone formation.
The combination of the bone phase and cartilage phase will provide a novel solution for repair/restoration of osteochondral defect in clinical relevant animal models.
The aim of this project is to develop a novel natural collagen scaffold and combine these scaffolds with 3D printed scaffolds, epigenetic modified stem cells as well as multi-layered cell sheet technology for osteochondral tissue engineering in vitro and in vivo.
The project fits very well within EPSRC's Healthcare and Technologies Theme - Developing Future Therapies. The objectives include:
A) Development of novel collagen scaffolds using MLCS technology.
B) Fabricate cartilage phase in vitro using epigenetic modified stem cell, MLCS technology, novel collagen scaffolds.
C) Fabricate bone phase in vitro using epigenetic modified stem cell, MLCS technology and PepGEN P-15 enhanced 3D printed porous polymer scaffold (in collaboration Otago University, UCL and University of Manchester).
D) Osteochondral tissue engineering in vivo using the bone and cartilage constructs formed above.
MLCS technology is a novel engineering method.
A novel natural collagen scaffolds will be developed with unique architecture similar to natural articular cartilage, which could be patentable.
A combination of MLCS technology, novel collagen scaffolds and 3D printed polymer scaffolds will provide a novel approach for complex tissue engineering.
Planned Impact
Regenerative Medicine been defined as "an interdisciplinary approach, spanning tissue
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
Organisations
People |
ORCID iD |
| Xuebin Yang (Primary Supervisor) | |
| Thomas Braxton (Student) |